Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[CH2:14][C@H:13]([CH3:15])[O:12][C@@H:11]([CH3:16])[CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:9]1[CH2:10][C@H:11]([CH3:16])[O:12][C@@H:13]([CH3:15])[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(C(=O)c2ccccc2)C[C@H](C)O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CN(Cc2ccccc2)C[C@H](C)O1
Temperature: 55 °C

Procedure:
(2S,6S)-4-benzoyl-2,6-dimethylmorpholine (759 mg, 3.46 mmol) is dissolved in anhydrous THF (40 mL) and treated with LiAlH4 (1.0M in THF, 6.9 mL, Aldrich). The mixture is stirred with heating at 55° C. for 18 hours. An additional equivalent of LiAlH4 is added and the mixture is stirred with heating at 55° C. for an additional 6 hours. The reaction is quenched by adding water (0.4 mL) followed by 6.0M NaOH (0.4 mL) followed by water (1.2 mL). The white slurry is diluted with Et2O and filtered. The inorganic salts are washed with and additional portion of Et2O and the combined ethereal washes are dried over Na2SO4. The product is purified on a Biotage Flash 40M+ using a 15% Et2O in pentane as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum yielding a colorless oil.
Reaction SMILES: CCC[CH2:4][CH2:5][CH2:6][CH3:7].[CH2:8]1CC[CH2:11][CH2:10][CH2:9]1.[CH3:14][CH:15]([CH2:24][CH2:25][CH3:26])[CH2:16][O:17][CH2:18][CH:19]([CH3:23])[CH2:20][CH2:21][CH3:22].[Mg:27]>CCCCCCC>[CH3:23][CH:19]([CH2:20][CH2:21][CH3:22])[CH2:18][O:17][CH2:16][CH:15]([CH3:14])[CH2:24][CH2:25][CH3:26].[Mg:27].[CH2:8]([Mg:27][CH:6]([CH2:5][CH3:4])[CH3:7])[CH2:9][CH2:10][CH3:11]
Reactant: C1CCCCC1
Reactant: CCCCCCC
Agent: CCCC(C)COCC(C)CCC
Agent: [Mg]
Product: CCCC[Mg]C(C)CC

Procedure:
A 10 ml portion of the heptane-cyclohexane solution of magnesium 2-methyl-1-pentyloxide (6.6 mmoles) of Example I is mixed with 6.1 ml of 1.085M DBM solution in heptane. A clear solution of the 1:1 Molar complex of magnesium 2-methyl-1-pentyloxide and n-butyl-sec-butylmagnesium is obtained. Assuming total scrambling of alkyl and alkoxy groups, this complex can be represented as (n,s)-butylmagnesium 2-methylpentyloxide. The complex can also be prepared by the addition of 13.2 mmoles (1.63 ml) of neat 2-methyl-1-pentanol to 13.2 mmoles (12.2 ml) of 1.085M DBM solution in heptane.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)COc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
t-Butyl 4-nitrophenoxyacetate (19.3 g, 76.0 mmol) was dissolved in ethanol (100 ml) and 10% palladium-carbon (1.0 g) was added. The mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. The reaction mixture was filtrated and low boiling matters were distilled away from the filtrate under reduced pressure to give 16.8 g of t-butyl 4-aminophenoxyacetate as a pale-brown solid (99%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:50])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[CH:8][C:7]=1[O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:38][CH:37]=1>>[CH2:13]([O:12][C:10]1[CH:9]=[CH:8][C:7]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:38][CH:37]=2)=[C:6]([CH:11]=1)[C:5]([OH:50])=[O:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(OCCCOc2ccc(OCc3ccccc3)cc2)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCOc1ccc(OCCCOc2ccc(OCc3ccccc3)cc2)c(C(=O)O)c1

Procedure:
Hydrolysis with sodium hydroxide of 5-(octadecyloxy)-2-[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid methyl ester gave 5-(octadecyloxy)-2-[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid, mp 93°-95°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][CH2:17][C:18]#[CH:19])=[N:4][C:5]2[CH:6]=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][C:10]=2[N:11]=1.OS(O)(=O)=O.[OH-].[Na+]>>[Cl:1][C:2]1[C:3]2[N:4]([C:18]([CH3:19])=[CH:17][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[CH:6]=2
Reactant: C#CCNc1nc2cc3ccccc3cc2nc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc2c(Cl)nc3cc4ccccc4cc3n12
Temperature: 80 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
2-Chloro-3-(propargylamino)benzo[g]quinoxaline (0.420 g, 1.57 mmol) was treated with 4 mL of concentrated H2SO4 and the mixture was stirred at 80° C. for 1 hour, cooled to RT and poured into ice water. The mixture was cautiously neutralized with aqueous NaOH, and the resulting precipitate was filtered, washed with water, and dried in vacuo to give the title compound as a beige solid (0.124 g, 30%); mp 221-223° C.; IR (KBr, cm−1) 1538, 1479, 1456, 1398, 1101, 919; 1H NMR (DMSO) δ 8.79 (s, 1H), 8.53 (s, 1H), 8.23 (d, J=8.1, 1H), 8.13 (d, J=8.5, 1H), 7.69-7.59 (m, 3H), 3.04 (s, 3H); LC/MS 100% (220 nm), m/z (M+H+) 268.
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([C:19](=[O:21])[CH3:20])=[CH:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:19]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:8]([CH2:7][C:6]([OH:22])=[O:5])[CH:9]=1)(=[O:21])[CH3:20]
Reactant: COc1ccc2c(c1)c(C(C)=O)cn2CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)c(C(C)=O)cn2CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (3-acetyl-5-methoxy-indol-1-yl)-acetic acid tert-butyl ester (520 mg, 1.71 mmol) in CH2Cl2 (15 mL) was added TFA (1.32 mL, 17.1 mmol). The reaction mixture was stirred at RT overnight. Volatiles were evaporated, then the crude material was taken up in 5 mL of 1M aqueous NaOH solution and washed with CH2Cl2 which was discarded. The water phase was acidified to pH=1 by adding a 6M aqueous HCl solution, and then was extracted twice with AcOEt. The combined organic phases were dried (Phase separator) and evaporated to give the title compound. MS (LC/MS): 248.1 [M+H]+, 246.1 [M−H]−; tR (HPLC conditions c): 3.47 min.
Reaction SMILES: C[Al](C)C.[F:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][CH:21]1[CH2:24][N:23]([CH2:25][C@H:26]([OH:31])[C:27](OC)=[O:28])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:13]([O:20][CH:21]1[CH2:24][N:23]([CH2:25][C@H:26]([OH:31])[C:27]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([F:5])=[CH:11][N:10]=2)=[O:28])[CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Nc1ccc(F)cn1
Reactant: COC(=O)[C@@H](O)CN1CC(O[Si](C)(C)C(C)(C)C)C1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CN(C[C@H](O)C(=O)Nc2ccc(F)cn2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
Trimethylaluminium (2M solution in toluene) (15.89 mL, 31.79 mmol) was added to 5-fluoropyridin-2-amine (3.10 g, 27.64 mmol) in toluene (80 mL) cooled to 0° C. under nitrogen over a period of 10 minutes. The resulting solution was stirred at 0° C. for 10 minutes. (S)-methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate (Intermediate AD3) (8 g, 27.64 mmol) in toluene (20 mL) was added over 10 minutes and the reaction was allowed to warm to room temperature and then heated at 90° C. for 2 hours. The reaction mixture was cooled and poured into a 20% solution of Rochelle's salt (50 mL), diluted with ethyl acetate (200 mL) and stirred for 2 hours. The organic phase was separated, washed with water and brine, dried (MgSO4) filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 80 to 100% EtOAc in isohexane to afford the product (5.28 g, 51.7%). 1H NMR (400 MHz, CDCl3) δ 0.028 (3H, s), 0.033 (3H, s), 0.87 (9H, s), 2.90 (2H, d), 3.02-3.08 (2H, m), 3.68-3.74 (2H, m), 4.00 (1H, t), 4.41-4.48 (1H, m), 7.41-7.45 (1H, m), 8.15 (1H, d), 8.21-8.24 (1H, m), 9.85 (1H, s); m/z (ES+) (M+H)+=370; HPLC tR=1.97 min.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([F:42])=[C:22]([C@:24]34[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]3[CH2:28][S:27][C:26]([NH:34]C(=O)OC(C)(C)C)=[N:25]4)[CH:23]=2)=[O:16])=[N:13][CH:14]=1.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)C>[NH2:34][C:26]1[S:27][CH2:28][C@@H:29]2[CH2:30][CH2:31][CH2:32][CH2:33][C@:24]2([C:22]2[CH:23]=[C:18]([NH:17][C:15]([C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][N:13]=3)=[O:16])[CH:19]=[CH:20][C:21]=2[F:42])[N:25]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3F)CCCC[C@H]2CS1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3F)CCCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
Trifluoroacetic acid (200 μL) was added to a solution of the compound of Example 1 (23.0 mg) in dichloromethane (1.00 mL), and the mixture was stirred at room temperature for four hours. The reaction solution was diluted with diethyl ether and neutralized with a sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by NH-silica gel column chromatography to obtain the title compound (18.0 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[Cl:12][C:13]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].ClC1C=C(F)C=CC=1C=O.CNC>>[Cl:12][C:13]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:14]=1[CH:15]([N:16]([CH3:18])[CH3:17])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1]
Reactant: C[N+](C)=Cc1ccc(F)cc1Cl
Reactant: Cc1cc2ccccc2[nH]1
Agent: CNC
Agent: O=Cc1ccc(F)cc1Cl
Agent: [Cl-]
Product: Cc1[nH]c2ccccc2c1C(c1ccc(F)cc1Cl)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-1H-indole and (2-chloro-4-fluoro-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2-chloro-4-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([CH3:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[Br:16]Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:16][C:9]1[CH:10]=[CH:11][C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]([CH:8]=1)[CH:6]=[O:7]
Reactant: BrBr
Reactant: CC(C)c1ccccc1C=O
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)c1ccc(Br)cc1C=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 34.8 %

Procedure:
A solution of 2-isopropyl benzaldehyde (1.5 g, 10.13 mmole) in DCM (10 mL) was added to a solution of AlCl3 (2.6 g, 20.26 mmole) in DCM (10 mL) at 0° C. followed by addition of a dilute solution of Br2 (0.67 mL, 13.1 mmole in 20 mL DCM) to the reaction mixture. The solution was stirred at 0° C. for 6 hours then stirred overnight at room temperature. The reaction mixture was basified using saturated aqueous sodium bicarbonate and extracted with DCM (30×2 mL). The organic layers were combined and the crude product was obtained by evaporation of the solvent. The crude product was purified by column chromatography using 1% EtOAc in Hexane to yield 5-bromo-2-isopropylbenzaldehyde (800 mg).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:10]1([N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>O1CCCC1>[C:10]1([N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C(=NN(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 500 parts of tetrahydrofuran were dissolved 23.8 parts of 4- 5-(5H-dibenzo b,f!azepinyl)!benzaldehyde and 26.5 parts of N,N-diphenylhydrazine hydrochloride. This solution was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into 2,000 parts of water, and the crystals precipitated were taken out by filtration. The crystals obtained were washed with ethyl alcohol and then dried at reduced pressure. The crystals dried were dissolved in 100 parts of ethyl acetate, and this solution was poured into 1,000 parts of methyl alcohol to recrystallize the reaction product. Thus, 28.9 parts (yield, 77.9%) of 4- 5-(5H-dibenzo b,f!azepinyl)!benzaldehyde N,N-diphenylhydrazone was obtained. This compound had a melting point of 178.0° to 179.0° C. The results of elemental analysis are shown in Table 4 below, together with calculated values for C33H25N3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11](Br)=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=1B(O)O>CCO.C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:29]3[CH:30]=[C:31]([C:34]([F:36])([F:37])[F:35])[CH:32]=[CH:33][C:28]=3[Cl:27])=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Reactant: CCOC(=O)c1cc(-c2ccnc(N)n2)[nH]c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccnc(N)n2)[nH]c1-c1cc(C(F)(F)F)ccc1Cl
