Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21]([CH2:28][N+:29]([O-])=O)[CH2:22][C:23]([O:25]CC)=O)([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Ni]>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21]2[CH2:28][NH:29][C:23](=[O:25])[CH2:22]2)([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C[N+](=O)[O-])C1(NC(=O)OC(C)(C)C)CC(OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(C2CNC(=O)C2)CC(OCc2ccccc2)C1
Temperature: 50 °C
Reaction time: 5 h
Yield: 70.8 %

Procedure:
A 35.12 g (80.46 mmol) portion of ethyl 3-[1-benzyloxy-3-(tert-butoxycarbonylamino)cyclobutan-3-yl]-4-nitrobutanoate was dissolved in 700 ml of ethanol to which, under an atmosphere of nitrogen, was subsequently added 50 ml of Raney nickel. After replacing the atmosphere with hydrogen, this was stirred at 50° C. for 5 hours. After cooling in an ice bath, the reaction solution was filtered through celite and then the solvent was evaporated under a reduced pressure. Thereafter, the resulting residue was purified by a silica gel column chromatography to give 20.53 g (70.8%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]CC2C=CC=CC=2)=[CH:6][C:5]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[NH:18][C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1
Reactant: [H][H]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(OCc2ccccc2)c(Cl)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(O)c(Cl)cc1F
Yield: 74.8 %

Procedure:
A mixture of 4.27 g (10.3 mmol) of 3-[4-chloro-2-fluoro-5-(phenylmethoxy)phenyl]-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione and 420 mg of 10% palladium on charcoal in 70 mL of ethyl acetate was placed in a Paar bottle and was agitated under 45 psi hydrogen over a 16 hour period. It was filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo and the resultant crude product flash chromatographed over silica gel, eluting with a 95:5 v:v mixture of dichloromethane and methanol to give 2.50 g of the title compound as a pale orange solid, m.p.: 68°-72° C.; 1 -NMR (DMSO-d6): ppm 7.5 (d, 1H), 7.0 (d, 1H), 6.4 (s, 1H).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([CH:7](Br)C(Br)CC(O)=O)=[CH:3][CH:2]=1.ClCCl.CO.[C:26]([OH:29])(=[O:28])[CH3:27]>>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([C:7]#[C:27][C:26]([OH:29])=[O:28])=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: O=C(O)CC(Br)C(Br)c1ccc(-c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C#Cc1ccc(-c2ccccc2)cc1

Procedure:
Prepared analogously to Example 3.4.b. from 3-biphenyl-4-yl-2,3-dibromopropanecarboxylic acid. Yield: 2.8 g (96.8% of theory); C15H10O2 (M=222.24); melting point: 170° C.; calc.: molecular ion peak (M+H)+: 223; found: molecular ion peak (M+H)+: 223; Rf value: 0.4 (silica gel, dichloromethane/methanol/acetic acid (90:10:1)).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:13]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[Br:13][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([CH3:12])[C:2]([OH:1])=[CH:11][CH:10]=1
Reactant: BrBr
Reactant: COC(=O)c1cccc(O)c1C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(Br)ccc(O)c1C
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a solution of methyl 3-hydroxy-2-methylbenzoate (114a, 3.557 g, 21.40 mmol) in dichloromethane (100 mL) in a dry ice/acetonitrile bath (˜−45° C.) was added bromine (1.15 mL, 22.5 mmol) dropwise. The reaction was stirred at −45° C. for 2 hours before Na2S2O3 (sat. aq., 2 mL) was added. The reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with dichloromethane and washed with water. The dichloromethane layer was concentrated under vacuum, and the resulting crude product was purified by column chromatography (0-40% ethyl acetate/heptane) to give methyl 6-bromo-3-hydroxy-2-methylbenzoate (114b, 4.8 g, 92% yield) as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14](O)[C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[C:5]1=[O:24])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:26]>O1CCOCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14]([Cl:26])[C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[C:5]1=[O:24])(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)N1C(=O)C(=C(O)c2ccc(C#N)cc2)c2ccc(Cl)cc21
Solvent: C1COCCO1
Product: CC(=O)N1C(=O)C(=C(Cl)c2ccc(C#N)cc2)c2ccc(Cl)cc21
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A suspension of 7.0 g of 1-acetyl-3-[1-hydroxy-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone (starting material VI.18) and 6.39 g of phosphorus pentachloride in 150 ml of dioxane is stirred at 100° C. for 6 hours. After addition of a further 1.0 g of phosphorus pentachloride, the mixture is stirred at 110° C. for another 4 hours. The solvent is then distilled off and the residue is washed with ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:3]=2)[CH:8]=1
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: Br[Mg]c1ccccc1
Product: COc1ccc2cc(-c3ccccc3)ccc2c1

