Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[NH2:12].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21]([CH3:24])(=[O:23])=[O:22].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[F:20][C:18]1[CH:19]=[CH:14][C:15]([S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([NH:12][CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][CH:2]2[CH3:1])[CH:17]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Reactant: CC1CCc2ccccc2C1N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CCc2ccccc2C1Nc1cc(F)ccc1S(C)(=O)=O
Temperature: 25 °C
Yield: 50 %

Procedure:
3,4-Dihydro-2-methylnaphthalen-1(2H)-one (5.2 g, 33.0 mmol), titanium(IV) isopropoxide (19.3 mL, 66.0 mmol) and 2 M solution of ammonia in ethanol (82.0 mL, 165 mmol) were stirred at room temperature for 6 h. The reaction was cooled to 0° C. and sodium borohydride was added portionwise during 10 min. (1.87 g, 49.5 mmol); the resultant mixture was stirred at rt for an additional 3 h. The reaction was quenched by pouring it into ammonium hydroxide (2 M, 20 mL), the precipitate that formed was filtered off and washed with ethyl acetate (20 mL×3). The organic layer was separated and the remaining aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with 1 M HCl (15 mL). The acidic aqueous extracts were washed with ethyl acetate (30 mL), then treated with aqueous sodium hydroxide (2 M) to pH 10-12, and extracted with ethyl acetate (20 mL×3). The combined organic extracts were washed with brine (15 mL), dried (Na2SO4), and concentrated in vacuo to afford the desired product (1.20 g, 22.6% yield). The compound was used without further purification for the following reaction. A solution of 1,2,3,4-tetrahydro-2-methylnaphthalen-1-amine (63.0 mg, 0.39 mmol), 2,4-difluoro-1-(methylsulfonyl)benzene (85.0 mg, 0.43 mmol) and diisopropylethylamine (200 mg, 1.56 mmol) in N,N-dimethylformamide (1 mL) was stirred at 110° C. for 16 h. The reaction was cooled to room temperature, poured over water and extracted with diethyl ether. The solvent was concentrated in vacuo and the residue was purified by silica chromatography (10% ethyl acetate in hexanes) to give 65.0 mg (50%) of the desired product. 1H NMR (400 MHz, CDCl3) δ 7.79 (dd, 1H), 7.20 (m, 4H), 6.52 (m, 3H), 4.25 (t, 1H), 2.99 (s, 3H), 2.86 (t, 1H), 2.65-1.65 (m, 4H), 1.16 (d, 3H); MS (ESI) m/z: 333.6 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:5]=1[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:25][CH3:26])=[C:14]([O:17]CC3C=CC=CC=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH3:27])([O-])=O.C(O)C.[ClH:39]>CO.[Pd]>[ClH:39].[ClH:39].[NH2:1][C:4]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[CH:28][C:5]=1[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:25][CH3:26])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH3:27]
Reactant: COc1cc(CC2c3cc(OCc4ccccc4)c(OC)cc3CCN2C)c([N+](=O)[O-])cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: COc1cc2c(cc1O)C(Cc1cc(OC)c(OC)cc1N)N(C)CC2
Yield: 81 %

