Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2].[CH2:41](I)[CH2:42][CH2:43][CH3:44]>>[CH2:41]([O:14][C:13]1[CH:12]=[C:11]2[C:6]([C:7]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:36](=[O:37])[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=5)[N:29]([CH3:39])[C:28]4=[O:40])[CH2:23][CH2:22]3)=[N:8][C:9]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:10]2)=[CH:5][C:4]=1[O:3][CH2:1][CH3:2])[CH2:42][CH2:43][CH3:44]
Reactant: CCCCI
Reactant: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1O
Product: CCCCOc1cc2nc(N3CCOCC3)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OCC
Yield: 39 %

Procedure:
The same procedure as in Example 48 was repeated, using 335 mg (0.61 mmol) of Compound 47 obtained in Example 47, except that butyl iodide was used in place of methyl iodide, to give 144 mg (yield: 39%) of Compound 51 as white crystals.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:10]([CH3:12])([CH3:11])[C:8](=[O:9])[N:7]([CH2:13][CH2:14]O)[C:5]1=[O:6].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH3:11][C:10]1([CH3:12])[N:4]([CH:3]=[CH2:2])[C:5](=[O:6])[N:7]([CH:13]=[CH2:14])[C:8]1=[O:9]
Reactant: CC1(C)C(=O)N(CCO)C(=O)N1CCO
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=CN1C(=O)N(C=C)C(C)(C)C1=O
Reaction time: 2 h
Yield: 67 %

Procedure:
Alternatively, 5,5-dimethyl-1,3-divinylhydantoin was prepared by acetylating at 80° C. for two hours 216 grams (1 mole) of 1,3-bis(2-hydroxyethyl)-5,5-dimethylhydantoin with 408 grams (4 moles) of acetic anhydride in the presence of 20 ml. of pyridine to form the corresponding diacetate ester. Pyrolysis of said diacetate ester by passing through a hot tube at 550° C. gave the above product in a 67% yield (at 39% conversion), boiling at 89°-92° C./0.2 mm. (Compound 1).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.Cl.C(OC(=O)[NH:39][CH2:40][C@@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1)(C)(C)C>>[NH2:39][CH2:40][C@@H:41]1[CH2:45][CH2:44][CH2:43][N:42]1[CH2:29][C:17]1[C:16]2[C:21](=[CH:22][CH:23]=[C:14]([C:8]3[CH:7]=[C:6]([CH:11]=[C:10]([F:12])[C:9]=3[CH3:13])[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:31])[CH:15]=2)[C:20](=[O:24])[N:19]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH:18]=1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCN1
Agent: Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCC[C@H]3CN)c2c1

Procedure:
The title compound was prepared according to the method of Example 81 using the product of Example 75 step i) and (S)-1-pyrrolidine-2-ylmethyl-carbamic acid tert-butyl ester hydrochloride. The product was purified using SCX ion-exchange chromatography (eluting with methanol followed by 3N ammonia in methanol), followed by HPLC.
Reaction SMILES: FC1C=CC=C(F)C=1C(NC1C=CC=C(C2C(C3C=CN=C(NC4C=CC(OC[C@@H]5CCCN5C)=C(F)C=4)N=3)=C3C=CC=CN3N=2)C=1)=O.[F:49][C:50]1[CH:55]=[C:54]([N+:56]([O-])=O)[CH:53]=[CH:52][C:51]=1[O:59][CH2:60][CH2:61][CH2:62][N:63]([CH3:65])[CH3:64]>>[CH3:65][N:63]([CH3:64])[CH2:62][CH2:61][CH2:60][O:59][C:51]1[CH:52]=[CH:53][C:54]([NH2:56])=[CH:55][C:50]=1[F:49]
Reactant: CN(C)CCCOc1ccc([N+](=O)[O-])cc1F
Agent: CN1CCC[C@H]1COc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)cc1F
Product: CN(C)CCCOc1ccc(N)cc1F

Procedure:
In an analogous procedure to Example 125, 343 mg of the title compound was prepared from {3-[(2-fluoro-4-nitrophenyl)oxy]propyl}dimethylamine to give the desired intermediate as brown oil: 1H NMR (CDCl3, 400 MHz) δ 1.89-1.96 (m, 2H), 2.24 (s, 6H), 2.44 (t, 2H, J=7.1 Hz), 3.49 (brs, 2H), 3.99 (t, 2H, J=6.5 Hz), 6.36 (d, 1H, J=8.6 Hz), 6.45 (dd, 1H, J=12.6 and 2.7 Hz), and 6.81 (dd, 1H, J=9.0 and 9.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[CH2:14]([NH:21][CH2:22]C(O)=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CS(C)=O>O>[CH2:14]([N:21]1[C:7](=[O:9])[C:6]2[CH:13]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Solvent: O
Solvent: CS(C)=O
Product: O=C1CN(Cc2ccccc2)C(=O)c2cc(Br)ccc2N1
Temperature: 200 °C
Yield: 98.2 %

Procedure:
A mixture of 5-bromoisatoic anhydride (1 g, 4.13 mmol), N-benzylglycine (0.628 g, 4.13 mmol) and DMSO (3 mL) was heated in the microwave at 200° C. for one hour. After cooling, the mixture was diluted with water and the precipitate was filtered off, washed with water and dried, giving 4-benzyl-7-bromo-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (1.4 g, 98%) as an off-white powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH2:11][CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=O)=[CH:20][CH:19]=1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[CH2:11][CH3:12])=[CH:20][CH:19]=1
Reactant: CCC(=O)c1ccc2c(c1)CCO2
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a suspension of Zn (595 mg, 6 eq) in 20 mL anhydrous THF was added TiCl4 (0.5 mL, 3 eq) dropwise at 0° C. under nitrogen. The mixture was then heated to reflux for 1 h and cooled to rt. Then a solution of 1-(2,3-dihydrobenzofuran-5-yl)propan-1-one (670 mg, 2.5 eq) and (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (420 mg, 1.0 eq) in 10 mL anhydrous THF was added dropwise at 0° C. After the addition, the reaction mixture was heated to reflex for 1 h, cooled and quenched with sat. NaHCO3, filtered and the filtrate was extracted with EtOAc. The extract was dried and evaporated under reduced pressure. The residue was purified by column chromatography to give the desired product (500 mg, 78%, Z/E=1/1).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)[O:3]1.F[B-](F)(F)F.[CH2:24]([O+](CC)CC)[CH3:25]>C(OCC)(=O)C>[CH2:24]([N:14]1[CH:13]=[C:12]2[C:16]([CH:17]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:18])([CH3:1])[O:3]3)[CH:10]=[CH:11]2)=[N:15]1)[CH3:25]
Reactant: CC1(C)OB(c2ccc3cn[nH]c3c2)OC1(C)C
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: CCn1cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.63 g, 2.56 mmol) in ethyl acetate (7.5 mL) was added triethyloxonium tetrafluoroborate (0.65 g, 3.33 mmol). The mixture was stirred at rt for 5 h under nitrogen (turned to a white suspension after about 0.5 h). The mixture was diluted with ethyl acetate (50 mL) and washed with saturated, aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL), the combined organic layers were dried over MgSO4, filtered and concentrated. The crude purified using an ISCO® instrument using 0-40% ethyl acetate in hexanes. LC-MS [M+H]+=2732, RT=3.27 min.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH:3]=[N:4][NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1.C1C(=O)N([Br:31])C(=O)C1.C(OCC)(=O)C.O>CN(C=O)C.[Cl-].[Na+].O>[Br:31][C:3](=[N:4][NH:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:10][CH2:11]1)[C:2]([F:1])([F:22])[F:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(OCc1ccccc1)N1CCC(NN=CC(F)(F)F)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(NN=C(Br)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a stirred solution of 110 (2.881 g, 8.75 mmol) in DMF (29.2 ml) was added NBS (1.713 g, 9.62 mmol) and the resulting solution was allowed to stir for 1 h at room temperature. Ethyl acetate was added followed by brine and water (50/50), and the AcOEt extracts were washed with water and brine, dried over MgSO4, filtrated and concentrated. The residue was purified via Biotage (5% to 20% EtOAc/Hexane; 25M column) to afford 111 (1.685 g, 47.2% yield) as yellow oil. LRMS (ESI): calc. 407.05 and 409.04; found 408.2 and 410.2 (MH)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:33][CH2:32][N:7]2[C:8]3[C:13]([C:14]([C:15]4[C:16](=[O:31])[NH:17][C:18](=[O:30])[C:19]=4[C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH3:29])[CH:21]=4)=[C:6]2[CH2:5]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl.C(=O)([O-])O.[Na+]>[C:34]([NH:2][CH2:3][CH:4]1[CH2:33][CH2:32][N:7]2[C:8]3[C:13]([C:14]([C:15]4[C:16](=[O:31])[NH:17][C:18](=[O:30])[C:19]=4[C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH3:29])[CH:21]=4)=[C:6]2[CH2:5]1)=[CH:12][CH:11]=[CH:10][CH:9]=3)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CN)C4)C(=O)NC2=O)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CNC(=O)c3ccccc3)C4)C(=O)NC2=O)c2ccccc21
Reaction time: 17 h

