Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.Cl.[C:10]([NH:14][C:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([NH:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:7][C:4]2[S:5][CH:6]=[C:2]([Br:1])[CH:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=Cc1cc(Br)cs1
Reactant: CC(C)(C)NC(=O)C1CCNCC1
Agent: Cl
Product: CC(C)(C)NC(=O)C1CCN(Cc2cc(Br)cs2)CC1

Procedure:
The title compound is prepared according to the reaction 3.01c described above using 4-bromo-thiophene-2-carbaldehyde and piperidine-4-carboxylic acid tert-butylamide hydrochloride as in 3.01c: LC-MS A: tR=0.65 min; [M+H]+=360.95.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([NH:14][S:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:31]I.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([N:14]([CH3:31])[S:15]([C:17]([CH3:20])([CH3:18])[CH3:19])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)cc2)(NS(=O)C(C)(C)C)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(S(=O)C(C)(C)C)C1(Cc2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
To a solution of 4-(4-chlorobenzyl)-4-(2-methylpropane-2-sulfinylamino)-piperidine-1-carboxylic acid tert-butyl ester (205 mg, 0.478 mmol) in DMF (4.8 mL) at 0° C. was added sodium hydride (25 mg of a 60% dispersion in mineral oil, 0.621 mmol). After 15 min methyl iodide (33 □l, 0.526 mmol) was added, and the solution warmed to rt. After 12 h, sodium hydride (120 mg, 60% dispersion in mineral oil, 3.00 mmol) and methyl iodide (165 □l, 2.65 mmol) were added. After 30 min water (20 mL) was added and the solution extracted with ethyl acetate (3×20 mL). Organic extracts were combined, dried over magnesium sulphate and the resulting crude product was purified by silica column chromatography, eluting with 66% ethyl acetate-hexanes, to give the title product as an oil (163 mg, 77%). LC-MS (LCT2) m/z 465 [M+Na+], Rt 8.41 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[CH:2]=1.[H][H]>CC(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[CH:2]=1
Reactant: N#CCCCC#Cc1cccnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: N#CCCCCCc1cccnc1
Reaction time: 48 h
Yield: 81.1 %

Procedure:
A solution of 62.82 g of 6-(3-pyridinyl)-5-hexynenitrile in 500 ml of 2-propanol was hydrogenated over 3.0 g of 10% palladium on carbon at atmospheric pressure. Two additional 3.0 g charges of catalyst were added as the rate of hydrogen uptake slowed. After two days, the reaction mixture was filtered, concentrated, the residue was evaporatively distilled and the distillate was dissolved in 300 ml of 2-propanol and was reduced over 3.0 g of 10% palladium on carbon. Filtration, evaporation, and distillation gave 52.15 g (82%) of 6-(3-pyridinyl)hexanenitrile, bp 150°/0.3 mm which gave a main peak consisting of 93% of the total by gas chromatography analysis. A portion was further purified by silica gel chromatography eluting with 1:1 ethyl acetate-hexane containing 1% triethyl amine and was evaporatively distilled to give an analytical sample.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:21]=[CH:20][C:9]([CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[OH:19])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[CH3:22]I.O>CN(C=O)C>[CH:3]([C:6]1[CH:21]=[CH:20][C:9]([CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[O:19][CH3:22])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)cc(C)c1Cc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a mixed solution of sodium hydride (a 60% liquid paraffin dispersion, 757 mg, 18.9 mmol) in DMF (50 mL) was added dropwise 2-(4-isopropylbenzyl)-3,5-dimethylphenol obtained in Reference Example 148 (4.01 g, 15.8 mmol) in DMF (15 mL) under argon atmosphere at 0° C., and the mixture was stirred for 30 minutes. To the reaction solution was added dropwise a solution of methyl iodide (2.69 mL, 18.9 mmol) in DMF (8 mL) at the same temperature, and the mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature, water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain 3.49 g (yield 82%) of the title compound. Oily matter.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[C:22](=[O:23])[C:21]2[C:16](=[N:17][C:18](Cl)=[CH:19][CH:20]=2)[N:15]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH:14]=1)=[O:12])[CH3:9].Cl.Cl.[CH3:32][O:33][C@H:34]1[C@H:38]([NH:39][CH3:40])[CH2:37][NH:36][CH2:35]1>C(#N)C>[CH2:8]([O:10][C:11]([C:13]1[C:22](=[O:23])[C:21]2[C:16](=[N:17][C:18]([N:36]3[CH2:37][C@@H:38]([NH:39][CH3:40])[C@H:34]([O:33][CH3:32])[CH2:35]3)=[CH:19][CH:20]=2)[N:15]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH:14]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cn(-c2nccs2)c2nc(Cl)ccc2c1=O
Reactant: CN[C@@H]1CNC[C@H]1OC
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2nccs2)c2nc(N3C[C@@H](NC)[C@H](OC)C3)ccc2c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.2 %

Procedure:
Triethylamine (18 ml) was added to a suspension composed of 7-chloro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester (7.1 g) obtained in Example A-1 (4), trans-3-methoxy-4-methylaminopyrrolidine dihydrochloride (6.0 g) and acetonitrile (150 ml). The resulting reaction mixture was stirred at room temperature for 5 hours, and was then concentrated under reduced pressure. Then, an aqueous solution of sodium hydrogencarbonate was added, and the resultant mixture was extracted with chloroform. After the obtained extract was dried over anhydrous sodium sulfate, solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel column chromatography (eluent chloroform:methanol=6:1), and thus, there was obtained 1,4-dihydro-7-(trans-3-methoxy-4-methylamino-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester (6.1 g).
Reaction SMILES: O[CH2:2][C:3]12[CH2:11][CH:7]3[CH2:8][CH:9]([CH2:10]1)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH2:6]3)[CH2:4]2.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[O:25]=[C:23]1[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:30])[N:24]1[CH2:2][C:3]12[CH2:11][CH:7]3[CH2:6][C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])([CH2:4]1)[CH:9]([CH2:8]3)[CH2:10]2
Reactant: CC(C)(C)OC(=O)NC12CC3CC1CC(CO)(C3)C2
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC12CC3CC1CC(CN1C(=O)c4ccccc4C1=O)(C3)C2
Temperature: 90 °C
Yield: 45.4 %

Procedure:
To a stirred solution of tert-butyl [1-(hydroxymethyl)tricyclo[3.3.1.03,7]non-3-yl]carbamate (as obtained in step VI preparation 3) (0.67 g, 2.5 mmol) in toluene (10 mL) was added phthalimide (0.52 g, 3.5 mmol), triphenylphosphine (1.05 g, 4.0 mmol), and diisopropylazodicarboxylate (0.8 mL, 4.0 mmol). The reaction mixture was heated to 90° C. for 4 h. The volatiles were removed under reduced pressure and the residue was purified by column chromatography to obtain tert-butyl [2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]carbamate (0.45 g) as a viscous liquid in 46% yield. m/z (M+1) 397; 1H NMR (CDCl3) 300 MHz δ 7.90-7.80 (m, 2H), 7.77-7.68 (m, 2H), 4.75 (s (br), 1H), 3.60 (s, 2H), 2.47-2.35 (m, 1H), 2.36-2.29 (m, 1H), 2.02-1.84 (m, 4H), 1.77-1.65 (m, 2H), 1.64-1.35 (m, 5H), 1.41 (s, 9H), 1.34-1.24 (m, 1H).
Reaction SMILES: Cl[CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].[C:7]([OH:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C>[C:7]([O:15][CH:2]([CH3:6])[C:3](=[O:5])[CH3:4])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)C(C)Cl
Reactant: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)C(C)OC(=O)c1ccccc1

Procedure:
A mixture of 3-chlorobutanone (10.6 g), benzoic acid (15.0 g), triethylamine (30 ml) and acetonitrile (100 ml) was heated under reflux for 1 hour 30 minutes. The mixture was cooled and filtered to remove precipitated triethylamine hydrochloride. The acetonitrile was removed from the filtrate under reduced pressure and the residue dissolved in ethyl acetate and washed with water. The organic extracts were dried over magnesium sulphate, filtered over active carbon and the solvent was removed from the filtrate under reduced pressure, to give a yellow oil of 3-benzoyloxybutan-2-one. Yield 16.7 g. The oil was used directly without further purification in the next step.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[C:9]([O:33][CH3:34])=[N:10][CH:11]=[CH:12][C:13]=1[C:14]([OH:32])([CH2:30][CH3:31])[CH2:15][C:16](N1[C@H](C2C=CC=CC=2)COC1=O)=[O:17])(C)(C)C.[Li+].[OH-:38].OO.[OH-].[Na+]>C1COCC1>[OH:32][C@:14]([C:13]1[CH:12]=[CH:11][N:10]=[C:9]([O:33][CH3:34])[C:8]=1[CH2:7][OH:6])([CH2:30][CH3:31])[CH2:15][C:16]([OH:17])=[O:38]
Reactant: [OH-]
Reactant: CCC(O)(CC(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccnc(OC)c1C(C)(C)O[SiH2]C(C)(C)C
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@](O)(CC(=O)O)c1ccnc(OC)c1CO
Reaction time: 0.5 h

Procedure:
To a solution of 3.11 g (R)-3-{3-[3-(tert-butyl-dimethyl-silanyloxymethyl)-2-methoxy-pyridin-4-yl]-3-hydroxy-pentanoyl}-4-phenyl-oxazolidin-2-one (6.04 mmol), as obtainable from example 18, in 35 mL THF were added at 0° C. 37.8 mL aqueous LiOH solution (0.8 M, 30.2 mmol, 5.0 eq) and 3.02 mL aqueous H2O2 solution (10.0 M, 30.2 mmol, 5.0 eq). After 30 min, 220 mL aqueous NaOH solution (2 M) were added and the ice bath was removed. The reaction was monitored by HPLC. After 2 h (<0.2% area (R)-3-{3-[3-(tert-butyl-dimethyl-silanyloxymethyl)-2-methoxy-pyridin-4-yl]-3-hydroxy-pentanoyl}-4-phenyl-oxazolidin-2-one), the resulting emulsion was extracted 7 times with 100 mL, in total 700 mL TBME. The aqueous phase was acidified with aqueous HCl in order to adjust pH 3.0 and extracted nine times with 100 mL, in total 900 mL dichloromethane/ethanol (4:1). After evaporation in a rotary evaporator (40° C., 5 mbar), the title product was obtained as a colorless semisolid (700 mg, 2.74 mmol, yield of 45% w/w, or 85% when calculated over the two steps) and in a purity of 89.2% as determined by HPLC (er=80.47:19.53, see Chiral HPLC method below).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[CH2:4][S:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][CH:9]=1)[CH3:7].[OH:23]O.C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:22][N:2]([CH3:1])[C:3](=[O:21])[CH2:4][S:5]([CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][CH:9]=1)[CH3:7])=[O:23]
Reactant: CC(SCC(=O)N(C)C)c1ccc(-c2ccccc2F)cc1
Reactant: OO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)N(C)C
Yield: 57 %

Procedure:
The difficultly soluble isomer of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid dimethylamide was prepared analogous to Example 51 from [1-(2'-fluoro-4 -biphenylyl)-ethylthio]-acetic acid dimethylamide by oxidation with hydrogen peroxide in glacial acetic acid. Yield: 57% of theory; m.p. 131°-133° C (from toluene)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH:11]1([NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>O.CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]([CH:11]2[CH2:12][CH2:13]2)[CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)CCCNC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CCCN(c1ccc(Br)cc1C=O)C1CC1
Yield: 23 %

Procedure:
5-bromo-2-fluorobenzaldehyde (20 g), t-butyl N-cyclopropyl-4-aminobutyrate (14.5 g), sodium carbonate (13.8 g), water (70 ml) and DMSO (70 ml) were heated at 80° C. for 5 days and at 110° C. for 3 days, which was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give t-butyl N-(4-bromo-2-formylphenyl)-N-cyclopropyl-4-aminobutyrate (6.4 g) as red oil.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)([O-:19])=[O:18].CS(O)(=O)=O.C>C(O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:24]([C:23]4[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: C
Agent: CS(=O)(=O)O
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc([N+](=O)[O-])cc3)nc(=O)c1-2
Reaction time: 6 h
Yield: 16.7 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (2.0 g, 9 mmol), 4-nitrobenzaldehyde (2.04 g, 13.5 mmol), methanesulfonic acid (0.25 ml) and xylenes (50 ml) was heated at reflux overnight, followed by an additional 6 hours. Ethanol (200 ml) was added to the reaction mixture, which was then refluxed and then treated with DARCO®. The reaction mixture was filtered, concentrated to 100 ml and then cooled. Yellow needles formed, which were collected by filtration and washed with ether to afford 0.53 g (17%) of 1-cyclopentyl-3-ethyl-6-(4-nitrophenyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 321-323° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[NH:10][C:9](=[O:18])[N:8]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:7]2=[O:24])([O-])=O>[Pd].CCO.CC(O)=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[C:14]([F:16])([F:15])[F:17])[NH:10][C:9](=[O:18])[N:8]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:7]2=[O:24]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c([N+](=O)[O-])cc2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(N)cc2c1=O
Yield: 60.9 %

Procedure:
A solution of N-(6-nitro-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (109 mg) in 1:1 EtOH:CH3CO2H (6 mL) was hydrogenated in the presence of 10% palladium on carbon (30 mg). After disappearance of the starting material (TLC control), the reaction mixture was diluted with EtOH and CH3CO2H and slightly warmed up. The catalyst was filtered off and the filtrate concentrated to dryness. Trituration of the residue with EtOAc gave N-(6-amino-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (61 mg, 61%) as a yellow powder, m.p. 240° C. (decomp.). 1H-NMR (DMSO-d6, 400 MHz): 3.12 (s, 3H), 5.66 (s, 2H), 7.24 (s, 1H), 7.46 (s, 1H), 10.3 (br s, 1H), 11.4 (br s, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8]([CH3:10])=[N:9][C:5]=2[CH:4]=1.[N:13]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl>[CH3:10][C:8]1[NH:7][C:6]2[CH:11]=[CH:12][C:3]([NH:2][NH2:13])=[CH:4][C:5]=2[N:9]=1
Reactant: O=N[O-]
Reactant: Cc1nc2cc(N)ccc2[nH]1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1nc2cc(NN)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
5-Amino-2-methyl-1H-benzimidazol hydrochloride (16.51 g) was dissolved in concentrated hydrochloric acid (200 ml), and this was cooled to 0° C. An aqueous solution (15 ml) of sodium nitrite (7.59 g) was added dropwise thereto at 0° C. over 20 minutes. This was stirred for 20 minutes. Then, a concentrated hydrochloric acid solution (20 ml) of tin (II) chloride dihydrate (55.7 g) was added dropwise thereto at 0° C. over one hour, and then this was stirred for 30 minutes. The precipitated solid was collected by filtration, and washed with water, and dried. Thus, crude (2-methyl-1H-benzimidazol-5-yl)-hydrazine dihydrochlide was obtained.
Reaction SMILES: [N:1]1([CH:11]=[O:12])[C:8]2[N:4]([N:5]=[CH:6][C:7]=2[CH:9]=O)[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19]>>[N+:18](/[CH:21]=[CH:9]/[C:7]1[CH:6]=[N:5][N:4]2[CH2:3][CH2:2][N:1]([CH:11]=[O:12])[C:8]=12)([O-:20])=[O:19]
Reactant: O=Cc1cnn2c1N(C=O)CC2
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=CN1CCn2ncc(/C=C/[N+](=O)[O-])c21

Procedure:
A solution of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1,7-dicarbaldehyde (1 g) and ammonium acetate (653 mg) in nitromethane (20 ml) was refluxed for 4 hours. The reaction mixture was evaporated under reduced pressure and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 7-[(E)-2-nitroethenyl]-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-1-carbaldehyde (1.00 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH2:37].[N:39]([CH2:42][C:43]1[O:44][CH:45]=[CH:46][CH:47]=1)=[C:40]=[O:41]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:40]([NH:39][CH2:42][C:43]1[O:44][CH:45]=[CH:46][CH:47]=1)=[O:41]
Reactant: Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=NCc1ccco1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccco1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 34 %

Procedure:
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine bis(trifluoroacetate) and 2-(isocyanatomethyl)furan as the starting materials in 34% yield. LCMS for C23H21ClN7O2(M+H)+: m/z=462.1. 1H NMR (400 MHz, DMSO-d6): δ 9.96 (s, 1H), 9.31 (s, 1H), 8.97 (m, 1H), 8.30 (m, 2H), 8.18 (s, 1H), 7.89 (m, 1H), 7.71 (d, 1H), 7.60 (d, 1H), 7.56 (d, 1H), 6.95-7.02 (m, 2H), 6.41 (dd, 1H), 6.28 (dd, 1H), 4.29 (d, 2H), 2.96 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[O:5][N:4]=[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]=1[CH:18]=[CH2:19]
Reactant: CCOC(=O)c1noc(-c2ccccn2)c1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=Cc1c(C(=O)OCC)noc1-c1ccccn1
Yield: 414.3 %

Procedure:
A solution of ethyl 4-bromo-5-(pyridin-2-yl)isoxazole-3-carboxylate (2-C) (170 mg, 0.572 mmol), tributyl(vinyl)tin (0.504 mL, 1.72 mmol), dichlorobis(triphenylphosphine)-palladium(II) (24.1 mg, 0.034 mmol), and 1-butyl-3-methylimidazolium hexafluorophosphate (0.012 mL, 0.057 mmol) in dioxane (3 mL) was heated to 170° C. via microwave for 120 minutes. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (10 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. Concentration gave a crude product which was purified by silica gel chromatography with hexanes/ethyl acetate (4/1) to give ethyl 5-(pyridin-2-yl)-4-vinylisoxazole-3-carboxylate (60 mg, 2.37 mmol, 41% yield). The compound had an HPLC retention time=2.80 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH—90% Water—0.2% H3PO4; Solvent B=90% MeOH—10% water—0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=245.2. 1H NMR (400 MHz, MeOD) δ ppm 1.42 (t, 3H), 4.47 (q, J=7.19 Hz, 2H), 5.49 (dd, J=11.80, 1.25 Hz, 1H), 5.85 (dd, J=18.07, 1.51 Hz, 1H), 7.26 (dd, J=18.07, 11.80 Hz, 1H), 7.51 (ddd, J=7.03, 5.02, 1.76 Hz, 1H), 7.93-8.02 (m, 2H), and 8.72-8.75 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Br[CH2:34][C:35]([NH2:37])=[O:36].[Br-]>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)[CH2:34][C:35]([NH2:37])=[O:36])=[CH:4][CH:3]=1
Reactant: NC(=O)CBr
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)cc4)CC3)cc2o1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CN(CCCc1ccc(F)cc1)C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 19.1 %

Procedure:
To a stirred suspension of 6-{trans-4-[3-(4-fluorophenyl)propylamino]-cyclohexyl}-3H-benzoxazol-2-one (110 mg, 0.81 mmol) in DMF (15 mL) was added NaHCO3 (140 mg, 1.6 mmol) and bromoacetamide (300 mg, 0.74 mmol). After 16 hours the reaction mixture was warmed to 50° C. After 4 hours, additional bromide (150 mg, 0.37 mmol) and NaHCO3 (31 mg, 0.37 mmol) were added, and the temperature was increased to 75° C. After 4 hours, the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organics were washed with water, saturated NaCl, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 95:4.75:0.25 CH2Cl2:MeOH:NH4OH) followed by conversion to the HCl salt gave compound 2-{[3-(4-fluorophenyl)propyl]-[4-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-cyclohexyl]amino}acetamide (60 mg, 17%), as a white solid: mp 266-270° C.; IR (KBr): 3331, 3149, 2943, 1762, 1691 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 11.47 (s, 1H), 9.08 (br s, 1H), 7.96 (br s, 1H), 7.73 (br s, 1H), 7.29-7.25 (m, 2H), 7.17-7.01 (m, 3H), 6.99 (s, 2H), 4.05-4.02 (m, 1H), 3.81-3.78 (m, 1H), 3.47-3.38 (m, 1H), 3.22-3.12 (m, 3H), 2.63 (t, J=8 Hz, 2H), 2.57-2.52 (m, 1H), 2.14-1.87 (m, 6H), 1.71-1.49 (m, 4H); ESI-MS (m/z): 426 [M+H]+; HPLC: method A, 5.44 minutes (98.0%); HPLC: method E, 6.50 minutes (>99%); Anal. Calcd for C24H28FN3O3.HCl: C, 61.80; H, 6.37; N, 9.01. Found: C, 61.78; H, 6.27; N, 8.80.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[CH2:14](O)[CH2:15][OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:15]1[O:16][C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)([CH2:4][CH2:3][CH2:2][Cl:1])[O:6][CH2:14]1
Reactant: OCCO
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Fc1ccc(C2(CCCCl)OCCO2)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of γ-chloro-p-fluorobutyrophenone (50 g. 025 mole, commercially available); ethylene glycol (50 mL); p-toluene sulfonic acid (0.1 g) in 300 mL benzene is refluxed for 18 h with water of reaction being removed by means of a Dean Stark water trap. Upon cooling to room temperature, the reaction mixture is washed with dilute sodium bicarbonate, dried (MgSO4), filtered and the benzene removed by concentration in vacuo. The residual oil was distilled to give 57.7 g (93%) of product, b.p. 106-112/0.01 Torr.