Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH:7]=[C:8]([P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14])[C:9]([CH3:11])=O)([O-:3])=[O:2].[NH2:21]/[C:22](/[CH3:28])=[CH:23]\[C:24]([O:26][CH3:27])=[O:25]>C(O)(C)C>[CH3:14][O:13][P:12]([O:15][CH3:16])([C:8]1[CH:7]([C:6]2[CH:18]=[CH:19][CH:20]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([CH3:28])[NH:21][C:9]=1[CH3:11])=[O:17]
Reactant: COP(=O)(OC)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(P(=O)(OC)OC)C1c1cccc([N+](=O)[O-])c1
Yield: 44.1 %

Procedure:
To a mixture of 1.85 grams of dimethyl 1-(3-nitrobenzylidene)-acetonylphosphonate and 0.75 gram of methyl 3-aminocrotonate was added 25 ml of isopropanol and the mixture was heated to reflux for four hours with stirring. The reaction mixture was concentrated in vacuo, to the residue was added ether, the resulting crystals were collected by filtration, and recrystallized from ethyl acetate to afford 1.08 grams (yield 42%) of methyl 5-dimethoxyphosphinyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate, pale yellow crystals, melting point 221°-3° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.CC(C)([O-])C.[K+].[CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][C:35]=1[CH:44]1[CH2:46][O:45]1.C(OCC)(=O)C>CS(C)=O>[CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][C:35]=1[CH:44]([OH:45])[CH2:46][O:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:4]1
Reactant: OCC1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCO1
Reactant: c1ccc2cc(C3CO3)ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: OC(COCC1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCO1)c1ccc2ccccc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
A mixture of 6.0g of 2-hydroxymethyl-4-tritylmorpholine, 1.0 g of potassium tert-butoxide and 6 ml of dimethyl sulfoxide was heated to 80° C. Thereto was dropwise added, at 80°-85° C. in 2 hours, a solution of 2.8 g of 2-(2-naphthyl)oxirane dissolved in 6 ml of dimethyl sulfoxide. The resulting mixture was stirred at the same temperature for 3 hours. The reaction mixture was cooled and added to a mixture of 60 ml of ice water and 60 ml of ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 9.0 g of oily 1-(2-naphthyl)-2-[(4-tritylmorpholin-2-yl)methoxy]ethanol (compound No. 254).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8]C)=O.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: COCC(=O)CC(=O)OC
Reactant: C1COCCN1
Product: COCC(=O)CC(=O)N1CCOCC1
Reaction time: 3 h

Procedure:
0.346 mol (50.5 g) of methyl 4-methoxy-acetoacetate and 0.363 mol (31.6 g) of morpholine was stirred for 20 h at 110° C. in a Dean-Stark apparatus. There were further added 0.069 mol (6.02 g) of morpholine and stirred further 3 hours. Subsequently, the excess starting materials were distilled off on a rotary evaporator. 67.3 g of crude product was chromatographed over 600 g silica gel with ethyl acetate/ethanol 9/1. There were 36.9 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[N:9]=[C:8]([C:24]([F:27])([F:26])[F:25])[CH:7]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:14]1[CH2:15][CH2:16][CH:11]([N:10]2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][C:8]([C:24]([F:25])([F:26])[F:27])=[N:9]2)[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1cc(C(F)(F)F)nn1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(F)(F)F)nn1C1CCNCC1
Temperature: 21 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 93 (1.014, 2.59 mmol) in CH2Cl2 (13 ml) was added TFA (3 ml, 38.9 mmol). The resulting solution was allowed to stir at 21° C. for 2 h. After the usual work-up, crude 94 was obtained as colorless oil. LRMS (ESI): calc. 291.3; found 292.2 (MH)+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10](Cl)[C:11]([CH3:16])([N+:13]([O-:15])=[O:14])[CH3:12])=[CH:4][C:3]=2[O:2]1.Cl(O)(=O)(=O)=O.C(O)C>[H][H].C(OCC)(=O)C.[C].[Pd]>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([CH3:16])([N+:13]([O-:15])=[O:14])[CH3:12])=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)(C(Cl)c1ccc2c(c1)OCO2)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(Cc1ccc2c(c1)OCO2)[N+](=O)[O-]
Yield: 89 %

Procedure:
A mixture of 7.0 g of 1-(3,4-methylenedioxyphenyl)-1-chloro-2-methyl-2-nitropropane, 7.7 g of 70% perchloric acid, 2.8 g of 10% palladium-carbon and 100 ml of ethanol is shaken at room temperature for 3 hours in hydrogen gas atmosphere under 3 atmospheres. After the reaction, insoluble materials are removed by filtration, and the filtrate is condensed. The residue is dissolved in ethyl acetate, and the solution is washed with water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution, successively. The washed solution is dried and then evaporated to remove solvent. 5.4 g of 1-(3,4-methylenedioxyphenyl)-2-methyl-2-nitropropane are thereby obtained as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH3:11])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: CCc1ccc(Br)cc1C=O
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C=O
Temperature: 25 °C

Procedure:
A suspension of 5-bromo-2-ethylbenzaldehyde (1.0 g, 4.7 mmol), 2,4-dichlorophenyl boronic acid (1.34 g, 7.0 mmol) and sodium carbonate (0.99 g, 7.98 mmol) in a mixed solvent system of 1,2-dimethoxyethane (12 ml) and distilled water (4 ml) is stirred under a nitrogen atmosphere, then flushed with nitrogen (×2). [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II)chloride (1.15 g, 1.41 mmol) is then added in one portion and the suspension is again flushed with nitrogen, then heated at reflux overnight. After cooling to room temperature the reaction mixture is diluted with distilled water (10 ml) and extracted with dichloromethane (10 ml). The aqueous phase is extracted again with dichloromethane (×2), and the combined organic fractions are finally washed with brine then dried over magnesium sulfate. The crude product is purified by flash column chromatography (isohexane to 75:25 isohexane/ethyl acetate ratio eluant) to afford 2′,4′-dichloro-4-ethylbiphenyl-3-carbaldehyde as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:22]([CH2:26][CH3:27])[C:23](=O)[CH3:24])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH2:28][NH2:29]>>[OH:1][C:2]1[CH:3]=[C:4]([C:10]2[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=3[CH:22]([CH2:26][CH3:27])[C:23]([CH3:24])=[N:29][N:28]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCC(C(C)=O)c1cc(OC)c(OC)cc1C(=O)c1ccc(OC)c(O)c1
Reactant: NN
Product: CCC1C(C)=NN=C(c2ccc(OC)c(O)c2)c2cc(OC)c(OC)cc21

Procedure:
Annulation of 3-{2-[(3-hydroxy-4-methoxyphenyl)carbonyl]-4,5-dimethoxyphenyl}pentan-2-one by reaction with hydrazine to yield 1-(3-hydroxy-4-methoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:13]C(=O)OC(C)(C)C)[CH2:11][CH3:12])[N:7](COC)[C:6]=2[CH:24]=1.[Br-].[CH:26]1([Zn+])[CH2:29][CH2:28][CH2:27]1.O1CCCC1.B(Br)(Br)Br>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH:26]1([C:2]2[CH:3]=[CH:4][C:5]3[NH:9][C:8]([CH:10]([NH2:13])[CH2:11][CH3:12])=[N:7][C:6]=3[CH:24]=2)[CH2:29][CH2:28][CH2:27]1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(Br)cc2n1COC
Reactant: [Zn+]C1CCC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: BrB(Br)Br
Solvent: C1CCOC1
Product: CCC(N)c1nc2cc(C3CCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 120 h
Yield: 13 %

