Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:37]=O)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1.[I:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:37][NH:44][C:43]2[CH:45]=[CH:46][C:40]([I:39])=[CH:41][CH:42]=2)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1
Reactant: Nc1ccc(I)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(I)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (1.3 g, 6.0 mmol) was added to a DCM solution (6 mL) of methyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate (1.0 g, 3.0 mmol) and 4-iodoaniline (723 mg, 3.3 mmol), and the resulting mixture was stirred at room temperature. After 3 h the resulting mixture diluted with DCM and saturated aqueous Na2CO3 and the layers were separated. The aqueous phase was extracted with DCM and the combined organics were dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:33]=[CH:32][C:8]([CH2:9][NH:10][C:11]([C@H:13]2[CH2:18][NH:17][CH2:16][CH2:15][N:14]2[S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[O:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH3:34][O:35][C:36]([C:38]1[CH:43]=[N:42][C:41](Cl)=[CH:40][N:39]=1)=[O:37].C(N(CC)CC)C>CN(C)C=O>[CH3:34][O:35][C:36]([C:38]1[N:39]=[CH:40][C:41]([N:17]2[CH2:16][CH2:15][N:14]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C@@H:13]([C:11](=[O:12])[NH:10][CH2:9][C:8]3[CH:7]=[CH:6][C:5]([CH:2]([CH3:4])[CH3:3])=[CH:33][CH:32]=3)[CH2:18]2)=[N:42][CH:43]=1)=[O:37]
Reactant: CC(C)c1ccc(CNC(=O)[C@H]2CNCCN2S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)[C@@H](C(=O)NCc3ccc(C(C)C)cc3)C2)cn1
Temperature: 60 °C
Reaction time: 14 h
Yield: 102.7 %

Procedure:
A mixture of the compound (61 mg) obtained in Example 1, 5-chloropyrazine-2-carboxylic acid methyl ester (25 mg) and triethylamine (42 μl) in N,N-dimethylformamide (0.3 ml) was stirred at 60° C. for 14 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (5% methanol/chloroform) to give the title compound (75 mg).
Reaction SMILES: [CH3:1][CH2:2][O:3]CC.Br[C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]=2[CH:17]=1.C(=O)C.[NH4+].[Cl-]>C1COCC1>[CH3:15][C:12]1([CH3:16])[C:11]2[CH:17]=[C:7]([CH:2]([OH:3])[CH3:1])[CH:8]=[CH:9][C:10]=2[O:14][CH2:13]1
Reactant: CC1(C)COc2ccc(Br)cc21
Reactant: CCOCC
Agent: CC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)C(C)(C)CO2
Reaction time: 1.5 h
Yield: 682 %

