Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([OH:11])[CH2:9][CH2:8][CH2:7][C@@H:6]1[N:12]=[N+:13]=[N-:14])(=[O:3])[CH3:2].N1C=CC=CC=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@@H:10]([OH:11])[CH2:9][CH2:8][CH2:7][C@@H:6]1[N:12]=[N+:13]=[N-:14])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](O)CCC[C@@H]1N=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](N=[N+]=[N-])CCC[C@@H]1O
Temperature: 50 °C
Yield: 64 %

Procedure:
To a solution of 4 (416 mg, 2.09 mmol) and pyridine (506 μL, 6.27 mmol) in CH2Cl2 (10 mL), Tf2O (421 μL, 2.51 mmol) was dropwise added at −10° C. The mixture was left to react for 10 min when it was diluted (CH2Cl2), washed (HCl(aq) 5%, NaHCO3(aq) sat, brine), dried (MgSO4), filtered and concentrated. The crude was then dissolved in DMF (20 mL). Bu4NNO2 (1810 mg, 6.27 mmol) was added and the mixture was heated to 50° C. After 1 h the mixture was cooled to room temperature. and concentrated. Purification was made by flash chromatography using EtOAc:n-heptan (1:1) as eluent. The reaction yielded 64% of 8. 1H-NMR (CDCl3) 4.79 (dd, J=4.78, 9.75 Hz, 1 H), 4.17 (m, 1 H), 3.83 (ddd, J=4.58, 9.84, 11.29 Hz, 1 H), 2.18 (s, 3 H), 2.00-2.10 (m, 1 H), 1.85-1.95 (m, 1 H), 1.70-1.80 (m, 1 H), 1.50-1.65 (m, 2 H), 1.30-1.45 (m, 1 H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][NH2:10])=[C:6]([OH:8])[CH:7]=1.C[C:12]1[CH:17]=[CH:16]C(S([O-])(=O)=O)=[CH:14][CH:13]=1.C(CC(=O)C)(=O)C>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[C:17]([CH3:16])=[CH:12][C:13]([CH3:14])=[N:10]2)=[C:6]([OH:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: NNc1ccc(Br)cc1O
Solvent: CC(=O)CC(C)=O
Solvent: CCO
Product: Cc1cc(C)n(-c2ccc(Br)cc2O)n1
Temperature: 25 °C
Yield: 101.2 %

Procedure:
5-bromo-2-hydrazinylphenol 4-methylbenzenesulfonate (0.9 g) and acetylacetone (0.8 g) were added to ethanol (25 mL) refluxed for 1 h. Then the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and washed with saturated sodium bicarbonate solution (20 mL×2). The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel column eluted with hexane/ethyl acetate (4:1) to yield the title compound (650 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1.[C:11](OCC)(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].N1CCCCC1>CCO>[CH2:16]([O:15][C:13]([C:12]1[C:11](=[O:18])[NH:1][C:2]2[C:7]([CH:8]=1)=[CH:6][C:5]([Br:10])=[CH:4][N:3]=2)=[O:14])[CH3:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1ncc(Br)cc1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cc(Br)cnc2[nH]c1=O
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A mixture of 2-amino-5-bromo-pyridine-3-carbaldehyde (4.00 g, 14.2 mmol), diethyl malonate (21.6 mL, 142 mmol) and piperidine (7.00 mL, 71.0 mmol) in EtOH (70 mL) was heated to reflux overnight. The mixture was cooled to room temperature and the solid was collected by filtration to give the title compound (2.41 g, 57%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 12.65 (s, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H), 8.45 (s, 1H), 4.29 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([C:12]1[C:13](=[O:23])[O:14][C:15]([OH:22])=[C:16]([C:19](=O)[CH3:20])[C:17]=1[OH:18])(=[O:11])[CH3:10]>CO>[C:9]([C:12]1[C:13](=[O:23])[O:14][C:15](=[O:22])[C:16](=[C:19]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[Cl:1])[CH3:20])[C:17]=1[OH:18])(=[O:11])[CH3:10]
Reactant: Nc1ccccc1Cl
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccccc2Cl)C(=O)OC1=O

Procedure:
o-Chloroaniline (2.55 g., 0.02 m.) is added to 4.24 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml. of methanol and the mixture is refluxed overnight. The reaction mixture is concentrated, cooled and filtered to give 5-acetyl-3-[1-(o-chlorophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 143°-145° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[F:38])[CH:33]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:33][C:32]3[CH:35]=[CH:36][C:37]([F:38])=[C:30]([F:29])[CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(F)c(F)c1
Product: Fc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1F

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3,4 difluorobenzaldehyde. MS (ESI) m/z 505.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:26][C:27]=3[C:28]([F:31])([F:30])[F:29])=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.CO.CCOCC>[N:11]1([C:14]2[N:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:26][C:27]=3[C:28]([F:30])([F:31])[F:29])=[O:22])=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Nc1ccc(N2CCNCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.2 %

Procedure:
4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (300 mg, 0.58 mmol) from above was suspended in methylene chloride (5 mL) and methanol (5 mL). To this mixture was added hydrogen chloride in ether (4N, 3 mL). The mixture was stirred at room temperature overnight. The solvents were evaporated and the residue was dried in vacuum. The resulting solid was triturated with dry ether and then filtered to give a hydrochloride salt of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide (274 mg). LC-MS calcd C20H18F3N5O2 (m/e) 417.39, obsd 418.0 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][C:7](=[O:9])[NH:6][CH:5]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:4]2[NH:3]1.[CH2:15]1[O:17][CH2:16]1>C(O)C.C1C=CC=CC=1>[OH:17][CH2:16][CH2:15][N:3]1[CH:4]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:5]2[NH:6][C:7](=[O:9])[CH2:8][C:2]1([CH3:14])[CH3:1]
Reactant: C1CO1
Reactant: CC1(C)CC(=O)NC2CCCCC2N1
Solvent: c1ccccc1
Solvent: CCO
Product: CC1(C)CC(=O)NC2CCCCC2N1CCO

Procedure:
38.6 g 4,4-dimethyl-decahydro-1,5-benzodiazepin-2-one is placed in a 250 ml flask with a slight molar excess of ethylene oxide (about 13.2 g) dissolved in ethyl alcohol. The reaction is run in an autoclave at 170°-180° C. A viscous brown paste is obtained which is dissolved in benzene. Upon recrystallization from benzene a white solid is obtained having a melting pt. 154°-156° C.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.O1CCCC1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>O>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([NH:20][CH2:17][CH2:18][CH3:19])=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCCN
Solvent: O
Solvent: C1CCOC1
Product: CCCNC(=O)c1ccc(C=O)cc1
Reaction time: 3 h

Procedure:
A mixture of 15.0 g. of 4-carboxybenzaldehyde, 17.0 g. of N,N'-carbonyldiimidazole and 100 ml. of tetrahydrofuran is allowed to stand at room temperature for 3 hours, then 9.8 ml. of N-propylamine are added. The reaction mixture is allowed to stand at room temperature for 18 hours and is then heated at reflux temperature for one hour, diluted with water and concentrated. The oil which separates is washed twice with water and then purified by partition chromatography to yield p-formyl-N-propylbenzamide, m.p. 71°-74° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[H][H]>[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: [H][H]
Reactant: COc1ccc(-c2[nH]c3ccccc3c2CCNCCc2ccc([N+](=O)[O-])cc2)cc1OC
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Product: COc1ccc(-c2[nH]c3ccccc3c2CCNCCc2ccc(N)cc2)cc1OC
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a stirred solution of [2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethyl]-[2-(4-nitrophenyl)ethyl]amine (45 mg in 4 mL methanol) was added 2N hydrochloric acid (0.020 mL) and 18 mg of 10% palladium hydroxide on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 40 minutes the reaction was flushed with nitrogen, filtered over diatomaceous earth, concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol, 96:4) to provide the title compound (32 mg). m/e=416 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1.[C:20]1([C@H:26]([NH2:28])[CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:28][C@@H:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:27])=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COC(=O)C1CCN(c2cc(C=O)ccc2Cl)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)C1CCN(c2cc(CN[C@H](C)c3ccccc3)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.8 %

Procedure:
To a solution of methyl 1-(2-chloro-5-formylphenyl)piperidine-4-carboxylate 68 (0.180 g, 0.64 mmol) in DCE (3 mL) was added (R)-1-phenylethanamine (0.10 mL, 0.79 mmol), acetic acid (0.040 mL, 0.69 mmol), and NaBH(OAc)3 (0.168 g, 0.79 mmol). The reaction mixture was stirred at room temperature for 20 h, quenched with saturated NaHCO3, and diluted with EtOAc. The organic phase was washed with saturated NaHCO3 (1×), brine (1 x), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 50% to 100% EtOAc in hexanes) gave (R)-methyl 1-(2-chloro-5-((1-phenylethylamino)methyl)phenyl)piperidine-4-carboxylate 69 (0.215 g, 87% yield) as a colorless oil. Mass spectrum: calculated for C22H27ClN2O2 386.2. found 387.2 (M++1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>[OH-].[Na+]>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCNS(=O)(=O)c1ccc(Cl)cc1

Procedure:
A solution of 7-aminoheptanoic acid in 10% sodium hydroxide solution was treated with 4-chlorobenzenesulphonyl chloride in the manner of Example 1 to give the title compound which, after recrystallisation from aqueous ethanol, had a melting point of 128°-129° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[NH2:29][C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1>C1COCC1>[OH:36][C:32]1[CH:31]=[C:30]([NH:29][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[S:24][CH:25]=[CH:26][CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:28])[CH:35]=[CH:34][CH:33]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CO
Solvent: C1CCOC1
Product: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CNc1cccc(O)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 45, 100 mg, 0.256 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (34 mg, 0.3116 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 84% yield (0.104 g, 0.2159 mmol).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(Cl)Cl.[OH:11][C:12]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>N1C=CC=CC=1>[C:1]([O:11][C:12]1[CH:20]=[C:19]([O:21][CH:22]2[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:26][CH2:27]2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)N1CCC(Oc2ccc(C(=O)O)c(O)c2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(OC2CCN(S(C)(=O)=O)CC2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, pyridine (0.12 mL) and acetic anhydride (0.065 mL) were sequentially added to a methylene chloride (1.8 mL) suspension of the obtained 2-hydroxy-4-((1-(methylsulfonyl)piperidin-4-yl)oxy)benzoic acid (0.18 g), followed by stirring at room temperature for 1 hour. Under ice-cooling, pyridine (0.023 mL) and acetic anhydride (0.016 mL) were sequentially added to the reaction mixture, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and 1 mol/L hydrochloric acid and ethyl acetate were added to the residue. The organic layer was separated, washed with 1 mol/L hydrochloric acid, water, and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.18 g of 2-acetoxy-4-((1-(methylsulfonyl)piperidin-4-yl)oxy)benzoic acid as a white solid.
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH:17]=[CH:18]2)[C@H:14]2[C@H:5]1[C@:6]1([CH3:26])[C@@H:11]([CH2:12][CH2:13]2)[CH2:10][C@H:9]([OH:22])[C@@H:8]([O:23][CH2:24][CH3:25])[CH2:7]1)[CH3:3]>C(OCC)(=O)C.[Pd]>[CH3:1][N:2]([C@@H:4]1[CH2:21][C@@:19]2([CH3:20])[C@@H:15]([CH2:16][CH2:17][CH2:18]2)[C@H:14]2[C@H:5]1[C@:6]1([CH3:26])[C@@H:11]([CH2:12][CH2:13]2)[CH2:10][C@H:9]([OH:22])[C@@H:8]([O:23][CH2:24][CH3:25])[CH2:7]1)[CH3:3]
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](N(C)C)C[C@]2(C)C=CC[C@@H]32)C[C@@H]1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](N(C)C)C[C@]2(C)CCC[C@@H]32)C[C@@H]1O
Temperature: 25 °C
Yield: 45.6 %

Procedure:
A solution of 11α-N,N-dimethylamino-2β-ethoxy-5α-androst-16-en-3α-ol (181 mg) in ethyl acetate (20 ml) containing 10% palladium on charcoal (180 mg) was stirred at room temperature under hydrogen. The catalyst was removed by filtration through Kieselguhr and the solvent was evaporated in vacuo. Purification of the residue by preparative thin layer chromatography over silica (ethyl acetate:petroleum ether 1:1) and crystallization from aqueous methanol yielded the title compound (83 mg), m.p. 54°-59°, [α]D -16.7°.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][C:8]([NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:13])[CH2:9][C:10](=[O:12])[CH3:11].[CH2:23]([O:25][CH:26]([O:32][CH2:33][CH3:34])[C:27](OCC)=[O:28])[CH3:24]>C(O)C>[CH2:23]([O:25][CH:26]([O:32][CH2:33][CH3:34])[C:27](=[O:28])[CH2:11][C:10](=[O:12])[CH2:9][C:8]([NH:14][C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:7])[CH3:13])[CH3:24]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: CC(=O)CC(C)(C)NC(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(OCC)C(=O)CC(=O)CC(C)(C)NC(=O)c1ccccc1
Yield: 88.6 %

Procedure:
Sodium tert-butoxide (5.98 g, 62.2 mmol) was added to a solution of 4-methyl-4-benzamido-2-pentanone (12.4 g, 56.5 mmol) and ethyl diethoxyacetate (11.0 g, 62.2 mmol) in ethanol (40 mL), and the reaction was heated at reflux under a nitrogen atmosphere for 3.5 hours. The solvent was removed under reduced pressure, and the residue was partitioned between saturated aqueous ammonium chloride and tert-butyl methyl ether. The aqueous solution was extracted twice with tert-butyl methyl ether, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 17.5 g of N-(6,6-diethoxy-1,1-dimethyl-3,5-dioxohexyl)benzamide as a brown oil.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])=[N:25][CH:26]=[N:27]2)=[CH:22][C:21]=1[O:39][CH3:40])(O)=[O:14].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:24]2[C:23]3[C:28](=[CH:29][C:20]([O:19][CH2:18][CH2:17][CH2:16][C:13]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[O:14])=[C:21]([O:39][CH3:40])[CH:22]=3)[N:27]=[CH:26][N:25]=2)=[C:32]([F:38])[CH:33]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCC(=O)O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.3 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (94 mg, 4.9 mmol) was added to a mixture of 7-(3-carboxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (164 mg, 0.4 mmol), morpholine (0.11 g 1.26 mmol) and 4-dimethylaminopyridine (200 mg, 1.64 mmol) in DMF (5 ml). The reaction mixture was stirred at ambient temperature for 24 hours and the volatiles were removed by evaporation. Water was added to the residue and the aqueous mixture was extracted with methylene chloride (3×30ml). The extracts were combined and the solvent removed by evaporation. The residue was triturated with ether and the precipitate was collected by filtration. The solid was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (100/8/1). The purified product was triturated with acetone, collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-morpholinocarbonylpropoxy)quinazoline (88 mg, 46%).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[NH2:5]>CO>[CH3:1][CH:2]([CH3:12])[CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[NH2:5]
Reactant: CC(C)CC(N)c1ccccn1
Solvent: CO
Product: CC(C)C[C@H](N)c1ccccn1
Reaction time: 0.08 h

Procedure:
To a hot solution of (L)-DBTA (7.2 g, 20 mmol) in MeOH (75 mL) with stirring was added a solution of racemic 3-methyl-1-(pyridin-2-yl)butan-1-amine (3.3 g, 20 mmol) in MeOH (30 mL) dropwise. After addition, the resulting suspension was stirred for 5 min under reflux and cooled in air for about 5 min. The resulting precipitate was collected by vacuum filtration, washed with cold MeOH, air-dried and recrystallized from MeOH (200 mL) to give (L)-DBTA salt of (S)-3-methyl-1-(pyridin-2-yl)butan-1-amine as white solid (1.95 g, 95.6% ee). The ee of the compound was determined by acetylating small samples with acetyl chloride and analyzing the products by chiral HPLC: Daicel Chiralpak AD-H, 90:10 v/v hexanes-IPA (+0.5% Et3N), 1.0 ml min−1, λ=254 nm, Rt=5.8 mins (R), Rt=7.5 min (S).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([OH:8])=[N:6][CH:7]=1.[O:10]1[CH2:15][CH2:14][CH:13](O)[CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([O:8][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1O
Reactant: OC1CCOCC1
Product: Cc1cc(Br)cnc1OC1CCOCC1

Procedure:
The title compound was prepared from 5-bromo-2-hydroxy-3-methylpyridine and tetrahydro-4H-pyran-4-ol in analogy to Example 9c): colorless solid.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH2:3]([N:10]([CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CNCCCSc2ccncc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1ccccc1)N(CCCSc1ccncc1)Cc1ccccc1
Yield: 50.2 %

Procedure:
To a solution of 400 mg (1.21 mmol) of 4-[3-(N-benzylamino)propylthio]pyridine dihydrochloride and 0.55 ml (4.00 mmol) of triiethylamine in 5 ml of methylene chloride, 0.17 ml (1.45 mmol) of benzoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 0.22 g of the desired compound (yield: 50.4%, yellow oil).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])(=[O:13])=[O:12])[CH2:8][N:7]1[CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[O:5])C.[OH-].[Li+]>>[O:27]1[CH2:26][CH2:25][CH:24]([N:7]2[CH2:8][CH:9]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:22])([F:23])[F:21])(=[O:13])=[O:12])[CH2:10][CH:6]2[C:4]([OH:5])=[O:3])[CH2:29][CH2:28]1
Reactant: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1C1CCOCC1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1C1CCOCC1

Procedure:
In analogy to the procedure described in example 253e, 1-(tetrahydro-pyran-4-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid ethyl ester was saponified in the presence of lithium hydroxide to give the title compound as white solid which was used in the next step without further purification. MS (ESI): m/z=408.4 [M+H]+.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([N:18]([CH3:35])[C@@H:19]([C@@H:31]([CH3:34])[CH2:32][CH3:33])[C@H:20]([O:29][CH3:30])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1>CO.[Pd]>[CH3:30][O:29][C@@H:20]([C@@H:19]([N:18]([CH3:35])[C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH2:11])[C@@H:31]([CH3:34])[CH2:32][CH3:33])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](N)C(C)C
Reaction time: 1 h

Procedure:
500 mg (1 mmol) of tert-butyl (3R,4S,5S)-4-[{N-[(benzyloxy)carbonyl]-L-valyl}(methyl)amino]-3-methoxy-5-methylheptanoate (Intermediate 1) were dissolved in 50 ml of methanol and, after addition of 100 mg of 10% palladium on activated carbon, hydrogenated at RT under atmospheric pressure for 1 h. The catalyst was then filtered off and the solvent was removed under reduced pressure. This gave 370 mg (quant.) of the title compound as an almost colourless oil.