Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:7])[C:4](=[NH:6])[NH2:5].Br[C:9]1[C:10](=O)[CH2:11][CH2:12][C:13]=1[O:14]C.C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O>[CH3:2][CH:3]([C:4]1[NH:5][C:10]2[CH2:11][CH2:12][C:13](=[O:14])[C:9]=2[N:6]=1)[CH3:7]
Reactant: COC1=C(Br)C(=O)CC1
Reactant: CC(C)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1nc2c([nH]1)CCC2=O
Temperature: 100 °C
Yield: 61.8 %

Procedure:
A mixture of 2-methylpropanimidamide hydrochloride (0.770 g), 2-bromo-3-(methyloxy)-2-cyclopenten-1-one (1 g) and potassium carbonate (2.17 g) in N,N-dimethylformamide (15 mL) were heated at 100° C. for 4.5 hr and then heated at 110° C. for 1 hour. The reaction mixture was cooled down to room temperature and dichloromethane was added. The white suspension (potassium carbonate) was filtered off and the filtrate concentrated under vacuum. The residue was purified by reverse phase chromatography using an acetonitrile—0.1% NH3:water—with an ammonium carbonate buffer modifier using a 5%-95% gradient. The desired fractions were combined and concentrated under vacuum to yield the title compound (531 mg). LC/MS MH+ 165, Rt 0.36 min (2 minute run).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[N:4]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([Cl:29])[CH:23]=1)=[O:18])C>>[Cl:29][C:24]1[CH:23]=[C:22]([CH:20]2[CH2:21][CH:19]2[C:17]([OH:18])=[O:16])[CH:27]=[CH:26][C:25]=1[O:28][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[N:4]=1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Reactant: ClCc1cccc(SCC2CC2)n1
Product: O=C(O)C1CC1c1ccc(OCc2cccc(SCC3CC3)n2)c(Cl)c1
Yield: 89 %