Procedure:
250 mg of the pyrroledione product of Example 2 were stirred in a mixture of 25 ml of dichloromethane and 15 ml of 5% aqueous sodium hydrogen carbonate. The mixture was treated with 1 ml of benzoyl chloride and stirred for 17 hours. The phases were separated and the organic phase was dried and evaporated. Chromatography of the residue on silica gel with methanol/dichloromethane (7:93) followed by trituration with n-hexane gave 220 mg of 3-[8-(benzamidomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 297°-303° C.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C@H:10]1[CH2:15][CH2:14][C@@H:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=[N+]=[N-]>[Pd].CO>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@@H:13]2[CH2:14][CH2:15][C@H:10]([N:6]3[CH2:7][CH2:8][CH2:9][C@H:5]3[CH2:4][NH2:1])[CH2:11][CH2:12]2)=[CH:22][CH:21]=1
Reactant: [N-]=[N+]=NC[C@@H]1CCCN1[C@H]1CC[C@@H](Cc2ccc(F)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: NC[C@@H]1CCCN1[C@H]1CC[C@@H](Cc2ccc(F)cc2)CC1

Procedure:
(2S)-2-(azidomethyl)-1-[cis-4-(4-fluorobenzyl)cyclohexyl]pyrrolidine (45 mg), 10% Pd/C (10 mg, Aldrich) and 5 ml of methanol were hydrogenated for 16 hours at 50 PSI. The reaction was filtered through fiberglass filter paper under nitrogen. The filtrate was stripped to yield 58 mg of an amber oil as product. MS (ESI) detects 291 (M+H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Cs+].[CH3:15][CH:16]([CH3:23])[C:17]([O:19][CH2:20][CH2:21]Cl)=[O:18]>CN1C(=O)CCC1>[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:21][CH2:20][O:19][C:17](=[O:18])[CH:16]([CH3:23])[CH3:15])=[O:5]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: CC(C)C(=O)OCCCl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCCOC(=O)C(C)C
Yield: 88.7 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (0.39 g, 3.0 mmol) in NMP (8 mL) was reacted with CsHCO3 (0.69 g, 3.6 mmol) and chloroethyl 2-methylpropanoate (0.63 g, 4.2 mmol) to afford 0.65 g (89% yield) of the title compound (42) after isolation and purification. 1H NMR (CDCl3, 400 MHz): δ 6.93 (q, J=5.2 Hz, 1H), 6.88 (d, J=16.0 Hz, 1H), 6.81 (d, J=15.6 Hz, 1H), 3.81 (s, 3H), 2.55 (heptet, J=6.8 Hz, 3H), 1.54 (d, J=5.2 Hz, 3H), 1.18 (d, J=6.8 Hz, 6H). MS (ESI): m/z 245.05 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O)(=[O:3])[CH3:2].[C:10](Cl)(=O)[C:11](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C1C=CC=CC=1.ClCCl.CN(C)C=O>[C:7]([CH2:6][CH2:5][CH2:4][C:1](=[O:3])[CH3:2])(=[O:9])[C:11]1[CH:10]=[CH:5][CH:4]=[CH:1][CH:2]=1
Reactant: CC(=O)CCCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)CCCC(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a -10° C. solution of 4-acetylbutyric acid (1 mm, 130 mg) in benzene (1.5 cc) and dichloromethane (1.5 cc) was added oxalyl chloride (1.1 mm, 140 mg) followed by a drop of N,N-dimethylformamide; the mixture was then brought to 25° C. for 30 minutes. It was then cooled to -10° C. and AlCl3 (2 mm, 266 mg) was added portion wise and the mixture held at 0° C. for 1 hour. Ice was added, followed by 1N HCl. Then the product was extracted with ethyl acetate (2×10 cc). The organic phase was washed with dilute NaHCO3 /brine and the solvents removed in vacuo to afford the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].N1C=CC=CC=1>O1CCCC1>[C:24]([S:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(-c2ccc(S(N)(=O)=O)cc2)n(-c2ccc(S)cc2)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Sc1ccc(-n2cc(C)cc2-c2ccc(S(N)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