Procedure:
A mixture of the precursor ether (0.21 g 0.9 mmol), Mg turnings (1.0 g 0.041 g at) and dry THF (2 mL) was heated (heat gun) under N2 until the mixture turned cloudy (ca 15 min). Dry THF (15 mL) was added to the mixture which was then heated to reflux. A solution of ether (42) (2.92 g, 12.9 mmol) in dry THF (25 mL) was added dropwise to the vigorously stirred mixture over a period of 0.75 hours. After vigorous stirring at reflux for 2.75 hours, another 0.25 g (0.010 g at) of Mg turnings were added. The new mixture was stirred at reflux for 0.75 hour and with no external heat for 0.5 hours. Upon cooling the mixture to -5° to -10° C. (ice-salt bath), a solution of freshly distilled acetaldehyde (2.0 g, 0.045 mol) in dry THF (20 mL) was added dropwise to the vigorously stirred mixture over a period of 0.7 hours. This reaction mixture was stirred in an ice-salt bath (-5° to -10° C.), for 1.5 hours, after which time a solution of acetaldehyde (0.9 g, 0.020 mol) in dry THF (5 mL) was added dropwise (over a period of about 0.2 h) and the new mixture was stirred 0.3 hours. With continued cooling (-5° to -10° C.), saturated aqueous NH4Cl (3 mL) was added and the excess Mg turnings were removed by filtration. Saturated aqueous NH4Cl (10 mL) and ether rinses (of glassware and Mg turnings, 60 mL) were added to the filtrate. After separating the organic layer, the aqueous phase (pH≥8) was acidified (pH 6.5 to 7) with saturated aqueous NH4Cl (15 mL) and 4% H2SO4 (14 mL). The aqueous solution was extracted with ether (5 ×40 mL) and ether (90 mL) was added to the combined organics. The organic solution was washed with saturated aqueous NaHCO3 (75 mL) and brine (50 mL). After drying (MgSO4) the solution, the solvent was removed, and the residual oil was chromatographed through a circular silica gel plate (4 mm) spun by a Chromatotron (Model 7924T, Harrison Research, 840 Moana Court, Palo Alto, Calif.). Half of the product was eluted with ether/petroleum ether (bp 50°-110° C.) 20:1, 8:1, and 4:1 and then the same solvent system was used to elute the other half. In both separations, the 4:1 ratio was required to elute the title compound. Concentration of the eluent in the desired fractions gave 1.18 g (44%) of the alcohol as a light yellow, viscous oil. TLC analysis (1:4 ether:petroleum ether, bp 50°-110° C.) indicated the compound was essentially pure.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([S:18][CH2:19][CH3:20])=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:17])=[O:5])C.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[C:7]([S:18][CH2:19][CH3:20])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[OH:16]
Reactant: CCOC(=O)c1c(SCC)nc2c(Cl)cccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCSc1nc2c(Cl)cccc2c(O)c1C(=O)O
Yield: 95.3 %

Procedure:
To a solution of 8-chloro-2-ethylsulfanyl-4-hydroxy-quinoline-3-carboxylic acid ethyl ester (19.81 g, 63.5 mmol) in THF:MeOH (1:1, 150 mL) at room temperature was added 1N NaOH. The reaction was allowed to stir at reflux for 24 hours, monitoring by HPLC. Upon the completion of the reaction, the mixture was acidified with 4N HCl and extracted 3 times with dichloromethane. The organic phases were combined, dried over Mg2SO4, and concentrated in vacuo to afford 8-chloro-2-ethylsulfanyl-4-hydroxy-quinoline-3-carboxylic acid (17.17 g, 95% yield). LCMS found 383.88 [M+H]+.
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]([C:26]([OH:28])=O)=[CH:22][CH:21]=[N:20]2)=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.[CH3:38][O:39][C:40]1[CH:75]=[CH:74][C:43]([CH2:44][N:45]2[C:49]3=[N:50][CH:51]=[CH:52][C:53]([O:54][C:55]4[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][C:56]=4[F:62])=[C:48]3[C:47]([NH:63][CH:64]3[CH2:69][CH2:68][N:67]([CH2:70][CH2:71][O:72][CH3:73])[CH2:66][CH2:65]3)=[N:46]2)=[CH:42][CH:41]=1>C(Cl)Cl>[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:44][N:45]2[C:49]3=[N:50][CH:51]=[CH:52][C:53]([O:54][C:55]4[CH:60]=[CH:59][C:58]([NH:61][C:26]([C:23]5[C:24](=[O:25])[N:19]([C:16]6[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=6)[N:20]=[CH:21][CH:22]=5)=[O:28])=[CH:57][C:56]=4[F:62])=[C:48]3[C:47]([NH:63][CH:64]3[CH2:65][CH2:66][N:67]([CH2:70][CH2:71][O:72][CH3:73])[CH2:68][CH2:69]3)=[N:46]2)=[CH:74][CH:75]=1
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COCCN1CCC(Nc2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(N)cc4F)c23)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCC(Nc2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
EDCI (47 mg, 0.24 mmol) was added to a stirred mixture of 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (57 mg, 0.24 mmol, prepared according to the procedure for Example 19, Step C), HOBt-hydrate (38 mg, 0.24 mmol), and DIEA (0.070 mL, 0.404 mmol) in DCM (1 mL) at ambient temperature, and the reaction was stirred for 15 minutes at ambient temperature. 1-(4-Methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-N-(1-(2-methoxyethyl)piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (42 mg, 0.0807 mmol) was added, and the resulting solution was stirred for 2 days at ambient temperature. The crude reaction mixture was loaded directly on to a preparative TLC plate (2 mm thickness) and eluted with 10% MeOH/DCM. The product was obtained as a waxy solid (45 mg, 76%). LRMS (APCI+): 100% purity, 220 nm, m/z 737 (M+1) detected.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH3:24])[CH2:13][CH2:12]1)=[O:10].Cl[CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>>[O:30]=[S:29]1(=[O:31])[CH2:28][CH2:27][CH2:26][N:1]1[C:2]1[CH:7]=[C:6]([N:8]2[CH2:26][CH2:27][CH2:28][S:29]2(=[O:31])=[O:30])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH3:24])[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3N)CC2)c(C)c1
Reactant: O=S(=O)(Cl)CCCCl
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1