Procedure:
2-Chloromethyl-6-cyclopropylmethylsulfanyl-pyridine (36 mg, 0.17 mmol) obtained in Step D of Preparation Example 20 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (45 mg, 0.18 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (59 mg, 83%).
Reaction SMILES: [OH:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=3[CH2:19]2)=O)=[CH:4][CH:3]=1.[N:37]1([C:45](=O)[CH2:46]Cl)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[N:37]1([CH2:45][CH2:46][O:1][C:2]2[CH:36]=[CH:35][C:5]([CH2:6][CH2:8][NH:9][C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=3[CH:18]3[CH2:27][CH2:26][C:25]4[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=4[CH2:19]3)=[CH:4][CH:3]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C(CCl)N1CCCCCCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)cc2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCCCCCC3)cc2)c1
Yield: 12.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 1-azocan-1-yl-2-chloroethanone (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.5 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](Cl)=[O:12])=[C:9]([CH3:14])[S:8][C:7]=2[CH:15]=1.[CH3:16][NH2:17]>C1COCC1>[CH3:16][NH:17][C:11]([C:10]1[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][C:7]=2[S:8][C:9]=1[CH3:14])=[O:12]
Reactant: COc1ccc2c(C(=O)Cl)c(C)sc2c1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1c(C)sc2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of this crude 6-methoxy-2-methylbenzo[b]thiophene-3-carbonyl chloride in THF (50 ml) was combined with a 2.0 M solution of CH3NH2 in THF (20 ml, 40 mmole). The resultant reaction mixture was stirred at ambient temperature for 3 hours. The solvent was removed by concentration, in vacuo, and the residue obtained was partitioned between H2O (50 ml) and CH2Cl2 (50 ml). The layers were separated and the aqueous phase was extracted with CH2Cl2 (2×30 ml). The combined organic extracts were dried over Na2SO4 and concentrated, in vacuo, to give 0.8 g of an amber solid which was purified by silica gel chromatography. Elution with CH2Cl2: EtOAc (80:20) and evaporation of the appropriate fractions gave 693 mg (72%) of an off-white solid. 1H NMR (DMSO-d6) δ 8.15 (1H, q, J=4.6 Hz), 7.62 (1H, d, J=8.9 Hz), 7.47 (1H, d, J=2.4 Hz), 6.97 (1H, dd, J=2.4, 8.9 Hz), 3.79 (3H, s), 2.80 (3H, d, J=4.6 Hz), 2.53 (3H, s). Anal. Calcd. for C12H13NO2S: C, 61.25; H, 5.57; N, 5.95; S, 13.63. Found: C, 60.97; H, 5.56; N, 5.85; S, 13.44.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].[CH2:12]1[O:14][CH:13]1[CH2:15][CH2:16][CH:17]1[O:19][CH2:18]1>O>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][CH2:18][CH:17]2[O:19][CH:13]([CH2:12][OH:14])[CH2:15][CH2:16]2)[CH2:4][O:3]1
Reactant: C(CC1CO1)C1CO1
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC1(C)OCC(COCC2CCC(CO)O2)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
46.3 g of 2,2-dimethyl-1,3-dioxolane-4-methanol (0.35 mol) (Aldrich) is cooled to 0° in an ice bath and under a nitrogen atmosphere 2.1 g of sodium hydride (0.088 mol) (washed with hexane to remove the mineral oil) is slowly added to the rapidly stirred mixture. The addition of the sodium hydride is made at such a rate that the temperature remains below 20°. After the addition of the NaH has been completed the mixture is allowed to stir for 1/2 hour and slowly warmed to room temperature. Slowly, and with stirring 10.0 g of 1,5-hexadiene diepoxide (0.088 mol) is added to the mixture. After the addition of the diepoxide has been completed the reaction mixture is heated at reflux for 16 hours. The mixture is then cooled to room temperature and with stirring is poured into 350 ml of water. The aqueous mixture is extracted with two 200 ml portions of chloroform, the CHCl3 extracts are combined and dried over anhydrous sodium sulfate. The CHCl3 is removed in vacuo and the dark brown residue then vacuum distilled through a 10 cm vigreux distilling column. The fraction boiling at 135°-137° @ 0.3 mm is collected yielding 12.6 g (58%) of the above compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][N:7](COC(=O)C(C)(C)C)[C:6]2=[O:31].CO.N>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=[O:31]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCOCC1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
6-Methoxy-7-(3-morpholinopropoxy)-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (1.85 g) was stirred in methylene chloride (20 ml) and methanol (20 ml) and methanolic ammonia (2M, 100 ml) was added. The reaction was stirred at ambient temperature for 48 hours, evaporated to dryness, and then stirred in diethyl ether for 1 hour. The reaction mixture was filtered affording 6-methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one as a solid, (1.22 g, 90%); NMR: 1.9 (m, 2H), 2.4 (broad m, 6H), 3.55 (m, 4H), 3.88 (s, 3H), 4.12 (m, 2H), 7.1 (s, 1H), 7.41 (s, 1H), 7.94 (s, 1H); m/s: M+H+ 320.
Reaction SMILES: [O:1]=[C:2]1[C:11]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)S[C:8]3([CH:9]([C:19]#[N:20])[CH2:10]2)[N:3]1[CH2:4][CH2:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=13>C[O-].[Na+]>[O:1]=[C:2]1[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]([C:19]#[N:20])=[C:8]2[N:3]1[CH2:4][CH2:5][C:6]1[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=12
Reactant: N#CC1CC2(c3ccccc3)SC13c1ccccc1CCN3C2=O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1CC2