Procedure:
The title compound was prepared by reacting 2-bromo-6-methoxynaphthalene (1.97 g, 8.31 mmol) with phenylmagnesium bromide according to the method used to prepare intermedite 10 to yield 1.59 g (82%) of a white solid: mp 122–126° C.; 1H NMR (CDCl3): δ 3.94 (3H, s), 7.16–7.18 (2H, m), 7.34–7.37 (1H, m), 7.46–7.49 (2H, m), 7.69–7.72 (2H, m), 7.78–7.82 (2H, m), 7.97 (1H, t); MS (El) m/z 234.2 (M)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:26][CH2:25]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 1-methylpiperazine (1.2 equiv) to give 159 (17.7 mg, M+1 396.0)
Reaction SMILES: [N:1]1[N:2]([C:10]2[N:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]([NH:14][CH:15]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]([OH:20])[C:17](O)=[O:18])=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.Cl.[CH2:33]([O:35][NH2:36])[CH3:34]>>[CH2:33]([O:35][NH:36][C:17](=[O:18])[CH:16]([OH:20])[CH:15]([NH:14][C:12](=[O:13])[C:11]1[CH:28]=[CH:29][CH:30]=[N:31][C:10]=1[N:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][CH:6]=[CH:5]2)=[N:1]1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:34]
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1cc2ccccc2n1
Reactant: CCON
Agent: Cl
Product: CCONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2ccccc2n1

Procedure:
The reaction was carried out in analogy to reaction step 3.1 by reacting 3-[2-(2H-indazol-2-yl)nicotinamido]-2-hydroxy-4-phenylbutanoic acid and O-ethylhydroxylamine hydrochloride.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH:10]([OH:14])[CH2:11][CH2:12]Br.Cl>O>[CH:1]1([N:7]2[CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC(CBr)CCBr
Reactant: NC1CCCCC1
Agent: Cl
Solvent: O
Product: OC1CCN(C2CCCCC2)C1

