Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:57])[C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:56])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@H:26]2[C@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=3[F:38])[C@:29]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[F:48])([C:39]#[N:40])[C@H:28]([CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51])[NH:27]2)=[O:25])=[C:19]([O:54][CH3:55])[CH:18]=1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH3:57])[C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:56])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@H:26]2[C@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=3[F:38])[C@:29]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[F:48])([C:39]#[N:40])[C@H:28]([CH2:49][C:50]([CH3:52])([CH3:53])[CH3:51])[NH:27]2)=[O:25])=[C:19]([O:54][CH3:55])[CH:18]=1)=[O:11]
Reactant: COc1cc(C(=O)OCCOC(=O)[C@H](C)NC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)OCCOC(=O)[C@H](C)N)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of chiral 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-((S)-2-tert-butoxycarbonylamino-propionyloxy)-ethyl ester (Example 3, 98.2 mg, 0.118 mmol) in methylene chloride (4 mL) at 0° C. was added trifluoroacetic acid (2 mL) slowly and the mixture was allowed to stir at 0° C. for 1 h. The mixture was concentrated and the residue was taken up in methylene chloride (100 mL), washed successively with aqueous sodium carbonate and water and concentrated. The material was treated with acetonitrile and water and lyophilized to give chiral 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-((S)-2-amino-propionyloxy)-ethyl ester as a white solid (78 mg, 90% yield). MS (ES+) m/z calcd. for C36H39Cl2F2N4O6 [(M+H)+]: 731. found: 731.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)C.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[C:15]1([C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([S:21]([C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)(=[O:22])=[O:23])[C:6]=2[CH2:4][OH:3])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2ccccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c(CO)c(-c3ccccc3)c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 85.5 %

Procedure:
To a stirred solution of 3-phenyl-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester (3.24 g, 7.72 mmol) in toluene (40 mL) at −78° C. and under a nitrogen atmosphere was added 1.0M DIBAL-H in toluene (23.2 mL, 23.2 mmol). The reaction mixture was stirred at −78° C. for 15 min then at −10° C. for 30 min. After re-cooling to −78° C., the reaction mixture was quenched with water (20 mL) then allowed to warm to RT. The mixture was partitioned between EtOAc and 1.0M HCl and the aqueous phase was extracted with additional EtOAc (×3). The combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane) affording the title compound as a white foam (2.49 g, 85%). LCMS (Method C): RT 4.77 min [M+Na]+ 400.1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][N:12]=1)[CH2:9][CH3:10].[NH3:29]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH2:29])=[O:19])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: N
Reactant: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)O)cn1
Solvent: CN(C)C=O
Product: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[N-(5-bromo-2-benzyloxybenzyl)-N-ethylamino]pyridine-5-carboxylic acid (1.4 g) [table 1a, compound 2] and 1,1-carbonyldiimidazole (0.62 g) were heated in DMF at 55° C. for 3 hours. The mixture was cooled to ambient temperature, aqueous ammonia (20 ml) was added and the mixture was stirred for 18 hours. The solvent was evaporated and the residue purified by MPLC eluting with methanol: dichloromethane (5:95) to give 2-[N-(5-bromo-2-benzyloxybenzyl)-N-ethylamino]pyridine-5-carboxamide (671 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:23][CH2:24][CH:25]=[CH2:26].O>O1CCCC1>[CH2:10]([O:9][C:7](=[O:8])[C:6]([CH2:4][CH2:3][CH:2]=[CH2:6])([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:23][CH2:24][CH:25]=[CH2:26])[CH3:11]
Reactant: C=CCCBr
Reactant: CCOC(=O)Cc1cccs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(CCC=C)(C(=O)OCC)c1cccs1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-(thiophen-2-yl)acetate (2.35 g) was dissolved in tetrahydrofuran (30 mL) and cooled to −78° C. Lithium bis(trimethylsilyl)amide (2.31 g) in THF (1M solution, 13.8 mL) was added and the solution was stirred for 30 minutes. 4-Bromo-but-1-ene (1.4 mL) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was re-cooled to −78° C. and lithium bis(trimethylsilyl)amide (2.31 g) in THF (1M solution, 13.8 mL) was added and the solution was stirred for 30 minutes. 4-Bromo-but-1-ene (1.4 mL) was added and the reaction mixture was allowed to warm to room temperature and stand overnight. HPLC-MS analysis indicated that the reaction was incomplete so the reaction was again cooled to −78° C. and further aliquots of lithium bis(trimethylsilyl)amide (1M solution, 10 mL) and 4-bromo-but-1-ene (1.0 mL) were added following the procedure outlined above. After stirring for a further 2 hours, water (30 mL) was added and the reaction was extracted with diethyl ether (2×60 mL). The combined organic extracts were dried (MgSO4) and evaporated. The resulting oil was purified by column chromatography on silica eluting with ethyl acetate/isohexane (1/99) afford the sub-titled compound (3.18 g).
Reaction SMILES: [C:1]1(=O)[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]=[CH:6][CH:5]=[C:4]3[CH2:3][CH2:2]1.Cl.[NH2:16]O.CO.C([O-])(=O)C.[Na+]>O>[CH:1]1([NH2:16])[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]=[CH:6][CH:5]=[C:4]3[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCc2cccc3cccc1c23
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC1CCc2cccc3cccc1c23
Yield: 71.6 %

Procedure:
To a stirred mixture of 2,3-dihydro-phenalen-1-one (1.32 g, 7.24 mmol), hydroxylamine hydrochloride (0.85 g, 12.2 mmol) and water (6 ml) was added dropwise at 75° C. MeOH (7.5 ml) and afterwards a solution of sodium acetate (2.58 g, 19.0 mmol) in water (4 ml). Stirring was continued over a period of 1.5, h, water (20 ml) was added and after cooling (ice bath) the solid was collected by filtration. After drying in vacuo the crude product was dissolved in 3.5 N NH3 /MeOH (100 ml) and hydrogenated over Raney-Nickel (0.5 g, washed with MeOH) at RT for 17h. The catalyst was filtered off, the solution evaporated in vacuo and the residue purified by column chromatography on silica gel (dichloromethane/MeOH 9:1) to yield (RS)-2,3-dihydro-1H-phenalen-1-yl-amine (0.95 g) as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[OH-].[Li+].CCOC(C)=O>O1CCCC1.CC(O)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:13]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OC)cc1OCCNC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(OCCNC(=O)OC(C)(C)C)c1
Yield: 91 %

Procedure:
Methyl 2-[2-(tert-butoxycarbonylamino)ethoxy]-4-methoxybenzoate (1.0 g, 3.07 mmol) was suspended in 20 ml of 3:1 tetrahydrofuran (THF):water, then chilled on ice for 30 min with stirring. Next there was added solid lithium hydroxide monohydrate (284 mg, 6.76 mmol) to the suspension, and the mixture was stirred at room temperature for 20 h at which time TLC (50:50:1 hexanes:EtOAc:AcOH) showed complete consumption of starting ester. The slurry was diluted with water (50 ml), washed twice with ethyl ether, then the aqueous layer was acidified to pH 2 with 1 N NaHSO4 to yield a heavy white slurry. The slurry was extracted twice with EtOAc, then the EtOAc layers were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo to provide 2-[2-(tert-butoxycarbonylamino)ethoxy]-4-methoxybenzoic acid (870 mg, 91%) as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].Cl.[NH:17]1[CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>>[N:17]1([S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])[CH2:20][CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCC2)c1Cl
Yield: 47.6 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.0 g, 3.44 mmol), azetidine hydrochloride (320 mg, 3.44 mmol) and triethylamine(1.44mL, 10.32 mmol) were reacted to form the desired product (510 mg, 48%). 1H NMR (MeOD-d4): δ 7.94 (d, 1H), 7.79 (d, 1H), 4.16 (t, 4H), 2.29 (m, 2H).
Reaction SMILES: [CH2:1]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([O:31]C)=[O:30])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:21]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:29]([OH:31])=[O:30])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCC)cc3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN1CCC(C(=O)O)=Cc2cc(-c3ccc(OCCOCCC)cc3)ccc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 78.5 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 1-butyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.5 g). To the solution was added 1N sodium hydroxide solution (17 ml), and the mixture was heated to stir at 50° C. for 5 hours, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 1-butyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.38 g) as yellow crystals.