Procedure:
1.7 g of 1,2,3,4,6,7-hexahydro-4-oxo-3-phenyl-3,11b-epithio-11bH-benzo[a]quinolizine-1-carbonitrile were heated at reflux for 2 hours together with a sodium methylate solution (prepared from 156 mg of sodium in 40 ml of methanol). After cooling, the crystallized-out product was removed by filtration under suction and recrystallized from isopropanol. There was obtained pure 6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1carbonitrile of m.p. 204°-205°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:19])[C:13]=3[CH:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:20](OC(=O)C)(=[O:22])[CH3:21].C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[C:14]([O:19][C:20](=[O:22])[CH3:21])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(-n2ccc3c(O)cccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc2c1ccn2-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In 8 mL of methylene chloride, 387 mg (1.52 mmol) of 1-(4-nitrophenyl)-1H-indole-4-ol was dissolved, and 0.186 mL (2.00 mmol) of acetic anhydride and 0.318 mL (2.28 mmol) of triethylamine were added thereto and the mixture solution was stirred at room temperature for 14 hours. The reaction solution was partitioned between methylene chloride (50 mL) and a saturated ammonium chloride aqueous solution (20 mL) and washed with a saturated sodium chloride solution, and the organic layer was dried and then concentrated under reduced pressure to obtain acetic acid 1-(4-nitrophenyl)-1H-indol-4-yl ester. The product was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])[CH:3]=1.Br[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[N:29][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N:29]1[CH:30]=[C:25]([CH2:24][N:20]2[CH2:21][CH2:22][CH:17]([CH2:16][NH:15][C:13](=[O:14])[C:4]3[CH:3]=[C:2]([NH2:1])[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=3)[CH2:18][CH2:19]2)[CH:26]=[CH:27][C:28]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: CCOc1nc(C(=O)NCC2CCNCC2)cc(N)c1C#N
Reactant: BrCc1ccc(-c2ccccn2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1nc(C(=O)NCC2CCN(Cc3ccc(-c4ccccn4)nc3)CC2)cc(N)c1C#N

Procedure:
The compound prepared in Example 334 (0.009 g), 5-(bromomethyl)-2,2′-bipyrdine (0.008 g, prepared according to the reported preparation in Journal of the American Chemical Society, 2006, 128(1), 250-256) and cesium carbonate (0.019 g) were heated to 80° C. for 16 hours in N,N-dimethylformamide (2 mL). The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organics were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 1-4% (9:1 methanol:ammonium hydroxide)/ethyl acetate) to furnish the title compound (0.006 g) having the following physical data.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20](=O)/[CH:21]=[CH:22]/N(C)C>>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[N:2]([C:4]2[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=2)[N:3]=[CH:22][CH:21]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1ccc(F)cc1F
Agent: Cl
Product: N#Cc1ccnc(-n2nccc2-c2ccc(F)cc2F)c1
Yield: 83 %

Procedure:
The title compound was prepared in 83% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-1-(2,4-difluorophenyl)-3-(dimethylamino)prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 6.51 (1H, d, J=1.6 Hz), 6.77-6.82 (1H, m), 6.92-6.97 (1H, m), 7.34-7.40 (2H, m), 7.80 (1H, d, J=2.0 Hz), 8.20 (1H, s), 8.27 (1H, dd, J=5.2, 1.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@@H:15]([CH3:17])[C@H:14]([CH2:18][C:19](O)=[O:20])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:22]([O:24][C:25]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)=[O:26])[CH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@@H:15]([CH3:17])[C@H:14]([CH2:18][C:19](=[O:20])[NH:31][C:30]3[CH:32]=[CH:33][C:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])=[CH:28][CH:29]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: C[C@@H]1Cc2cc(Br)cc3[nH]c(=O)c(=O)n(c23)[C@H]1CC(=O)O
Product: CCOC(=O)c1ccc(NC(=O)C[C@H]2[C@H](C)Cc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 82.8 %

Procedure:
A procedure similar to that described in Example 52 was carried out with trans-9-bromo-5-carboxymethyl-6-methyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (50 mg, 0.14 mmol) and p-ethoxycarbonylaniline (24 mg, 0.15 mmol) to give 58 mg of the title compound (82%): mp 282°~292° C.; 1H NMR (270 MHz, DMSO-d6) δ12.09 (s, 1H), 10.33 (s, 1H), 7.90 (d, 2H, J=8.6 Hz), 7.70 (d, 2H, J=8.6 Hz), 7.21 (s, 1H), 7.18 (s, 1H), 4.92~5.02 (m, 1H), 4.28 (q, 2H, J =6.9 Hz), 3.20 (dd, 1H, J=17.8, 5.9 Hz), 2.52~2.66 (m, 3H), 2.28~2.42 (m, 1H), 1.32 (t, 3H, J=6.9 Hz), 0.87 (d, 3H, J=6.9 Hz).
Reaction SMILES: [C:1]([C:3]1[C:19]([CH2:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][C:7]=1[CH3:15])#[N:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl>[C:1]([C:3]1[C:19]([CH2:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:4]=1[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:51][CH2:52][C:53]2[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=2[CH3:59])=[O:12])=[CH:8][C:7]=1[CH3:15])#[N:2]
Reactant: CCc1cccc(Oc2ccc(C(=O)O)cc2C)c1C#N
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cccc(Oc2ccc(C(=O)NCc3c(C)cc(C)nc3O)cc2C)c1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.5 %

