Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[N:13][CH:14]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:15][O:16][S:24]([CH3:27])(=[O:26])=[O:25])[CH:12]=[N:13][CH:14]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2cncc(CO)c2)OCCO1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2cncc(COS(C)(=O)=O)c2)OCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-3-yl]-methanol (195 mg, 1.00 mmol) in dry CH2Cl2 (5.0 mL) was treated at 0° C. with Et3N (0.18 mL, 1.29 mmol) followed by DMAP (12 mg, 0.10 mmol) and Ms-Cl (0.10 mL, 1.26 mmol). After stirring at 0° C. for 2 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a pale yellow oil. LC-MS-conditions 02: tR=0.66 min; [M+H]+=274.27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][CH2:14][O:15][CH2:16]Cl.C(OCC)C.[H-].[Na+].CN1CCCC1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:12][CH2:13][CH2:14][O:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: ClCCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: N#CC1(c2ccc(Cl)cc2)CCCOC1
Reaction time: 12 h

Procedure:
A mixture of 2-(4-chlorophenyl)acetonitrile (73 g, 483 mmol) and 1-chloro-3-(chloromethoxy)propane (69.1 g, 483 mmol) in ethoxyethane (242 mL, 483 mmol) was added dropwise to a mixture of NaH (57 g, 1437 mmol) in 1-methylpyrrolidin-2-one (1208 mL, 483 mmol) at −20° C. The reaction was stirred for 12 hours and then slowly quenched with H2O. The reaction mixture was extracted with ether (5×), and the combined organic layers were washed with H2O (3×) and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo to give the desired nitrile as a yellow oil. MS m/e=223.2 (M+H)+.
Reaction SMILES: [CH:1]([N:4]([CH2:8][CH2:9][NH2:10])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[OH:11][C:12]1[CH:27]=[CH:26][C:15]([C:16](=O)[CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=O)=[CH:14][CH:13]=1>C(O)(=O)C.O.Cl>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[CH2:8][CH2:9][N:10]1[C:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=2[CH:17]=[C:16]1[C:15]1[CH:14]=[CH:13][C:12]([OH:11])=[CH:27][CH:26]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N(CCN)C(C)C
Reactant: O=C(CC1CCCCC1=O)c1ccc(O)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)N(CCn1c(-c2ccc(O)cc2)cc2c1CCCC2)C(C)C
Temperature: 25 °C

Procedure:
A solution of 5.77 g (0.04 mole) of diisopropylaminoethylamine and 9.3 g (0.04 mole) of 2-(p-hydroxyphenacyl) cyclohexanone in glacial acetic acid is refluxed under nitrogen for 14 hours, then cooled to ambient temperature and diluted with water and dilute hydrochloric acid. The aqueous solution is washed with ether, basified with 10% sodium carbonate and extracted with ether. After drying the ether solution over magnesium sulfate, the ether is removed to give a pale yellow solid. The solid is recrystallized from an ether-petroleum ether mixture to give pale yellow crystals of 1-(2-diisopropylaminoethyl)-2-(p-hydroxyphenyl)-4,5,6,7-tetrahydroindole as pale yellow crystals, m.p. 112°-114.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10](=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:22]I>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10](=[O:21])[C:9]=2[CH3:22])=[CH:6][CH:7]=1
Reactant: CI
Reactant: COc1ccc(N2CC(c3ccc(F)cc3)=CC2=O)cc1
Product: COc1ccc(N2CC(c3ccc(F)cc3)=C(C)C2=O)cc1

Procedure:
In a manner similar to that described in Preparation 4, 4-(4-fluorophenyl)-1,5-dihydro-1-(4-methoxyphenyl)-2H-pyrrol-2-one is reacted with methyl iodide to give the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]2)([OH:3])=[O:2].[OH:27]O>>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]2)=[O:27])([OH:3])=[O:2]
Reactant: OO
Reactant: O=C1CCc2cc(OCCCCSc3ccccc3C(=O)O)ccc2N1
Product: O=C1CCc2cc(OCCCCS(=O)c3ccccc3C(=O)O)ccc2N1
Yield: 77.2 %

Procedure:
Prepared analogous to Example 123 from 6-[4-(2-carboxyphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide. M.p.: 194°-196° C. Yield: 77.2% of theory.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3](=[O:14])[C@H:4]([CH3:13])[NH:5]C(OC(C)(C)C)=O.[ClH:16].CCOC(C)=O>CCOC(C)=O>[ClH:16].[CH3:1][N:2]([CH3:15])[C:3](=[O:14])[C@H:4]([CH3:13])[NH2:5]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](N)C(=O)N(C)C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of Boc-L-alanine N,N-dimethyl amide (250 mg, 1.1 mmol) in EtOAc (1 mL) was added HCl/EtOAc (4M, 3 mL) at 0° C. The solution was kept at room temperature for 30 min, and then concentrated under reduced pressure to give L-alanine N,N-dimethyl amide hydrochloride as a white solid (176 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](O)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[CH:34]([NH2:37])([CH3:36])[CH3:35].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:24])[NH:37][CH:34]([CH3:36])[CH3:35])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Reactant: CC(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)NC(C)C
Yield: 74.2 %

Procedure:
The same operation as in Example (247a) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (50a) (300 mg, 0.60 mmol), isopropylamine (0.10 mL, 1.20 mmol), WSC hydrochloride (345 mg, 1.80 mmol) and 1-hydroxybenzotriazole (81 mg, 0.60 mmol), to obtain 241 mg of the title compound as a white solid (74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][C:24]#[N:25])[CH:5]=[CH:6][CH:7]=1.[N-:26]=[N+:27]=[N-:28].[Na+].Cl.C(N(CC)CC)C.Cl>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCn1c(=O)c(CCC#N)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCn1c(=O)c(CCc2nnn[nH]2)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 130 °C
Reaction time: 20 h
Yield: 16.5 %

Procedure:
A mixture of 700 mg of 4-(3-chlorophenyl)-3-(2-cyanoethyl)-1-ethyl-7-methyl-1,8-naphthyridin-2-(1H)-one, 388 mg of sodium azide, 411 mg of triethylamine hydrochloride and 10 ml of 1-methylpyrrolidin-2-one were stirred at 130° C. for 20 hours. The reaction mixture was cooled to room temperature, acidified by adding 1M hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine and the solvent was evaporated. The residue was purified by a silica gel column chromatography (hexane-ethyl acetate) and then recrystallized from ethyl acetate-diisopropyl ether to obtain 130 mg of 4-(3-chlorophenyl)-1-ethyl-7-methyl-3-[2-(1H-tetrazol-5-yl)ethyl]-1,8-naphthyridin-2(1H)-one as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[C:6]([Sn](CCCC)(CCCC)CCCC)=[CH:5][CH:4]=1.I[C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].[F-].[NH4+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)C>[CH2:34]([O:33][C:31]([C:30]1[CH:36]=[CH:37][C:27]([C:6]2[C:7]3[O:12][CH2:11][CH2:10][O:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:28][CH:29]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)c2c1OCCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccc(OC)c3c2OCCO3)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
Compound 187a (0.93 g) obtained in Step A, ethyl 4-iodobenzoate (0.34 ml), palladium acetate (0.05 g), and sodium carbonate (0.54 g) were dissolved in DMF (10 ml), followed by stirring for 6 hours at 60° C. The reaction solution was mixed with an aqueous ammonium fluoride solution and diethyl ether, and then, filtered with Celite. The organic layer was extracted from the resultant, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate anhydride, and evaporated under reduced pressure for removing the solvent. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give Compound 187 (0.30 g, 50%) as colorless crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].[Cl:19][C:20]1[C:21]([C:30]([F:33])([F:32])[F:31])=[N:22][N:23]([CH2:26][C:27](O)=[O:28])[C:24]=1[CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[CH3:2][O:3][C:4]([C:6]1([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:7][CH2:8][N:9]([C:27](=[O:28])[CH2:26][N:23]2[C:24]([CH3:25])=[C:20]([Cl:19])[C:21]([C:30]([F:33])([F:32])[F:31])=[N:22]2)[CH2:10][CH2:11]1)=[O:5]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: COC(=O)C1(c2ccc(Cl)cc2)CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: COC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 25 mL flask was added 4-(4-chloro-phenyl)-piperidine-4-carboxylic acid methyl ester hydrochloride (1.87 mmol, 1.0 equiv), 453 mg of (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (1.87 mmol, 1.00 equiv), 990 mg BOP (2.24 mmol, 1.2 equiv), 1.04 mL TEA (7.46 mmol, 4.00 equiv) and 10 mL NMP. A stir bar was placed in the flask and the reaction mixture was stirred overnight at room temperature under N2 atmosphere. The crude product was purified by normal phase HPLC (EtOAc-hexane as the eluent) to yield 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid methyl ester: MS (ES) M+H expected=478.1, found=478.3.
Reaction SMILES: Cl[Si:2]([CH3:10])([CH3:9])[CH2:3][CH2:4][Si:5](Cl)([CH3:7])[CH3:6].[NH2:11][CH:12]1[C:33](=[O:34])[N:14]2[C:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[C:16]([Cl:19])[CH2:17][S:18][C@H:13]12.C(N(CC)CC)C>C(Cl)Cl>[Cl:19][C:16]1[CH2:17][S:18][C@@H:13]2[CH:12]([N:11]3[Si:5]([CH3:7])([CH3:6])[CH2:4][CH2:3][Si:2]3([CH3:10])[CH3:9])[C:33](=[O:34])[N:14]2[C:15]=1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21]
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si]1(C)CC[Si](C)(C)N1C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Temperature: 25 °C

Procedure:
A solution of 1,2-bis(chlorodimethylsilyl)ethane (3.2 g) in methylene chloride (20 ml) was added to a stirred mixture of p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (5.0 g) and triethylamine (4.9 ml) in methylene chloride (25 ml) under a nitrogen atmosphere. The mixture was stirred at reflux for 16 hours, then allowed to cool to room temperature, and washed with 8% aqueous sodium hydrogen phosphate solution. The organic layer was separated, dried with magnesium sulphate, and evaporated under reduced pressure to give the title compound as a gum, nmr (CDCl3) δ 0.17 (s, 12H), 0.78 (s, 4H), 3.38+3.82 (ABq, J=18 Hz, 2H), 4.76 (d, J=4 Hz, 1H), 4.93 (d, J=4 Hz, 1H), 5.28 (s, 2H), 7.3-8.1 (m, 4H).
Reaction SMILES: [O-]CC.[Na+].Cl.[NH2:6][C:7]([NH2:9])=[NH:8].ClCCl.[CH2:13]([O:15][C:16](=[O:27])[C:17]([C:21](=O)[C:22]([F:25])([F:24])[F:23])=[CH:18]OC)[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[C:21]([C:22]([F:23])([F:24])[F:25])=[N:8][C:7]([NH2:9])=[N:6][CH:18]=1)=[O:27])[CH3:14]
Reactant: N=C(N)N
Reactant: CCOC(=O)C(=COC)C(=O)C(F)(F)F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cnc(N)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Sodium ethoxide (2 eq, 83.8 mmol, 5.7 g) was added in one portion to a solution of guanidine hydrochloride (4 g, 41.9 mmol) in absolute ethanol (100 ml) and the resulting mixture was stirred at ambient temperature for 1 hour. A dichloromethane solution of 3-methoxy-2-(2,2,2-trifluoro-acetyl)-acrylic acid ethyl ester was then added and the mixture was stirred at ambient temperature for an additional 20 hours. The solvent was then removed by evaporation, water was added to the residue, and the mixture was stirred vigorously for 2 hours then allowed to stand at room temperature. The resulting solid was isolated by filtration, washed with water then dried in vacuo to afford 6.10 g (62% yield) of 2-amino-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl ester. m/z (M+H)=236.2.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1>C(O)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:14][CH2:15][NH:16]2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccnc(Cc2ccc(F)cc2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(Cc2ccc(F)cc2)C1
Yield: 73.6 %

Procedure:
Methyl 2-(4-fluorobenzyl)isonicotinate (5.06 g, 20.63 mmol) was dissolved in acetic acid (50 mL) and platinum(IV) oxide (0.234 g, 1.03 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator overnight at room temperature and 5 bar. The catalyst was filtered off and washed with MeOH and the eluate evaporated. DCM and 10% K2CO3 were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield methyl 2-(4-fluorobenzyl)piperidine-4-carboxylate (3.816 g, 73.6%) as a yellow oil. MS m/z 252 (M+H)+
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:16][CH2:17]1)([O-:10])=[O:9]
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)N1CCC(Nc2ccccc2[N+](=O)[O-])CC1
Temperature: 100 °C

Procedure:
A suspension of 2-fluoronitrobenzene (3.52 g, 25 mmol), 4-amino-1-(phenylmethyloxycarbonyl)piperidine† (4.0 g, 17 mmol) and potassium carbonate (64 g, 19 mmol) in DMSO (25 ml) was heated to 100° C. After 5 h the mixture was poured into ice/water and the resulting yellow solid was collected by filtration and washed with water. The solid was dried to give the title compound as a yellow solid (5.69 g, 16 mmol); NMR: 1.6 (m, 2H), 2.1 (d, 2H), 3.1 (t, 2H), 3.7 (m, 1H), 4.1 (d, 2H), 5.2 (s, 2H), 6.7 (t, 1H), 6.9 (d, 1H), 7.3-7.5 (m, 6H), 8.1 (d, 1H) and 8.2 (dd, 1H); MS: 356.
Reaction SMILES: C1C=C(SSC2N=CC=CC=2)N=CC=1.C(N(CC)CC)C.[SH:22][CH2:23][C:24]([OH:26])=[O:25].[CH2:27]([SH:31])[CH:28]([CH3:30])[CH3:29]>O1CCCC1.CCOCC>[CH2:27]([S:31][S:22][CH2:23][C:24]([OH:26])=[O:25])[CH:28]([CH3:30])[CH3:29]
Reactant: O=C(O)CS
Reactant: CC(C)CS
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)CSSCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 11 g (50 mmol) of 2-,2′-dipyridyl disulfide and 10.5 mL (75 mmol) of triethyl amine in 100 mL of tetrahydrofuran at 0° C. as added 3.5 mL (50 mmol) of mercaptoacetic acid in 5 mL of tetrahydrofuran. The ice bath was removed and after one hour 5.5 mL (50 mmol) iso-butyl thiol was added. The reaction was allowed to stir overnight at ambient temperature before diluting with ether and washing three times with 1N aqueous HCl. The product was then extracted into 10% aqueous NaOH. The aqueous phase was washed twice with ether and then acidified with HCl to pH ˜3.5. The product was extracted with ether, dried with Na2SO4, filtered and evaporated under reduced pressure to give a crude product. This material was distilled by Kugelrohr distillation to give 3.0 g (17 mmol, 33%) of partially purified product. This material was used in the next step without further purification.
Reaction SMILES: I.[NH:2]1[CH2:7][CH2:6][CH2:5][N:4]=[C:3]1[NH:8][NH2:9].Cl.[C:11](Cl)(=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[N:15]1[CH:16]=[CH:17][C:12]([C:11]2[N:4]3[CH2:5][CH2:6][CH2:7][NH:2][C:3]3=[N:8][N:9]=2)=[CH:13][CH:14]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: NNC1=NCCCN1
Agent: Cl
Agent: I
Solvent: c1ccncc1
Product: c1cc(-c2nnc3n2CCCN3)ccn1
Yield: 13.3 %

Procedure:
A solution of 750 mg (3.1 mmol) (1,4,5,6-tetrahydro-pyrimidin-2-yl)-hydrazine hydroiodide (ref. Krezel, Izabella; Pharmazie; EN; 49; 1; 1994; 27-31) and 552 mg (3.1 mmol) isonicotinoyl chloride hydrochloride in 3 ml pyridine was heated at 120° C. over night. The reaction mixture was cooled and diluted with K2CO3(sat) and extracted with 3×10 ml chloroform. The combined organic extracts were dried and concentrated. Flashchromatography (CH2Cl2/MeOH 10:1) afforded 83 mg (18%) of a white solid. 1H NMR (CDCl3), d (ppm): 1.91 (m, 2 H) 3.24 (m, 2 H) 4.13 (m, 2 H) 7.67 (m, 2 H) 8.65 (m, 2 H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[BH4-].[Na+].Cl>CC(O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([OH:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCCC(=O)c1ccc(CC(C)C)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CCCCCC(O)c1ccc(CC(C)C)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
To a solution of 4'-isobutylhexanophenone (10.5 g) in 2-propanol (60 ml) was added sodium borohydride (2.05 g), and the mixture was stirred at 50° C. for 6 hours. The mixture was poured into ice water and acidified with 6N hydrochloric acid. The aqueous solution was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over magnesium sulfate and evaporated to give 1-(4-isobutylphenyl)hexan-1-ol (9.32 g) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:34])[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([NH:14][C:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[O:17][C:16]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)=[O:25])=[O:13])[CH2:8][CH2:7]1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:42]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:34])[C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]([NH:14][C:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[O:17][C:16]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)=[O:25])=[O:13])[CH2:10][CH2:11]1)(=[O:44])[CH3:43]
Reactant: CC(=O)Cl
Reactant: CN(CCCN)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cccnc23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3cccnc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[({Trans-4-[(3-aminopropyl)(methyl)amino]cyclohexyl}-carbonyl)amino]-N-(5-chloropyridin-2-yl)furo[3,2-b]pyridine-2-carboxamide (113 mg) obtained in Example 121 and triethylamine (65 μl) are dissolved in chloroform (5 ml), and thereto is added acetyl chloride (25 μl) under ice-cooling. The mixture is warmed to room temperature and stirred for 1 hour. To the reaction solution is poured saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: ethyl acetate followed by ethyl acetate/methanol=10/1). The resulting solid is suspended in n-hexane-diisopropyl ether, and collected by filtration to give the title compound (90 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:15]=NC2C(Br)=CC=CC=2Br)[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[C:33]([F:34])=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:28]=1[NH2:29].C(C1C(O)=C(C=C(C(C)(C)C)C=1)C=O)(C)(C)C>>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:15]=[N:29][C:28]2[C:27]([F:26])=[C:33]([F:34])[C:32]([F:35])=[C:31]([F:36])[C:30]=2[F:37])[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)(C)c1cc(C=Nc2c(Br)cccc2Br)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Product: CC(C)(C)c1cc(C=Nc2c(F)c(F)c(F)c(F)c2F)c(O)c(C(C)(C)C)c1

Procedure:
Employing an analogous procedure to that described above for the synthesis of 2,4-bis(tert-butyl)-6-[[(2,6-dibromophenyl)imino]methyl]phenol, 2,3,4,5,6-pentafluoroaniline (0.54 g, 2.9 mmol) was added to 3,5-di-tert-butyl-2-hydroxybenzaldehyde (0.70 g, 2.9 mmol). The product was purified by recrystallisation from hot MeOH and isolated as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([NH2:14])=O)[CH2:8][CH2:7]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:14][CH2:12][CH:9]1[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][C:2]([F:16])([F:1])[F:15])[CH2:7][CH2:8]1
Reactant: NC(=O)C1CCN(CCCC(F)(F)F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC1CCN(CCCC(F)(F)F)CC1
Yield: 98.6 %

Procedure:
Prepared from 1-(4,4,4-trifluorobutyl)-piperidine-4-carboxamide (0.82 g, 3.3 mmol) and LAH (0.25 g, 6.6 mmol) according to general the procedure used for Example 8 (Step B) to give 0.73 g of title compound as a clear oil.