Procedure:
Argon was bubbled through a mixture of (S)-tert-butyl (1-(6-bromo-1-(methoxymethyl)-1H-benzo[d]imidazol-2-yl)propyl)carbamate (Preparation 19, 218 mg, 0.55 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(11) (45.0 mg, 0.0615 mmol), and cyclobutylzinc bromide in tetrahydrofuran (0.5 M, 5.5 mL, 2.8 mmol) for 5 minutes. The mixture was then heated at reflux for 18 hours. After cooling, the reaction was concentrated in vacuo, redissolved in ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to afford the fully protected intermediate as a brown oil. To this oil, cooled in an ice water bath, was added boron tribromide (0.5 mL, 5 mmol) and the reaction was allowed to warm to room temperature and stirred for 5 days. The resulting mixture was then purified by preparative HPLC to provide the title compound (32 mg, 13%) as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH2:11][OH:12].[NH:13]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14]1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:14]2)=[C:3]([CH2:11][OH:12])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N)cc2CO)C1

Procedure:
(2-Fluoro-5-nitrophenyl)methanol was treated with tert-butyl (R)-(+)-pyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 307.40 (C16H25N3O3); MS (ESI): 308 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][F:9].[Mg].Cl[SiH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:14][CH2:13]1>C1COCC1>[F:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][SiH:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:16][CH2:17]1
Reactant: FCCCCCCCBr
Reactant: Fc1ccc(C2CC[SiH](Cl)CC2)cc1F
Agent: [Mg]
Solvent: C1CCOC1
Product: FCCCCCCC[SiH]1CCC(c2ccc(F)c(F)c2)CC1
Yield: 93 %

Procedure:
3.0 g (20 mmol) of 1-bromo-7-fluoroheptane was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain Grignard's reagent. This reagent was then dripped into a 50 ml THF solution of 4.9 g (20 mmol) of 4-(4-chloro-4-silacyclohexyl) -1.2-difluorobenzene to obtain 4-(4-(7-fluoroheptyl)-4-silacyclohexyl)-1,2-difluorobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]2[N:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19](O)[CH:20]=[CH:21][C:22]3[CH:27]=CN=CN=3)[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(=O)CC.Cl.[Cl-].[Na+].O.[C:40]([CH3:50])(OCC)([O:44]CC)[O:41][CH2:42][CH3:43]>>[CH2:42]([O:41][C:40](=[O:44])[CH2:50][CH:21]([C:22]1[CH:27]=[N:14][CH:9]=[N:8][CH:7]=1)[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:30][CH:29]=2)[N:14]=1)[CH3:43]
Reactant: CCOC(C)(OCC)OCC
Reactant: COc1ccc(CNc2cccc(CCCCC(O)C=Cc3ccncn3)n2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCC(=O)O
Product: CCOC(=O)CC(C=CCCCCc1cccc(NCc2ccc(OC)cc2)n1)c1cncnc1
Temperature: 25 °C

Procedure:
A solution of the allylic alcohol 6-9 (1.6 g, 3.37 mmol) in (EtO)3CMe (10 mL) was treated with 100 uL of a 1 mL solution of (EtO)3CMe containing 10 uL of propionic acid. The yellow solution was heated at 150° for 90 minutes. The solution was cooled to room temperature and poured into 1N HCl/brine. The mixture was extracted with CHCl3, dried, concentrated, and purified on silica gel (5% MeOH/CHCl3) to give 2.01 g of 6-10.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=[O:27])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[N:11]=[C:5]2[NH:4][C:3]1=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[CH2:59]O>C1COCC1>[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[CH2:59][N:4]1[C:5]2=[N:11][N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[C:9]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=[O:27])=[C:6]2[C:7](=[O:8])[N:2]([CH3:1])[C:3]1=[O:32]
Reactant: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3cccc(C(=O)O)c3)c2c1=O
Reactant: OCc1ccccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3cccc(C(=O)O)c3)n(Cc3cccc4ccccc34)nc2n(Cc2ccccc2Cl)c1=O
Reaction time: 20 h