Reaction SMILES: [C:1]12([C:11]3[CH:25]=[CH:24][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[OH-].[Li+].Cl>O.C1COCC1>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:24][CH:25]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCOC(=O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution of ethyl 4-(4-(adamantan-1-yl)phenoxy)butanoate (1.1 g, 3.50 mmol) in H2O/THF (1 mL/1.20 mL) was added lithium hydroxide monohydrate (0.14 g, 7.00 mmol), and stirred at room temperature overnight. The reaction mixture was adjusted to acidic solution with 1 N aqueous HCl and extracted with dichloromethane. The organic layer was washed with H2O and brine, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give 4-(4-(adamantan-1-yl)phenoxy)butanoic acid as a white solid (0.98 g, 97.12% yield).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[O:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1>C1COCC1>[OH:7][C:8]1([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1cccs1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccs2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A solution of 2-bromothiophene in THF (25 ml) was added drop wise to a suspension of Mg turnings in THF (100 mL). The mixture was stirred for 30 minutes, cooled to 0° C., and a solution of tert-butyl 4-oxopiperidine-1-carboxylate (25.0 g, 125.4 mmol) in THF (25 mL) was added dropwise. The reaction mixture was slowly warmed to RT and stirred for 1 hour until complete consumption of 2-bromothiophene was indicated by TLC. The reaction was quenched with sat. aq. NH4Cl solution (50 mL), extracted with EtOAc (200 mL), washed with H2O (50 mL) and brine solution, dried (Na2SO4), filtered, and evaporated to afford crude product as light brown oil. Purification by silica gel chromatography (25% EtOAc/hexanes) yielded tert-butyl 4-hydroxy-4-(thiophen-2-yl)piperidine-1-carboxylate (14.0 g, 40% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH:11]([C:19]3[C:27]([S:28][CH3:29])=[CH:26][C:25]([CH3:30])=[C:24]4[C:20]=3[CH:21]=[CH:22][N:23]4[S:31]([C:34]3[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[NH:12]S(C(C)(C)C)=O)[N:8](COCC[Si](C)(C)C)[C:7]=2[CH:49]=1)#[N:2].C(C1C=CC2N(COCC[Si](C)(C)C)C(C(C3C(SC)=CC(C)=C4C=3C=CN4S(C3C=CC(C)=CC=3)(=O)=O)NS(C(C)(C)C)=O)=NC=2C=1)#N.Cl.CO>>[NH2:12][CH:11]([C:19]1[C:27]([S:28][CH3:29])=[CH:26][C:25]([CH3:30])=[C:24]2[C:20]=1[CH:21]=[CH:22][N:23]2[S:31]([C:34]1[CH:35]=[CH:36][C:37]([CH3:38])=[CH:39][CH:40]=1)(=[O:33])=[O:32])[C:9]1[NH:10][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:49][C:7]=2[N:8]=1
Reactant: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(NS(=O)C(C)(C)C)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(NS(=O)C(C)(C)C)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: Cl
Solvent: CO
Product: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(N)c1nc2cc(C#N)ccc2[nH]1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of a mixture of (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methyl)-2-methylpropane-2-sulfinamide and (±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methyl)-2-methylpropane-2-sulfinamide (1 g, 1.36 mmol), HCl in methanol (1.25 M) (22 mL, 27 mmol) was added and the reaction stirred at 60° C. for 2 h. The reaction was then evaporated, basified with NH4OH (33% NH3 in H2O) and extracted with EtOAc. The organic extract was dried over MgSO4 filtered and concentrated to give the title compound without the need for further purification. MS (ESI+) m/z 502.2 (M+H).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][N:7]([CH:9]([CH3:26])[CH2:10][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:12]#[N:13])[CH3:8].[OH-:27].[Na+]>O>[CH3:6][N:7]([CH:9]([CH3:26])[CH2:10][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:12]([NH2:13])=[O:27])[CH3:8]
Reactant: CC(CC(C#N)(c1ccccc1)c1ccccn1)N(C)C
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(CC(C(N)=O)(c1ccccc1)c1ccccn1)N(C)C
Temperature: 90 °C