Procedure:
A mixture of 1-(2'-nitro-4',5'-dimethoxy-benzyl)-2-methyl-6-methoxy-7-benzyloxy-1,2,3,4-tetrahydroisoquinoline (1.50 g) in absolute methanol (100 ml) containing palladium-charcoal catalyst (5%, 0.45 g) was stirred under hydrogen until absorption ceased. The catalyst was filtered, washed with methanol and the filtrate evaporated to give an oil. Absolute ethanol (10 ml) was added followed by absolute ethanol saturated with hydrochloric acid gas (10 ml) to give 1-(2'-amino-4',5'-dimethoxybenzyl)-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrochloride (4g) as a white solid (1.18 g, 81%), mp 177°-178°. An analytical sample was evaporated by recrystallization from ethanol, mp 177°-179°.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][O:4][C:3]1=[O:8].[Li+].[CH3:10]C([N-]C(C)C)C.CC(C)=O.C(=O)=O.CI>C1COCC1>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][O:4][C:3]1=[O:8]
Reactant: CC1CCCOC1=O
Reactant: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C)CCCOC1=O
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
The 3-methyltetrahydro-2H-pyran-2-one from Example 4(a) (5.6 g, 49.0 mmol) was slowly added to a cold (-78° C.) THF solution (50 ml) of LDA (54 mmol) so that the internal temperature did not exceed -65° C. After stirring for an additional 30 minutes, the acetone/CO2 bath was replaced with a CH3CN/CO2 bath and CH3I (10.4 g, 73.5 mmol) was added at a rate sufficient to maintain the internal temperature at -45° C. After stirring at -45° C. for an additional hour the reaction was allowed to warm to -30° C. and quenched by the dropwise addition of 10% HCl (21 ml). The resulting mixture was poured into ether (300 ml) and the ether layer was washed with saturated brine (50 ml), saturated NaHCO3 solution (20 ml), saturated brine (2×25 ml), dried (MgSO4) and evaporated to provide a pale yellow oil. This oil was distilled to give the title compound as a colorless liquid. b.p.0.2 54° C. NMR (CDCl3) δ 4.34 (2 H, m), 1.89 (2 H, m), 1.75 (2 H, m), 1.30 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([OH:18])=O)=[N:9]2)=[CH:4][CH:3]=1.ClC(OCC)=O.[Li].[CH3:26][S:27]([NH2:30])(=[O:29])=[O:28]>C1COCC1.CCOCC.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([NH:30][S:27]([CH3:26])(=[O:29])=[O:28])=[O:18])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(Cl)cc1
Reactant: CS(N)(=O)=O
Agent: CCOC(=O)Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cc(=O)c(C(=O)NS(C)(=O)=O)nn1-c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a mixture of 1.3 g of 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic acid and 0.73 ml of triethylamine in 50 ml of THF was added at -40° C., 0.53 ml of ethyl chloroformate, and the resulting mixture was allowed to reach room temperature over 2 hours with continued stirring. The mixture was then cooled to -78° C., and the monolithium salt of methanesulfonamide (prepared from 18 mmole of lithiodiisopropylamide and 15 mmole (1.42 g) of methanesulfonamide) in 25 ml of THF was added dropwise at -65° C. The resulting slurry was allowed to reach room temperature with continual stirring. After an additional hour of stirring the reaction mixture was diluted with 200 ml of ether and washed with 1N hydrochloric acid. The ether layer was then extracted with 5% sodium bicarbonate and the aqueous phase was acidified to pH2. The resulting precipitate was collected by filtration and recrystallized from methanol to yield 1.206 g of product, m.p. 225°-227°.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]#[N:9])#[N:2].[Br:10]Br>[OH-].[Na+]>[Br:10][C:5]1[NH:4][C:3]([C:1]#[N:2])=[C:7]([C:8]#[N:9])[N:6]=1
Reactant: N#Cc1nc[nH]c1C#N
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1nc(Br)[nH]c1C#N

Procedure:
4,5-Dicyanoimidazole (23.6 g) was dissolved in sodium hydroxide solution (0.1N, 500 ml) with stirring and then bromine (36 ml) was added dropwise with stirring at room temperature. The mixture was stirred at room temperature overnight and the resulting solid was filtered, washed with water and dried to give 2-bromo-4,5-dicyanoimidazole m.p. 141°-144°. This compound (20 g) in dimethylformamide (100 ml) was added with stirring to a suspension of sodium hydride (80% dispersion in oil, 3.05 g) in dimethylformamide (100 ml) at room temperature. The mixture was cooled to 5° and chloromethyl 2-trimethylsilylethyl ether (18 ml) was added dropwise with stirring. This mixture was allowed to stand at room temperature overnight and was then poured into water and extracted with ethyl acetate. Evaporation of solvent gave an oil which was purified by column chromatography to give 1-(2-trimethylsilylethoxymethyl)-2-bromo-4,5-dicyano-1H-imidazole m.p.47°-52°. In a similar manner, the following were obtained: 1-benzyl- 2-bromo-4,5-dicyano-1H-imidazole, nD23 : 1.601, and 1-allyl-2-bromo-4,5-dicyano-1H-imidazole, m.p. 85°-87°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C@H:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18]CC3C=C(C4C=CC(C(F)(F)F)=CC=4)C=CC=3)=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=[O:10])=[N:5][CH:4]=[N:3]1.[CH3:36]COC(C)=O>>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][N:5]=2)[CH2:8][C:9]([O:11][CH3:36])=[O:10])=[CH:13][CH:14]=1
Reactant: Cn1ncnc1[C@@H](CC(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Reactant: CCOC(C)=O
Product: COC(=O)C[C@@H](c1ccc(O)cc1)c1ncnn1C
Reaction time: 8 h

Procedure:
Methyltriazole M13.6 (2.78 g, 5.61 mmol) was dissolved in 50 mL of EtOAc, and nitrogen was bubbled through the solution for 5 minutes. 1 g of palladium on carbon (5 wt. %, wet contains 50% water) was added, and a hydrogen balloon was attached. After 8 hours, the mixture was filtered through a plug of silica with 10% MeOH in EtOAc. The organic layer was concentrated under reduced pressure and partitioned between ACN (100 mL) and hexane (50 mL). The ACN layer was washed with hexane (4×50 mL). The ACN layer was concentrated under reduced pressure to afford (S)-methyl 3-(4-hydroxyphenyl)-3-(2-methyl-2H-1,2,4-triazol-3-yl)propanoate M13 (1.30 g, 4.99 mmol) as a colorless oil. MS ESI (pos.) m/e: 262.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][C:20]4[S:21][C:22]5[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=5[N:24]=4)=[CH:15][CH:16]=3)[C:11]([CH2:29][C:30](O)=[O:31])=[C:10]2[CH3:33])=[CH:4][CH:3]=1.ClC(OCC)=O.[OH-].[NH4+:41]>O1CCCC1.C(N(CC)CC)C.O>[S:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[CH2:19][O:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10]([CH3:33])=[C:11]2[CH2:29][C:30]([NH2:41])=[O:31]
Reactant: [NH4+]
Reactant: Cc1c(CC(=O)O)c2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(N)=O)c2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a mixture containing the compound of Example 37(0.5 g, 1.05 mmol) in tetrahydrofuran (30 mL) and triethylamine (0.6 mL) at -10° C., is added slowly with stirring a solution of ethyl chloroformate (0.14 g, 1.29 mmol) in tetrahydrofuran (10 mL). After 30 minutes, 30% ammonium hydroxide (0.6 mL) is added and the mixture is stirred for 18 hours at 23° C. The mixture is diluted with water (100 mL) and is extracted with ethyl acetate (3×100 mL). The combined extract is washed with 2N HCl (200 mL) and brine (200 mL), dried over MgSO4 and concentrated to give crude product (0.55 g). Crystallization from acetonitrile gives pure title compound in 90% yield as a white solid, m.p. 169°-170° C.
Reaction SMILES: [CH2:1]([C:5]([CH2:10][CH3:11])([CH2:8][OH:9])[CH2:6][OH:7])[CH2:2][CH2:3][CH3:4].[P:12](Cl)(Cl)Cl.[CH2:16]([CH:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([C:5]1([CH2:10][CH3:11])[CH2:6][O:7][P:12]([O:31][CH:28]2[CH2:27][CH2:26][CH:25]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:30][CH2:29]2)[O:9][CH2:8]1)[CH2:2][CH2:3][CH3:4]
Reactant: ClP(Cl)Cl
Reactant: CCCCCCCCCC1CCC(O)CC1
Reactant: CCCCC(CC)(CO)CO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCC1CCC(OP2OCC(CC)(CCCC)CO2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 28 g (0.17 mole) of 2-butyl-2-ethyl-1,3-propandiol in 300 mL of toluene is added dropwise 16 mL (0.17 mole) of phosphorus trichloride at 70° C. After 1 h, the P31-NMR shows that the PCl3 (signal at 220 ppm) is fully reacted and a new product is formed (signal at 150 ppm). The temperature is raised to 80° C. At this temperature a solution of 35.8 g (0.17 mole) 4-nonylcyclohexanol, 200 mL (1.4 mole) of triethylamine in 200 mL of toluene is added rapidly dropwise (approx. 30 min). A suspension is obtained. The P31-NMR—after further 2 h of reaction time—shows that the educt (signal at 150 ppm) is fully reacted and a new product is formed (signal at 123 ppm). After filtration and removal of the toluene (rotary evaporator) the product is isolated. Yield: 68 g (0.165 mol=96% of theory) of the title compound as a crude slight yellow oil; P31-NMR signals at: 124 ppm (major peak); 123 ppm; Total reaction time: 3 h. % P(calc): 7.47; % P (found): 7.24.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].[O:29]1[C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=[N:30]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([C:34]([C:33]3[O:29][N:30]=[CH:31][CH:32]=3)=[O:35])[CH2:22][CH2:23]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: O=C(Cl)c1ccno1
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCNCC2)C1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCN(C(=O)c3ccno3)CC2)C1

Procedure:
Compound 763 was prepared from 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and isoxazole-5-carbonyl chloride using the method described for compound 759. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 10%–20%–30% acetonitrile/water/0.5% HCl) and isolated as a brown solid (0.0268 g, 22% yield). HRMS (M+H) calcd for C23H26N5Cl2O5: 522.13111. found: 522.1312.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Reactant: CCCCN
Solvent: c1ccccc1
Product: CCCCNc1c(C(=O)OCC)cnc2c1cnn2CC
Reaction time: 72 h

Procedure:
To a solution of 5.08 g of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.02 mol) in 20 ml of benzene is added 2.92 g of n-butylamine (0.04 mol). This mixture is kept at room temperature for 3 days. After this time, the separated butylamine hydrochloride is filtered under suction and the filtrate is evaporated in vacuo to dryness. The residue, 4-butylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethylester, is recrystallized from hexane, m.p. 82°-83°. The total yield amounts to 5.3 g = 91.5% of theory.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(#N)C.C[N:23](N=O)[C:24]([NH:26][N+:27]([O-:29])=[O:28])=N.C(N(CC)CC)C>C(O)(=O)C>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([CH3:9])([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:24]([NH2:23])=[N:26][N+:27]([O-:29])=[O:28])[CH:11]=1)[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(N)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC(C)(C)c1cccc(NC(N)=N[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
A mixture of the compound (145 mg) obtained in Example 2, acetonitrile (10 ml), N-methyl-N′-nitro-N-nitrosoguanidine (85 mg), triethylamine (0.08 ml) and acetic acid (0.03 ml) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1) to give 106 mg of the titled compound (yield, 54%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH2:11]1[O:13][CH2:12]1.[H-].[Na+].O>O1CCOCC1>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[O:1][CH2:11][CH2:12][OH:13])[CH:7]=[CH:8]1
Reactant: C1CO1
Reactant: Oc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCCOc1cccc2cc[nH]c12
Temperature: 100 °C
Reaction time: 120 h
Yield: 33.9 %

Procedure:
A mixture of 7-hydroxyindole (1.00 g, 7.51 mmol) and ethylene oxide (0.33 g, 7.50 mmol) in dioxane (3 mL) was placed in a reaction tube. NaH (60% in oil; 0.100 g, 2.45 mmol) was added and the reaction mixture was stirred at 100° C. for 5 days. The reaction mixture was poured into water, extracted with EtOAc, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel using toluene/EtOAc (1:1) as eluent to give 0.45 g (34%) of the title product. Pos-EI-MS shows M+ and 5 ions supporting the stated structure. HRMS m/z calcd for C10H11NO2 (M)+ 177.0790, found 177.0799.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](O[C:13](=O)[CH3:14])(=O)[CH3:10].[CH2:16]([N:19]1[C@H:24]([CH3:25])[CH2:23][N:22]([C@H:26]([C:41]2[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=2)[C:44](Cl)=[O:45])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][Si](C(C)(C)C)(C)C)[CH:28]=2)[C@@H:21]([CH3:50])[CH2:20]1)[CH:17]=[CH2:18]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH2:16]([N:19]1[C@H:24]([CH3:25])[CH2:23][N:22]([C@H:26]([C:41]2[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=2)[C:44]([N:6]([CH2:13][CH3:14])[C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[O:45])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[C@@H:21]([CH3:50])[CH2:20]1)[CH:17]=[CH2:18]
Reactant: Nc1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(CC)c3ccc(F)cc3)c2)C[C@H]1C
Product: CCNc1ccc(F)cc1

Procedure:
4-Fluoro-N-ethylaniline [NMR (200 MHz, DMSO-d6): δ 1.25 (t, J=7.1 Hz, 3H); 3.12 (q, J=7.1 Hz, 2H); 3.24 (br s, 1H); 6.57 (dd, J1 =4.5 Hz, J2 =9.0 Hz, 2H); 6.90 (t, J=8.9 Hz, 2H)] was prepared from 4-fluoroaniline and acetic anhydride, coupled with 3-((αR)-α-((2S ,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-(4-fluorophenyl)benzamide as an off-white powder. NMR (200 MHz, DMSO-d6): δ 0.91 (d, J=6.1 Hz, 3H); 0.98 (d, J=6.0 Hz, 3H); 1.08 (t, J=7.0 Hz, 3H); 1.71 (dd, J1 =7.0 Hz, J2 =11.3 Hz, 1H); 2.05 (dd, J1 =7.2 Hz, J2 =10.8 Hz, 1H); 2.31 (d, J=11.4 Hz, 1H) 2.36-2.57 (m, 2H); 2.69 (dd, J1 =2.2 Hz, J2 =10.7 Hz, 1H); 2.85 (dd, J1 =7.0 Hz, J2 =13.9 Hz, 1H); 3.18 (dd, J1 =5.3 Hz, J2 =13.9 Hz, 1H); 3.84 (q, J=7.0 Hz, 2H); 4.78 (s, 1H); 5.11 (d, J=10.0 Hz, 1H); 5.18 (d, J=16.4 Hz, 1H); 5.65-5.88 (m, 1H); 6.46 (d, J=7.4 Hz, 1H); 6.58 (s, 1H); 6.65 (d, J=8.1 Hz, 1H); 7.01-7.27 (m, 9H); 9.33 (s, 1H). Mass spectrum (CI--CH4) m/e: 502 (M+1, 90%), 348 (15%), 153 (100%). [α]D20 =+6.30° (abs. ethanol, c=1.1) The free amine (0.313 g) was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 3.95 followed by precipitation with diethyl ether from dichloromethane to give 0.263 g of the monohydrochloride salt as a hygroscopic white powder. Calc. for C31H36N3O2F HCl H2O: C, 66.95; H, 7.07; N, 7.56; Cl, 6.38. Found: C, 66.97; H, 7.10; N, 7.47; Cl, 6.41.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[O:9]C)(=[O:3])[CH3:2].CC(O)CC(O)C.CN1CCCC1=O>O.CCOC(C)=O>[C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[OH:9])(=[O:3])[CH3:2]
Reactant: COC1CCCN1C(C)=O
Agent: CC(O)CC(C)O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)N1CCCC1O

Procedure:
One g of N-acetyl-2-methoxypyrrolidine (largely E plus lesser an amounts of B, C and D), 0.9 g of 2,4-pentandiol and 240 mg of N-methyl-2-pyrrolidone internal standard were heated at 50°-55° C. in 1 mL of H2O. A separate sample was heated in 1 mL of EtOAc. Results in both samples were similar: rapid initial formation of a small peak at 8.02 min (cyclic hemiamidal of the diol?), followed by growth of major product peaks at 8.35 and 8.73 min, the epimeric cyclic acetals. Small quantities of dehydrated product; G (r.t.=4.75 min), and, in the aqueous sample, N-acetyl-2-hydroxypyrrolidine, F (before A at ~5.6 min) were also produced. One of the diols appeared to react faster and to a greater extent than the other. Measurements at 3-4 hr were close to the overnight values: ~87% conversion of A, 60-70% of B and essentially quantitative conversion of C and D.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.Cl[C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]>C(OCC)(=O)C>[C:33]([C:31]1[CH:30]=[CH:29][C:28]2[N:24]([CH2:23][CH2:22][O:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][CH:9]([NH:8][C:50]([O:52][CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)=[O:51])[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:19]=3)[C:25](=[O:41])[S:26][C:27]=2[CH:32]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)C(N)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
1.5 g of the compound obtained in Step A of Example 12 are dissolved in 20 ml of ethyl acetate; 1.06 ml of triethylamine are then added and the temperature is lowered to 0° C. 0.725 ml of benzyl chloroformate are added and the mixture is allowed to return to ambient temperature and is stirred overnight.
Reaction SMILES: [CH2:1]([C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@H:5]([CH2:16][OH:17])[NH:4]1)[CH3:2].[C:18](=[S:20])=[S:19].[CH2:21](N(CC)CC)[CH3:22].C(I)C>CS(C)=O>[CH2:1]([C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@H:5]([CH2:16][OH:17])[N:4]1[C:18]([S:20][CH2:21][CH3:22])=[S:19])[CH3:2]
Reactant: CC[C@@H]1N[C@@H](CO)Cc2c1[nH]c1ccccc21
Reactant: S=C=S
Reactant: CCN(CC)CC
Solvent: CCI
Solvent: CS(C)=O
Product: CCSC(=S)N1[C@@H](CO)Cc2c([nH]c3ccccc23)[C@@H]1CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
(1RS, 3SR)-trans-1-Ethyl-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (0.461 g) is dissolved in dimethylsulfoxide (2 ml), and thereto are added CS2 (0.27 ml) and triethylamine (0.61 ml). The mixture is stirred at room temperature for one hour, and thereto is added dropwise ethyl iodide (0.38 ml), and the mixture is stirred at room temperature for 2 hours. The reaction mixture is poured onto ice-water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate and then distilled to remove the solvent. The residue is recrystallized from aqueous ethanol to give the title compound (0.477 g, 71%) as colorless needles, m.p. 82°-84° C., NMR (CDCl3, δ): 1.40 (t, J=7.0 Hz, 3H, CSSCH2CH3); Mass m/e: 334 (M+), 272 (M+ --CH3CH2SH).