Procedure:
To a solution of 4-(2-cyano-3-ethylphenoxy)-3-methylbenzoic acid (0.10 g, 0.36 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10 g, 0.5 mmol) and N-hydroxybenzotriazole (0.07 g, 0.5 mmol) in dichloromethane (20 mL) was added triethylamine (0.4 g, 4 mmol). The reaction mixture was stirred at room temperature for 15 minutes, then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.06 g, 0.4 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water (30 mL). The organic phase was concentrated and purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give pure product 4-(2-cyano-3-ethylphenoxy)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-3-methylbenzamide as a white solid (0.062 g, 41%). LRMS (M+H+) m/z: calcd 415.19. found 415. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.31 (d, J=4.5 Hz, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 7.05-6.70 (m, 2H), 6.80 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 5.85 (s, 1H), 4.29 (d, J=4.5 Hz, 2H), 2.74 (q, J=7.5 Hz, 2H), 2.16 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.17 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]1[C@@H:15]2[CH2:16][NH:17][CH2:18][C@@H:14]2[CH2:13][N:12]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[CH3:7][N:6]1[C:2]([N:17]2[CH2:16][C@@H:15]3[CH2:11][N:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][C@@H:14]3[CH2:18]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Product: Cn1ncc([N+](=O)[O-])c1N1C[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C1
Yield: 86 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate gave (3aR,6aS)-tert-butyl 5-(1-methyl-4-nitro-1H-pyrazol-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate as a yellow oil (0.36 g, 86%). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 3.75 (s, 3H), 3.73-3.55 (m, 4H), 3.42-3.33 (m, 2H), 3.17-3.04 (m, 4H), 1.48 (s, 9H)
Reaction SMILES: [CH2:1]1[C:12]2[C:11]3[C:6](=[C:7]([C:13]([OH:15])=O)[CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21])[CH3:17].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]1[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:13]([NH:21][C@@H:20]([CH3:22])[C:19]([O:18][CH2:16][CH3:17])=[O:23])=[O:15])[C:6]=3[NH:5][C:4]=2[CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(O)c1cccc2c3c([nH]c12)CCC3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](C)NC(=O)c1cccc2c3c([nH]c12)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
To a stirred, cooled (0° C.) solution of crude 1,2,3,4-tetrahydrocyclopenta[b]indole-5-carboxylic acid (60 mmol, 12 g), L-alanine ethyl ester (72 mmol, 11 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (72 mmol, 14 g), 1-hydroxybenzotriazole (HOBT) (72 mmol, 10 g) in CH2Cl2 (100 mL) was slowly added diisopropylethylamine (360 mmol, 46 g). The reaction mixture was stirred overnight while warming to room temperature. The reaction was concentrated in vacuo and the resulting oil was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous NH4Cl, NaHCO3, and brine, dried over MgSO4, filtered and concentrated to a brown oil. The crude material was purified by chromatography through silica gel (Biotage) eluting with 15% ethyl acetate-hexanes to afford a yellow oil (8.4 mmol, 2.5 g, 16% yield over 2 steps).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][C:6]=1[C:15]([C:17]1[O:21][N:20]=[C:19]([C:22]([O:24]CC)=[O:23])[CH:18]=1)=[O:16].Cl>C(O)(=O)C>[Cl:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:15]([C:17]1[O:21][N:20]=[C:19]([C:22]([OH:24])=[O:23])[CH:18]=1)=[O:16])=[C:5]2[CH2:4][C:3]([OH:27])=[O:2]
Reactant: CCOC(=O)c1cc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)OC)on1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Cc1c(C(=O)c2cc(C(=O)O)no2)[nH]c2ccc(Cl)cc12
Temperature: 110 °C
Yield: 43 %

Procedure:
To a solution of methyl[5-chloro-2-[3-(ethoxycarbonyl)isoxazole-5-carbonyl]-1H-indol-3-yl]acetate (Example 259, 314 mg, 0.80 mmol) in acetic acid (20 ml) was added 2N aqueous HCl (6.0 ml) and the mixture was heated at 110° C. for 5 h. The mixture was then cooled to room temperature and concentrated. The residual yellow solids were washed with ethyl acetate and recrystallized from ethyl acetate/hexane to afford 120 mg (43%) of the title compound as pale yellow solids.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:12][O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=2)[CH2:18][CH2:17]1
Reactant: COCCN1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCCN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 125 °C
Reaction time: 24 h
Yield: 74.9 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (1.4 g, 8.1 mmol), 1-(2-methoxy-ethyl)-piperazine (2.0 g, 14.0 mmol) and anhydrous potassium carbonate (1.38 g, 10.0 mmol) in N,N-dimethylacetamide (3 ml) was stirred at 120-130° C. under nitrogen for 1 day. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water (15 ml) and stirred vigorously. The resulting yellow brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting yellow brown solid was slurried in diethyl ether (20 mL), filtered, washed with additional diethyl ether, dried to afford 5-[4-(2-methoxy-ethyl)-piperazin-1-yl]-2-nitro-phenylamine (1.7 g, 75%) as a yellow brown powder.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.NC(N)=[S:22].[OH-].[Na+].Cl>O.C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:6][C:2](=[S:22])[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: NC(N)=S
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCc1oc(=S)[nH]c1-c1ccc(Cl)cc1
Yield: 100 %

Procedure:
A mixture of methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (5.72 g), thiourea (4.57 g) and ethanol (70 ml) was stirred under reflux for 30 minutes. An aqueous solution of 2N sodium hydroxide (40 ml) was added to the reaction mixture, and stirred under reflux for an additional 30 minutes. Water was added to the reaction mixture, which was then neutralized with 6N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 3-[4-(4-chlorophenyl)-2-thioxo-4-oxazolin-5-yl]propionic acid (5.41 g, yield: 96%). This was recrystallized from ethanol to give colorless needles. mp 196-197° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[I-:28].[Na+]>[Cu]I>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([I:28])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: [I-]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Agent: [Cu]I
Agent: [Na+]
Product: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 82 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (979 mg) described in Preparation Example 110, sodium iodide (650 mg) and copper(I) iodide (205 mg) and by the reaction and treatment in the same manner as in Preparation Example 154, the title compound (886 mg) was obtained.
Reaction SMILES: C(O[C:4](=[O:19])[CH2:5][C@H:6]([CH3:18])[CH2:7][CH2:8][CH2:9][C@@H:10]([CH3:17])[CH2:11][CH2:12][CH:13](C)[CH2:14][CH3:15])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:26]COCC>>[CH3:18][C@H:6]([CH2:7][CH2:8][CH2:9][C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:26])[CH2:5][CH2:4][OH:19]
Reactant: CCOC(=O)C[C@H](C)CCC[C@@H](C)CCC(C)CC
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCO
Reaction time: 2 h
Yield: 97.4 %

Procedure:
3.13 g (0.01157 mol) of 3(R),7(R),10-trimethyl-dodecanoic acid ethyl ester in dry ether (35 ml) was added dropwise to a mixture of lithium aluminum hydride (3.0 g) in 150 ml of dry diethyl ether. The mixture was refluxed with stirring for 21/2 hr. The flask was cooled in an ice-bath and the excess of lithium aluminum hydride was destroyed by carefully adding water, followed by 450 ml of 2 N H2SO4. The aqueous phase was extracted with diethyl ether (3×150 ml). The ether extract was washed with water (3×50 ml), saturated aqueous NaHCO3 (3×50 ml), water (3×50 ml) and dried over anhydrous magnesium sulfate. Evaporation of ether to dryness at reduced pressure yielded 2.70 g of crude material which on distillation (Kugelrohr oven, 104°-110°/0.10 mmHg) afforded 2.572 g (97.4%) of 3(R),7(R),11-trimethyl-dodecanol as a colorless oil.