Procedure:
To 99 g. of cyclohexylamine at reflux temperature is added 115.5 g. of 1,4-dibromo-2-butanol at a rate which maintains reflux without external heating. The temperature of the reaction mixture is maintained at 130°-140° C. in an oil bath for two hours after addition is complete. Water (100 ml.) is added and this mixture is then acidified with concentrated hydrochloric acid, cooled and extracted with ether. The aqueous layer is made alkaline with 50% aqueous sodium hydroxide solution, saturated with solid potassium carbonate and extracted three times with chloroform. The combined chloroform extracts are dried over potassium carbonate, concentrated and the residue distilled in vacuo to give N-cyclohexyl-3-pyrrolidinol.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([C:28]([O:30]C)=[O:29])[CH2:27][CH2:26][CH2:25]4)=[CH:20][C:19]=3[Cl:32])=[CH:14][CH:13]=2)[C:9]([CH3:33])=[N:8][C:7]=1[CH3:34])(=[O:5])[NH2:4].Cl>C(O)(C)(C)C.C(O)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([C:28]([OH:30])=[O:29])[CH2:25][CH2:26][CH2:27]4)=[CH:20][C:19]=3[Cl:32])=[CH:16][CH:17]=2)[C:9]([CH3:33])=[N:8][C:7]=1[CH3:34])(=[O:5])[NH2:4]
Reactant: COC(=O)C1(c2ccc(-c3ccc(-c4nc(C(N)=O)c(C)nc4C)cc3)c(Cl)c2)CCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CCO
Product: Cc1nc(C)c(-c2ccc(-c3ccc(C4(C(=O)O)CCC4)cc3Cl)cc2)nc1C(N)=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
Powdered potassium hydroxide (56.9 mg, 1.01 mmol) was added in one portion to methyl 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)cyclobutanecarboxylate (Intermediate 7-1; 152 mg, 0.34 mmol)/in tert-butanol (10 mL) at 40° C. under nitrogen. The resulting suspension was stirred at 40° C. for 1 hour LCMS showed the reaction was complete. The reaction mixture was quenched with HCl (2.027 mL, 2.03 mmol) in ethanol (10 mL) and the resulting solution stirred for a further 20 minutes before being evaporated to dryness. The resulting solid was washed with water (50 mL) and dried in a dessicator to afford 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)cyclobutanecarboxylic acid (68.0 mg, 46.2%) as a cream solid.
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[N:7][N:8]=2)[CH2:3][CH2:2]1.[Li]CCCC.[Mg+2].[Br-].[Br-].O(CC)CC.[C:22]([O:26][C:27](=[O:34])[NH:28][CH:29]([CH:32]=[O:33])[CH2:30][CH3:31])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27](=[O:34])[NH:28][CH:29]([CH:32]([C:6]1[O:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:8][N:7]=1)[OH:33])[CH2:30][CH3:31])([CH3:23])([CH3:24])[CH3:25]
Reactant: CCC(C=O)NC(=O)OC(C)(C)C
Reactant: c1nnc(C2CC2)o1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(NC(=O)OC(C)(C)C)C(O)c1nnc(C2CC2)o1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 48.6 %

Procedure:
A solution of 2-cyclopropyl-[1,3,4]oxadiazole (2.16 g, 19.6 mmol) in dry THF (100 mL) is cooled to −78° C. nBuLi (1.6M in hexanes, 12.3 mL, 19.6 mmol) is added dropwise. The reaction mixture is stirred at −78° C. for 40 min. MgBr2.OEt2 (5.0692 g, 19.6 mmol) is added. The reaction mixture is allowed to warm up to −45° C. and stirred at that temperature for 1.5 hr. A solution of (1-formyl-propyl)-carbamic acid tert-butyl ester (3.7 g, 19.6 mmol) in THF (40 mL) is added. The reaction mixture is allowed to warm up to −20° C. and stirred at that temperature for 3.5 hrs. The reaction mixture is quenched with a solution of saturated NH4Cl solution and extracted with ethyl acetate. Combined organic extracts is washed with saturated NaCl solution and dried over MgSO4. The solvent is evaporated under reduced pressure and the crude is purified by column chromatography eluting with ethyl acetate and heptane mixture to give {1-[(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-propyl}-carbamic acid tert-butyl ester (2.83 g, 49%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43](C=O)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:51]1([C:57](OC(C)(C)C)=O)[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:57][N:51]6[CH2:52][CH2:53][NH:54][CH2:55][CH2:56]6)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2OC)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4CCNCC4)c3)ccc2OC)c1
Reaction time: 3 h
Yield: 63.1 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-4-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (54 mg, 0.00008 mol) in DCM with 1,1-dimethylethyl 1-piperazinecarboxylate (23.3 mg, 0.00012 mol) and sodium triacetoxyborohydride (34 mg., 0.00016 mol) and AcOH (6 μL) were agitated overnight on a shaker. LC-MS was used to monitor the reaction. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The residue was taken up in DCM (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on a Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a white solid [37.6 mg (63%)]. LC-MS m/z 745.4 (M+H)+.
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)([OH:22])=[O:21]>C(O)C>[C:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][CH:2]=[C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[O:5][CH:4]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:25][CH:24]=1)([OH:22])=[O:21]
Reactant: O=C1C(=CO)C(c2ccccc2)Oc2ccccc21
Reactant: NCc1ccc(C(=O)O)cc1
Solvent: CCO
Product: O=C(O)c1ccc(CNC=C2C(=O)c3ccccc3OC2c2ccccc2)cc1

