Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[N:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.COCC(O)C.C(N(CC)C(C)C)(C)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[CH:31][CH:32]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: Nc1ccc(OCCN2CCOCC2)cc1
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(OCCN4CCOCC4)cc3)nn12

Procedure:
Into a Microwave vial, [A] 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.116 g, 0.000404 mol), [B] 4-(2-Morpholin-4-yl-ethoxy)-phenylamine (0.197 g, 0.000888 mol), 1-Methoxy-2-propanol (0.971 mL, 0.00993 mol) and N,N-Diisopropylethylamine (0.155 mL, 0.000888 mol) were added. The reaction was microwaved on 300 watts, 170° C. for 50 minutes. The solvent was removed under vacuum. The desired product was isolated via ISCO column chromatography with DCM and methanol as eluant (0 to 12% methanol). The collected fractions afforded [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine a yellow solid (22 mg, 12%). MP 125-126° C. LCMS (E/I+) 446.8 (M+H). NMR 1H (DSMO-d6)-9.20 (s, 1H), 8.91 (s, 1H), 7.79 (dd, 1H, JJ=1.60, 6.04 Hz), 7.61 (d, 2H, J=9.00 Hz), 7.45 (dt, 1H, JJ=1.40, 7.12 Hz), 7.21 (d, 1H, J=8.36 Hz), 7.12 (t, 1H, J=7.53 Hz), 6.92 (d, 1H, J=4.56 Hz), 6.89 n (d, 1H, J=4.64 Hz), 6.80 (d, 2H, J=9.00 Hz), 4.02 (t, 2H, J=5.80 Hz), 3.79 (s, 3H), 3.3.58 (t, 4H, J=4.68 Hz), 2.65 (t, 2H, J=5.68 Hz), 2.46 (t, 4H, J=4.48 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[O:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].Cl[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:31][C:30]1[C:25]([O:1][C:2]2[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=2)[O:7][C:8]2[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=2[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:26][CH:27]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:29]=1
Reactant: COC(=O)COc1ccccc1Oc1cc(O)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccccc1Oc1cc(Oc2ncc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 27.2 %

Procedure:
A mixture of methyl [o-(5-hydroxy-2-nitrophenoxy)phenoxy]acetate (1.9 g, 5.9 mmol), 2,3-di-chloro-5-(trifluoromethyl)pyridine (1.92 g, 8.9 mmol) and potassium carbonate (1.23 g, 8.9 mmol) in N,N-di-methylformamide is heated at 100° C. for 12 hours, cooled to room temperature, poured into water and extracted with ether. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a yellow oil. Flash chromatography of the oil using silica gel and a (1:4) ethyl acetate/hexanes solution gives the title product as a yellow liquid (0.8 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15].O[N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28].Cl.C(N=C=NCCCN(C)C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16][N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28])=[O:15]
Reactant: COCCOCCOCCOCCC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-{2-[2-(2-Methoxyethoxy)ethoxy]ethoxy}propionate (131 mg, 0.45 mmol) was dissolved in trifluoroacetic acid and left at room temperature for 1 hour. The solvent was removed in vacuo and residual trifluoroacetic acid was removed by evaporation from dioxane. The deprotected intermediate was dissolved in dichloromethane and treated with N-hydroxysuccinimide (57 mg, 0.49 mmol) and ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg, 0.45 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed twice with water. The organic phase was dried over MgSO4 and concentrated in vacuo to provide 122 mg (82%).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[N:4][C:5]([I:8])=[CH:6][CH:7]=1.[NH:10]1[CH2:16][CH:15]([OH:17])[CH2:14][NH:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C>CCO>[Br:1][C:2]1[C:3]([N:10]2[CH2:16][CH:15]([OH:17])[CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][C:5]([I:8])=[CH:6][CH:7]=1
Reactant: Fc1nc(I)ccc1Br
Reactant: OC1CNCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: OC1CNCCN(c2nc(I)ccc2Br)C1
Yield: 87.2 %

Procedure:
A solution of 3-bromo-2-fluoro-6-iodopyridine (1.00 g, 3.4 mmol), 1,4-diazepan-6-ol (510 mg, 4.4 mmol), and DIPEA (2 mL) in EtOH (6 mL) in a sealed tube was stirred at 100° C. for 20 hours. The reaction mixture was concentrated under reduced pressure to give a residue (1.18 g), which was used for the next step without further purification. MS (ESI) m/z: 398 [M+H]+.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:10])(O)[C:5]1=[CH2:11])([CH3:3])=[CH2:2].C[O:13][CH:14](OC)[CH2:15][C:16]([CH3:18])=[CH2:17].Cl.N1C=CC=CC=1>CCOCC>[CH:14]([C:15](=[C:16]([CH3:18])[CH3:17])[CH2:11][C:5]1[CH:4]([C:1]([CH3:3])=[CH2:2])[CH2:8][CH2:7][C:6]=1[CH3:10])=[O:13]
Reactant: C=C(C)C1CCC(C)(O)C1=C
Reactant: C=C(C)CC(OC)OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=C(C)C1CCC(C)=C1CC(C=O)=C(C)C
Temperature: 100 °C
Yield: 59.6 %

Procedure:
A mixture of 7.6 g of 3-isopropenyl-1-methyl-2-methylene-cyclopentan-1-ol and 8.1 g of 1,1-dimethoxy-3-methyl-3-butene was heated under nitrogen in an oil bath of 100° C for 15 hours in the presence of 100 mg of freshly prepared dry pyridine hydrochloride with continuous removal of the methanol formed. The mixture was then heated for 7 hours to 150° C and finally poured on to a mixture of ice and ether. The ethereal phase was washed with bicarbonate solution and water, dried with anhydrous magnesium sulphate and concentrated under reduced pressure. After distillation of the oily crude product, there were obtained 6.5 g of 2-(2-formyl-3-methyl-2-butenyl)-3-isopropenyl-1-methyl-cyclopent-1-ene; boiling point 0.003 about 80° C; nD20 = 1.5148; IRfilm : νmax = 3100, 2780, 1675, 1635, 1440, 1375, 1155, 1060 and 895 cm-1. The compound has a woody, floral, fruitily sweetish fragrance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:16]([Cl:18])[CH:17]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([O:19][CH2:20][C:21]([F:23])([F:22])[F:24])=[C:16]([Cl:18])[CH:17]=2)=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:27])[CH3:26]
Reactant: Nc1nccc(C(=O)NCc2cnc(OCC(F)(F)F)c(Cl)c2)n1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1nccc(C(=O)NCc2cnc(OCC(F)(F)F)c(Cl)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)pyrimidine-4-carboxamide (10 mg, 0.03 mmol, Step-1) and acetyl chloride (7 mg, 0.08 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH2:29][CH2:28][CH2:27][CH:26]4[CH3:30])[N:20]=3)[C:12]3[N:13]([CH:15]=[CH:16][N:17]=3)[N:14]=2)[CH:6]=[CH:7][CH:8]=1.O=[C:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCl>[CH3:30][CH:26]1[CH2:27][CH2:28][CH2:29][N:25]1[C:21]1[N:20]=[C:19]([NH:18][C:11]2[C:12]3[N:13]([CH:15]=[CH:16][N:17]=3)[N:14]=[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[CH2:2][NH:1][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:10]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(CN)c3)nn3ccnc23)n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(CNC4CCN(C(=O)OC(C)(C)C)CC4)c3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
To a solution of 6-(3-(aminomethyl)phenyl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (50 mg, 1.52 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (38 mg, 0.188 mmol) and NaBH(OAc)3 (80 mg, 0.375 mmol) in dichloromethane (5 mL) was added HOAc (12 mg). The mixture was stirred at room temperature for 3 h. The solvent was concentrated in vacuo. The residue was purified by chromatography (silica, EtOAc) to give tert-butyl 4-(3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzylamino)piperidine-1-carboxylate (35 mg, 48%) as a yellow oil. LC/MS: 583.3 [M+H]+, tR=1.52 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:37])[CH2:25][N:26]2C(=O)C3=CC=CC=C3C2=O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].O.NN>C(O)C>[OH2:8].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:37])[CH2:25][NH2:26])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: Cc1nnc(CNC(=O)CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nnc(CNC(=O)CN)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 94 %

Procedure:
To a solution of 5-chloro-2-[3-(2-phthalimidoacetamidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]-benzophenone (2.3 g) in ethanol (20 ml), hydrazine hydrate (0.92 g) is added, and the resultant mixture is refluxed for 1 hour. The precipitated phthalylhydrazide is filtered off, and the filtrate is evaporated under reduced pressure. The residue is dissolved in methylene chloride, washed with saturated aqueous sodium bicarbonate and water in order, dried over sodium sulfate, and evaporated under reduced pressure. The residue is chromatographed on a column of silica gel, and the product obtained from the eluate by evaporation is recrystallized from ethyl acetate to give 5-chloro-2-(3-glycylaminomethyl-5-methyl-4H-1,2,4-triazol-4-yl)-benzophenone hydrate as crystals melting at 110° to 113° C. The yield is 94%.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[CH:7]1>>[C:1]([NH:5][C:6](=[O:12])/[CH:7]=[CH:8]\[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)/C=C\C(=O)O
Yield: 97 %

Procedure:
Similarly, t-butylamine is reacted with an equimolar amount of maleic anhydride to produce 97% yield of N-t-butyl maleamic acid, a white crystalline material melting at 138°-142° C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][NH:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Fc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(F)cccc21
Yield: 69.5 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 274 mg of 4-fluoro-2,3-dihydro-1H-indole, and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of N,N-dimethylformamide. 249 mg of 2-[2-(4-fluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:16]=[O:17])[C:7]2[C:12]([C:13]=1[OH:14])=[C:11]([CH3:15])[CH:10]=[CH:9][CH:8]=2)([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].O>N1C=CC=CC=1>[C:18]([O:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH3:15])[C:6]([CH:16]=[O:17])=[CH:5][C:4]=1[CH:1]([CH3:3])[CH3:2])(=[O:20])[CH3:19]
Reactant: Cc1cccc2c(C=O)cc(C(C)C)c(O)c12
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C(C)C)cc(C=O)c2cccc(C)c12

Procedure:
0.7 g of 3-isopropyl-4-hydroxy-5-methyl-1-naphthalenecarbaldehyde and 10 ml of acetic anhydride were dissolved in 10 ml of pyridine and reacted at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with dilute hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution and a saturated saline solution in this order, dried with anhydrous magnesium sulfate and concentrated under reduced pressure, thereby obtaining 0.5 g of the captioned compound as a black oily substances.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:5])C.[OH-].[Na+]>CO.O>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCc1cc2ccccc2n1-c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCc1cc2ccccc2n1-c1cccnc1

Procedure:
A solution of 1.0 g of 2-[4-(ethoxycarbonyl)butyl]-N-(3-pyridyl)indole and 0.25 g of sodium hydroxide in 5 ml of methanol and 5 ml of water is stirred for 17 hours at room temperature. The solvent is evaporated and the residue is redissolved in 10 ml of water and neutralized with 0.515 ml of concentrated hydrochloric acid. The resulting product is recrystallized from methanol to yield 2-(4-carboxybutyl)-N-(3-pyridyl)indole, m.p. 143°-144°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].N1C=CC=CC=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(Cl)Cl>[O:12]=[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][S:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:27])=[O:26])[CH:3]=2)[O:8][CH2:7][CH2:6]1
Reactant: Nc1ccc2c(c1)C(=O)CCO2
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1CCOc2ccc(NS(=O)(=O)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of 6-amino-2,3-dihydro-4H-chromen-4-one (330 mg, 2.02 mmol) in CH2Cl2 is treated with pyridine (1 mL) and benzenesulfonyl chloride (0.28 mL, 2.2 mmol), stirred at ambient temperature for 1 hour, poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic phase is washed sequentially with dilute hydrochloric acid until the pH of the wash is <2 and a saturated solution of sodium bicarbonate, dried over MgSO4 and concentrated in vacuo to afford the title compound as a beige solid, 460 mg (74% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: O=Cc1cc(F)ccc1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc(F)cc1C=O
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
To a mixture of 0.500 g (3.57 mmole) of 5-fluoro-2-hydroxy-benzaldehyde, 0.694 g (6.4 mmole) of triethylamine, and 5 mL of dichloromethane at 0 degrees was added dropwise, 0.444 g (3.90 mmole) of methanesulfonyl chloride. Stirring was continued for 15 minutes. The mixture was diluted with 30 mL of dichloromethane and washed with 20 mL of saturated ammonium chloride solution, 20 mL of water, 20 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.760 g of methanesulfonic acid 4-fluoro-2-formyl-phenyl ester as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=1.[Br-].[CH2:25]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:26][CH3:27].CC(C)([O-])C.[K+].O>C1COCC1>[F:23][C:17]1[CH:16]=[C:15]([C:3]2[CH:4]=[CH:5][C:6]([CH:8]3[CH2:13][CH2:12][C:11](=[CH:25][CH2:26][CH3:27])[CH2:10][CH2:9]3)=[CH:7][C:2]=2[F:1])[CH:20]=[C:19]([F:21])[C:18]=1[F:22]
Reactant: O=C1CCC(c2ccc(-c3cc(F)c(F)c(F)c3)c(F)c2)CC1
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCC=C1CCC(c2ccc(-c3cc(F)c(F)c(F)c3)c(F)c2)CC1
Temperature: -10 °C

Procedure:
12.5 g of 4-(2,3',4',5'-tetrafluorobiphenyl-4-yl)cyclohexanone and 15.5 g of propyltriphenylphosphonium bromide were introduced into 150 ml of THF, and the mixture was cooled to -10° C. with stirring and under nitrogen. A solution of 4.5 g of potassium tert-butoxide in 150 ml of THF was then added dropwise with stirring at -10° C., and the mixture was then stirred at room temperature for a further 2 hours. The yellow suspension was then cooled to 10° C., and 200 ml of water were added. The organic phase was separated off, and the aqueous phase was extracted once with 100 ml of methyl tert-butyl ether. The combined organic extracts were washed once with 50 ml of water, dried using sodium sulfate, filtered and evaporated to a residue. The residue was purified by means of a silica-gel frit, and the eluate was evaporated to a residue, giving 3,4,5,2'-tetrafluoro-4'-(4-propylidenecyclohexyl)bi-phenyl.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=5)=[O:24])[CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:41]=[CH:42][CH:43]=[CH:44][C:4]=2[N:3]=1.[C:45](Br)(=[O:47])[CH3:46].C(N(CC)C(C)C)(C)C>ClCCl>[C:45]([NH:34][S:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23]([N:20]2[CH2:21][CH2:22][C:17]([CH2:16][CH2:15][N:14]3[CH:12]4[CH2:11][CH2:10][CH:9]3[CH2:8][CH:7]([N:6]3[C:5]5[CH:41]=[CH:42][CH:43]=[CH:44][C:4]=5[N:3]=[C:2]3[CH3:1])[CH2:13]4)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:18][CH2:19]2)=[O:24])=[CH:30][CH:29]=1)(=[O:33])=[O:32])(=[O:47])[CH3:46]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccc(S(N)(=O)=O)cc2)CC1
Reactant: CC(=O)Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NS(=O)(=O)c1ccc(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To a precooled (0° C.) solution of 4-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-benzene-sulfonamide (20 mg, 0.033 mmol) in dichloromethane (2 mL) was added acetyl bromide (4.2 mg, 0.034 mmol) and N,N-diisopropylethyl amine (12 μL, 0.66 mmol). The resulting mixture was stirred overnight at ambient temperature. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 15-30% methanol in ethyl acetate to afford N-acetyl-4-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzene-sulfonamide as amorphous solid (14 mg, 66%). 1H NMR (300 MHz, DMSO-d6) δ 7.83 (d, J=8.1 Hz, 2H), 7.48-7.46 (m, 3H), 7.37-7.33 (m, 5H), 7.21 (br, 1H), 7.13-7.05 (m, 2H), 4.51 (t, J=8.1, 1H), 3.88 (br, 1H), 3.67-3.15 (m, 6H), 2.42 (s, 3H), 2.37-2.30 (m, 2H), 2.11-2.07 (br, 2H), 1.96-1.72 (m, 13H), 1.59 (d, J=7.4, 2H). HRMS m/z (M+H)+ calcd: 654.3114, obsd: 654.3095.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C>C(O)C>[N+:1]([C:4]1[C:9]([CH:10]=[N:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: NC1CCCCC1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(C=NC2CCCCC2)c([N+](=O)[O-])cc1OC
Yield: 80.4 %

Procedure:
A suspension of 42.2 g (0.2 mole) of 6-nitroveratraldehyde, 19.8 g (0.2 mole) cyclohexylamine, 1.0 ml. glacial acetic acid, and 1.25 l. ethanol was stirred and refluxed for 5 min., cooled, and filtered. The solid was washed with 100 ml. cold ethanol and air dried to give 47.0 g (80%) of the product, m.p. 160°-161°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([O:13][CH2:14][C@@H:15]([N:22]([CH3:35])[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[Cl:34])=[O:24])[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[O:12].[Li+].[OH-].Cl.C(OCC)(=O)C>O1CCOCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([O:13][CH2:14][C@@H:15]([N:22]([CH3:35])[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[Cl:34])=[O:24])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:12]
Reactant: COC(=O)CC[C@@H](COC(=O)Nc1nc2ccccc2s1)N(C)C(=O)NCc1cccc(F)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)O)COC(=O)Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.4 %

Procedure:
To a solution of (S)-methyl 5-(benzo[d]thiazol-2-ylcarbamoyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoate (2.3 g, 4.4 mmol) in 1,4-dioxane (15 mL) was added LiOH (2 N, 4.4 mL, 2 equiv.). The reaction mixture was stirred at RT for 2 h. The mixture was acidified to pH ˜3 with HCl (1 N, ˜10 mL), and ethyl acetate (50 mL) was added. The organic layer was extracted with EtOAc (3×20 mL), dried over Na2SO4 and concentrated. A small sample (30 mg) was purified by RP-HPLC (20-100% ACN in H2O) to give (S)-5-(benzo[d]thiazol-2-ylcarbamoyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoic acid as a white solid (8 mg). The remainder was used without further purification. LRMS (M−H+)=507.4.
Reaction SMILES: [CH:1]([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH3:14])[C:4]1=[O:15])=O.Cl.[NH2:17]O>CO>[CH3:14][O:13][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH2:12][C:3]1[CH:1]=[N:17][O:15][C:4]=12
Reactant: NO
Reactant: COc1cccc2c1CCC(C=O)C2=O
Agent: Cl
Solvent: CO
Product: COc1cccc2c1CCc1cnoc1-2

Procedure:
A mixture of the product obtained in step (i) (23.8 g, 0.11 mol) and hydroxylamine hydrochloride (8.2 g, 0.12 mol) in methanol (300 ml) is refluxed for ten minutes and then evaporated off under vacuum. Water is added thereto and the mixture is extracted with ethyl ether affording 19 g of the compound indicated in the title; m.p. 84°-86° C.