Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([N:10]=[C:11]=S)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:13])[CH:3]=1.[NH2:14][C:15]1[C:16]([NH:39][CH3:40])=[CH:17][C:18]([O:34][CH2:35][CH:36]([F:38])[F:37])=[C:19]([CH:33]=1)[C:20]([NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]([F:32])([F:31])[F:30])[CH2:25][CH2:24]1)=[O:21].CC(C)N=C=NC(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([C:6]#[N:7])=[CH:8][C:9]=1[NH:10][C:11]1[N:39]([CH3:40])[C:16]2[CH:17]=[C:18]([O:34][CH2:35][CH:36]([F:37])[F:38])[C:19]([C:20]([NH:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]([F:32])([F:31])[F:30])[CH2:25][CH2:24]3)=[O:21])=[CH:33][C:15]=2[N:14]=1
Reactant: CNc1cc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Reactant: N#Cc1cc(N=C=S)c(Cl)cc1F
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(C#N)c(F)cc2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)cc21

Procedure:
The sub-title compound was prepared in accordance with the procedure in Example 72, step (a) using 4-chloro-2-fluoro-5-isothiocyanatobenzonitrile (270 mg; 1.27 mmol), 5-amino-2-(2,2-difluoroethoxy)-4-(methylamino)-N-((trans)-4-(trifluoromethyl)cyclohexyl)benzamide [502 mg; 1.27 mmol, prepared from 4-trans-trifluoromethyl-cyclohexylamine and 2-(2,2-difluoroethoxy)-4-(methylamino)-5-nitrobenzoic acid in analogy to Example 66, step (f+g)], DIC (160 mg; 1.27 mmol) and DMF (10 mL). Yield: 210 mg (29%).
Reaction SMILES: C[Cl:2].C(OCCN(C)C)(=O)C=C.COC1C=CC(O)=CC=1.C([O-])(=O)C=C.O.C([O-])(=O)C=C.O=O.[C:35]([O:39][CH2:40][CH2:41][N+:42]([CH3:45])([CH3:44])[CH3:43])(=[O:38])[CH:36]=[CH2:37]>O>[Cl-:2].[C:35]([O:39][CH2:40][CH2:41][N+:42]([CH3:44])([CH3:43])[CH3:45])(=[O:38])[CH:36]=[CH2:37]
Reactant: CCl
Agent: C=CC(=O)OCCN(C)C
Agent: C=CC(=O)OCC[N+](C)(C)C
Agent: C=CC(=O)[O-]
Solvent: O
Product: [Cl-]
Temperature: 47 °C
Reaction time: 0.33 h

Procedure:
78 g of liquid methyl chloride are charged with stirring into a jacketed reactor. The temperature is raised to 47° C. and the pressure of the system equilibrates at 9.6 bars absolute. In the first stage 33 g of dimethylaminoethyl acrylate stabilized with the aid of 700 ppm of hydroquinone methyl ether are injected into the reactor over a period of 20 minutes (that is 16% of the total quantity of acrylate necessary for reaction) In a second stage the complement of the acrylate and the water are injected simultaneously and continuously in a water/acrylate weight ratio of the order of 0.4 over a period of 2 hours. Throughout the reaction the temperature is kept at 47° C. and the pressure in the reactor drops to 3.2 bars absolute at the end of the injection of reactants. 0.5 Nl/h of air is then injected continuously into the reactor and over a period of 1 hour the reactor pressure is returned progressively to atmospheric pressure while a blow-off exit flow rate lower than 1.5 Nl/h is maintained (whence a ratio of the blow-off volumetric flow rates to the oxygen introduced lower than 15). 71 g of water and 205 g of dimethylaminoethyl acrylate have been employed in this operation and 343 g of acryloyloxyethyltrimethylammonium at a concentration of. 80% in water are recovered. The final product is then subjected to an injection of air at a flow rate of 7 Nl/h for 1/2 hour hot and then for 1/2 hour at room temperature. The final product obtained has the following characteristics: water: 20.3% acrylic acid: 0.23% dimethylaminoethyl acrylate: 0.15% methyl chloride: 10 ppm polymer: nil storage stability: longer than 1 year.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[N:14]([CH3:17])[C:13](SC)=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[NH4+:27].[I-]>N.CCO>[NH2:27][C:13]1[N:14]([CH3:17])[C:15](=[O:16])[C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[O:8][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH2:10]2)[N:12]=1
Reactant: [NH4+]
Reactant: CSC1=NC2(CC(c3cccc(F)c3)Oc3ccc(Br)cc32)C(=O)N1C
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(c3cccc(F)c3)Oc3ccc(Br)cc32)N=C1N
Yield: 49.5 %

Procedure:
A solution of 6-bromo-2-(3-fluorophenyl)-1′-methyl-2′-(methylthio)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (80 mg, 0.18 mmol) and NH4I (52 mg, 0.36 mmol) in NH3/EtOH (4 mL, 1.5 N) was heated at 110° C. in a tube in a microwave reactor for 2-2.5 h. After cooling, the mixture was concentrated in vacuo to give a residue, which was purified by preparative TLC and then by preparative HPLC to afford 2′-amino-6-bromo-2-(3-fluorophenyl)-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (36 mg, 50%). 1H-NMR (MeOD): 2.16 (m, 2H), 3.12 (s, 3H), 5.87 (d, 1H), 6.90 (d, 1H), 7.08 (m, 2H), 7.25 (m, 2H), 7.33 (d, 1H), 7.41 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:23][O:24][CH2:25][CH2:26][NH2:27].O>CN1CCCC1=O>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:27][CH2:26][CH2:25][O:24][CH3:23])=[O:22]
Reactant: COCCN
Reactant: O=C(Nc1cccc2c(Cl)ccnc12)c1c(Cl)cccc1Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: COCCNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 120 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A mixture of 4-chloro-8-(2,6-dichlorobenzoylamino)quinoline (100 mg) and 2-methoxyethylamine (314 mg) in N-methylpyrrolidone (1 ml) was heated at 120° C. overnight. Water (3 ml) was added thereto under ice-cooling, and the mixture was stirred for 1 hour. The resulting precipitate was collected by filtration, and the residue was purified by preparative thin layer chromatography (methanoldichloromethane) to give 8-(2,6-dichlorobenzoylamino)-4-(2-methoxyethylamino)quinoline (65 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.[I-].C([NH3+])(C)(C)C>CO>[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][S:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(S)cc1
Reactant: COC(=O)CCCCCBr
Agent: CC(C)(C)[NH3+]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CCCCCSc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of 4-aminothiophenol (2.4 g, 18.9 mmol) in methanol (10 mL) was added triethylamine (2.70 mL, 19.2 mmol). A solution of 6-bromohexanoic acid methyl ester (3.0 g, 18.9 mmol) and tert-butylammonium iodide (350 mg, 0.95 mmol) in methanol (5 mL) was added. The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was taken up in ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (100 mL), distilled water (100 mL) and brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a yellow oil that was purified by flash chromatography (2:8 to 1:1 ethyl acetate:40-60° C. petroleum ether) to give the title compound (3.0 g, 62%) as a colourless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1>>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH2:9][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:17][CH:18]=1)[CH3:8])[NH2:6]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: Cl
Product: COC(=O)[C@@H](N)C(C)CCc1ccc(-c2ccccc2C#N)cc1

Procedure:
L-valine methyl ester hydrochloride is N-alkylated with 4-bromomethyl-2′-cyanobiphenyl, the product 4-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester thus formed is N-acylated with valeryl chloride to give N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester. N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester is treated with tributyltin azide to give valsartan methyl ester, which is then hydrolyzed under alkaline condition to give finally valsartan.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.[H-].[Na+].[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[Si:20]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(OCCO)nc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCCOc1ccc([N+](=O)[O-])cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 40.5 %

Procedure:
2-(2-Hydroxyethoxy)-5-nitropyridine (obtained as described in Annalen der Chemie., 1936, 521, 286) (114 g) was added portionwise to an ice-cooled, stirred suspension of sodium hydride (60% dispersion in mineral oil; 24.8 g) in N,N-dimethylformamide (DMF) (600 ml), at such a rate that the temperature did not exceed 10° C. The solution was stirred at 0° C. for 10 minutes, and then tert-butylchlorodiphenylsilane (171 g) was added dropwise at such a rate that the temperature did not exceed 10° C. The solution was stirred for 72 hours and then added to water (2 l). The mixture was extracted with ethyl acetate (2 ×1 l), and the extracts were washed with water (1 l) and saturated sodium chloride solution (500 ml), and then dried (MgSO4). Volatile material was removed by evaporation, and the residue was purified by flash chromatography, eluting with hexane to give 2-[2-(t-butyldiphenylsilyl)oxyethoxy]-5-nitropyridine (B) (106 g), as an oil which solidified on standing, m.p. 63°-64° C. (from hexane); NMR (d6 -DMSO): 1.0(s,9H), 4.0(t,2H), 4.55(t,2H), 7.0(d,1H), 7.3-7.5(m,6H), 7.55-7.75(m,4H), 8.45(dd,1H), 9.0(d,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](Cl)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:17][NH2:18]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([NH:18][CH3:17])[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 67 %

Procedure:
A solution of 4,4′-dichlorobenzhydryl chloride (3.22 g, 11.85 mmol) in a 1.85 M solution of methylamine in tetrahydrofuran (40 ml) was heated at 125° C. in a pressure vessel for 24 h. The cooled reaction mixture was diluted with ethyl acetate, washed with sodium carbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate 8:2) gave 2.12 g (67%) of the title amine as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.57 (3H, s, NCH3), 4.85 (1H, s, CH benzhydryl), 7.0-7.53 (8H, m, aromatics). MS (ESI+) (m/z): 266 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH2:18])[CH2:8][C@H:7]1[CH3:19])=[O:5])[CH3:2].[Br:20][C:21]1[CH:22]=[N:23][C:24](Cl)=[N:25][CH:26]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:24]2[N:25]=[CH:26][C:21]([Br:20])=[CH:22][N:23]=2)[CH2:8][C@H:7]1[CH3:19])=[O:5])[CH3:2]
Reactant: Clc1ncc(Br)cn1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](N)C[C@H]1C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(Br)cn2)C[C@H]1C
Temperature: 25 °C
Yield: 97.9 %

Procedure:
(2R*,4S*)-4-Amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (3.80 g), 5-bromo-2-chloropyrimidin (6.92 g) and N,N-diisopropylethylamine (6.23 ml) are dissolved in 1,4-dioxane (50 ml) and the mixture is heated under reflux for 4 hours. After cooling to room temperature, the reaction solution is partitioned by adding a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=9:1→6:4) to give (2R*,4S*)-4-(5-bromopyrimidin-2-yl)amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (5.92 g). MS (m/z): 422/424 [M+H]+
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C([O:25][C:26](=[O:33])[C@H:27]([CH2:29][C:30](=[O:32])[NH2:31])[NH2:28])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:28][C@H:27]([C:26]([OH:33])=[O:25])[CH2:29][C:30](=[O:32])[NH2:31])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CC(N)=O
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](CC(N)=O)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-asparagine tert-butyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared, via cleavage of the tert-butyl ester using trifluoroacetic acid in CH2Cl2, to provide a solid, mp=178-180° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][NH:11][C@@H:12]([CH3:15])[CH2:13][OH:14]>>[Cl:1][C:2]1[N:3]=[C:4]([N:11]([CH3:10])[C@H:12]([CH3:15])[CH2:13][OH:14])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CN[C@@H](C)CO
Product: C[C@H](CO)N(C)c1cc(Cl)nc(Cl)n1

Procedure:
The title compound was prepared by a procedure similar to that described for D27 starting from 2,4,6-trichloropyrimidine and (S)-2-(methylamino)propan-1-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:10][CH2:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(C)nc(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CCl)cc(F)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 13.6 %

Procedure:
2-Fluoro-4,6-dimethyl-pyridine (4.25 g, 34 mmol) was refluxed with N-chlorosuccinimide (4.99 g, 37.4 mmol) and benzoyl peroxide (822 mg, 3.4 mmol) in carbon tetrachloride (70 ml). After 3.5 hr., the mixture was cooled to room temperature and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:30)) to afford 740 mg (13%) of 4-chloromethyl-2-fluoro-6-methyl-pyridine as a yellow oil. 1H NMR (200 MHz, CDCl3) δ 2.51 (3H, s), 4.51 (2H, s), 6.77 (1H, s), 7.05 (1H, s).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.C[Si](Cl)(C)C.[Cl:25][CH:26]([O:30][C:31](Cl)=[O:32])[CH2:27][CH2:28][CH3:29]>ClCCl>[Cl:25][CH:26]([O:30][C:31]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:32])[CH2:27][CH2:28][CH3:29]
Reactant: CCCC(Cl)OC(=O)Cl
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(Cl)OC(=O)NCC1(CC(=O)O)CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
To a suspension of gabapentin (8.55 g, 50 mmol) in dichloromethane at 0° C. was added triethylamine (21 mL, 150 mmol) and TMSCl (6.4 mL, 50 mmol). The resulting suspension was stirred at 0° C. for 20 minutes and then a solution of chloroformate (132) (8.55 g, 50 mmol) in dichloromethane was added. The reaction was stirred for another hour at room temperature, then quenched with citric acid and extracted with dichloromethane. The combined organic phase was washed with water and brine and dried over Na2SO4. Filtration and evaporation gave 9.5 g of crude product (133), which was used directly in the subsequent step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[O:5][C:6]1[C:7]2[S:28][CH:27]=[CH:26][C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:11]=1.C([O-])(O)=O.[Na+].[O:37]1C[CH2:40][CH2:39][CH2:38]1.C(Cl)(=O)C=C>O>[CH3:25][N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:10]3[N:11]=[C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:38](=[O:37])[CH:39]=[CH2:40])[CH:31]=[CH:30][CH:29]=4)[C:7]4[S:28][CH:27]=[CH:26][C:8]=4[N:9]=3)=[CH:18][CH:17]=2)[CH2:24][CH2:23]1
Reactant: CN1CCN(c2ccc(Nc3nc(Oc4cccc(N)c4)c4sccc4n3)cc2)CC1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc3ccsc23)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
The compound (3.69 mmol) obtained in Step 5 and NaHCO3 (11.07 mmol) were distilled with tetrahydrofuran (40 mL) and distilled water (6 mL), and acryloyl chloride (3.69 mmol) was added thereto slowly at 0° C. with stirring for 15 min. After the reaction was complete, the reaction mixture was distilled with dichloromethane and then washed with sat. NaHCO3 aqueous solution. The organic layer was dried with anhydrous sodium sulfate and then filtered and distilled under a reduced pressure, and the residue was separated by column chromatography (chloroform:methanol=20:1 (volume ratio)) to obtain the title compound (yield: 68.2%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][C@@H:10]1[OH:29])[CH3:8])[CH3:3].C([O-])(=O)C.[Na+].CO>C(O)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[OH:28][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][C:10](=[O:29])[C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH2:17]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1[C@@H](O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Cr+6]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1C(=O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
To a solution of cholest-5-ene-3β,16β-diol (700 mg, 1.7 mmol) and sodium acetate (trihydrate) 4.6 g, 34 mmol) in glacial acetic acid (85 mL) was added dropwise, a solution of chromium trioxide in water (1.7 mL) and acetic acid (0.8 mL). After stirring for 16 hours, methanol (5mL) was added and the reaction mixture concentrated at reduced pressure. Water was added and the aqueous phase extracted using dichloromethane. Drying over magnesium sulphate, concentration and purification by flash chromatography gave the title compound (560 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[C:20]([CH:22]1[NH:27][CH2:26][CH2:25][NH:24][CH2:23]1)#[CH:21]>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:24]4[CH2:25][CH2:26][NH:27][CH:22]([C:20]#[CH:21])[CH2:23]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: C#CC1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: c1ccncc1
Product: C#CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Temperature: 140 °C
Yield: 13.5 %

Procedure:
A mixture of 1.23 g of 7 -chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.95 g of 3-ethynylpiperazine and 15 ml of pyridine is heated at 140° C. in a pressure bottle for 18 hours and then purified as described in Example 101, giving 210 mg of the desired product.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]([OH:26])=O)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:35][NH2:36]>>[OH:35][NH:36][C:24]([C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C@H:18]1[NH:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15])=[O:26]
Reactant: C[Si](C)(C)ON
Reactant: O=C(O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(NO)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Yield: 46.2 %

Procedure:
A solution of the acid obtained in Example 7 (1.00 g, 2.66 mmol) was reacted with oxalyl chloride (2M solution in CH2Cl2, 6.65 mL, 13.3 mmol) followed by O-(trimethylsilyl)hydroxylamine (2.8 g, 26.64 mmol) as described in Example 2 to obtain 0.48 g (46%) of the desired product. The melting point was 182-184° C. Mass spectrometry revealed a molecular ion (MH)+ peak at m/z 391. Proton NMR analysis in CDCl3 resulted in the following chemical shifts (δ): 0.98-1.96 (m, 8H, cyclohexyl methylenes), 2.05-2.16 (m, 1H, C-1H), 3.50-3.67 (broad hump, 1H, C-2H), 6.15 (broad hump, 1H, SO2NH), 7.01-7.88 (m, 9H, aryl-H), and 8.98 (broad s, 1H, CONH).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][N:9]=1)[CH3:4].Br[CH2:17][CH2:18]Br>CN(C)C=O>[CH2:3]([O:5][C:6]([C:7]1([C:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][N:9]=2)[CH2:18][CH2:17]1)=[O:15])[CH3:4]
Reactant: CCOC(=O)Cc1cc(Br)ccn1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2cc(Br)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaH (55% in mineral oil, 0.72 g) was added to a solution of (4-bromo-pyridin-2-yl)-acetic acid ethyl ester (1.80 g) in N,N-dimethylformamide (20 mL) chilled in an ice bath. The resulting mixture was stirred for 10 min at room temperature and then cooled again in an ice bath. 1,2-Dibromoethane (0.70 mL) was added dropwise and the cooling bath was removed. The mixture was stirred at room temperature overnight. Brine was added and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 95:5→1:1) to give the title compound as an oil. Yield: 1.28 g (64% of theory); Mass spectrum (ESI+): m/z=270/272 (Br) [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH2:19])[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41])(OCC)=O>O.C(#N)C>[C:32]1(=[O:41])[N:19]([CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]12
Reactant: CCCC(CCC)C(N)c1ccc(OC)c(OC)c1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCC(CCC)C(c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.5 %

Procedure:
To a stirred solution of 1-(3′,4′-dimethoxyphenyl)-2-propylpentylamine (0.40 grams, 1.60 mmol) and sodium carbonate (0.18 grams, 1.72 mmol) in a mixture of water (5 milliliters) and acetonitrile (10 milliliters) was added N-carbethoxyphthalimide (0.35 grams, 1.60 mmol). The resulting solution was stirred for 2.5 hours at room temperature, the acetonitrile was evaporated and a two phase mixture resulted. The organic phase was extracted into methylene chloride, dried over magnesium sulfate and concentrated in vacuo to afford 0.6 grams of crude product as an oil. The crude product was purified by flash chromatography (silica gel, 25% ethyl acetate/hexane) to afford 0.25 grams of the product as an oil which after a few days solidified. The white solid was dried in vacuo (60° C., <1 mm) to afford 0.24 grams of pure product as a white solid: mp 100-101° C.; 1H NMR (CDCl3) δ7.84-7.59(m, 4H), 7.27-7.02(m, 2H), 6.81-6.68(m, 1H), 5.01(d, J=12 Hz, 1H), 3.89(s, 3H), 3.84(s, 3H), 3.17-2.98(m, 1H), 1.49-0.66(m, 14H). 13C NMR (CDCl3) δ168.5, 148.7, 148.4, 133.8, 131.9, 131.8, 123.1, 121.6, 112.0, 110.7, 58.9, 55.9, 55.7, 36.2, 31.9, 31.8, 18.7, 18.1, 14.6, 14.3.