Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]#[N:12].[F:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>N1C=CC=CC=1>[C:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=3)(=[O:22])=[O:21])[CH:3]=2)[NH:7][N:6]=1)#[N:12]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: N#Cc1n[nH]c2ccc(N)cc12
Solvent: c1ccncc1
Product: N#Cc1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Yield: 84.3 %

Procedure:
N-(3-Cyano-1H-indazol-5-yl)-3-fluorobenzenesulfonamide can be obtained as described in Example 2 from 0.6 g of 5-amino-3-cyano-1H-indazole, 12 ml of pyridine and 0.73 g of 3-fluorobenzenesulfonyl chloride. 1 g of N-(3-cyano-1H-indazol-5-yl)-3-fluorobenzenesulfonamide is thus obtained in the form of a yellow solid melting at 227° C. (analysis C14H9FN4O2S % calculated C, 53.16; H, 2.87; F, 6.01; N, 17.71; O, 10.12; S, 10.14% found C, 52.86; H, 2.63; F, 5.67; N, 16.04).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([NH:7][C:8](=[O:19])OC1C=CC([N+]([O-])=O)=CC=1)[C:5]#[CH:6]>C1COCC1.ClCCl>[CH3:1][N:2]([CH3:3])[C:8]([NH:7][CH2:4][C:5]#[CH:6])=[O:19]
Reactant: CNC
Reactant: C#CCNC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#CCNC(=O)N(C)C
Yield: 79 %

Procedure:
Dimethylamine (3.0 ml of a 2.0M solution in THF, 6.0 mmol) and 4-nitrophenyl prop-2-yn-1-ylcarbamate (800 mg (80% purity), 2.91 mmol) in dichloromethane (7 ml) were stirred at room temperature for 4 hr. then the reaction solution purified by chromatography on silica using ethyl acetate as eluent to give N,N-dimethyl-N′-prop-2-yn-1-ylurea (289 mg, 79%) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([NH:20][C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.Cl[C:42]([O:44][CH3:45])=[O:43]>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:30]([F:31])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([N:20]([C:21]4[CH:26]=[N:25][CH:24]=[N:23][CH:22]=4)[C:42](=[O:43])[O:44][CH3:45])=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1cncnc1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)c1cncnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
In a solution of 0.25 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3-yl]-2-methyl-N-(5-pyrimidinyl)benzoic acid amide synthesized in Step 1 of Synthetic Example 14, 0.15 g of triethylamine and a catalytic amount of 4-(dimethylamino)pyridine in 4 mL of tetrahydrofuran, 0.15 g of methyl chloroformate was added, and stirred at room temperature for 16 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, 10 mL of ethyl acetate was added and insoluble material was filtered off. The solvent was distilled off under reduced pressure and the residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:1) to obtain 0.14 g of the aimed product as white crystal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)(=[O:17])=[O:16])[C@@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:37])C=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N+:23]([O-:37])[CH:22]=[CH:21]3)(=[O:16])=[O:17])[C@@H:10]([CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1S(=O)(=O)c1ccc2cnccc2c1
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1S(=O)(=O)c1ccc2c[n+]([O-])ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
340 mg of (S)-6-(4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline was dissolved in 20 mL of dichloromethane, and 244 mg of m-chloroperbenzoic acid was added at 0° C. The reaction solution was stirred at room temperature for 16 hours and then concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate:methanol=8:1) to obtain 320 mg of the compound of interest as a colorless oil (91%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:7][CH2:6]2)=O.Cl.[OH:18][NH2:19].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:18][N:19]=[CH:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:7][CH2:6]2
Reactant: CCC(=O)NC1CCc2cc(C=O)ccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(=O)NC1CCc2cc(C=NO)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
1.18 g of N-(5-formylindan-1-yl)propionic acid amide were suspended in 20 ml of ethanol and 10 ml of water. 0.57 g of hydroxyamine hydrochloride and 0.67 g of sodium acetate were added to this suspension followed by stirring overnight at room temperature. The reaction liquid was concentrated under reduced pressure followed by pouring into ice water and extracting with ethyl acetate. After washing the organic layer with saturated aqueous sodium bicarbonate and saturated brine, the organic layer was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.25 g of the target compound. Yield: 100%
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:12])=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CSc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc(CBr)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a mixture of 4-(methylthio)benzyl alcohol (2.00 g) and carbon tetrabromide (6.45 g) in dichloromethane (40 mL) was added triphenylphosphine (4.08 g), and the mixture was stirred for an hour at ambient temperature. After evaporation of the solvent, the residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1) to give 4-(methylthio)benzyl bromide (2.00 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[CH:21][N:20]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([Cl:18])[CH:24]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1ccnc(Cl)c1
Product: Cc1c2n(c3c(-c4ccnc(Cl)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (47 mg, 54%), MS (ISP) m/z=346.4 [(M+H)+], mp 270° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 2-chloro-pyridin-4-ylboronic acid (51.1 mg, 0.325 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH2:17]([NH:19][O:20][CH:21]([CH3:23])[CH3:22])[CH3:18]>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:19]([CH2:17][CH3:18])[O:20][CH:21]([CH3:23])[CH3:22])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: CCNOC(C)C
Agent: Cl
Product: CCCNc1nc(NCCC)nc(N(CC)OC(C)C)n1
Yield: 88 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) was reacted with N-ethyl-O-isopropyl-hydroxylamine hydrochloride (LXXV) as described in Example 13, yielding N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylamine (LXXVI) (88% yield). ESI-MS (m/z): 297 [M+H]+.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:10]=[C:11]([C:19]([F:22])([F:21])[F:20])[C:12]([CH:15]([CH3:18])[C:16]#[N:17])=[N:13][CH:14]=1)([O-])=O>CC(=O)OCC>[NH2:6][C:9]1[CH:10]=[C:11]([C:19]([F:22])([F:20])[F:21])[C:12]([CH:15]([CH3:18])[C:16]#[N:17])=[N:13][CH:14]=1
Reactant: CC(C#N)c1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C#N)c1ncc(N)cc1C(F)(F)F
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Tin(II) chloride dihydrate (135 mg, 0.600 mmol) was added to a solution of 2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (73.6 mg, 0.300 mmol) in EA (15 mL). The mixture was at 50° C. for 3 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)propanenitrile (55 mg, 0.256 mmol, 85.0% yield) was used to next step without further purification. TLC (PE/EA=5:1, Rf=0.5): 1H NMR (400 MHz, CDCl3) δ: 8.25 (s, 1H), 7.17 (d, J=2.2 Hz, 1H), 4.15-4.28 (m, 1H), 1.66 (d, J=7.1 Hz, 3H); ES-LCMS m/z 216.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].[CH3:21][Mg]Br>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]([OH:19])[CH3:21])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(C=O)cc(C(=O)OCC)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(C)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
Treat a solution of 5-formyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (400 mg, 1.44 mmol) in THF (10 mL) at 0° C. with methylmagnesium bromide (3.0 M in diethyl ether, 0.58 mL, 1.73 mmol). Stir at 0° C. for 1 h and quench with saturated aqueous ammonium chloride solution. Extract with ethyl acetate (100 mL), dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 40:60 to 70:30 ethyl acetate:hexanes) to give the title compound (250 mg, 59%).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:17]1[CH:21]2[CH2:22][NH:23][CH2:24][CH:20]2[CH2:19][N:18]1[C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1>>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([N:23]1[CH2:22][CH:21]2[CH2:17][N:18]([C:25]3[CH:34]=[N:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[CH2:19][CH:20]2[CH2:24]1)(=[O:9])=[O:8]
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Product: O=S(=O)(c1ccccc1-c1ccccc1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title prophetic compound may be synthesized using biphenylsulfonylchloride and Intermediate 35. MS (ESI) mass calcd. for C26H24N4O2S, 456.16.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:18][S:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:29])=[O:28])[CH:15]=3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC1Cc2ccc(O)cc2C1)c1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(NC1Cc2ccc(OS(=O)(=O)c3ccccc3)cc2C1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
95 mg (0.35 mmol) 4-fluoro-N-(5-hydroxy-indan-2-yl)-benzamide were dissolved in 2 ml of pyridine, 120 mg (0.72 mmol) of benzenesulfonic acid chloride were added, and the mixture was stirred for 5 h at 70° C.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[S:5][C:6]2[CH:13]=[CH:12][C:11]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:10]=3[C:9](=[O:19])[C:7]=2[N:8]=1>CO.ClCCl>[Cl:3][C:4]1[S:5][C:6]2[CH:13]=[CH:12][C:11]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:10]=3[CH:9]([OH:19])[C:7]=2[N:8]=1
Reactant: O=c1c2ccc(Cl)cc2ccc2sc(Cl)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OC1c2ccc(Cl)cc2C=Cc2sc(Cl)nc21

Procedure:
Sodium borohydride (0.159 g) was added to a suspension of the product from step (vi) (1.27 g) in methanol (20 ml) and dichloromethane (5 ml) at room temperature. After 3 h the mixture was partitioned between 2N NaOH and dichloromethane. The organic phase was collected, dried, (MgSO4) and solvent evaporated to leave a colourless foam. Yield: 1.27 g Used directly in the next step.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=O>[OH-].[K+].CCO>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=[C:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:10]=2)[C:15]1=[O:19]
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccco2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 67.1 %

Procedure:
According to the method of Example 6, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.250 g, 0.98 mmol) was reacted with 2-furaldehyde (0.151 g, 1.57 mmol) in 3.0 mL of 4% KOH in EtOH for 15 hours at room temperature to afford 0.220 g (67%) of the title compound as a light tan solid, mp 109-110° C.: CI-MS m/e 334 (M+), 335 M++1);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[Cl:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(OCc2ccccc2)c(Cl)c1
Yield: 95.9 %

Procedure:
A mixture of 6.59 g (0.025 moles) of the 4-benzyloxy-3-chloro nitrobenzene (example 4), 4.19 g (0.075 moles) of iron powder, and 12.04 g (0.225 moles) of ammonium chloride in 100 ml of ethanol and 25 ml of water was stirred mechanically and refluxed for half an hour. The reaction was allowed to cool and stir for 1 hour. The mixture was filtered and solids were washed with ethanol. The combined filtrates were taken to dryness in vacuo. This solid was dissolved in methylene chloride and passed through Magnesol. Removal of the solvent from the filtrate in vacuo gave 5.60 g of title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:36][NH:37][C:38]([C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39]>>[CH3:36][NH:37][C:38]([C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:41][CH2:42][N:43]([CH2:29][CH2:28][C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH2:44][CH2:45]1)=[O:39]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CNC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: CNC(=O)C1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)CC1

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3yl]-ethyl-methanesulfonate (5 mmol) and 4-phenylpiperidine-4-carboxylic acid methyl-amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([C:21]2[CH:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([C:21]2[CH:22]=[N:23][C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(Cl)nc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=C(Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(-c2ccccc2)nc1
Temperature: 80 °C

Procedure:
To a solution of 5-chloro-2-(6-chloropyridin-3-yl-carbonylamino)-N-(5-chloropyridin-2-yl)benzamide (Intermediate E-2, 0.42167 g, 1 mmol) in 10 mL of DME was added phenyl boronic acid (0.134 g, 1.1 mmol) and an aqueous solution of potassium phosphate (0.6 mL, 1 molar solution). The reaction mixture was degassed and tetrakistriphenyl-phosphine palladium (60 mg) was added. The mixture was heated at 80° C. overnight, cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water, saturated sodium bicarbonate, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the crude product was purified by RPHPLC [ethyl acetate/hexane (3:7)]. Yield=0.280 g.
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[O:7])=[C:4]([O:20][CH2:21][CH2:22][S:23][CH3:24])[CH:3]=1.I([O-])(=O)(=O)=[O:26].[Na+]>Cl>[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[O:7])=[C:4]([O:20][CH2:21][CH2:22][S:23]([CH3:24])=[O:26])[CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSCCOc1cc(N)c(Cl)cc1C(=O)NC1CN2CCC1CC2
Agent: Cl
Agent: [Na+]
Product: CS(=O)CCOc1cc(N)c(Cl)cc1C(=O)NC1CN2CCC1CC2

Procedure:
The product from Example 81 was oxidized in 1.4N HCl solution with sodium metaperiodate at 0°-5° C. for 2 h to give the title compound.
Reaction SMILES: [C:1]1([S:7]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[OH:10][C:11]1[CH:16]=[C:15]([CH3:17])[O:14][C:13](=[O:18])[CH:12]=1.[Cl-].[Na+]>C1C=CC=CC=1>[OH:10][C:11]1[CH:16]=[C:15]([CH3:17])[O:14][C:13](=[O:18])[C:12]=1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClSc1ccccc1
Reactant: Cc1cc(O)cc(=O)o1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: c1ccccc1
Product: Cc1cc(O)c(Sc2ccccc2)c(=O)o1
Yield: 100 %

Procedure:
Benzenesulfenyl chloride (7.2 g., 0.050 mol) dissolved in benzene (15 ml.) was added to a rapidly stirred slurry of the monosodium salt of 4-hydroxy-6-methyl-2-pyrone (7.4 g., 0.050 mol) in benzene (110 ml.) over a period of 12 minutes. The reaction temperature was maintained at 25°-27°C. with cooling during the addition; then the reaction mixture was heated at reflux for 30 minutes. The benzene was removed by distillation in vacuo and the residue triturated with water (100 ml.) to remove the by-product sodium chloride. The crude product was removed by filtration, 10.9 g., m. 158°-163°C., 93 percent yield. A portion was recrystallized from ethanol, m. 164.5°-165.5°C. Evaporation of the aqueous filtrate to dryness in vacuo produced 2.9 g. (100 percent yield) of the by-product sodium chloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=3[N:16]=[C:15]2[O:24][CH2:25][CH3:26])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:25]([O:24][C:15]1[N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:18]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=2[N:16]=1)[CH3:26]
Reactant: CCOc1nc2cc(C)ccc2n1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1nc2cc(C)ccc2n1C1CCNCC1

Procedure:
4-(2-ethoxy-5-methylbenzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (367 mg, 1.02 mmol) was dissolved in CH2Cl2 (2 mL) and TFA (1 mL) and the solution was stirred at rt for 1 hour. The mixture was evaporated to dryness and the residue was extracted with CH2Cl2, brine and 2N NaOH solution. The organic layer was washed with brine and dried over Na2SO4. After the evaporation of solvents, an oily residue was obtained (217 mg, 0.84 mmol) as 4-(2-ethoxy-5-methylbenzoimidazol-1-yl)-piperidine which was then was mixed with (S)-(2-iodomethyl-indan-5-yl)-carbamic acid tert-butyl ester (224 mg, 0.60 mmol) and cesium carbonate (817 mg, 2.51 mmol) in acetonitrile (10 mL). The mixture was stirred at 85° C. for 16 hrs. The reaction mixture was filtered and solvents were evaporated. The residue was purified through a Biotage flash column chromatography using 5% CH3OH in CH2Cl2 to give a brownish fluffy material (206 mg, 68%) as (S)-{2-[4-(2-ethoxy-5-methylbenzoimidazol-1-yl)-piperidin-1-ylmethyl]-indan-5-yl}-carbamic acid tert-butyl ester.
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:7]=[C:8]([F:20])[C:9]([F:19])=[C:10]([CH:18]=2)[C:11]([O:13]C2CCC2)=[O:12])[CH2:4][CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O>[CH:1]1([O:5][C:6]2[CH:7]=[C:8]([F:20])[C:9]([F:19])=[C:10]([CH:18]=2)[C:11]([OH:13])=[O:12])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OC1CCC1)c1cc(OC2CCC2)cc(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(OC2CCC2)cc(F)c1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A mixture of cyclobutyl 5-cyclobutoxy-2,3-difluorobenzoate (49 g, 174 mmol), ethanol (300 mL), sodium hydroxide (20 g, 500 mmol) and water (300 mL) stirred at 60° C. overnight. The mixture was cooled to room temperature and extracted with petroleum ether (2×100 mL). The pH of the aqueous layer was adjusted to 5 with 6 M hydrochloric acid, and then it was extracted ethyl acetate (3×300 mL). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 5-cyclobutoxy-2,3-difluorobenzoic acid (38 g, 96%) as a white solid. MS (ESI, neg. anion) m/z 227 [M−H]−.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:1][C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:6][CH:7]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13]1
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOc3ncccn3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (9), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 53 (c)] with 2-chloro-pyrimidine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[2-(pyrimidin-2-yloxy)-ethoxy]-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 556 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:29]([O:33][C:34](=[O:37])[CH2:35]Br)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:37])[CH2:35][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=3[O:27][CH3:28])[CH2:17][CH2:18]2)=[O:12])=[CH:7]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)OC(C)(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid tert-butyl ester gave the title compound.