Temperature: 100 °C
Yield: 81.8 %

Procedure:
To a solution of ethyl 5-(2-aminopyrimidin-4-yl)-2-bromo-1H-pyrrole-3-carboxylate (prepared according to WO2007/110344, 2.0 g, 6.43 mmol) dissolved in EtOH (20 mL) and toluene (20 mL), LiCl (408 mg, 9.64 mmol), 1 M aq Na2CO3 (17 mmol), 2-chloro-5-trifluoromethylphenylboronic acid (1.875 g, 8.35 mmol) and (Ph3P)2PdCl2 (470 mg, 0.67 mmol) were added and the reaction mixture was heated at 100° C. for 5 h. After cooling to room temperature, the precipitate was filtered and the filtrate was evaporated under reduced pressure, dissolved in DCM and washed with water. The organic layer was then dried over sodium sulfate and concentrated. The crude material was chromatographed on silica gel (DCM/EtOAc 50/50) to afford the title compound (2.16 g, 82%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH:38][C:39](=O)[CH2:40][C:41]3[C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[NH:43][CH:42]=3)[CH2:32][CH2:31]2)=[CH:15][CH:14]=1.[OH-].[Na+]>O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH:38][CH2:39][CH2:40][C:41]3[C:49]4[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=4)[NH:43][CH:42]=3)[CH2:32][CH2:31]2)=[CH:15][CH:14]=1
Reactant: O=C(Cc1c[nH]c2ccccc12)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(NC3CCN(CCNCCc4c[nH]c5ccccc45)CC3)nc3ccccc32)cc1
Yield: 25.5 %

Procedure:
To a stirred mixture of 0.8 parts of lithium aluminum hydride and 135 parts of tetrahydrofuran were added slowly 4 parts of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-1H-indol-3-acetamide. The whole was stirred and refluxed overnight. The reaction mixture was cooled in an ice bath and decomposed by the successive additions of 1 part of water, 4.5 parts of a sodium hydroxide solution 15% and 3 parts of water. The whole was filtered over Hyflo and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 1 part (25.5%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[[2-(1H-indol-3-yl)ethyl]amino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 169.7° C. (compound 107).
Reaction SMILES: Cl.Cl.Cl.[CH2:4]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH2:25])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34]>C(#N)C>[CH2:4]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[CH2:18][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:25][C:33]2=[O:34])[CH2:15][CH2:16]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1CNC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1Nc2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
In this reference example, 4.04 g of 1-benzyl-4-[N-(o-aminobenzyl)-amino]-piperidine trihydrochloride, 3.04 g of triethylamine, 2.03 g of 1,1'-carbonyldiimidazole and 50 ml of acetonitrile are mixed and stirred at room temperature for 4 hours. Then, 0.8 g of 1,1'-carbonyldiimidazole is further added to the mixture and the resultant mixture is refluxed with heating for 20 minutes. The solution is cooled to room temperature. The crystals deposited are separated by filtration, washed with water and dried to obtain 2.50 g of a crude product. The crude product is recrystallized from hot ethanol to obtain 1.75 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.C([O:13][CH:14]=[C:15]([C:21](OCC)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[CH2:19]([O:18][C:16]([C:15]1[C:14](=[O:13])[C:8]2[C:6](=[C:5]([CH3:10])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=2)[NH:7][CH:21]=1)=[O:17])[CH3:20]
Reactant: COc1ccc(N)c(C)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c[nH]c2c(C)cc(OC)cc2c1=O
Yield: 59.5 %

Procedure:
4-Methoxy-2-methylaniline (3.0 g) and diethyl ethoxymethylenemalonate (5.7 g) were reacted in the same manner as in Experimental Example 1 to obtain 3-ethoxycarbonyl-6-methoxy-8-methyl-4(1H)-quinolone (3.4 g). The compound (2.0 g) was subjected to hydrolysis and decarboxylation in the same manner as in Experimental Example 2 to obtain 6-methoxy-8-methyl-4(1H)-quinolone (compound 20, 0.7 g).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:13])[NH:5][CH2:4][C:3]1=[O:14].CC(C)([O-])C.[K+].I[CH2:22][CH2:23][CH2:24][CH3:25].C(OCC)(=O)C.CCCCCC>CN(C)C=O.C(Cl)Cl>[CH2:22]([N:5]1[C:6](=[O:13])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:14])[CH2:4]1)[CH2:23][CH2:24][CH3:25]
Reactant: CN1C(=O)CNC(=O)c2ccccc21
Reactant: CCCCI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN1CC(=O)N(C)c2ccccc2C1=O
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 13 mmol of 3,4-dihydro-1-methyl-1H-1,4-benzodiazepin-2,5-dione (Tett. Lett. 1994, 50(30), 9051, incorporated herein by reference) in 30 mL dry dimethylformamide is treated, dropwise at 0° C. under nitrogen cover, with one equivalent of potassium-t-butoxide (Aldrich; 1.0 M in THF). After forty-five minutes at 0° C., iodobutane is introduced via syringe over several minutes. The reaction mixture is stirred at ambient temperature seventy-five minutes, diluted with methylene chloride, and then washed with water and saturated sodium chloride. The organic solution is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. Flash column chromatography (silica gel; ethyl acetate/hexane (7/1) eluent) provides pure material as a colorless oil (90% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][C:4](=[O:6])[OH:5].[NH:12]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:13]([C:24](ON1C(=O)CCC1=O)=[O:25])[C@@H:14]([CH3:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.Cl>C1COCC1.CN(C=O)C>[NH:12]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[C@H:13]([C:24]([NH:1][C@H:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][C:4](=[O:5])[OH:6])=[O:25])[C@@H:14]([CH3:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: CCOC(=O)[C@@H](N)CC(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a suspension consisting of 2.3 g of H-Asp-OEt, 5.8 g of Boc-Thr(Bzl)-OSu in 20 ml of THF and 20 ml of DMF, was added 2 ml of triethylamine under an ice-cooling condition and the mixture was stirred for 1 hour so as to the pH of the reaction mixture was adjusting to about pH 7, and the reaction was continued for 36 hours. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was acidified by adding 1N-hydrochloric acid, and extracted with ethyl acetate (80 ml×3 times). The organic layer was washed with water, then with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, The ethyl acetate extract was concentrated under reduced pressure and the residue thus obtained was crystallized and recrystallized from diethyl ether-petroleum ether. 5.59 Grams (yield: 86.6%) of the above-mentioned objective product was obtained.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:20]=[O:21])[N:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[Cl:19])[CH:12]=1.CC(C)=[O:24].[OH-].[Na+]>O>[Br:7][C:8]1[CH:9]=[C:10]([C:20]([OH:24])=[O:21])[N:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[Cl:19])[CH:12]=1
Reactant: O=Cc1cc(Br)cn1-c1ccncc1Cl
Reactant: CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Br)cn1-c1ccncc1Cl
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of 2.0 g of potassium permanganate in 10 ml of water was added dropwise to a mixture of 1.2 g of 4-bromo-1-(3-chloro-4-pyridinyl)-1H-pyrrole-2-carbaldehyde and 30 ml of acetone while the mixture was maintained at 40° C. The resulting mixture was stirred at 60° C. for 1 hour. A precipitate was filtered off to obtain a filtrate. The filtrate was adjusted to pH 10-12 by an addition of a 2N aqueous sodium hydroxide solution, and then washed with chloroform two times. The aqueous layer was adjusted to around pH 3 by an addition of 2N hydrochloric acid, and then extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.43 g of 4-bromo-1-(3-chloro-4-pyridinyl)-1H-pyrrole-2-carboxylic acid of the formula: