Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.C1COCC1.C([Li])CCC.CON(C)[C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CCOC(C)=O>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:37]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:44])=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: CON(C)C(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C(=O)c4ccccc4)cc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
To a −78° C. solution of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 0.76 mmol) and THF (5 mL) is added 1.30 M n-Bu-Li (0.50 mL, 0.80 mmol). After 30 minutes N-methoxy-N-methyl-benzamide (0.13 mL, 0.84 mmol) is added, the solution is warmed to ambient temperature, and stirred overnight. The solution is diluted with EtOAc (20 mL), washed with sat. NH4Cl (15 mL), water (15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) furnish the title compound (0.066 g, 0.16 mmol, 21%). 1H NMR (CDCl3), δ 0.89 (t, J=7.4 Hz, 6H), 1.74-1.93 (m, 4H), 2.18 (s, 3H), 2.52 (s, 3H), 2.54 (s, 3H), 3.29-3.38 (m, 1H), 6.71 (s, 1H), 7.49-7.54 (m, 2H), 7.56 (s, 1H), 7.57-7.62 (m, 1H), 7.89-7.94 (m, 2H). LC/MS (m/z): calcd. for C25H27N3OS (M+H)+: 418.2; found: 418.2.
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.[CH3:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[CH:37][C:34]([CH:35]=O)=[C:33]([N+:41]([O-:43])=[O:42])[CH:32]=1>>[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][CH2:35][C:34]3[CH:37]=[C:38]([O:39][CH3:40])[C:31]([O:30][CH3:29])=[CH:32][C:33]=3[N+:41]([O-:43])=[O:42])[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: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Product: COc1cc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c([N+](=O)[O-])cc1OC

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4,5-dimethoxy-2-nitro-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 574.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:9][C@H:10]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:11]([CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)[C:12]([OH:14])=[O:13])=O.O1CCCC1>CO>[OH:9][C@H:10]([CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C@H:11]([CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)[C:12]([OH:14])=[O:13]
Reactant: O=CO[C@H](CCc1ccccc1)[C@H](CCn1nnc2ccccc2c1=O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@@H](CCn1nnc2ccccc2c1=O)[C@H](O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (0.11 g) was added to a solution of the compound obtained from step c above (0.3 g) in methanol (4 mL) and tetrahydrofuran (4 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The solvents were evaporated, and the residue was taken into water and ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to obtain a residue which was purified by column chromatography over silica gel using 10% methanol in dichloromethane as eluant to afford the title compound (0.020 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([NH:18][OH:19])([CH3:17])([CH3:16])[CH3:15]>CO>[C:14]([N+:18]([O-:19])=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=CCCCCCc1ccccc1
Reactant: CC(C)(C)NO
Solvent: CO
Product: CC(C)(C)[N+]([O-])=CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
To a solution of 6-phenyl 1-hexanal (4.93 g, 28.0 mmol, 1 equiv) in methanol (50 ml) was added N-tert-butylhydroxylamine (3.00 g, 33.6 mmol, 1.2 equiv), and the mixture was stirred at rt. for 4 h. Concentration of the mixture gave a light colored oil which was purified by flash chromatography (EtOAc) to give N-tert-butyl-C-(5-phenylpentyl)nitrone (4.39 g, 89.0%) as a colorless oil: 1H NMR (CD3OD) δ 7.28–7.11 (m, 6H), 2.66–2.24 (m, 4H,), 1.72–1.24 (m, 15H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])/[C:5](/[O:24][CH2:25][CH3:26])=[CH:6]/[C:7]1[C:15]2[O:14][CH:13]=[CH:12][C:11]=2[C:10]([O:16]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:27])[CH:5]([O:24][CH2:25][CH3:26])[CH2:6][C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:16])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)c2ccoc12)OCC
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(Cc1ccc(O)c2c1OCC2)OCC
Yield: 74.8 %

Procedure:
A solution of 3-(4-benzyloxy-benzofuran-7-yl)-2Z-ethoxy-acrylic acid ethyl ester (420 mg, 1.15 mmol) (example 120 c]) in methanol (17 ml) was hydrogenated over 10% palladium on charcoal (100 mg) at ambient temperature for 20 h. The catalyst was filtered off, the solvent evaporated under reduced pressure and the residue chromatographed (silica gel, hexane/AcOEt=4/1) to give 240 mg (0.86 mmol, 75%) of the title compound as colorless liquid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:20]1[CH:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][C:23]([CH3:33])([CH3:32])[N:22]2[N:34]=[CH:35][C:36]([C:37](=[O:47])[CH:38]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)[CH3:39])=[C:21]12)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.IC>C1COCC1>[CH2:13]([N:20]1[CH:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][C:23]([CH3:33])([CH3:32])[N:22]2[N:34]=[CH:35][C:36]([C:37](=[O:47])[C:38]([CH3:1])([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)[CH3:39])=[C:21]12)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)NC(C)C
Reactant: Cc1ccc(C(C)C(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)C(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
To 0.110 mL (0.785 mmol) of diisopropyl amine dissolved in 5 mL of THF at −78° C. was added 0.314 mL (0.785 mmol) of a 2.5 M solution of n-butyllithium in hexanes. After stirring for 30 min, 0.28 g (0.604 mmol) of 5 was added as a solution in 1 mL of THF. The reaction was stirred at room temperature for 1 h before 0.049 mL (0.79 mmol) of iodomethane was added as a solution in 1 mL of THF. After 1 h the reaction was quenched by addition of approximately 0.5 mL of saturated aqueous ammonium chloride, diluted with AcOEt and dried over sodium sulfate. Filtering the solution through a short plug of silica gel and concentrating in vacuo provided the crude product. Purification by flash chromatography eluting with 90% hexanes/AcOEt gave 0.067 g (23%) of the title compound as an off white solid. MS Calcd.: 477. Found: 478 (M+H).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)=[CH:3][CH:2]=1.[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1>>[CH:14]1([C:17]([N:9]2[CH2:10][CH:11]3[C:7]([C:4]4[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=4)([CH2:12]3)[CH2:8]2)=[O:18])[CH2:16][CH2:15]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(C23CNCC2C3)cc1
Product: Cc1ccc(C23CC2CN(C(=O)C2CC2)C3)cc1

Procedure:
In a like manner 1-(p-tolyl)-3-azabicyclo[3.1.0]-hexane (Example 36) is reacted with cyclopropanecarbonyl chloride to give 3-cyclopropanecarbonyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane which is reduced as above to give 3-cyclopropylmethyl-1-(p-tolyl)-3-azabicyclo[3.1.0]hexane hydrochloride as colorless crystals, m.p. 180°-182° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][O:17][CH3:18])[C:13]([NH2:15])=[O:14])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+]>Cl.O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[C:12](=[N:16]\[O:17][CH3:18])/[C:13]([NH2:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CON=C(C(N)=O)c1ccccc1COC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CO/N=C(/C(N)=O)c1ccccc1COC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
A mixture of 2-(2-acetoxymethylphenyl)-2-methoxyiminoacetamide (793 mg, E/Z=56/44) was dissolved in a 6N hydrogen chloride/dioxane solution (6.3 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into an ice-cooled saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate twice. The combined ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the crude product (700 mg). This crude product was crystallized from ethyl acetate-hexane. The crystallization mother liquor was concentrated under reduced pressure and purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) to obtain the title compound (616 mg in total, yield: 77.6%, pale yellow crystals).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.Cl.N1CCC(C2NN=C(C3C=CC(Cl)=CC=3)C=2C2C=CN=CC=2)C[CH2:28]1>>[CH3:28][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:9]=2[C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[CH2:6][CH2:7]1
Reactant: Clc1cccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)c1
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Agent: Cl
Product: CN1CCC(c2[nH]nc(-c3cccc(Cl)c3)c2-c2ccncc2)CC1

Procedure:
By following the method of Example C-75 and substituting 5-(4-piperidyl)-4-(4-pyridyl)-3-(3-chlorophenyl)pyrazole hydrochloride (Example C-88), for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 353 (base peak).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][O:9][C:10]1[C:15](C)=[CH:14][N+:13]([O-])=[C:12](C)[C:11]=1[CH3:19]>C(Cl)(Cl)Cl>[C:5]([O:4][CH2:1][C:2]1[C:15]([CH3:14])=[C:10]([O:9][CH3:8])[C:11]([CH3:19])=[CH:12][N:13]=1)(=[O:7])[CH3:6]
Reactant: COc1c(C)c[n+]([O-])c(C)c1C
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1c(C)cnc(COC(C)=O)c1C

Procedure:
215 ml of acetic anhydride were added dropwise at room temperature to a solution of 81.5 g of 4-methoxy-2,3,5-trimethylpyridine 1-oxide in 290 ml of chloroform. After boiling under reflux for 4 hours the solution was evaporated, the residue was dissolved in 200 ml of toluene and again evaporated. The residue was taken up in 500 ml of ethyl acetate and extracted three times with 250 ml of saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated in vacuo. The product which remains behind as the residue was chromatographed on 400 g of silica gel with ether. There was obtained (4-methoxy-3,5-dimethyl-2-pyridyl)methyl acetate in the form of an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)=[C:9]1[CH:20]=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([I:19])=[CH:17][CH:18]=2)=[C:9]1[CH2:20][OH:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc(-c2ccc(I)cc2)c1C=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc(-c2ccc(I)cc2)c1CO
Yield: 82.7 %

Procedure:
A solution of 6 (400 mg, 1.0 mmol) in anhydrous THF (12 mL) under argon was cooled to −20 to −25° C. and LiBH4 (55 mg, 2.5 mmol) was added in portions. The reaction was monitored by TLC (silica, hexanes/ethyl acetate (4:1)), and when no starting material was detected (20-25 min), the reaction was quenched with cold water (30 mL). The aqueous layer was extracted with CH2Cl2 and the organic layer was dried (Na2SO4), concentrated, and purified by flash column chromatography [silica; hexanes/ethyl acetate containing 1% Et3N (3:1)] yielding a gum (330 mg, 82%). 1H NMR δ1.62 (s, 9H), 3.61 (br, 1H), 4.66 (d, J=7.2 Hz, 2H), 6.25 (d, J=3.6 Hz, 1H), 7.18 (d, J=8.1 Hz, 2H), 7.22 (d, J=3.6 Hz, 1H), 7.71 (d, J=8.1 Hz, 2H); 13C NMR δ27.8, 55.3, 84.7, 92.4, 111.2, 121.3, 127.9, 130.0, 130.4, 134.1, 137.5, 149.8; FAB-MS obsd 399.0336, calcd 399.0331 (C16H18INO3).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]3[N:33]([C:41]4[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=4)[N:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=3)=[O:30])=[C:24]([CH3:48])[N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[C:37]([C:35]1[CH:36]=[C:32]([NH:31][C:29]([NH:28][C:25]2[C:24]([CH3:48])=[N:23][C:22]([O:21][CH:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)=[CH:27][CH:26]=2)=[O:30])[N:33]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[N:34]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)nc2C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OC3CCNCC3)nc2C)cc1
Temperature: 22 °C
Reaction time: 0.42 h
Yield: 98.3 %

Procedure:
Add trifluoroacetic acid (10 mL) to a cold solution of 4-{5-[3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-6-methyl-pyridin-2-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (746 mg, 1.33 mmol) in dichloromethane (20 mL). Stir the reaction mixture at 22° C. for 25 min. After removal of solvent, treat the residue with 1 N sodium hydroxide (20 mL) and extract three times with dichloromethane (20 mL each). Dry the combined organic phases over sodium sulfate. Removal of solvent provides a white solid (605 mg, 98% yield). MS(ES+): m/z=463.2 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[C:11](=[O:20])[C:10]=1[OH:21])=[O:8].[CH3:27][C:28]1[C:32]([S:33]([NH2:36])(=[O:35])=[O:34])=[C:31]([CH3:37])[O:30][N:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:36][S:33]([C:32]2[C:28]([CH3:27])=[N:29][O:30][C:31]=2[CH3:37])(=[O:34])=[O:35])=[O:18])[C:11](=[O:20])[C:10]=1[OH:21])=[O:8]
Reactant: Cc1noc(C)c1S(N)(=O)=O
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Product: Cc1noc(C)c1S(=O)(=O)NC(=O)CCCN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O

Procedure:
Compound 756 was prepared from 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid and 3,5-dimethyl-isoxazole-4-sulfonic acid amide using the method described for compound 751. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 40% acetonitrile/water/0.5% TFA) and isolated as a white powder (0.0296 g, 21% yield). HRMS (M−H) calcd for C22H23N4Cl2O7S: 557.06645. found: 557.0663.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([F:19])([F:18])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CC(C)=[O:22].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([O:3][P:4]([C:9]([F:19])([F:18])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:22])=[O:17])=[CH:12][CH:11]=1)([O:5][CH2:6][CH3:7])=[O:8])[CH3:2]
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(C=O)cc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(C(=O)O)cc1
Yield: 98 %

Procedure:
To a solution of [Difluoro-(4-formyl-phenyl)-methyl]-phosphonic acid diethyl ester (260 mg, 0.9 mmol) in acetone (25 mL) at room temperature was added Jones reagent (5 mL). The reaction was quenched by addition of ethanol (5 mL). The reaction was then concentrated under reduced pressure to 5 mL. The residue was diluted with ethyl acetate and washed with water (2×20 mL), saturated sodium chloride (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a white crystalline solid (268 mg, 98%). 1H NMR (400 MHz, DMSO): δ 8.09 (d, 2H), 7.70 (d, 2H), 4.15 (m, 4H), 1.22 (t, 6H); Mass Spectrum (Chemical Ionization, 1% NH in CH4) m/z 309 (M+H).
Reaction SMILES: C([N:4]1[C:16]2[CH:15]=[C:14]([C:17]([C:19]3[CH:20]=[CH:21][C:22]([Cl:29])=[C:23]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:24]=3)=[O:18])[CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=O)C>[OH-].[K+]>[CH:15]1[C:16]2[NH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]=2[CH:12]=[CH:13][C:14]=1[C:17]([C:19]1[CH:20]=[CH:21][C:22]([Cl:29])=[C:23]([S:25]([NH2:28])(=[O:26])=[O:27])[CH:24]=1)=[O:18]
Reactant: CC(=O)n1c2ccccc2c2ccc(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)cc21
Agent: [K+]
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)c2ccc3c(c2)[nH]c2ccccc23)ccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 0.5 g of 5-(9-acetyl-9H-carbazole-2-carbonyl)-2-chloro-benzenesulfonamide and 20 mL of potassium hydroxide solution (10% in water) is heated at reflux overnight and is allowed to cool to room temperature. The reaction mixture is extracted with ethyl acetate, washed with water then a saturated sodium chloride solution, and dried over sodium sulfate. After concentration the residue is loaded on Celite and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to give 5-(9H-carbazole-2-carbonyl)-2-chloro-benzenesulfonamide as dark orange crystals. MS (m/z): 385 (M+1).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH2:13].[O-]S([O-])(=O)=O.[Mg+2].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl.CC#N>[C:17]([O:16][C:14]([NH:12][N:13]=[C:8]1[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN=C1CCC(C(C)(C)C)CC1
Reaction time: 18 h
Yield: 98.7 %

Procedure:
To a solution of 4-tert-butylcyclohexanone (3.95 g, 25.6 mmol) in CH2Cl2 (50 mL) was added tert-butyl hydrazinecarboxylate (3.83 g, 25.6 mmol). A 1:1 mixture of MgSO4/Na2SO4 was added to the reaction to make a slurry and the reaction was stirred vigorously. After 18 h, the reaction was diluted with CH3CN and filtered. The solvent was removed from the filtrate under reduced pressure to give 6.78 g of N′-(4-tert-butyl-cyclohexylidene)-hydrazinecarboxylic acid tert-butyl ester as a white foam. This material was used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 2.93 (d, J=15 Hz, 1H), 2.30 (d, J=13 Hz, 1H), 2.08 (m, 1H), 1.89 (m, 2H), 1.66 (m, 1H), 1.43 (s, 9H), 1.25 (m, 1H), 1.13 (m, 1H), 1.03 (m, 1H), 0.85 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]1[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][C:5]2=1.C(Cl)(=O)C(Cl)=O.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=1)=[O:14])[C:6]1[CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][C:5]2=1
Reactant: CN1CCc2c(n(CC(=O)O)c3ccc(Cl)cc23)C1
Reactant: Nc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCc2c(n(CC(=O)Nc3ccc(F)cc3)c3ccc(Cl)cc23)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)acetic acid (0.1 g, 0.39 mmol) was dissolved in dichloromethane (4 mL) and was cooled to 0° C., using an ice-bath; oxalyl chloride (0.04 mL, 0.43 mmol) was added drop-wise to the reaction mixture. Catalytic amount (1 drop) of dimethyl formamide was added and the reaction mixture was stirred for 1 h at room temperature. Excess oxalyl chloride was distilled away under reduced pressure. A solution of 4-fluoroaniline (0.042 g, 0.43 mmol) in dichloromethane (2 mL) and 4-dimethylaminopyridine (0.017 g, 0.143 mmol) was added to the residue under nitrogen at room temperature and the reaction mass was stirred for 30 min. The reaction mixture was quenched with water and neutralized with 10% NaHCO3, extracted with dichloromethane (2×10 mL). The combined organic layer was dried over sodium sulfate and concentrated by rotary evaporation to obtain 2-(6-chloro-1,2,3,4-tetrahydro-2-methylpyrido[3,4-b]indol-9-yl)-N-(4-fluorophenyl)acetamide (6 mg) after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection volume 5 mL). 1H NMR (DMSO): 11.4 (s, 1H), 10.6 (s, 1H), 7.6 (m, 3H), 7.4 (d, 1H), 7.3-7.1 (m, 3H), 5.1 and 4.9 (d, 2H), 4.4 (q, 2H), 4.1-3.9 (bs, 2H), 3.5 (s, 3H), 3.2-3.1 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:20]([O:27][C:28](=[O:36])[CH2:29][C@@H:30]([NH2:35])[CH2:31][N:32]([CH3:34])[CH3:33])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28](=[O:36])[CH2:29][C@@H:30]([NH:35][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:31][N:32]([CH3:33])[CH3:34])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=C(O)CCCCCCCCc1ccccc1
Agent: Cl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCc1ccccc1

Procedure:
The title compound, m/e=361.5 ([M−H]−), was produced in analogy with intermediate 1, steps 3 and 4. Thus, commercially available 9-phenylnonanoic acid was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-(9-phenyl-nonanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: B(F)(F)F.CCOCC.[CH:10]1([CH2:13][N:14]([CH2:22][C@@H:23]([OH:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][CH2:11]1.[N:31]1([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:33][C@@H:32]1[C:34]([O:36][CH3:37])=[O:35]>C(Cl)(Cl)Cl>[CH2:41]([O:40][C:38]([NH:31][C@@H:32]([C:34]([O:36][CH3:37])=[O:35])[CH2:33][O:30][C@@H:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][N:14]([C:15]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[CH2:13][CH:10]1[CH2:12][CH2:11]1)=[O:39])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](O)c1ccccc1
Reactant: COC(=O)[C@H]1CN1C(=O)OCc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](CO[C@H](CN(CC1CC1)C(=O)OC(C)(C)C)c1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 27.4 %

Procedure:
Boron trifluoride diethyl etherate (0.10 mL, 0.84 mmol) was added to a solution of tert-butyl cyclopropylmethyl[(2S)-2-hydroxy-2-phenylethyl]carbamate (2.45 g, 8.39 mmol) and 1-benzyl 2-methyl (2R)-aziridine-1,2-dicarboxylate (1.97 g, 8.39 mmol) in chloroform (20 mL). After 3 h, the reaction was concentrated. Purification by silica gel chromatography (100% hexanes→30% ethyl acetate/hexanes) gave the title compound (1.21 g).