Procedure:
Using (2,4-diaminophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (847 mg) described in Preparation Example 150 and 3-chloropropane-1-sulfonyl chloride (0.85 mL) and by the reaction and treatment in the same manner as in Example 78, the title compound (843 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]([NH2:25])=[O:24].C=O.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[CH2:35](O)C>ClCCCl>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]([NH:25][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:24]
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(N)=O
Reactant: CCO
Agent: C=O
Solvent: ClCCCl
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)NCN1CCN(C)CC1

Procedure:
A mixture of 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxamide (5 g), formalin (37%, 1.35 ml), N-methylpiperazine (2.25 g), ethanol (50 ml) and 1,2-dichloroethane (25 ml) was refluxed for 6 hours. After evaporating the solvent in vacuo, the residue was chromatographed on alumina (200 ml) and eluted with chloroform. The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 6-methyl-N-(4-methylpiperazin-1-ylmethyl)-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxamide (1.90 g).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:17][C:16]1([CH3:30])[CH3:29])=O)(C)(C)C>C(Cl)Cl>[CH3:29][C:16]1([CH3:30])[CH2:17][N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[C:19](=[O:21])[CH2:20][NH:15]1
Reactant: Cc1ccccc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1N1CC(C)(C)NCC1=O
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
0.97 ml of trifluoroacetic acid (12.6 mmol) was added to a solution of 0.4 g of 2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (51c) (1.26 mmol) in methylene chloride (1.9 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate aqueous solution was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=10/1) to obtain 230 mg of the title compound (yield: 84%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[S:9][C:10]([Br:28])=[CH:11][C:12]=1[S:13](=[O:27])(=[O:26])[N:14]([CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[CH3:15])([CH3:4])([CH3:3])[CH3:2].[C:30](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[N:7]([C:8]1[S:9][C:10]([Br:28])=[CH:11][C:12]=1[S:13](=[O:26])(=[O:27])[N:14]([CH2:16][CH:17]([C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[OH:18])[CH3:15])[CH3:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1cc(Br)sc1NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)c1sc(Br)cc1S(=O)(=O)N(C)CC(O)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a solution of (5-bromo-3-{[2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-sulfamoyl}-thiophene-2-yl)-carbamic acid t-butyl ester (the compound of Preparation Example 97) (1 g) and potassium carbonate (278 mg) in N,N-dimethylformamide was added methyl iodide (0.75 mL). After stirred for 2 hours, ethyl acetate was added, and insoluble matter was removed by filtration. The residue resulting form evaporating the filtrate in vacuo was purified by silica gel column chromatography (hexane/ethyl acetate), and a colorless oily matter (958 mg) was obtained.
Reaction SMILES: Cl.[F:2][C:3]([F:30])([F:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(Cl)Cl.[OH:34][CH:35]([CH2:40][CH3:41])[C:36]([O:38][CH3:39])=[O:37].C(N(CC)CC)C>CCOCC>[F:2][C:3]([F:30])([F:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:34][CH:35]([C:36]([O:38][CH3:39])=[O:37])[CH2:40][CH3:41])=[O:25])=[CH:22][CH:21]=1
Reactant: CCC(O)C(=O)OC
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCC(OC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10.0 g. 4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride in 200 ml. methylene chloride is added dropwise a solution of 3 g. methyl α-hydroxybutyrate and 5 g. triethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several portions of ether. The ether solution is washed with water, dried and evaporated to yield the product as a white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C@H:15]3[C@H:19]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[N:30]#[C:31]Br>CC#N.O.C(OCC)(=O)C>[C:31]([N:17]1[CH2:18][C@@H:19]([C:20]([O:22][CH3:23])=[O:21])[C@H:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[CH2:16]1)#[N:30]
Reactant: N#CBr
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)[C@@H]1CN(C#N)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Reaction time: 24 h
Yield: 51.3 %

Procedure:
To a solution of trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-(methoxycarbonyl)pyrrolidine (300 mg, 0.94 mmol) and K2CO3 (195 mg, 1.5 mmol) in 5 mL of CH3CN at 0° C. was added cyanogen bromide (120 mg, 1.13 mmol). The solution was stirred for 24 hr, diluted with H2O and ethyl acetate, and washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated to an oil. Silica gel chromatography (3:1, hexanes:ethyl acetate) provided trans-1-cyano-3-(3-cyclopentoxy-4-methoxyphenyl)-4-(methoxycarbonyl)pyrrolidine as a white solid (166 mg, 51%).m.p. 78°-80° C. Anal. Calcd for C19H24N2O4 : C, 66.26; H, 7.02; N, 8.13. Found: C, 66.30; H, 7.04; N, 8.15.
Reaction SMILES: [Cl:1]C1C=C2C(=C(Cl)C=1)CN(C)CC2C1C=C(N)C=CC=1.[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([Cl:32])[CH:31]=1)[CH2:28][N:27]([CH3:33])[CH2:26][CH:25]2[C:34]1[CH:35]=[C:36]([NH:40][C:41](=[O:52])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)[CH:37]=[CH:38][CH:39]=1.ClC1C=C2C(=C(Cl)C=1)CN(C)CC2C1C=CC([C@@](O)([C@@H](O)[C@H](O)[C@H](O)CO)C(N)=O)=CC=1.ClC([O:88][C:89]1[CH:94]=[CH:93][C:92]([N+:95]([O-:97])=[O:96])=[CH:91][CH:90]=1)=O>ClCCl>[ClH:1].[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([Cl:32])[CH:31]=1)[CH2:28][N:27]([CH3:33])[CH2:26][CH:25]2[C:34]1[CH:35]=[C:36]([NH:40][C:41](=[O:52])[O:88][C:89]2[CH:94]=[CH:93][C:92]([N+:95]([O-:97])=[O:96])=[CH:91][CH:90]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(N)c2)C1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)c2)C1
Agent: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc([C@](O)(C(N)=O)[C@@H](O)[C@H](O)[C@H](O)CO)cc2)C1
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)C1
Product: Cl
Reaction time: 4.5 h