0.90 g (2.6 mmol) of 1-(4-mercaptophenyl)-4-methyl-2-(4-sulfamoylphenyl)-pyrrole (prepared as described in Example 129) was dissolved in 15 ml of tetrahydrofuran, and 0.27 ml (2.9 mmol) of acetic anhydride was added to the resulting solution. 0.53 ml (6.5 mmol) of pyridine was then added to the mixture, which was then stirred at room temperature overnight. The reaction mixture was then concentrated by evaporation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue. The resulting mixture was then extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous magnesium sulfate, after which it was concentrated by evaporation under reduced pressure. The residue thus obtained was applied to a silica gel chromatography column and eluted with a 3:2 by volume mixture of hexane and ethyl acetate, to give 0.44 g (yield 43%) of the title compound as a white powder, melting at 149-152° C.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]N=C(C1C=CC=CC=1)C#N)=O)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[C:28]([SH:29])=[N:27][N:26]=[N:25]1.C(N(CC)CC)C>O1CCOCC1.O>[C:1]([O:5][C:6]([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[C:28]([SH:29])=[N:27][N:26]=[N:25]1)=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCCn1nnnc1S
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCn1nnnc1S
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 74.1 %

Procedure:
A solution of 2-t-butoxycarbonyloxyimino-2-phenylacetonitrile (12.3 g) in dioxane (30 ml) was added under ice-cooling to a stirred solution of 1-(3-aminopropyl)-1H-tetrazole-5-thiol hydrochloride (9.78 g) and triethylamine (11.1 g) in a mixture of dioxane (25 ml) and water (25 ml), and then the resulting mixture was stirred for 1.75 hours at ambient temperature. Dioxane was distilled off and to the residue were added diethyl ether and a small amount of water. After shaking, the aqueous layer was separated and the organic layer was extracted twice with 10% potassium carbonate. The extracts combined with the separated aqueous layer were washed three times with diethyl ether, adjusted to pH 1 with hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried and evaporated in vacuo. The residual oil (10.92 g) was pulverized with diisopropyl ether to give 1-[3-(N-t-butoxycarbonylamino)propyl]-1H-tetrazole-5-thiol (9.6 g), mp. 75° to 77° C.
Reaction SMILES: O[CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:20]=1[CH3:28])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C@H:5]1[CH2:17][OH:18].C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1>[CH3:28][C:20]1[C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=1[CH:2]1[O:18][CH2:17][C@@H:5]2[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:8][CH2:9][N:4]2[CH2:3]1
Reactant: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)cccc1[N+](=O)[O-]
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Product: Cc1c(C2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)cccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
(3S)-tert-Butyl 4-(2-hydroxy-2-(2-methyl-3-nitrophenyl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (2.15 g, 5.44 mmol) was dissolved in benzene (30 mL) then added cyanomethylenetribuylphosphorane (2.362 g, 9.79 mmol). The mixture was degassed then heated to 100° C. overnight. After cooling, the benzene was evaporated off and the residue was purified by chromatography through a 330 g ISCO Redi-sep column eluting with 5-10% acetone: methylene chloride to yield the title compound: LC-MS (IE, m/z): 378 [M+1]+
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=3)[CH2:30][CH2:29]2)=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(OC)cc3)CC2)nn1C(C)(C)C

Procedure:
70 mg (71%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-(4-methoxyphenyl)piperazine (44 mg, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[C:7]([Cl:26])[CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[Cl:11][C:9]1[CH:10]=[C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])[CH:6]=[C:7]([Cl:26])[C:8]=1[O:12][CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1
Reactant: COC(=O)C(=O)c1cc(Cl)c(OCCOc2ccc3ccccc3c2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(=O)c1cc(Cl)c(OCCOc2ccc3ccccc3c2)c(Cl)c1
Yield: 99.2 %

Procedure:
A solution of 3,5-dichloro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.6 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from benzene-hexane provided 0.575 g of purified 3,5-dichloro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid (6:1) molar benzene solvate as a colorless solid, mp 108°-110° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]([CH3:29])([CH2:16][N:17]1[CH:25]=[C:24]2[C:19]([C:20]([Cl:28])=[C:21]([Cl:27])[CH:22]=[C:23]2[Cl:26])=[N:18]1)[C:14]#[N:15]>C1COCC1>[C:14]([C:13]([NH:12][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])([CH3:29])[CH2:16][N:17]1[CH:25]=[C:24]2[C:19]([C:20]([Cl:28])=[C:21]([Cl:27])[CH:22]=[C:23]2[Cl:26])=[N:18]1)#[N:15]
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(F)cc1F

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 2,4-difluorobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (13.9 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=443, RT=0.71 min.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:14]3[CH:13]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[NH:11][C:10]=3[CH2:9][CH:8]=2)=[CH:3][CH:2]=1>[Pd]>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:2]=[CH:3][C:4]([CH:7]2[C:14]3[CH:13]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[NH:11][C:10]=3[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc2c([nH]1)CC=C2c1ccc(-c2ccccc2)cc1
Agent: [Pd]
Product: COC(=O)c1cc2c([nH]1)CCC2c1ccc(-c2ccccc2)cc1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (300 mg, 1.67 mmol) and biphenyl-4-ylmagnesium bromide (13.4 mL, 6.70 mmol; 0.5 M in THF) were reacted according to General Procedure 3 to give the endo olefin-containing compound methyl 4-(biphenyl-4-yl)-1,6-dihydrocyclopenta[b]pyrrole-2-carboxylate, which was then hydrogenated according to General Procedure 6 (with 10% Pd/C), and was purified column chromatography (Isco CombiFlash) eluting with a gradient of 0-40% EtOAc/heptane to afford the title compound. 430 mg. 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.23-2.33 (m, 1H), 2.74-2.84 (m, 1H), 2.85-3.01 (m, 2H), 3.75 (s, 3H), 4.26 (t, J=7.20 Hz, 1H), 6.55 (d, J=1.76 Hz, 1H), 7.29-7.36 (m, 3H), 7.41-7.47 (m, 2H), 7.55-7.60 (m, 2H), 7.62-7.66 (m, 2H), 10.66 (s, 1H); LCMS-MS (ESI+) 340.2 (M+Na).
Reaction SMILES: [N:1]1C=CC=C(C(N)C)C=1.[CH3:10][N:11]1[C:19]2[C:14](=[C:15]([C:20](=O)[CH3:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.N.CO.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:10][N:11]1[C:19]2[C:14](=[C:15]([CH:20]([NH2:1])[CH3:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1
Reactant: CC(N)c1cccnc1
Reactant: CC(=O)c1cccc2c1ccn2C
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(N)c1cccc2c1ccn2C
Yield: 48 %

Procedure:
The title compound was prepared by the same procedure for preparing 1-pyridin-3-yl-ethylamine from 1-(1-methyl-1H-indol-4-yl)-ethanone (1.75 g, 10 mmol), 2 M ammonia solution in methyl alcohol (25 mL, 50 mmol, Aldrich), acetic acid (15 mL, J. T. Baker) and sodium cyanoborohydride (2.5 g, 40 mmol, Aldrich). The title compound was purified by column chromatography (silica gel, 2 M ammonia solution in methyl alcohol/ethyl acetate 1/10) in form as light yellow oil in 48% yield (0.83 g, 4.8 mmol).