Procedure:
A mixture of 5 g 3-hydroxymethylidene-flavanone and 9 g 4-carboxybenzylamine in 50 ml dry ethanol is stirred under nitrogen and reflux for 30 minutes. After filtration and washing of the solid with warm ethanol, the filtrate is cooled with an ice bath. A yellow precipitate forms which is filtered, dried and recrystallized in toluene. Pure yellow crystalline 3-[N-(4-carboxybenzyl)amino]methylidene-flavanone is obtained; m.p. 195°-200° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][CH:40]([NH:1][CH2:2][CH:3]([OH:4])[C:5]4[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=4)[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1OC
Product: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(NCC(O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from N-[5-(2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamid, and Reference Example 73, N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as a yellow solid; mp 205-218° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.15-1.30 (m, 2H), 1.70-1.90 (m, 2H), 2.50-3.00 (m, 5H), 2.89 (s, 3H), 3.62 (s, 3H), 3.65 (s, 3H), 3.65-3.85 (m 2H), 4.40-4.50 (m, 1H), 6.50-7.10 (m, 8H), 7.45 (d, 2H), 9.11 (s, 1H); MS (ES) m/z: 621.0 (MH+); HRMS Calcd. for C28H37N4O8S2 (MH+): 621.2053. Found: 621.2058.
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH:6]=1.C(O)(=O)C.[C-:14]#[N:15].[K+]>CO>[CH3:7][C:4]1([CH3:8])[CH2:5][C:6]([C:14]#[N:15])=[CH:2][C:3]1=[O:9]
Reactant: CC1(C)CC=C(Br)C1=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1(C)CC(C#N)=CC1=O
Temperature: 27.5 °C
Reaction time: 4.5 h

Procedure:
To a stirred solution of 2-bromo-5,5-dimethylcyclopent-2-enone (prepared according to procedure reported in Organic Letters 2002, 4, 71-74, 17 g, 90 mmol) in methanol (200 ml) was added acetic acid, (5.15 ml, 90 mmol) at 25-30° C. Solid potassium cyanide (11.71 g, 180 mmol) was added and continued stirring the reaction mass for 4-5 h at 25-30° C. The progress of reaction was monitored by TLC. After completion of reaction, filtered the reaction mass through cotton filter and then filtrate was concentrated under reduced pressure. A crude oily compound was dissolved in Ethyl acetate (500 ml) and washed with water (100 ml) to remove the unreacted potassium cyanide. Organic layer was dried over sodium sulphate and concentrated under reduced pressure till dryness. Crude compound was purified over silica gel (100-200 mesh) by using 10% ethylacetated in hexane as eluent to obtain title produced (7.1 g)
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]O)=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].S(Cl)([Cl:25])=O>C1(C)C=CC=CC=1>[Cl:25][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:6]3=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]3[N:4]=[C:3]2[CH2:1][CH3:2])=[CH:15][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCO)cc1
Solvent: Cc1ccccc1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCCl)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethanol (step 6, 2.2 g, 7.4 mmol) in toluene (40 mL) was added thionyl chloride (2.0 mL, 23.6 mmol), and the resulting mixture was stirred at 80° C. for 3 h. The volatile components were removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 2:1 to 1:1) to afford 2.1 g (90%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.41 (2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz), 6.90 (1H, s), 3.78 (2H, t, J=7.4 Hz), 3.15 (2H, t, J=7.4 Hz), 2.83 (2H, q, J=7.6 Hz), 2.71 (3H, s), 2.54 (3H, s), 1.28 (3H, t, J=7.6 Hz).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[C:18](=O)([O-])[OH:19]>CN(C=O)C>[O:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][C:4]([CH:18]=[O:19])=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: c1ccc(N2CCOCC2)cc1
Reactant: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N2CCOCC2)cc1
Temperature: 60 °C
Reaction time: 22 h

