Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C.C(O[C:7]([NH:9][C@H:10]([C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=1)CC(C)C)=[O:8])(C)(C)C.[C:25]([NH:35][C@H:36](C(O)=O)[CH2:37][CH:38]([CH3:40])[CH3:39])([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(N[C@H](C(N[C@H](C(O)=O)CC(C)C)=O)CC(C)C)(OCC1C=CC=CC=1)=O>>[CH2:28]([O:27][C:25]([NH:35][C@@H:36]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:7]([NH:9][CH2:10][C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=1)=[O:8])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)c1csc([C@H](CC(C)C)NC(=O)OC(C)(C)C)n1
Agent: C
Agent: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Product: CCOC(=O)c1csc(CNC(=O)[C@H](CC(C)C)NC(=O)OCc2ccccc2)n1

Procedure:
Following the procedure of Example 13, except substituting 1-(tert-butoxycarbonyl)amino -1-4-carboethoxythiazol-2-yl)methane for (1S)1-(tert-butoxycarbonyl)amino-1-(4carboethoxythiazol-2-yl)-3-methylbutane, and N-Cbz-L-leucine for N-Cbz-L-leucinyl-L-leucine, the title compound was prepared (0.120 g, 32%). MS (MH+): 434.2.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)(=O)=O.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>C1COCC1>[N:35]1([C:5]2[N:10]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=3)[C:8]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:7]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[N:6]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CS(=O)(=O)c1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: Fc1ccc(Oc2nc(N3CCCC3)nc(-c3ccc(Cl)cc3Cl)c2-c2ccc(Cl)cc2)cc1F
Temperature: 60 °C

Procedure:
To a sealed tube fitted with a magnetic stirrer bar was added 2-methylsulfonyl-4-(3,4-difluorophenoxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (from Example 20) (30 mg, 0.06 mmol), 10 eq. of pyrrolidine and THF, flushed with nitrogen. The reaction was heated at 60° C. overnight in the sealed tube. The solvent was removed under reduced pressure. Flash column chromatography on silica gel (eluted with 90/10 hexanes/ethyl acetate) afforded the title compound: HPLC/MS: m/e=532 (M++1); Rt=4.9 min. 1H-NMR 500 MHz (CDCl3): 1.91-2.00 (m, 4H), 3.23-3.40 (s, 2H1), 3.45-3.62 (s, 2H), 6.89-6.94 (m, 1H), 7.08-7.21 (m, 8H), 7.35 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]([F:55])([F:54])[CH:49]1[CH2:53][CH2:52][CH2:51][NH:50]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:50]4[CH2:51][CH2:52][CH2:53][CH:49]4[C:48]([F:55])([F:54])[F:47])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: FC(F)(F)C1CCCN1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N2CCCC2C(F)(F)F)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2-trifluoromethyl-pyrrolidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H49F3Cl2N5O3 [(M+H)+] 786.3159, observed 786.3157.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:25])=[O:24])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Ic1c[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)n1cc(I)c2cccnc21
Yield: 73.9 %

Procedure:
3-Iodo-1H-pyrrolo[2,3-b]pyridine (4.55 g, 18.7 mmol) and K2CO3 (7.73 g, 55.9 mmol) were dissolved in acetonitrile (200 mL). Benzenesulfonyl chloride (4.76 mL, 37.3 mmol) was added, and the reaction mixture was heated to reflux for 10 hours. The reaction mixture was cooled and partitioned between EtOAc and water. The organic layer was washed with water (2×), brine, and dried over Na2SO4 and concentrated. The resulting residue was purified by column chromatography (4:1 to 0:1 hexane/DCM) giving 3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (5.31 g, 74.1%).
Reaction SMILES: [CH2:1](N=C=O)C.[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:10]=[CH:9][C:8]=1[C:19](=[O:32])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])[CH:21]=1>>[NH2:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:10]=[CH:9][C:8]=1[C:19](=[O:32])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([NH:29][CH:30]([CH3:1])[CH3:31])=[O:28])[CH:21]=1
Reactant: CCN=C=O
Reactant: CCNC(=O)Oc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Product: CC(C)NC(=O)Oc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1

Procedure:
Replacing isopropyl isocyanate with ethyl isocyanate was made 5-amino-1-(4-fluorophenyl)-4-[3-ethylaminocarbonyloxybenzoyl]pyrazole (84). Mpt. 201.2-202.8° C.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[S:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO>[NH2:1][C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[S:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Sc2ccccc21
Reactant: [H][H]
Solvent: CO
Product: Nc1ccc(C(=O)N2Cc3ccccc3Sc3ccccc32)cc1
Yield: 89.2 %

Procedure:
A mixture of 2.2 g of 10,11-dihydro-10-(4-nitrobenzoyl)dibenz[b,f][1,4]thiazepine in 150 ml of methanol is shaken in a Parr hydrogenator under 50 pounds per square inch of hydrogen for 72 hours. The mixture is filtered through diatomaceous earth and the filtrate evaporated in vacuo. The residue is re-crystallized from chloroform-hexane to give 1.8 g of crystals, m.p. 52°-55° C.
Reaction SMILES: Br.[C:2]([N:5]1[CH2:9][C:8]([CH2:12]C)([CH2:10]C)[NH:7][C:6]1=[O:14])(=[NH:4])[NH2:3].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[CH:37]1([CH2:40][N:41]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=2)[C:42](=[O:50])[C:43]([C:48]#[N:49])=[CH:44]OCC)[CH2:39][CH2:38]1>>[C:48]([C:43]([C:42](=[O:50])[N:41]([CH2:40][CH:37]1[CH2:39][CH2:38]1)[C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:58])([F:60])[F:59])[CH:52]=1)=[CH:44][NH:3][C:2](=[NH:4])[N:5]1[CH2:9][C:8]([CH3:10])([CH3:12])[NH:7][C:6]1=[O:14])#[N:49]
Reactant: CCC1(CC)CN(C(=N)N)C(=O)N1
Reactant: CCOC=C(C#N)C(=O)N(CC1CC1)c1cccc(C(F)(F)F)c1
Agent: Br
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Product: CC1(C)CN(C(=N)NC=C(C#N)C(=O)N(CC2CC2)c2cccc(C(F)(F)F)c2)C(=O)N1
Yield: 35.4 %

Procedure:
Starting from 6.58 g (24.8 mmol) of 1-amidino-4,4-diethyl-2-oxoimidazolidine hydrobromide (comp. III: R1, R2 =C2H5 ; R3 =H as hydrobromide) and 3.87 g (26.1 mmol) of diazabicycloundecene (DBU) as auxiliary base and 7.40 g (24.8 mmol) of a compound IV (R4 =CH3 ; R5, R6 =H; R7 =C3H5) by the procedure described in Examples 82-84, 3.94 g (=36.4% yield) of pure 1-cyano-1-[N-methyl-N-(3-trifluoromethylphenyl)carbamoyl]-2-[imino(4,4-diethyl-2-oxo-1-imidazolidinyl)methylamino]ethene (comp. II: R1, R2 =C2H5 ; R3, R5, R6 =H; R4 =CH3) were obtained, melting point 184°-87°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:14])[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:19]O>>[F:1][C:2]1[CH:3]=[C:4]([OH:14])[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: CO
Reactant: O=C(O)c1cc(F)cc(O)c1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(F)cc(O)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 41 %

