Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH4+:15].[OH-].C(O)(C)C>>[Br:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([NH2:15])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(NC2CCCC2)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1ncc(Br)c(NC2CCCC2)n1
Yield: 66 %

Procedure:
A solution of 1 (45 g, 200 mmol) in 28% NH4OH/iso-propanol (1/1, 400 mL) was heated at 120° C. in a sealed tube for 22 h. The product was extracted with dichloromethane and the organic layers were washed with brine and dried. The solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with 25% ethyl acetate in hexanes to give the titled compound (2) as a white solid (34 g, 66%). 1H NMR (500 MHz, DMSO-d6) δ 7.77 (1H, s), 6.19 (2H, br. s), 6.12 (1H, d, 1H, J=7.3 Hz), 4.33 (1H, m) 1.90 (2H, m), 1.69 (2H, m), 1.49-1.55 (4H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 257.0, Calculated 257.0.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:5]2[C:10]([N:11]=[C:12]3[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.C([N+](CCCC)(CCCC)CCCC)CCC>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:3][C:4]2[C:5]3[C:10]([N:11]=[C:12]4[C:17]=2[C:16](=[O:18])[CH2:15][CH2:14][CH2:13]4)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:22][CH:21]=1
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Reactant: Fc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C1CCCc2nc3ccccc3c(NCc3ccc(F)cc3)c21

Procedure:
In 300 ml of toluene and 200 ml of 30% potassium hydroxide were added 8.00 g of 9-amino-3,4-dihydroacridin-1(2H)-one and 1.92 g of tetrabutylammonium hydrogn sulfate catalyst. The mechanically stirred biphasic solution was heated to reflux and 9.4 ml of 4-fluorobenzyl bromide in 50 ml of toluene was added dropwise. Reflux was continued for a total of 2 hours. The reaction was poured onto ice and the toluene layer was separated. The aqueous phase was extracted with ethyl acetate. The organics were combined, washed with saturated NaCl solution, dried over anhydrous magnesium sulfate, filtered and evaporated to a solid. The solid was recrystallized from 1:1 ethyl acetate/hexane to yield 5.89 g of product, mp 158°-159° C.
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.FC(F)(F)C1N=CNC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:7]1[C:8]2[C:3](=[CH:2][N:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][C:6]1=[O:12]
Reactant: O=c1ccc2c(Br)nccc2[nH]1
Agent: FC(F)(F)c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccc2cnccc2[nH]1
Reaction time: 29 h

Procedure:
In a third run a mixture containing 3.5 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 8.5 g of 4-(trifluoromethyl)-1H-imidazole, 8.7 g of potassium carbonate and 150 ml of dimethylformamide was refluxed with stirring for 29 hours and following a work-up procedure as described in the preceding paragraphs, 1.9 g of the crude product was obtained. The three fractions of product were combined, recrystallized three times from isopropyl alcohol and dried in an oven at 100° C. for two days to yield 1.95 g of 5-[(4-trifluoromethyl)-1H-imidazol-1-yl)]-1,6-naphthyridin-2(1H)-one, m.p. 216°-218° C.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C(N(CC)CC)C.[F:19][C:20]1[C:25]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])=[CH:24][C:23]([S:37](Cl)(=[O:39])=[O:38])=[C:22]([O:41][CH3:42])[CH:21]=1.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:19][C:20]1[C:25]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])=[CH:24][C:23]([S:37]([N:1]2[C:2]3[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=3[CH2:4][CH2:5][CH2:6][CH2:7]2)(=[O:38])=[O:39])=[C:22]([O:41][CH3:42])[CH:21]=1
Reactant: c1ccc2c(c1)CCCCN2
Reactant: COc1cc(F)c(N2C(=O)c3ccccc3C2=O)cc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(F)c(N2C(=O)c3ccccc3C2=O)cc1S(=O)(=O)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.7 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-1H-benzo[B]azepine (0.24 g), triethylamine (0.23 mL) and 4-dimethylaminopyridine (17 mg) in methylene chloride (8 mL) was added 4-fluoro-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-methoxybenzenesulfonyl chloride (0.5 g), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 5-fluoro-2-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-ylsulfonyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)anisole (0.57 g). This material was dissolved in tetrahydrofuran (11 mL). To the solution was added hydrazine monohydrate (0.29 mL), and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=2/3) to give the title compound (0.32 g).
Reaction SMILES: [OH:1]C(P(O)O)(C1C=CC(C)=CC=1)C.ClCC(O)C.CN(C1C=CC=CN=1)C.[CH:28]1([N:34]=[C:35]=[N:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCCC1.CCOCC>[C:35]([NH:34][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)([NH:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:1]
Reactant: Cc1ccc(C(C)(O)P(O)O)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(O)CCl
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
1-hydroxy-1-p-tolylethylphosphonous acid (0.2 g., 0.01M), 1-chloro-2-propanol (0,094 g., 0.01M) and dimethylaminopyridine (0.01 g) are stirred in tetrahydrofuran (5 ml.) at 5° C. Dicyclohexylcarbodiimide (0.23 g., 0.001M) is added portionwise over 1 hour. On completion of the reaction (monitored by 31P NMR) ether (10 ml) is added and the dicylohexylurea formed is filtered off. Evaporation of the filtrate gives an oil which is purified by chromatography on silica using 5% methanol in chloroform as eluant. There is obtained 1-chloromethylethyl (1-hydroxy-1-p-tolylethyl)phosphinate.
Reaction SMILES: [C:1](=O)([S:3][CH2:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)C.C[O-].[Na+].CI.C(=O)(O)[O-].[Na+]>CO>[CH3:1][S:3][CH2:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: CC(=O)SCc1ccc(-c2cccnc2)o1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: CSCc1ccc(-c2cccnc2)o1
Reaction time: 0.17 h
Yield: 52.8 %

Procedure:
(See FIG. 7.) To a solution of 13 (27 mg, 0.12 mmol) in anhydrous CH3OH (3 mL) at 0° C. under argon was added a solution of sodium methoxide (15 mg, 0.28 mmol) in anhydrous CH3OH (1 mL) dropwise, over 10 min and the resultant solution was stirred for 30 min. To the solution was added methyl iodide (17 μL, 0.28 mmol) in anhydrous CH3OH (1 mL) dropwise over 1 min and the resultant solution was stirred for 30 min. The reaction was stopped by the addition of aqueous sodium bicarbonate (satd. soln., 10 mL). The CH3OH was removed in vacuo and the aqueous fraction was extracted with EtOAc (3×10 mL). The combined organic fractions were dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (EtOAc/Hex, 25/75, Rf=0.2) to afford the title compound 15 (13 mg, 54% yield) as an off white solid: mp=67-68° C.; 1H NMR (CDCl3) δ 8.90 (br s, 1H), 8.46 (m, 1H), 7.90 (m, 1H), 7.29 (m, 1H), 6.66 (d, J=3.3 Hz, 1H), 6.29 (d, J=3.3 Hz, 1H), 3.74 (s, 2H), 2.14 (s, 3H); LRMS (ESI) m/z calcd for C11H12NOS [M+H]+ 206. found 206.
Reaction SMILES: Br[C:2]1[C:7]2[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:31][C@H:32]1[CH2:37][O:36][CH2:35][CH2:34][NH:33]1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:31][C@H:32]1[CH2:37][O:36][CH2:35][CH2:34][N:33]1[C:4]1[CH:3]=[CH:2][C:7]2[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][O:12][C:6]=2[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2cccc(Br)c2C1
Reactant: C[C@H]1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H]1COCCN1c1ccc2c(c1)OCCN(C(=O)OC(C)(C)C)C2
Yield: 79.3 %

Procedure:
A solution of tert-butyl 6-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (500 mg, 1.52 mmol), (3S)-3-methylmorpholine p-toluenesulfonate (416 mg, 1.52 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl(X-phos) (58.0 mg, 0.122 mmol), tris(dibenzylideneacetone)dipalladium(0) (27.8 mg, 0.0304 mmol), sodium tert-butoxide (365 mg, 3.80 mmol) and toluene (6 ml) was stirred under an argon atmosphere at 100° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (420 mg, 79.2%) as an oil.
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[C:22]([F:23])=[C:21]2[C:8]([CH2:9][C:10]3([C@H:19]4[C@H:27]([CH3:28])[O:26][C@H:25]([CH3:29])[CH2:24][N:20]42)[C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12][C:11]3=[O:18])=[CH:7][C:6]=1[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O>CO.N1C=CC=CC=1>[F:4][C:5]1[C:22]([F:23])=[C:21]2[C:8]([CH2:9][C:10]3([C@H:19]4[C@H:27]([CH3:28])[O:26][C@H:25]([CH3:29])[CH2:24][N:20]42)[C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12][C:11]3=[O:18])=[CH:7][C:6]=1/[C:30](=[N:2]/[OH:3])/[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NO
Reactant: C[C@@H]1CN2c3c(cc(C(=O)c4ccccc4)c(F)c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: C[C@@H]1CN2c3c(cc(/C(=N/O)c4ccccc4)c(F)c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 90 °C

Procedure:
Hydroxylamine hydrochloride (77 mg, 0.001 mmol) was added to a solution of (2R,4S,4aS)-rel-9,10-difluoro-2,4-dimethyl-8-(phenylcarbonyl)-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione (Intermediate 13, 280 mg, 0.6 mmol) in methanol:pyridine (1:1, 3 mL) and the solution was heated to 90° C. for 12 hours. Solvents were removed and the residue was subjected to silica gel column chromatography using a gradient of ethyl acetate in pet. ether to give the title compound as a racemic mixture. Yield: 120 mg (42%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[C:19]([CH3:24])=[N:20][N:21]([CH3:23])[CH:22]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[C:19]([CH3:24])=[N:20][N:21]([CH3:23])[CH:22]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(C)cc1Nc1cnc2c(n1)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nn(C)cc1Nc1cnc2[nH]cc(C(=O)NC(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
To a solution of N-tert-butyl-2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (89 mg, 194 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (443 mg, 300 μL, 3.89 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.45 mL) and the mixture stirred at room temperature for 2 h. The reaction mixture was concentrated then purified by chromatography (silica, 5-8% methanol in dichloromethane) to give N-tert-butyl-2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (40 mg, 122 μmol, 63%) as a light brown solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.13 (s, 1H), 8.44 (s, 1H), 7.91 (s, 1H), 7.87 (d, J=3.2, 1 H), 7.82 (s, 1H), 7.81 (s, 1H), 3.71 (s, 3H), 2.09 (s, 3H), 1.35 (s, 9H); MS (EI/CI) m/z: 328.1 [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:12])=[O:13])=[CH:6][CH:5]=1
Reactant: NS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: O=[Pd]
Solvent: CCO
Product: Nc1ccc(CS(N)(=O)=O)cc1
Yield: 77.1 %

Procedure:
A suspension of 4-nitrobenzenemethanesulphonamide (7.11 g) and 5% palladium oxide on charcoal (1.4 g) in ethanol (1.1 l) was hydrogenated at room temperature and pressure. The reaction was terminated after 2.5 l of hydrogen had been absorbed and the catalyst was removed by filtration. The filtrate was concentrated to give the title compoun as a solid (4.72 g). Recrystallisation of a sample from ethanol gave analytically pure material m.p. 166° (bubbles).
Reaction SMILES: O[C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@:8]3([OH:23])[CH2:9][CH2:10][C@@H:11]2[CH:21]=O)[CH2:3]1.P([O-])([O-])(O)=O.[Na+].[Na+].[CH3:31][C:32]([OH:34])=[O:33]>>[C:32]([O:34][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@:8]3([OH:23])[CH2:9][CH2:10][C@@H:11]2[CH3:21])[CH2:3]1)(=[O:33])[CH3:31]
Reactant: CC(=O)O
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C)CC[C@]32O)C1

Procedure:
A solution of 9.1 g of 3β,14β-dihydroxy-5β-androstane-17β-carboxaldehyde (Boutagy J. and Thomas R., Aust. J. Chem., 1971, 24, 2723), and p-toluensulphonyl hydrazide (5.6 g) in AcOH (60 mL) was stirred at room temp. for 3 hrs and then poured in a saturated aqueous solution of di-sodium hydrogen phosphate. The mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was dissolved in MeOH (200 mL) and zinc iodide (1.2 g) was added. To this solution sodium cyanoborohydride (2.6 g) was added portionwise and the temperature was raised to the boiling point of the reaction mixture. After 3 hrs the solvent was evaporated to dryness under reduced pressure, the crude product was dissolved in ethyl acetate and neutralised with 0.1 N NaOH, the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by chromatography (SiO2) using n-hexane/ethyl ether 75/25 as eluant to give 5.7 g of 3β-acetoxy-14β-hydroxy-17β-methyl-5β-androstane (VIII-a) as a white solid.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15]2)C1C=CC=CC=1>C(O)C.[Pd]>[ClH:1].[OH:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15]2
Reactant: CCOC(=O)c1cc2cccc(OCc3ccccc3)c2cc1OCCN1CCCCC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc2cccc(O)c2cc1OCCN1CCCCC1
Yield: 61 %

Procedure:
A solution of 8.8 g (0.019 mole) of ethyl 5-benzyloxy-3-(2-piperidinoethoxy)-2-naphthoate hydrochloride in 240 cc ethanol was treated with 1.0 g of 10 percent palladium on carbon and hydrogenated at room temperature. The reaction mixture was filtered and the solvent removed in vacuo. The residue, weighing 7.5 g on recrystallization from acetonitrile furnished ethyl 5-hydroxy-3-(2-piperidinoethoxy)-2-naphthoatehydrochloride, m.p. 153°-6° C. in 61 percent yield (4.4 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[OH-].[Na+]>O>[N:5]1[CH:6]=[CH:7][C:2]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:3][CH:4]=1
Reactant: Brc1ccncc1
Reactant: C1CNCCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cc(N2CCCNCC2)ccn1
Temperature: 100 °C
Yield: 40.1 %

Procedure:
A mixture of 2 g of 4-bromopyridine and 10 g of homopiperazine is heated at 100° C. for 4 hours. 100 ml of water are added to the reaction mixture and the resulting mixture is basified to pH 10 by addition of 10% NaOH solution and extracted three times with 100 ml of chloroform, the organic phase is dried over Na2SO4 and the solvent is evaporated off under vacuum. 0.9 g of the expected product is obtained.
Reaction SMILES: NC1C(C)=CC(Cl)=CC=1C(NC)=[O:5].ClCCl.[Cl:17][C:18]1[C:19]([N:25]2[C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[N:26]2)=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=1.C(N(CC)CC)C>O>[Cl:17][C:18]1[C:19]([N:25]2[C:29]([C:30]([OH:5])=[O:31])=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[N:26]2)=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: CNC(=O)c1cc(Cl)cc(C)c1N
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 125.7 %

Procedure:
To a 100 mL flask, 2-amino-5-chloro-N,3-dimethylbenzamide (0.24 g, 1.22 mmol), dichloromethane (20 mL), 1-(3,5-dichloropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride (0.42 g, 1.22 mmol) and triethylamine (0.12 g, 1.22 mmol) were added sequentially. The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was washed with saturated sodium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the compound 3 (0.50 g) as a white solid in 81% yield.
Reaction SMILES: C1(COC2C(C3N(CC4C=CC(CCC(O)=O)=CC=4)C4C=C(F)C(F)=CC=4N=3)=CC=CN=2)CC1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46]([CH2:47][CH:48]3CC[CH2:51][CH2:50][CH2:49]3)[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH2:61]C2C=CC=CC=2Cl)[CH:37]=1.BrCCCCC>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH3:61])[CH:37]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3OCc3ccccc3Cl)n(CC3CCCCC3)c2cc1F
Agent: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Solvent: CCCCCBr
Product: CCCCCn1c(-c2ccc(Cl)cc2OC)nc2cc(F)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 1-bromo-pentane (CAS Reg. No. 10-53-2). Brown powder (81%). MS (Turbo Spray): m/z=364.8 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[OH:15][CH2:16][C:17]1[CH:18]=[C:19]([S:23]([C:26]2[CH:27]=[C:28]3[C:33](=[C:34]([CH3:36])[CH:35]=2)[N:32]=[CH:31][C:30]([C:37]([NH2:39])=[O:38])=[C:29]3[NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=2)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>>[CH3:1][S:2]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([C:26]2[CH:27]=[C:28]3[C:33](=[C:34]([CH3:36])[CH:35]=2)[N:32]=[CH:31][C:30]([C:37](=[O:38])[NH2:39])=[C:29]3[NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=2)(=[O:25])=[O:24])[CH:18]=1)(=[O:4])=[O:3]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(CO)c4)cc23)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(COS(C)(=O)=O)c4)cc23)c1
Reaction time: 1 h
Yield: 118.8 %

Procedure:
Methanesulfonyl chloride (0.06 mL, 1.474 mmol) and DIEA (0.243 mL, 1.394 mmol) were added to a stirring solution of Intermediate 134 (330 mg, 0.697 mmol) at rt. The reaction was monitored by LC/MS and additional methanesulfonyl chloride (0.06 mL, 1.474 mmol) and DIEA (0.243 mL, 1.394 mmol) were added after 3 h. The resulting reaction mixture was stirred for an additional 1 h then quenched with satd. NaHCO3 (50 mL). The aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with H2O (100 mL), brine (100 mL), dried over Na2SO4 (s), and concentrated to give the title compound (460 mg) as a yellow solid. The compound was used with no further purification. ES/MS calcd. for C26H26N3O7S2+ 556.1. Found m/z=556.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]1[O:15][N:14]=[C:13]([C:16]([O:18]CC)=[O:17])[CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]1[O:15][N:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc([C@@H](C)NC(=O)OC(C)(C)C)on1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)c1cc(C(=O)O)no1
Reaction time: 1 h
Yield: 44.8 %

Procedure:
To a stirred solution of (R)-tert-butyl but-3-yn-2-ylcarbamate (262.5 g, 1.56 mol) and (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (78.2 g, 0.52 mol) in DMF (1 L) was added dropwise Et3N (216 mL, 1.56 mol) at 90° C. The mixture was stirred for 5 hr, and then concentrated in vacuo. The residue was re-dissolved in ethyl acetate. The ethyl acetate solution was washed with water, dried over Na2SO4, and evaporated to provide the crude compound (R)-ethyl 5-(1-(tert-butoxycarbonylamino)ethyl)isoxazole-3-carboxylate. To a solution of (R)-ethyl 5-(1-(tert-butoxycarbonylamino)ethyl)isoxazole-3-carboxylate in THF (2 L) was added aqueous 2.5 N LiOH (1 L) at RT. The mixture was stirred for 1 hr, and then evaporated under reduced pressure to remove THF. The residue was partitioned between water (1 L) and ethyl acetate (0.5 L). The organic layer was separated and the aqueous layer was extracted with ethyl acetate twice. The aqueous layer was adjusted to pH 2 with 10% HCl and extracted with ethyl acetate (2×1 L). All the organic layers were combined, washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dried under vacuum to give the crude product N.4, (R)-5-(1-(tert-butoxycarbonylamino)ethyl)isoxazole-3-carboxylic acid (55.2 g, 44.8%), which was used without further purification. 1H NMR (CDCl3) δ 6.57 (s, 1H), 4.12 (q, 1H), 1.56 (d, 3 H), 1.37 (s, 9H).
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:7]=1[C:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9].[CH3:22]O>>[OH:5][C:6]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:7]=1[C:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:22])=[O:15])=[O:9]
Reactant: O=C(O)CCCNC(=O)c1cc(O)ccc1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCNC(=O)c1cc(O)ccc1O
Temperature: 25 °C

Procedure:
After dropwise adding 8.5 g (71 mmol) of thionyl chloride to 30 ml of anhydrous methanol at 10° C. during 30 minutes under cooling by ice while stirring, the solution was stirred at the same temperature for additional 45 minutes, then 5.1 g (20 mmol) of 4-[N-(2,5-dihydroxybenzoyl)amino]butyric acid (compound of Example 36) were portionwise added. The reaction mixture was allowed to warm to room temperature and stirred at 80° C. for 8 hours. After filtering the precipitate by and washing with methanol 3.7 g (68%) of the aimed compound were obtained, m.p.: 155°-159° C.