Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])C1C=CC=CC=1.CC(O)=O>CO>[OH:8][CH2:9][CH:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12]
Reactant: CC(C)(C)OC(=O)NC(COCc1ccccc1)C(=O)N1CCOCC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CO)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
tert-butyl-3-(benzyloxy)-1-morpholino-1-oxopropan-2-ylcarbamate (31) (1.4 g, 4.0 mmol, 1.0 equiv.) was added to a 250 mL RBF followed by MeOH (40 mL). The reaction flask was flushed with N2 (g) and charged with 10% Pd/C (290 mg). The flask was equipped with 2H2 (g) balloons and stirred at rt for 30 min. AcOH (230 μL, 4.0 mmol, 1.0 equiv) was then added and the reaction was allowed to stir for 10 h. The solution was filtered through a pad of celite, washing with additional MeOH (200 mL). The solution was concentrated on a rotary evaporator, and dried under vacuum to give 1.2 g of crude material. The residue was purified by flash column chromatography (100% EtOAc) to give 970 mg (88%) of 32 as a colorless oil which crystallized to a white solid. Rf=0.26 (100% EtOAc); mp=45-47° C.; IR (film) 3418, 3315, 2972, 2927, 2859, 1706, 1631, 1444, 1166 cm−1; 1H NMR (500 MHz, CDCl3) δ 5.87 (d, J=8.5 Hz, 1H, carbamate-NH), 4.67 (br d, J=4 Hz, 1H, Boc-NH—CH), 3.79 (br s, 2H, CH—CH2), 3.68-3.62 (m, 9H, morpholine CH2's & OH), 1.44 (s, 9H, t-butyl-CH3); 13C NMR (125 MHz, CDCl3) δ 169.7, 155.7, 80.2, 66.8, 66.7, 64.0, 51.4, 46.3, 42.6, 28.4.
Reaction SMILES: [NH2:1][C@@:2]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[F:15])([CH3:7])[C:3]([CH3:6])([OH:5])[CH3:4].C(=O)([O-])O.[Na+].[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([C@:2]([NH:1][C:23](=[O:24])[CH2:22][Cl:21])([CH3:7])[C:3]([OH:5])([CH3:4])[CH3:6])[CH:13]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(O)[C@](C)(N)c1cc(Br)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(O)[C@](C)(NC(=O)CCl)c1cc(Br)ccc1F
Reaction time: 1 h

Procedure:
A solution of (R)-3-amino-3-(5-bromo-2-fluoro-phenyl)-2-methyl-butan-2-ol (2.91 g, 10.5 mmol) in dichloromethane (35 ml) was stirred intensively together with a saturated sodium hydrogen-carbonate solution (30 ml) at 0° C. Chloroacetyl chloride (0.92 ml, 11.6 ml) was added and stirring continued for 1 hour at 0° C. For the workup, the aqueous layer was separated and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, then evaporated. The title compound was obtained as a white solid (3.5 g, 94% of theory) which was used in the next step without further purification. Mass (calculated) C13H16BrClFNO2 [352.629]; (found) [M+H]+=352, [M+2-H]+=354.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[C:4]([CH3:23])[CH:3]=1.[CH3:24][C@H]1CN(CC2C=CC(NC)=CC=2)CCN1C(OC(C)(C)C)=O>>[CH3:22][C@H:11]1[CH2:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:24])=[CH:3][C:4]=2[CH3:23])[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16]
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: Cc1cc(N)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(C)c1

Procedure:
The title compound was prepared from D7 using a method similar to that described for D3.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[CH3:16][N:17]([C:32](OC1C=CC([N+]([O-])=O)=CC=1)=[O:33])[C@H:18]([C:20]([C@:22]([CH3:31])([OH:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:21])[CH3:19].O>C(Cl)Cl>[CH3:16][N:17]([C:32]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:33])[C@H:18]([C:20]([C@:22]([CH3:31])([OH:30])[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])=[O:21])[CH3:19]
Reactant: C[C@@H](C(=O)[C@](C)(O)C(=O)OC(C)(C)C)N(C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](C(=O)[C@](C)(O)C(=O)OC(C)(C)C)N(C)C(=O)N1CCOCC1

Procedure:
0.65 g (5.0 mmol) of N,N-diisopropylethylamine (“Hünig's base”) and 0.45 g (5.0 mmol) of morpholine are added at room temperature to a solution of 2.0 g (5.0 mmol) of tert-butyl N-methyl-N-(4-nitro-phenoxy)carbonyl-L-alanyl-D-lactate in 40 ml of methylene chloride, and the mixture is stirred at reflux temperature for 18 hours. During the course of this a strong yellow colouration of the reaction mixture occurs. The reaction solution is shaken twice with water, and the organic phase is separated off and concentrated in vacuo after drying over sodium sulphate. The residual crude product is chroratographed on a silica gel column (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the eluent cyclohexane:ethyl acetate (1:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][C:27]1([CH3:33])[O:31][C:30](=[O:32])[NH:29][CH2:28]1>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:28][C:27]([CH3:33])([CH3:26])[O:31][C:30]4=[O:32])=[CH:3][C:4]=3[F:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CC1(C)CNC(=O)O1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3F)CC2)c(C)c1
Yield: 28.3 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (1 g) described in Preparation Example 100 and 5,5-dimethyloxazolidin-2-one (437 mg) described in Preparation Example 43, the title compound (307 mg) was obtained.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:16](=[O:25])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.CC([O-])(C)C.[Na+].[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:17]2[C:16](=[O:25])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]2[C:5]2[CH:6]=[N:7][C:2]([N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])=[CH:3][CH:4]=2)=[CH:19][CH:20]=1
Reactant: CCNCC
Reactant: O=c1c2ccccc2nc(-c2ccc(Br)nc2)n1-c1ccc(Cl)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)cn1
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
2-(6-bromopyridin-3-yl)-3-(4-chlorophenyl)quinazolin-4(3H)-one (0.035 g, 0.085 mmol), Pd(OAc)2 (0.002 g, 0.009 mmol), DPPF (0.004 g, 0.007 mmol), NaOt-Bu (0.011 g, 0.110 mmol), and diethylamine (0.020 mL, 0.19 mmol) were combined in toluene (2 mL) in a microwave tube under nitrogen. The mixture was microwaved at 80° C., 300 W, for 30 minutes. Additional diethylamine (0.040 mL, 0.38 mmol) was added and the microwaving was continued at 90° C. for 2.5 hours. The mixture was concentrated and purified by flash chromatography on silica gel, eluting with 30% ethyl acetate/heptane to 100% ethyl acetate, to afford the title compound as a white solid (0.017 g, 49%). 1H-NMR (300 MHz, DMSO-6): δ 8.14-8.17 (m, 1H), 8.08 (d, J=2.8 Hz, 1H), 7.85-7.91 (m, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.35-7.58 (m, 6H), 6.43 (d, J=9.0 Hz, 1H), 3.44 (q, J=7.0 Hz, 4H), 1.05 (t, 6.9 Hz, 6H). MS (APCI) m/z: 405 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([O:23]C)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)c(Br)c1

Procedure:
In analogy to the procedure of Example XV, the title compound is prepared from 3 g (7.77 mmol) of the compound from Example XX and 12 ml of 1N sodium hydroxide solution (12 mmol).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[C:19]([C:23](Cl)=[O:24])[CH:18]=1>O>[CH:9]1([CH2:8][CH2:7][CH2:6][C@H:2]([NH:1][C:23](=[O:24])[C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([CH3:26])[CH:18]=2)[C:3]([OH:5])=[O:4])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: N[C@@H](CCCC1CCCCC1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(C(=O)N[C@@H](CCCC2CCCCC2)C(=O)O)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 49.9 %

Procedure:
L-Styryl alanine 1 (50 mg, 0.26 mmol) was dissolved in MeOH (5 mL) and placed into a Parr-hydrogenation apparatus. Catalytic amounts of rhodium (5% on Al2O3) were added and the reaction vessel was placed under a hydrogen at 55 psi. The mixture was shaken for 20 h at room temperature, then filtered over celite. The organic solvent was removed in vacuo to yield (S)-2-Amino-5-cyclohexyl-pentanoic acid 2 (52 mg, quant.) as a white solid: 1H-NMR (400 MHz, CD3OD) δ=3.50 (dd, J=5.2, J=6.9, 1H), 1.88–1.64 (m, 7H), 1.47–1.37 (m, 2H), 1.31–1.11 (m, 6H), 0.94–0.86 (m, 2H). MS calcd. for C11H22NO2 (M+H+) 200.17. found 200.4. Step B: (S)-2-Amino-5-cyclohexyl-pentanoic acid 2 (24 mg, 0.12 mmol) was dissolved in H2O (1 mL) containing equimolar amounts of NaOH (5 mg, 0.12 mmol). The solution was cooled to 0° C., then m-Toluic acid chloride (16 μL, 0.12 mmol) was added dropwise under vigorous stirring. The mixture was allowed to warm to room temperature and stirred for approx. 12 h. After acidification with 1 M HCl (1 mL), the product was extracted from the reaction mixture with DCM (4 mL). The organic layer was separated and the solvent was removed in vacuo to yield (S)-5-Cyclohexyl-2-(3-methyl-benzoylamino)-pentanoic acid 3 (19 mg, 50%) as a white solid: 1H-NMR (400 MHz, CD3OD) δ=7.67–7.62 (m, 2H), 7.37–7.31 (m, 2H), 4.56 (dd, J=5.0, J=9.4, 1H), 2.40 (s, 3H), 1.96–0.84 (m, 17H). MS calcd. for C19H28NO3 (M+H+) 318.21. found 318.4. Step C: (S)-5-Cyclohexyl-2-(3-methyl-benzoylamino)-pentanoic acid 3 (19 mg, 0.06 mmol) was dissolved in DCM (2 mL), HOBt (20 mg, 0.14 mmol) and DIC (23 μL, 0.14 mmol) were added and the solution was stirred for 10 min at room temperature. N-(4-Methoxyphenyl)-ethane-1,2-diamine (24 mg, 0.14 mmol) was added and the solution was stirred for 3 h at room temperature. The solvent was removed in vacuo, and the remainder was purified by reverse HPLC to afford the title compound (S)-N-{4-Cyclohexyl-1-[2-(4-methoxy-phenylamino)-ethylcarbamoyl]-butyl}-3-methyl-benzamide 4 (15 mg, 0.03 mmol, 50%) as a white solid: 1H-NMR (400 MHz, CD3OD) δ=7.70–7.65 (m, 2H), 7.38–7.32 (m, 4H), 7.03–6.99 (m, 2H), 4.39 (dd, J=6.4, J=8.4, 1H), 3.80 (s, 3H), 3.67–3.61 (m, 1H), 3.54–3.41 (m, 3H), 2.38 (s, 3H), 1.88–1.80 (m, 2H), 1.72–1.66 (m, 5H), 1.64–1.36 (m, 2H), 1.29–1.07 (m, 6H), 0.92–0.83 (m, 2H). MS calcd. for C28H40N3O3 (M+H+) 466.31. found 466.5.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:6][N:7]=1.[NH2:20][OH:21]>C(O)C.O>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:20][OH:21])=[NH:15])[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(C#N)c2)cnc1N
Reactant: NO
Solvent: CCO
Solvent: O
Product: CNC(=O)c1nc(-c2cccc(C(=N)NO)c2)cnc1N
Temperature: 25 °C
Yield: 71.6 %

Procedure:
3-Amino-6-(3-cyanophenyl)-N-methylpyrazine-2-carboxamide (155 mg, 0.61 mmol) was suspended in ethanol (2 mL) followed by addition of 50% aqueous hydroxylamine (250 uL, 4.1 mmol) and the mixture was heated to reflux for 30 minutes then allowed to cool to room temperature. The suspension was diluted with water (2 mL) and the solid product collected by filtration and dried in vacuo to give crude 3-amino-N-methyl-6-{3-[(hydroxyamino)(imino)methyl]phenyl}pyrazine-2-carboxamide (125 mg, 72% yield) as a yellow solid which was carried forward without further purification: MS (EI) for C13H15N6O2: 287 (MH+).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:11]=[C:12]([Cl:23])[S:13][C:14]=1[C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])(C(C)(C)C)(C)C.O.[OH:25]S(O)(=O)=O>CC(C)=O.C(O)(C)C.O>[Cl:23][C:12]1[S:13][C:14]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[C:10]([C:9]([OH:8])=[O:25])[N:11]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(Cl)sc1C(=O)N1CCOCC1
Solvent: CC(C)=O
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1nc(Cl)sc1C(=O)N1CCOCC1
Temperature: 25 °C

Procedure:
A solution of 173 mg (1.7 mmol) CrO3 in 1 ml of 4:1 water/H2SO4 was added to as solution of 310 mg (0.82 mmol) of 4-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-1,3-thiazol-5-yl]carbonyl}morpholine (Intermediate 216) in 3 ml acetone cooled in an ice water bath. The mixture was stirred with warming room temperature over 90 min. A few drops of isopropanol were added, and the mixture was diluted with water and extracted 2 times with EtOAc. The EtOAc extracts were washed with brine, dried (MgSO4) and concentrated to give 190 mg of a white solid. MS (ES) (MH+): 277 for C9H9ClN2O4S; NMR (d6-DMSO): 3.3 (m, 4H), 3.6 (m, 4H), 13.7 (s, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].C1(C)C=CC=CC=1.O>C(OCC)(=O)C>[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])c(NCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 3-fluoro-4-nitrobenzoic acid (5.20 g), 2,4-dichlorobenzyl-amine (14.8 g) and toluene (35 ml) was refluxed under heating for 24 hr. The mixture was heated to room temperature, and water and ethyl acetate were added. The mixture was stirred and precipitated crystals were collected by filtration. The chloroform layer of the filtrate was separated and the solvent was distilled away. Ether was added to the residue and the precipitated crystals were collected by filtration. The crystals were combined, washed with ether and dried to give 3-(2,4-dichlorobenzyl-amino)-4-nitrobenzoic acid. Sulfuric acid (2.3 g) was added thereto, and the mixture was refluxed under heating in ethanol for 6 hr. The reaction mixture was concentrated and poured into a saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with ethyl acetate, washed with saturated brine and dried. The solvent was distilled away and the residue was crystallized from a mixed solvent of ethyl acetate and hexane. The crystals were collected by filtration and dried to give the objective compound (4.0 g).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24].[OH-].[Na+]>O1CCOCC1.[Na].O>[C:7]1([CH:2]([NH:1][S:23]([C:16]2[C:17]([Cl:22])=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=2[Cl:14])(=[O:25])=[O:24])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: NC(CC(=O)O)c1ccccc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC(NS(=O)(=O)c1c(Cl)cc(Cl)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
1.15 g of 3-amino-3-phenylpropionic acid are dissolved in 25 ml of dioxane and 7 ml of 1N sodium. hydroxide and 1.95 g of 2,4,6-trichlorobenzenesulphonyl chloride in 5 ml of dioxane are gradually added, while maintaining the pH at 10.5-11 by addition of 1N sodium hydroxide. After stirring for 2 hours at RT, the mixture is diluted with 100 ml of water, extracted twice with EtOAc and acidified to pH=2 by addition of 6N HCl. The solid formed is drained, washed with water and dried at 40° C. 2.09 g of the expected product are obtained, m.p.=218-219° C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=4)[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:26][C:24]1[CH:23]=[C:22]([C:27]2[CH:28]=[N:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=2)[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=2)[N:25]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2ccnc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.3 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic-acid tert-butylamide (0.11 g) in dichloromethane (3 ml) was added TFA (3 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by column chromatography on silica gel (dichloromethane/MeOH/NH4OH 16:1:0.1) and crystallization (MeOH, diethyl ether) yielded the title compound as a white solid (0.016 g, 7%). MS (ISP) 478.1 [(M+H)+]; mp 289° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:12]=[C:11]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]2=[CH:9][C:8]=1[CH3:18].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=[O:26])[CH:20]=1.O>CCCCCC.C1(C)C=CC=CC=1>[CH3:18][C:8]1[CH:9]=[C:10]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]2=[N:12][C:7]=1[CH:25]([C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)[OH:26]
Reactant: O=Cc1cccnc1
Reactant: Cc1cc2c(nc1Br)CCCCC2
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: Cc1cc2c(nc1C(O)c1cccnc1)CCCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.4 %

Procedure:
To a solution of 1.6M n-butyl lithium in n-hexane (16.5 ml) in toluene (20 ml) at -20° C., under nitrogen, was added a solution of 2-bromo-6,7,8,9-tetrahydro-3-methyl-5H-cyclohepta[b]pyridine (6 g, 0.025 m) in toluene (30 ml) and kept at -20° C. for 0.25 hours. This was blown over into a solution of 3-pyridine carboxaldehyde (2.7 g) in toluene (30 ml) kept at -20° C. The solution was allowed to warm up to room temperature and water added. The organic phase was separated, dried (MgSO4) and evaporated. The solid was recrystallised from ether (twice) to give 1-(6,7,8,9-tetrahydro-3-methyl-5H-cyclohepta[b]pyrid-2-yl)-1-(pyrid-3-yl)methanol (4.32 g, 64%) m.p. 124°-6° C.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[H-].[Na+].[CH3:19][N:20]([CH2:22][CH2:23]Cl)[CH3:21].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CN(C)C=O>[CH3:1][N:2]([CH3:16])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:23][CH2:22][N:20]([CH3:21])[CH3:19])[C:6]=2[CH2:5][CH2:4]1
Reactant: CN(C)CCCl
Reactant: CN(C)C1CCc2[nH]c3ccccc3c2C1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [H-]
Solvent: CN(C)C=O
Product: CN(C)CCn1c2c(c3ccccc31)CC(N(C)C)CC2

Procedure:
Following the procedure given in Example 11 and using 6.7 g. of 3-(dimethylamino)-1,2,3,4-tetrahydrocarbazole, 1.35 g. of sodium hydride and 3.37 g. of dimethylaminoethyl chloride in 75 ml. of dimethylformamide there was otained 5.6 g. of 3-(dimethylaino)-9-[2-(dimethylamino)ethyl]-1,2,3,4-tetrahydrocarbazole in the form of its dihydrochloride salt which melted at 269°-270°C. (dec.) (corr.)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=3[CH3:23])[CH2:32][CH2:33]2)=[O:22])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: COc1nc(C)c(C(C)=O)cc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C(C)=O)cc1NC(=O)N1CCN(c2cccc(C)c2C)CC1
Yield: 81 %

Procedure:
Pheny N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,3-dimethylphenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound.
Reaction SMILES: C(Cl)CCCCC.[CH3:8][N:9]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][N:11]=[C:10]1[C:17]1[C:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([CH2:28]CN)[CH3:27])=[CH:20][O:19][N:18]=1.C[N:32](C)C=O>>[CH3:8][N:9]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][N:11]=[C:10]1[C:17]1[C:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([CH2:28][NH2:32])[CH3:27])=[CH:20][O:19][N:18]=1
Reactant: CN(C)C=O
Reactant: CC(CCN)CCCCc1conc1-c1ncc([N+](=O)[O-])n1C
Solvent: CCCCCCCl
Product: CC(CN)CCCCc1conc1-c1ncc([N+](=O)[O-])n1C

Procedure:
The product prepared above is treated in a similar fashion with hexyl chloride in dimethylformamide for 2 hours. The recrystallized product is identified as 1-methyl-2-(5-aminoethylhexylisoxazol-3-yl)-5-nitroimidazole.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>O1CCCC1>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20]([CH2:1][NH:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: CNCCC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCNCS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
A solution of 1.0 g (6.28 mmol) of tert.-butyl N-methyl-β-alaninate, 1.54 g (6.28 mmol) of 2,3-dichlorobenzenesulphonyl chloride and 0.70 g (6.92 mmol) of triethylamine in 30 ml of tetrahydrofuran was stirred at room temperature overnight and then evaporated to dryness. About 50 ml of water were added to the residue, and the mixture was extracted three times with in each case 20 ml of ethyl acetate. The organic extracts were washed with about 20 ml of saturated sodium chloride solution and then evaporated to dryness. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: dichloromethane).
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([NH:28][CH:29]=[O:30])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(CCC(=[O:51])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[CH:29]([NH:28][C@@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:51])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]3)[CH2:16]1)=[O:30]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CCCCC1[C@@H](NC=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1[C@@H](NC=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 96 %

Procedure:
The title compound II-bc was prepared in 96% yield from 3,3:17,17-bis(ethylendioxy)-6α-formamidoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 8.02-7.56 (m, 2H), 3.74 (m, 1H), 2.54-0.70 (m, 20H), 1.04 (s, 3H), 0.80 (s, 3H).