Procedure:
Crude 5-fluoro-3-hydroxy-2-nitrobenzoic acid (2.60 g, 12.92 mmol), was suspended in CH3OH (50 mL) and cooled to 0° C. Thionyl chloride (9.4 ml, 129.26 mmol) was added drop wise at 0° C. The mixture was allowed to warm to ambient temperature then heated to reflux for 17 h. The reaction mixture was allowed to cool to ambient temperature, and the solvent removed under reduced pressure. The crude material was purified by column chromatography (silica gel, 0 to 20% CH3OH in CH2Cl2) to afford methyl 5-fluoro-3-hydroxy-2-nitrobenzoate (1.15 g, 41%) as a white solid. 1H NMR and MS consistent.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.Cl.Cl.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C@H:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)N[C@H](C)c1ccc(CCl)cc1
Agent: Cl
Product: CC(=O)N[C@H](C)c1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using (R)-N-(1-(4-chloromethylphenyl)ethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(4-fluorophenyl)piperazine dihydrochloride instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=114-115° C.
Reaction SMILES: [N+]([C:4]([CH:7]1[CH:11]([O:12]C)[O:10][C:9](=[O:14])[CH2:8]1)([CH3:6])[CH3:5])([O-])=O.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH:11]([C:7](=[C:4]([CH3:6])[CH3:5])[CH2:8][C:9]([OH:14])=[O:10])=[O:12]
Reactant: COC1OC(=O)CC1C(C)(C)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)=C(C=O)CC(=O)O
Temperature: 0 °C
Reaction time: 120 h
Yield: 74.6 %

Procedure:
A solution of 18.2 g of the product of Step A in 25 ml of methanol were added all at once to a solution of 18.9 g of sodium carbonate in 180 ml of water cooled to 0° C. and the mixture stood at room temperature for 120 hours. The mixture was washed with ether and cooled to 0° C. after which concentrated sulfuric acid was added to the mixture under an inert atmosphere until the pH was ≃1. The mixture was extracted with chloroform and then with ethyl acetate and the combined organic phases were dried and evaporated to dryness under reduced pressure to obtain 9.5 g of residue. The latter was crystallized from water to obtain 7.4 g of pure 3-formyl-4-methyl-pent-3-one-1-oic acid melting at 102° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[ClH:14]>C1C=CC=CC=1.[Cl-].[Cd+2].[Cl-]>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:2]1[CH:10]=[CH:9][C:8]([Cl:14])=[CH:7][CH:3]=1)=[O:5]
Reactant: Cl
Reactant: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Agent: [Cd+2]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1c(C(=O)c2ccc(Cl)cc2)cccc1[N+](=O)[O-]
Temperature: 8 °C
Reaction time: 18 h

Procedure:
A mixture of 30 g of magnesium and 450 ml of ether was refluxed and then a solution of 191 g of p-chlorobromobenzene in 600 ml of ether was slowly added and reflux was continued for 11/2 hours after the addition. The mixture was cooled to 20° C to obtain an ether solution of 0.7N p-chlorophenyl magnesium bromide. After cooling 800 ml of the solution to 10° C, 55.7 g of cadmium chloride were added thereto and the ether was distilled off while adding benzene as a replacement. After obtaining 1 1 of distillate, it was cooled to 8° C and a solution of 110 g of 2-methyl-3-nitro-benzoyl chloride in 550 ml of benzene was added thereto. The mixture stood for 18 hours and was then added to a mixture of 3,650 ml of icewater and 134 ml of hydrochloric acid. The mixture was filtered and the benzene phase was decanted. The aqueous phase was extracted with benzene and the combined benzene phases were washed with N hydrochloric acid, with water, with saturated aqueous sodium bicarbonate and finally with water. The organic phase was dried over sodium sulfate and evaporated to dryness under reduced pressure to obtain 147.3 g of 2-methyl-3-nitro-4'-chloro-benzophenone which was used as is in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].O>C1CCN2C(=NCCC2)CC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:22][CH2:23][C:24]([OH:26])=[O:25])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCC(=O)O
Reactant: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)CNc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Temperature: 150 °C

Procedure:
A mixture of (3-chloro-phenyl)-[4-(2-chloro-pyridin-4-yl)-pyrimidin-2-yl]-amine (10.0 g, 0.03 mol) and glycine (4.8 g, 0.06 ml) in DBU (100 ml) is heated at 150° C. under an atmosphere of argon for 40 hours. The still hot reaction mixture is poured into water. After washing the aqueous phase with ethyl acetate the pH is adjusted to 5 by adding citric acid. The resulting precipiate is filtered and recrystallized from dimethylformamide/ethanol to give the product in form of yellow crystals, m.p. 136–138° C. (with decomposition).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C@@H:15]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][N:16]2C(OC(C)(C)C)=O)=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([C@@H:15]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][NH:16]2)=[O:14])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCc1ccc(NC(=O)[C@@H]2Cc3ccccc3CN2)cc1
Reaction time: 2.5 h
Yield: 86 %