Procedure:
Conc. sulfuric acid (11 ml) was added to 4-(N,N-dimethylamino)-2-phenyl-2-(2-pyridyl)-valeronitrile (6.3 g) at 0° C. and then water (1 ml) was added thereto. After being heated at 90° C. for 3 hours, the mixture was poured into ice-water, adjusted to pH 10 with 10% aqueous sodium hydroxide and extracted with ethyl acetate (50 ml×3). The extracts were combined, and washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The obtained crude crystal was recrystallized from diethyl ether to give 4-(N,N-dimethylamino)-2-phenyl-2-(2-pyridyl)-valeramide (1.89 g). mp 132°-134° C.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([O:16][CH3:17])=[N:11][CH:12]=[CH:13][C:14]=1[CH3:15])=O)(C)(C)C.Cl>CCOC(C)=O>[NH2:8][C:9]1[C:10]([O:16][CH3:17])=[N:11][CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: COc1nccc(C)c1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1nccc(C)c1N
Yield: 99.8 %

Procedure:
3-(tert-Butoxycarbonylamino)-2-methoxy-4-methylpyridine (0.7 g, 2.9 mmol) was treated with 25 mL of 4M HCl in EtOAc at room temperature overnight. The resulting suspension was carefully washed with sat. NaHCO3, dried (MgSO4) and concentrated to give 0.4 g of the free amine as an oil (100%). m.p. (HCl salt): 199° C. (d).
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[C:12]([NH:22][C@H:23]([CH:28]=O)[CH2:24][CH:25]([CH3:27])[CH3:26])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:12]([NH:22][C@@H:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH:28]=[CH2:1])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OCc1ccccc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 12 g of methyltriphenylphosphonium bromide in 100 ml of dry tetrahydrofuran was added 19.5 ml of n-butyl lithium (as a 1.6 mole hexane solution) under an argon atmosphere, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was cooled below 5° C., and a solution of 7.5 g of N-carbobenzoxy-L-leucinal in 20 ml of dry tetrahydrofuran was added to the reaction mixture. The mixture was stirred for 1 hour at room temperature. An aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: dichloromethane) to obtain 1.6 g of (3S)-3-carbobenzoxyamino-5-methyl-1-hexene as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]4[C:26]5[CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32][C:27]=5[N:28]([CH3:31])[C:29]=4[CH:30]=3)[C:18](=[O:43])[CH:17]=2)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][N:19]([C:22]3[CH:23]=[CH:24][C:25]4[C:26]5[CH2:35][NH:34][CH2:33][CH2:32][C:27]=5[N:28]([CH3:31])[C:29]=4[CH:30]=3)[C:18](=[O:43])[CH:17]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C(=O)OC(C)(C)C)C5)c(=O)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCNC5)c(=O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl 7-(4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (74 mg, 0.15 mmol) in CH2Cl2 (1 mL) under N2 and stirred for 2 h at ambient temperature. The mixture was concentrated, and the residue was partitioned between CH2Cl2 and saturated NaHCO3 solution. The organic phase was removed, and the aqueous phase was extracted with CH2Cl2 (4×25 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4 and concentrated under reduced pressure. Flash column chromatography (12 g ISCO CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes to 0:100 over 20 column volumes and hold for 5 column volumes) yielded the title compound (46 mg, 78%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J=9.0 Hz, 2H), 7.50-7.46 (m, 2H), 7.36 (d, J=2.0 Hz, 1H), 7.05 (dd, J=8.5, 2.0 Hz, 1H), 7.00 (d, J=8.5 Hz, 2H), 6.86 (d, J=1.5 Hz, 1H), 6.49 (dd, J=7.0, 2.0 Hz, 1H), 4.08 (s, 2H), 3.87 (s, 3H), 3.63 (s, 3H), 3.27 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.5 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][C:6]1[N:11]=[C:10]([C:12]2[NH:16][C:15]([CH3:17])=[N:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1.[C:21](=O)(O)O.C1(NC(N)=N)C=CC=CC=1>>[NH:5]([C:6]1[N:11]=[C:10]([C:12]2[N:16]([CH3:21])[C:15]([CH3:17])=[N:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1)[C:4]1[CH:18]=[CH:19][CH:20]=[CH:2][CH:3]=1
Reactant: Cc1ncc(-c2ccnc(Nc3cccc(Cl)c3)n2)[nH]1
Reactant: O=C(O)O
Agent: N=C(N)Nc1ccccc1
Product: Cc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C
Yield: 26.3 %

Procedure:
5-(3-Dimethylaminoprop-2-enoyl)-1,2-dimethylimidazole (Method 1; 314 mg, 1.62 mmol) and phenylguanidine hydrogen carbonate (321 mg, 1.62 mmol) were treated as described in Example 1 to give the title compound 113 mg, (26%) as a solid. NMR: 2.37 (s, 3H), 3.93 (s, 3H), 6.95 (t, 1H), 7.08 (d, 1H), 7.28 (t, 2H), 7.59 (s, 1H), 7.69 (d, 2H), 8.35 (d, 1H), 9.43 (s, 1H); m/z: 266.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)[CH3:15]>C(O)CCC>[CH3:15][C:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CC(=O)c1ccccc1
Agent: Cl
Solvent: CCCCO
Product: CC1(c2ccccc2)NCCc2c1[nH]c1ccccc21
Yield: 56.4 %

Procedure:
1-Methyl-1-phenyl-1,3,4,9-tetrahydrobeta-carboline was prepared by the addition of tryptamine-HCl (500 mg, 2.54 mmol), 1-butanol (12 mL), and acetophenone (1.5 mL, 13 mmol) to a 25 mL flask attached with Dean-Stark Trap. Azeotropic removal of a butanol/H2O mixture was conducted during a vigorous reflux period of 4 hours. The concentrated solution was allowed to stir near reflux for an additional 14 hours. The solution was concentrated under reduced pressure. The residue was taken up into EtOAc (70 mL), washed with sat. NaHCO3 (40 mL×3), washed with H2O (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was chromatographed (SiO2 100% DCM to 5% MeOH) to provide 376 mg of 1-methyl-1-phenyl-1,3,4,9-tetrahydrobeta-carboline; 1H NMR (CDCl3) δ 7.74 (1H, br s), 7.54 (1H, d), 7.23-7.32 (6H, m), 7.09-7.21 (2H, m), 3.13 (1H, m), 2.71-2.94 (3H, m), 1.84 (3H, s); 13C NMR (CDCl3) δ 146, 138, 136, 128, 127, 127, 126, 122, 119, 118, 110, 110, 57, 40, 28, 23; TLC (SiO2, 10:1 DCM/MeOH) Rf=0.3; MS (ESI): 263 (MH+).