Procedure:
Diisipropylazodicarboxylate (0.157 g) was added to a mixture of resin bound 3-[5-methyl-2-(1-naphthylmethyl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]benzoic acid (0.120 g), triphenylphosphine (0.204 g), and 2-chlorophenylmethanol in dry THF (2 mL) at −15° C. Reaction temperature was allowed to come to room temperature and shaken for 20 h. The resin was filtered, washed (3 times) DMF, CH2Cl2, MeOH, CH2Cl2, and dried in vacuum. The dry resin was treated with 15% TFA in dichloromethane (1 mL) for 2 h, and filtered and washed (2 times) with dichloromethane. Combined filtrates were concentrated, and dried in vacuum to give the title compound (0.062 g). Mass 548.80 (M+H).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][N:17]2[C:19]([CH:22]=[O:23])=[CH:20][N:21]=[C:16]2[C@H:15]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:14][CH2:13]1>O1CCCC1>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][N:17]2[C:19]([CH:22]([OH:23])[CH3:1])=[CH:20][N:21]=[C:16]2[C@H:15]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:14][CH2:13]1
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C=O)cnc21
Solvent: C1CCOC1
Product: CC(O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
Methylmagnesium bromide (3.0 M in ether; 0.33 mL, 1.0 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-formyl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (130 mg, 0.33 mmol) in tetrahydrofuran (3 mL) at 0° C. After 10 min, the reaction was quenched with water and the mixture was extracted with dichloromethane (3×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 408.1 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21](Cl)=[O:22])=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[Cl:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36][C:21]([C:17]2[C:18]3[C:19](=[CH:20][C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[C:10]5[C:5]=4[CH:4]=[CH:3][N:2]=[CH:1]5)=[CH:12][CH:13]=3)[CH:14]=[CH:15][CH:16]=2)=[O:22])=[CH:34][CH:33]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(Cl)c1cccc2cc(-c3cccc4cnccc34)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)c1cccc2cc(-c3cccc4cnccc34)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(isoquinolin-5-yl)-1-naphthoyl chloride (0.85 g, 0.27 mmol) was suspended in CH2Cl2 (1 mL) and triethylamine (0.057 mL, 0.4 mmol) was added followed by 4-chloroaniline (33 mg, 0.26 mol). The mixture was stirred at room temperature for 2 h, 0.1 mL of DMF was added and the mixture was stirred for an additional 72 h. A solution of aqueous NaHCO3 was added and mixture was extracted with CH2Cl2. Organic phase was dried, filtered and evaporated. Residue was purified by prep plate (ethyl acetate) to give a white solid. MS (ESI pos. ion) m/z: 409 (M+H). Calc'd Exact Mass for C26H17ClN2O: 408.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][C:20]#[N:21].O>CN(C=O)C.C(O)(=O)C>[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[O:13][CH2:17][CH2:18][CH2:19][C:20]#[N:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCCCBr
Reactant: Oc1cccc(CN2CCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: N#CCCCOc1cccc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
3-(Pyrrolidinomethyl)phenol (10 g) was dissolved in DMF (50 ml). The solution was cooled in ice and sodium hydride (2.98 g) added over 45 minutes. After stirring for a further 60 minutes 4-bromobutyronitrile (6.2 ml) was added dropwise. The mixture was then stirred at room temperature for a further 40 hours. Water was added (150 ml) and the pH of the solution adjusted to about 5 with glacial acetic acid. The solution was extracted with ether (3×100 ml). The aqueous layer was adjusted to pH 10 with K2CO3 and re-extracted with chloroform (3×100 ml). The chloroform extracts were washed with water, dried (MgSO4) and evaporated to give a light brown oil (33.49 g). To remove residual DMF this oil was dissolved in ethyl acetate and the solution extracted (×6) with water. The ethyl acetate solution was finally dried (MgSO4) and evaporated to give the product as a light brown oil (11.16 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B#B.[H][H].Cl.[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: [H][H]
Agent: B#B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (19.3 g, 84.0 mmol) in THF (100 mL) was added diborane (185 mL, 1.0 M solution in THF) over a period of 10 min at 0° C. Hydrogen gas was rapidly evolved and after gas evolution had ceased the reaction was stirred at room temperature for 1 h. The reaction mixture was again cooled to 0° C., and 1 M aqueous HCl was added dropwise to the reaction mixture with further evolution of hydrogen. Addition of HCl was continued until the evolution of hydrogen had almost ceased. The mixture was then stirred for 10 min and made basic (pH 13-14) by the addition of 1 M NaOH solution. The aqueous solution was extracted with ethyl acetate, the organic phase washed with brine, dried and concentrated under reduced pressure to yield 4-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (18.12 g, 100%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCC[O:25]C1.[O-][Mn](=O)(=O)=O.[K+]>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:11](=[O:25])[C:10]=3[C:5]2=[CH:4][CH:3]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CC2
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cn1c2c(c3ccc(Br)nc31)C(=O)N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 17 h
Yield: 176.2 %

Procedure:
To a stirred solution of tert-butyl 2-bromo-9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (732 mg, 2.0 mmol) in CH2Cl2 (20 mL) at room temperature was added 18-crown-6 (53 mg, 0.20 mmol) followed by addition of KMnO4 (474 mg, 3.0 mmol) in small portions over 20 min. The reaction mixture was stirred at room temperature for 17 h, quenched with saturated sodium metabisulfite solution (20 ml) and extracted with CH2Cl2 (3×20 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated. Flash chromatography (40 g ISCO column, 100:0 to 65:35 hexanes/EtOAc gradient) gave the title compound (134 mg, 18%) as an orange solid: 1H NMR (500 MHz, DMSO-d6) δ 8.30 (d, J=8.1 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 4.22 (t, J=6.4 Hz, 2H), 3.80 (s, 3H), 3.05 (t, J=6.4 Hz, 2H), 1.59 (s, 9H); ESI MS m/z 380 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])#[N:2].CO.[ClH:13].[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1>C(Cl)Cl>[ClH:13].[CH2:15]1[CH2:16][CH:14]1[CH2:17][NH:18][C:1]([CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])=[NH:2]
Reactant: NCC1CC1
Reactant: N#CCCN1CCOC1=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: N=C(CCN1CCOC1=O)NCC1CC1
Temperature: -15 °C
Reaction time: 6 h
Yield: 55 %

Procedure:
A solution of N-(cyanoethyl)oxazolidinone 18 (30 g, 0.21 mol) in dry methanol (10.9 g, 0.34 mol) and dry CH2Cl2 (60 mL) was saturated with dry HCl at -15° to 0° C. The mixture was then stirred for 6 h at 0°-20° C. The mixture was evaporated and dried in vacuo for 1 h. The crystalline imidoester hydrochloride was dissolved in dry methanol (120 mL) and cooled to -15° C. To the stirred solution cyclopropylmethylamine (31.2 g, 0.44 mol) was added in drops over a period of 20 min while maintaining the temperature at -15 to 0° C. The mixture was then stirred at -10° C. for 45 min and evaporated. The residue was dissolved in methanol, treated with ether until turbid and was refrigerated for 6 days. The colorless crystalline material was collected and dried to give 59 (28.7 g, 55%), mp 86°-88° C. 1H NMR (DMSO--d6) δ 0.28 (m, 2, --CH--CH2), 0.55 (m, 2, --CH--CH2), 1.05 (m, 1, --CH), 2.68 [t, 2, --CH2 --C(N=)], 3.07 (d, 2, --NH--CH2), 3.54 [t, 2, --CH2 --CH2 --C(N=)], 3.67 (t, 2, --O--CH2 --CH2). 4.30 (t, 2, --OCH2).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1Cl>C1COCC1>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: Clc1ccncc1Br
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1cnccc1OCC1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of cyclopropylmethanol (0.562 g, 7.79 mmol) in THF (Volume: 15.06 ml) was added NaH (0.270 g, 6.76 mmol). The reaction was stirred at room temperature for 30 min, and then cooled to 0° C. To this mixture was added 3-bromo-4-chloropyridine (1 g, 5.20 mmol). The resulting mixture was refluxed for 16 hours, cooled to room temperature, and quenched with water. The mixture was evaporated to remove the THF and then extracted with DCM (2×). The combined organic layers were washed with water and brine, dried, and concentrated to give an oil. The oil was purified by silica gel chromatography (hexane: ethyl acetate 50:50) to afforded the title compound as a colorless oil. MS (ES): m/z=229 [M+H]+. Intermediate 66 was used in the synthesis of Example 255.