Procedure:
The product of step 1 was dissolved in methylene chloride (40 mL) and treated with trifluoroacetic acid (20 mL). After stirring for 2.5 hours the reaction was concentrated and the residue was partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic layer was removed and the aqueous layer was further basified with concentrated ammonium hydroxide (ca., 20 mL) and extracted with additional methylene chloride. The combined organic layers were dried (sodium sulfate) and concentrated. The resulting tacky, golden solid was triturated with diethyl ether and vacuum oven dried to afford 8.34 g (86%) of product as colorless platelets: 1H NMR (CDCl3) δ 9.25 (s, 1H), 7.54-7.48 (m, 2H), 7.26-7.04 (m, 6H), 4.10-3.98 (m, 2H), 3.67 (dd, J=10.4, 5.5 Hz, 1H), 3.35 (dd, J=16.4, 5.5 Hz, 1H), 2.90 (dd, J=16.4, 10.4 Hz, 1H), 2.57 (t, J=7.6 Hz, 2H), 1.64-1.54 (m, 2H), 1.39-1.24 (m, 4H), 0.88 (t, J=6.8 Hz 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Br[CH2:17][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:17][CH2:18][CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH2:8][CH2:7]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1

Procedure:
A solution of the product from Example 1 step (ii) (2.0 g), 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione (1.61 g) and triethylamine (2.5 ml) in dichloromethane (40 ml) was heated under reflux for 48 h. The reaction mixture was partitioned between ethyl acetate/water, the organic layer dried and evaporated under reduced pressure. Purification was by chromatography eluting with 4% methanol/dichloromethane. Yield 0.839 g
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>CN(C)C=O>[Cl:25][CH2:24][CH2:23][CH2:22][N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: ClCCCBr
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(CCCCl)c2ccc(F)cc2)cc1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 10.6 parts of N-(4-fluoro-phenyl)-4-methylbenzenesulfonamide in 68 parts of N,N-dimethylformamide were added portionwise 2.1 parts of a sodium hydride dispersion 50%: temp. roses to 35° C. After stirring for 20 minutes, the whole was cooled in an ice-bath (about 15° C.) and 12.6 parts of 1-bromo-3-chloropropane were added quickly. Stirring was continued first for 20 minutes at room temperature, then for 3 hours at 75° C. and further overnight at room temperature. The reaction mixture was poured onto ice-water and the prcduct was extracted with methylbenzene. The extract was washed three times with water, dried, filtered and evaporated. The residue was crystallized from petroleumether. The product was filtered off and recrystallized from 2,2'-oxybispropane, yielding 11.37 parts (83.2%) of -N-(3-chloropropyl)-N-(4-fluorophenyl)-4-methylbenzenesulfonamide (intermediate 83).
Reaction SMILES: O.[CH2:2]([CH:8]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:17](O)[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:2]([CH:8]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCO
Reactant: CCCCCCC1C(=O)CCC1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCC1C(=O)CCC1C(=O)OCC

Procedure:
In a 1 L flask, to which is attached a water separator under a reflux condenser, is placed a solution of 20 g of 2-n-hexyl-3-oxo-cyclopentanecarboxylic acid, 9,5 g of absolute ethanol and 1 g of p-toluenesulphonic acid in 500 ml of benzene. The reaction mixture is refluxed until no more water separates. The reaction mixture is then cooled and washed successively with water and sodium carbonate solution and dried over anhydrous sodium sulphate. The solvent is removed by distillation at atmospheric pressure and the residue is distilled through a short Vigreux column. Ethyl 2-n-hexyl-3-oxo-cyclopentanecarboxylate is collected at 102°C/0.25 mm, yield 19,5 g (86%), nD20 1.4535.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH3:32])[CH2:28][CH2:27]4)[C:15]([C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH2:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:33]3[NH:37][C:36](=[O:38])[O:35][N:34]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:39][O-:40].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:25][C@H:26]4[CH2:27][CH2:28][C@H:29]([CH3:32])[CH2:30][CH2:31]4)[C:15]([CH:17]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:18][O:40][CH3:39])=[N:16][C:12]=3[CH:11]=[C:10]([C:33]3[NH:37][C:36](=[O:38])[O:35][N:34]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: C=C(c1ccccc1)c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Agent: [Na+]
Solvent: CO
Product: COCC(c1ccccc1)c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 75 °C

Procedure:
3-[4-(5-Chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(1-phenylethenyl)-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one (Example 9.1, 130 mg, 0.247 mmol) was taken up in methanol (1.644 mL) at room temperature, and sodium methoxide (1.2 mL of 25 wt % in methanol, 5.25 mmol) was added. The mixture was capped and heated to 75° C. for 24 hours. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified via automated reverse phase HPLC (methanol/water+0.1% TFA modifier) to afford 3-{4-(5-chloropyridin-3-yl)-2-(2-methoxy-1-phenylethyl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (TFA salt) as a white solid. MS ESI calcd. for C30H31ClN6O3 [M+H]+ 559. found 559. 1H NMR (500 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.83 (s, 2H), 8.40 (s, 1H), 8.32 (s, 1H), 7.58-7.48 (m, 2H), 7.31-7.25 (m, 3H), 4.80-4.75 (m, 1H), 4.21-4.15 (m, 1H), 3.90-3.80 (m, 3H), 3.25 (s, 3H), 1.42-1.35 (m, 1H), 1.29-1.20 (m, 2H), 1.04-0.94 (m, 1H), 0.75-0.64 (m, 5H), 0.40-0.29 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH3:2].C(=O)(OCC)O[CH2:12][CH3:13].[Mg].[Al]>>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:12][CH3:13])[CH3:2]
Reactant: CCOC(=O)OCC
Reactant: CCOCCOCCO
Agent: [Al]
Agent: [Mg]
Product: CCOCCOCCOCC
Reaction time: 1 h

Procedure:
A mixture of 2-(2-ethoxyethoxy)ethanol (1 mole) and diethyl carbonate (3 mole) was passed through 11.5 grams of a magnesium:aluminum mixed metal oxide (3/16 inch pellets, Mg/Al 3:1) at a temperature of 225° C. and at a liquid feed rate of 0.29 milliliters/minute. After a period of one hour, a total of 30.2 grams of liquid was collected. Analysis was performed by capillary gas chromatography (FID) using a DB-1701 column. The results were (area %) as follows:
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]([CH3:25])([CH3:24])[CH:14](O)[CH2:15][C:16]2[N+:21]([O-:22])=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)#[N:7].C(N(CC)CC)C>ClCCl>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]([CH3:24])([CH3:25])/[CH:14]=[CH:15]/[C:16]2[N+:21]([O-:22])=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:26][CH:27]=1)#[N:7]
Reactant: CC(C)(Oc1ccc(C#N)cc1)C(O)Cc1ccnc[n+]1[O-]
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(/C=C/c1ccnc[n+]1[O-])Oc1ccc(C#N)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
0.23 g of methanesulphonyl chloride was added to a solution of 0.59 g of 6-[3-(4-cyanophenoxy)-2-hydroxy- 3-methylbutyl]pyrimidine 1-oxide and 0.2 g of triethylamine in 10 ml of dichloromethane. The mixture was stirred at 20° C. for 2 hours and then a further 0.46 g of methanesulphonyl chloride and 0.4 g of triethylamine were added. After 2 hours a further 0.6 g of triethylamine was added and the mixture was stirred for 1.5 hours. The mixture was then washed with water and evaporated. The residue was chromatographed on silica gel using ethyl acetate for the elution to give 0.25 g of (E)-6-[3-(4-cyanophenoxy)-3-methyl-1-butenyl]pyrimidine 1-oxide in the form of a pale yellow solid of melting point 101°-102° C.