Procedure:
350 mg (1.1 mmol) of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (Example compound 2, intermediate 1) were dissolved in 17.5 ml of dichloromethane and admixed with stirring with 230 mg (1.1 mmol) of 4-nitrophenyl chloroformate. After 4.5 hours, a further 0.1 equivalent (23 mg) of 4-nitrophenyl chloroformate was added and the solution was stirred overnight. For workup, the resulting precipitate was filtered off and washed with dichloromethane. The crude product obtained in this way could be reacted further without further purification.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][N:17]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27]C(O)=O.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([N:8]([CH3:27])[CH2:9][CH2:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][N:17]=2)=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: NC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)nc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(CCc1ccc(Oc2ccc(C(N)=O)cn2)cc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine amine (65 mg, 0.20 mmol) from example 1, AcOH (70 μL, 1.2 mmol), formaldehyde (0.6 mmol) and NaBH(OAc)3 (0.40 mmol) in 1,2-DCE (2 mL). Stir the mixture at room temperature overnight. Dilute the mixture with CH2Cl2 and wash with NaHCO3 sat. Extract the aqueous layer with CH2Cl2, combine the organic layers and dry over Na2SO4. Purify by flash chromatography on silica gel (eluent: EtOAc). Electrospray MS M+1 ion=362, 1H-NMR (CDCl3, 400 MHz): 8.58 (d, 1H, J=2.6 Hz), 8.15 (dd, 1H, J=2.6 and 8.6 Hz), 7.32-7.22 (m, 7H), 7.06-7.04 (m, 2H), 6.95 (d, 1H, J=8.6 Hz), 3.61 (bs, 2H), 2.91-2.84 (m, 2H), 2.74-2.66 (m, 2H), 2.32 (s, 3H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>>[C:21]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])(=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)Cl
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: C=CC(=O)N=C(OCC)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and acryloyl chloride, there is obtained ethyl N-(acryloyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 320 (11), 291 (19), 194 (100), 55 (15);
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][OH:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:25])[CH3:9])=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1>>[OH:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:25])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([CH3:26])[CH:32]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccccc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCO)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=0.928 min, m/z=444.4; 1H NMR (CDCl3) 1.50 (d, 3H), 2.05-2.18 (m, 2H), 2.26-2.39 (m, 6H), 2.82 (s, 3H), 2.94 (m, 1H), 3.51 (m, 1H), 3.72 (m, 1H), 5.54 (m, 1H), 7.00 (d, 2H), 7.24-7.38 (m, 7H), 7.57 (s, 1H), 7.64 (d, 1H), 8.75 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].F[C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[C:41]([C:40]1[CH:43]=[CH:44][C:37]([N:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:4]3[N:5]([CH3:26])[C:6]4[C:15]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[N:9]([CH2:16][C:17](=[O:24])[C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[C:8](=[O:25])[C:7]=4[C:3]=3[O:2][CH3:1])=[O:28])[CH2:35][CH2:34]2)=[CH:38][CH:39]=1)#[N:42]
Reactant: N#Cc1ccc(F)cc1
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1c(C(=O)NC2CCN(c3ccc(C#N)cc3)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 19.9 %

Procedure:
A solution of the compound of Example 77 (300 mg, 0.64 mmol), 4-fluorobenzonitrile (115 mg, 0.95 mmol) and potassium carbonate (176 mg, 1.3 mmol) in N-methylpyrrolidone (3.0 mL) was stirred at 120° C. for 16.5 hr. The reaction mixture was diluted with water, and extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/hexane=30/70-100/0) and recrystallized from THF-diethyl ether to give the title compound (73 mg, 20%) as a pale-yellow solid.
Reaction SMILES: BrCC[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O(CC1CCNCC1)C1C=CC=CC=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: c1ccc(OCC2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2[nH]ccc2c1
Yield: 41 %

Procedure:
A mixture of 8.96 g (0.04 mole) of 3-(2-bromoethyl)-indole, 7.65 g (0.04 mole) of 4-phenoxymethylpiperidine, 7.76 g (0.06 mole) of N-ethyl-diisopropylamine and 100 ml of dioxane is heated under reflux for 9 hours. After cooling, the reaction mixture is filtered, the filtrate is evaporated in a vacuum and the residue is taken up in diethy ether, washed with water, dried over anhydrous sodium sulfate and evaporated. After recrystallization from isopropanol/ligroin, there are obtained 5.55 g of 3-[2-(4-phenoxymethyl)-piperidino)-ethyl]-indole (41% of theory); m.p. 113°-114° C.