Procedure:
N-Phenylmorpholine (77.2 g) was dissolved in DMF (150 ml) and phosphorus oxychloride (67.1 ml) was dropwise added in an ice bath. After the dropwise addition, the mixture was stirred at 60° C. for 22 hr. Ice water was added portionwise to the reaction mixture in an ice bath and the mixture was neutralized with a saturated aqueous hydrogencarbonate solution. The mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Isopropyl ether was added to the residue, and the precipitated crystals were collected by filtration to give the objective 4-morpholinobenzaldehyde (70.7 g), melting point 55° C.
Reaction SMILES: [CH:1]1(O)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.N1C=CC=CC=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:14]([CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1)(=[O:21])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1C=CCCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccccc1)C1C=CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 104.6 %

Procedure:
To a solution of 0.320 g (3.26 mmol) of 2-cyclohexen-1-ol and 0.76 mL (9.40 mmol) of pyridine in 20 mL of CH2Cl2 was added 1.04 mnL (8.96 mmol) of benzoyl chloride via syringe. The reaction mixture was yellow with a white precipitate. The reaction was stirred at room temperature for 17 h. The reaction was quenched by the addition of 50 mL of H2O; the aqueous layer was washed with 4×50 mL of Et2O, and the combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (35 mm, 20 cm, 10% CH2Cl2/hexane) gave 0.635 g (99%) of 3-benzoylcyclohexene as a pale yellow oil: TLC Rf=0.35 (10% CH2Cl2/hexane); IR (CCl4) 3100 (w), 3081 (w), 3038 (w), 2931 (s), 1725 (s), 1550 (s); 1H NMR (CDCl3) δ1.66-2.12 (m, 6H), 5.49 (bs, 1H), 5.79-5.83 (m, 1H), 5.97-6.01 (m, 1H), 7.41 (t, J=7.7, 2H), 7.52 (t, J=7.4, 1H); 8.02-8.04 (m, 2H); 13C NMR (CDCl3) δ19.0, 25.0, 28.4, 68.6, 125.8, 128.3, 129.6, 130.9, 132.7, 132.8, 166.2; LRMS (EI) 203 ((M+1), 3), 202 ((M+), 20), 105 (100); HRMS (EI) calculated for C13H14O2 202.0994 (M+), found 202.1003. The IR, 1H NMR, and 13C NMR matched spectral data reported by Akemark, B. et al., J. Org. Chem. 59:5729-5799 (1994).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[H-].[Na+].[C:11]([C:13]1[CH:14]=[C:15]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1F)#[N:12].Cl>O1CCCC1.O>[C:11]([C:13]1[CH:14]=[C:15]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1[O:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)#[N:12]
Reactant: OCC1CCOCC1
Reactant: N#Cc1cc(S(N)(=O)=O)ccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(S(N)(=O)=O)ccc1OCC1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To (tetrahydro-2H-pyran-4-yl)methanol (0.206 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.284 g) and the reaction stirred at room temperature for 20 minutes. The reaction was cooled to 0° C. and 3-cyano-4-fluorobenzenesulfonamide (0.355 g) in tetrahydrofuran (2 mL) was added dropwise and the reaction was allowed to warm to room temperature. After 3 hours, the reaction was poured into water, made acidic (pH=1) with 1N HCl and extracted with dichloromethane (2×75 mL). The organics were combined, washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound.