Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH:7]2[O:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][CH2:8]2)C(=O)C2=CC=CC=C12.NCCO>>[NH2:5][CH2:6][CH:7]1[O:16][C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[CH2:9][CH2:8]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CCc2cccnc2O1
Solvent: NCCO
Product: NCC1CCc2cccnc2O1
Yield: 94.1 %

Procedure:
3.2 g (11 mmol) of the compound from Example VII and 9.2 g (150 mmol) of 2-aminoethanol are heated under nitrogen to 80° C. After 5 minutes the mixture is cooled, and the reaction mixture is partitioned between 70 ml of toluene and 92 ml of 5% strength NaCl solution. The phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried and evaporated in vacuo. 1.7 g of the title compound are obtained as a light yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[NH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)=O)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.[OH-].[Na+]>C1COCC1>[CH2:8]([N:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:23]2[NH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][CH2:20]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(c1cc2ccccc2[nH]1)N1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN2CCN(Cc3cc4ccccc4[nH]3)CC2)cc1
Temperature: 25 °C
Yield: 25 %

Procedure:
Lithium aluminium hydride in THF (1M, 11.25 mmol) was slowly added to a suspension of 2-(4-benzylpiperazin-1-yl)carbonyl indole hydrochloride (2.0 g, 5.6 mmol) in THF (40 ml) under a nitrogen atmosphere and the resultant solution heated at reflux for 90 min. The mixture was cooled to room temperature and treated sequentially with water (0.5 ml), sodium hydroxide (4M, 0.5 ml) and water (1.5 ml). The mixture was filtered and the filtrate evaporated in vacuo. The residue was recrystallised from toluene to afford the title compound as a white solid (428 mg, 25%), m.p. 157°-159° C.; (Found: C, 78.44; H, 7.63; N, 13.66. C20 H23N3 requires C, 78.65; H, 7.59; N, 13.76%); δH (DMSO-d6) 2.40 (8H, br s, 4×piperazinyl CH2), 3.45 (2H, s, CH2), 3.59 (2H, s, CH2), 6.23 (1H, s, 3-H), 6.90 (1H, m, ArH), 6.95 (1H, m, ArH), 7.20-7.32 (6H, m, ArH), 7.42 (1H, d, J 7.7 Hz, ArH), and 10.93 (1H, br s, NH); m/z (CI+, NH3) 306 (M+1)+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][O:20][CH3:21])[CH2:13]2)[N:3]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH3:48])[C:26]2[O:30][C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:33]=3)=[N:28][C:27]=2[CH:47]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][O:20][CH3:21])[CH2:13]3)[N:3]=[C:2]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29]4[O:30][C:26]5[C:25]([CH3:48])=[CH:24][C:23]([CH3:22])=[CH:47][C:27]=5[N:28]=4)=[CH:37][CH:36]=3)[C:10]=12
Reactant: COCCN1CCCC(n2nc(I)c3c(N)ncnc32)C1
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COCCN1CCCC(n2nc(-c3ccc(Nc4nc5cc(C)cc(C)c5o4)cc3)c3c(N)ncnc32)C1
Temperature: 80 °C
Yield: 82.5 %

Procedure:
The mixture of 3-iodo-1-[1-(2-methoxyethyl)-3-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.16 g, 0.0004 mol), N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.17 g, 0.00048 mol), tetrakis(triphenylphosphine)palladium (0.023 g, 0.00002 mol) and sodium carbonate (0.11 g, 0.001 mol) in ethylene glycol dimethyl ether (25 mL) and water (5 mL) was heated at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish solid which was purified by flash column chromatography on silica using 2%-10% methanol/dichloromethane as a mobile phase to give N2-(4-{4-amino-1-[1-(2-methoxyethyl)-3-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine (0.17 g, 0.00033 mol). 1H NMR (DMSO-d6, 400 MHz) δ 10.85 (s, 1H), 8.22 (s, 1H), 7.95 (d, 2H), 7.65 (d, 2H), 7.14 (s, 1H), 6.80 (s, 1H), 4.79 (br, 1H), 3.50 (m, 2H), 3.25 (s, 3H), 3.10 (br, 1H), 2.90 (br, 1H), 2.55 (br, 2H), 2.54(br, 1H), 2.40 (s, 3H), 2.35 (s, 3H), 2.05 (br, 3H), 1.80 (br, 1H), 1.70 (br, 1H). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 9.9 min. MS: MH+ 513
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]1([CH3:44])[CH:22]=[CH:21][C:20]([C:23]([C@:25]([C:41]([OH:43])=[O:42])([OH:40])[C@:26]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)=[O:32])([OH:30])[C:27]([OH:29])=[O:28])=[O:24])=[CH:19][CH:18]=1>C(O)C>[C:17]1([CH3:44])[CH:22]=[CH:21][C:20]([C:23]([C@:25]([C:41]([OH:43])=[O:42])([OH:40])[C@:26]([C:31]([C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)=[O:32])([OH:30])[C:27]([OH:29])=[O:28])=[O:24])=[CH:19][CH:18]=1.[NH2:1][C@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]1[OH:16]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Agent: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@H](N)[C@H]1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 58.7 %

Procedure:
A mixture of trans-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (32.74 g) and (+)-di-p-toluoyl-D-tartaric acid (57.95 g) was dissolved in ethanol (85 ml) under reflux. The mixture was cooled to room temperature and stood for 4 days to give a white precipitate. This precipitate was collected by filtration, washed with a mixture of ethanol and diisopropyl ether (100 ml, 1:2), and recrystallized from ethanol (80 ml) to give (+)-di-p-toluoyl-D-tartaric acid salt of (3R,4S)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (19.20 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=1[CH:5]=O.[N:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:13]=[N-:14].C(#N)C.C(=O)=O.C([O-])(=O)C.[Na+].[NH4+].[Cl-]>CCO>[N:12]([C:15](=[CH:5][C:4]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N+:13]=[N-:14]
Reactant: COc1ccc(F)cc1C=O
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: CC(=O)[O-]
Agent: O=C=O
Agent: [Cl-]
Solvent: CCO
Solvent: CC#N
Product: CCOC(=O)C(=Cc1cc(F)ccc1OC)N=[N+]=[N-]
Temperature: 0 °C

Procedure:
To a solution of the 2-methoxy-5-fluorobenzaldehyde (1.00 g, 6.49 mmol) and ethyl azidoacetate (14.0 g, 32.4 mmol) in EtOH (20 ml) at −20° C. (acetonitrile/dry ice) was added a solution of sodium acetate in EtOH over 20 minutes. When the addition was completed, the reaction was allowed to slowly warm to 0° C., where it was maintained for 2 hours. The suspension was then poured over a mixture of ice and solid NH4Cl, stirred until all the ice had melted, and the product was collected. The crude product was dissolved in CH2Cl2 and MgSO4 was added. The suspension was filtered through a small plug of silica gel and washed with CH2Cl2. Concentration provided ethyl 2-azido-3-(5-fluoro-2-methoxyphenyl)acrylate as a yellow solid which was used without further purification (1.68 g, 98%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([OH:30])[C@H:26]([NH2:29])[CH2:27][OH:28])=[CH:21][CH:20]=1)([O-:18])=[O:17].Cl>CCO>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([OH:30])[C@H:26]([NH2:29])[CH2:27][OH:28])=[CH:23][CH:24]=1)([O-:18])=[O:17].[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2CC1C(=O)O
Agent: Cl
Agent: N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CC(=O)N1c2ccccc2C[C@H]1C(=O)O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
25 g N-acetyl-indoline-2-carboxylic acid (purity 96.5%) was dissolved in 300 ml absolute EtOH while being heated to 70° C. and with mechanical stirring. 17.25 g/0.69 eq. (1R,2R)-1-(4-nitrophenyl)-2-amino-1,3-propanediol (99.5% chemically pure, [a]20D =-28.5° (c=0.4, 1N HCl)) was dosed in portions in 30 min. at 66-70° C. Spontaneous crystallization occurred. After 30 minutes' subsequent stirring at 69-70° C., cooling to 18° C. took place in 2.5 hours, followed by another 30 minutes' stirring. After filtration over a P4 glass filter 3 washings with 30 ml EtOH took place. After air-drying, 20.7 g yellow (S)-N-acetyl-indoline-2-carboxylic acid-(1R,2R)-1-(4-nitrophenyl)-2-amino-1,3-propanediol salt was obtained, corresponding to a yield of 42.0%. Enantiomeric excess=95.9% (chiral HPLC).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[CH3:18][O:19][C:20]1[CH:41]=[CH:40][C:23]([C:24](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([O:7][CH2:6][C@H:5]2[O:8][C@@H:1]([N:9]3[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]3=[O:11])[CH2:2][C@@H:3]2[OH:4])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:23]2[CH:40]=[CH:41][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 2 h

Procedure:
Thymidine (1.918 g, 8.0 mmol) was dried under reduced pressure for a while, pyridine was then added in an argon atmosphere, and the mixture was stirred. 4,4′-Dimethoxytrityl chloride (DMTr-Cl) was added at 0° C., and the mixture was allowed to return to room temperature over about 2 hours with stirring. After confirmation of completion of the reaction by TLC, the reaction was quenched with water. This solution was concentrated under reduced pressure, the concentrate was dissolved in dichloromethane, and the solution was washed with a saturated aqueous solution of copper sulfate and with brine. The organic layer was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (MeOH:CH2Cl2=1:9). The eluate fraction was evaporated under reduced pressure, and the residue was dissolved in a small amount of ethyl acetate. Hexane was added to this solution for reprecipitation to give the title compound 5′-DMTr-Thd. Yield 3.67 g, 82.7%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([C:8]([C:7]4[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[O:10])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3cccnc3Cl)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2-chloropyridine-3-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (44% yield). 1H NMR (500 MHz, CDCl3) δ 8.50, 8.08, 7.99, 7.71, 7.37, 7.02, 4.05-4.13, 3.78-3.95, 3.34-3.60, 1.51, 0.71-0.80, 0.45-0.49, 0.08-0.12. MS (ES+) m/z 415 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[C:12]([CH2:13][CH2:14][CH3:15])=[CH:11][C:10]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:9][C:8]=1[CH2:31][CH2:32][CH3:33])C.[OH-].[Na+]>C1COCC1.CO>[CH3:24][C:23]1[O:22][C:21]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:20][C:19]=1[CH2:18][CH2:17][O:16][C:10]1[CH:9]=[C:8]([CH2:31][CH2:32][CH3:33])[C:7]([O:6][CH2:5][C:4]([OH:34])=[O:3])=[C:12]([CH2:13][CH2:14][CH3:15])[CH:11]=1
Reactant: CCCc1cc(OCCc2nc(-c3ccccc3)oc2C)cc(CCC)c1OCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1cc(OCCc2nc(-c3ccccc3)oc2C)cc(CCC)c1OCC(=O)O
Temperature: 55 °C

Procedure:
A solution of {4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-2,6-dipropyl-phenoxy}-acetic acid ethyl ester (244 mg, 0.524 mmol) in THF (3 mL) and MeOH (6 mL) was treated with 2.5N aqueous NaOH (2 mL). The solution was heated at 55° C. for 2.5 h, cooled to ambient temperature, and concentrated in vacuo. The residue was treated with ice water (1 mL) and acidified with 5N aqueous HCl (2 mL). The mixture with CH2Cl2 (3 mL) was transferred to a ChemElute cartridge (5 g) and eluted with CH2Cl2 (40 mL). The eluent was concentrated to a white foam (228 mg, 100%): 1H NMR (400 MHz, CDCl3) δ 0.94 (t, 6H, J=7.3 Hz), 1.60 (sextet, 4H, J=7.6 Hz), 2.37 (s, 3H), 2.50-2.54 (m, 4H), 2.98 (brt, 2H), 4.19 (brt, 2H), 4.37 (s, 2H), 6.56 (s, 2H), 7.42-7.43 (m, 3H), 7.98-7.99 (m, 2H); MS (ES) m/e 438.2 [M+1].
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])=[CH:13][CH:12]=2)[CH:7]=1)=[O:5])C.[K+].[Br-]>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18](=[O:19])[NH:17][C:14]2[CH:13]=[CH:12][C:11]([C:8]3[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[O:10][N:9]=3)=[CH:16][CH:15]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3)cc2)no1
Agent: [Br-]
Agent: [K+]
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(-c2cc(C(=O)O)on2)cc1
Yield: 95.2 %

Procedure:
The title compound was prepared from 3-{4-[3-(4-fluoro-phenyl)-ureido]-phenyl}-isoxazole-5-carboxylic acid ethyl ester using the procedure as set forth in Example 8 and was obtained in 95.2% yield. Mass (ES+): 342 (M++1); IR (KBr): 3307, 3004 (br), 2871 (br), 1711, 1640, 1601, 1546; 1H NMR (DMSO-d6) δ: 7.08 (t, 2H), 7.43 (m, 2H), 7.49 (d, 2H), 7.67 (s, 1H), 7.84 (d, 2H), 8.77 (s, 1H), 8.93 (s, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[C:6](=[O:7])[O:5][C:4](=[O:8])[NH:3]1.[C:9](Cl)(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CN1CCOCC1>C(OCC)(=O)C>[C:9]([N:3]1[C@@H:2]([CH3:1])[C:6](=[O:7])[O:5][C:4]1=[O:8])(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C[C@@H]1NC(=O)OC1=O
Reactant: CCCCCCCCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCCCCCCCCC(=O)N1C(=O)OC(=O)[C@@H]1C
Reaction time: 2 h
Yield: 65 %

Procedure:
(S)-4-methyl-2, 5-oxazolidinedione (L-alanine-NCA) (345 mg, 3 mmol) was dissolved in ethyl acetate (20 mL), followed by the addition of decanoyl chloride (744 mg, 3.9 mmol) under ice cooling. Further, a solution of N-methylmorpholine (394 mg, 3.9 mmol) in ethyl acetate (10 mL) was added dropwise under ice cooling over 20 minutes, and the resulting mixture was then stirred at the same temperature for 2 hours, the reaction mixture was treated in a similar manner as in Synthesis Process 5 of Example 8 to afford the title compound (525 mg, 65%) as a colorless clear syrup. A portion of the thus-obtained syrup was recrystallized from hexane to obtain white crystals (280 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24]>C(O)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=[N:23][OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)c2cc(OCc3ccccc3)ccc2O1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC1(C)CC(=NO)c2cc(OCc3ccccc3)ccc2O1
Yield: 105.1 %

Procedure:
By heating 11.3 g (40 mmol) of 6-benzyloxy-2,2-dimethylchroman-4-one with 3.1 g (44 mmol) of hydroxylamine hydrochloride in 27 ml of ethanol and 27 ml of pyridine to 70° C. for 3 h, 12.5 g of product, m.p. 105-108° C., were obtained after distilling off the solvt in vac. and precipitating with water. The product was dissolved in EA, dried, concentrated and crystallized using petroleum ether; m.p. 118-120° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16]CC)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20](C)[C:21]([C@H]1CCCNC1)=O.C(N(C(C)C)CC)(C)C.C(Br)C1C=CC=CC=1>>[CH3:19][N:20]([CH3:21])[C:14]([C@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[O:16]
Reactant: CN(C)C(=O)[C@H]1CCCNC1
Reactant: CCOC(=O)C1CCCN(Cc2ccccc2)C1
Agent: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)[C@H]1CCCN(Cc2ccccc2)C1

Procedure:
This reaction was run in the same manner as ethyl 1-benzyl-3-piperidinecarboxylate, starting with (S)-N,N-dimethyl-3-piperidinecarboxamide (275 mg; 1.76 mmol), diisopropylethylamine (310 μl; 1.78 mmol), and benzyl bromide (210 μl; 1.77 mmol). Crude product was purified by chromatography on silica eluting with 5% methanol/95% dichloromethane, giving (S)-N,N-dimethyl 1-benzyl-3-piperidinecarboxamide (322.2 mg) as a colorless oil. MS m/z (positive ion) 247 (MH+; 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Cl.[Mg].[CH3:12][C:13]([CH3:15])=[O:14].Cl>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:13]([CH3:15])([OH:14])[CH3:12])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)=O
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(O)Cc1ccc(Cl)c(Cl)c1
Yield: 56.2 %

Procedure:
A solution of 3,4-dichlorobenzylchloride (49.2 g, 0.254 mole) in dry ether (125 ml) was added dropwise during one hour to magnesium (6.08 g, 0.250 mole) in a three-necked flask equipped with stirrer and reflux condenser. Refluxing was continued until all the magnesium was dissolved and the solution was then cooled. Acetone (15.0 g, 0.258 mole) was added dropwise and the solution heated to reflux for three hours. After cooling the reaction mixture was poured out on ice (125 ml) and a concentrated hydrochloric acid (23 ml). The phases were separated and the organic layer was washed with water, dried (Na2SO4) and evaporated in vacuum. The residual oil was distilled affording 1-(3,4-dichlorophenyl)-2-methyl-2-propanol (bp. 81°-83° C./0.2 mm Hg; 31.3 g, 57% yield). After several recrystallizations from petroleum ether the compound melted at 40°-41° C. The substituted propanol above (21.9 g, 0.100 mole) was mixed with dimethylaniline (12.4 g, 0.102 mole) and ether (50 ml). The solution was cooled and α-bromopropionyl bromide (21.4 g, 0.099 mole) was added dropwise during 40 minutes. Stirring at room temperature for 48 hours gave a crystalline precipitate of dimethylaniline hydrobromide, which was filtered off and washed with ether. The etheral solutions were combined and evaporated in vacuo. The residual oil was distilled affording 2-bromopropanoic acid 1-(3,4-dichlorophenyl)-2-methyl-2-propolyester (bp. 135°-143° C./0.2 mm Hg; 19.2 g, 55% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[Br-].[CH:10]1([Zn+])[CH2:12][CH2:11]1.C([O-])(O)=O.[Na+]>O1CCCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH:10]2[CH2:12][CH2:11]2)[CH:7]=1
Reactant: [Zn+]C1CC1
Reactant: Brc1ccnc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccnc(C2CC2)c1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
To a solution of 2,4-dibromopyridine (3.00 g, 12.66 mmol) in dry tetrahydrofuran (10 mL) under an atmosphere of argon was added tetrakis(triphenylphosphine)palladium(0) (0.435 g, 0.38 mmol). The reaction vessel was put in a water-bath (˜20° C.) and cyclopropylzinc(II) bromide, 0.5M in tetrahydrofuran (30.1 mL, 15.05 mmol) was added is over a period of 10 minutes. The reaction mixture was stirred at 20° C. for 80 minutes. More cyclopropylzinc(II) bromide, 0.5M in tetrahydrofuran (7.52 mL, 3.76 mmol) was added and the reaction mixture was stirred for another 40 minutes before it was poured into saturated aqueous NaHCO3 (100 mL) and diluted with EtOAc (100 mL). The layers were separated and the aqueous layer extracted with EtOAc (50 mL). The organics were combined, dried (Na2SO4), filtered and the solvent was evaporated at reduced pressure. The crude was purified by flash chromatography on silica gel to afford 2.12 g (85%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+].[CH3:24][C:25]1([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:27][O:26]1>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:24][C:25]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)([OH:26])[CH3:27])[C:4]=2[CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(c2cccnc2)CO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)C(c2ccccc2)N(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
2,6-Dimethyl-1-phenyl-2,3,4,9-tetrahydro-1H-β-carboline (300 mg, 1.08 mmol) was dissolved in DMF (4 mL). Sodium hydride (172 mg, 4.32 mmol) was added and the mixture was stirred at RT for 30 min. 3-(2-Methyl-oxiranyl)-pyridine (733 mg, 5.43 mmol) in 1 mL DMF was added dropwise into the reaction mixture, which was stirred for 5 h at RT. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction was quenched with ice and extracted with EtOAc (2×100 mL). The organic layer was washed with water (2×100 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude that was purified by column chromatography (silica gel 100-200 mesh, Eluent: 6% MeOH in DCM) to obtain 120 mg of 1-(2,6-dimethyl-1-phenyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-2-pyridin-3-yl-propan-2-ol (racemate) and followed by chiral separation. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.25 (s, 1H), 8.2 (d, 1H), 7.6 (d, 1H), 7.4 (m, 3H), 7.2 (s, 1H), 7.19 (m, 3H), 6.65 (d, 1H), 6.4 (d, 1H), 5.5 (s, 1H), 4.0 (d, 1H), 3.43 (d, 1H), 3.2 (m, 1H), 3.0 (m, 3H), 2.6 (s, 3H), 2.3 (s, 3H), 1.6 (s, 3H). Separation by chiral HPLC provided diastereomers II-112a-b.