Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[O:19][C:18]([C:20]([O:22][CH3:23])=[O:21])=[N:17][N:16]=2)[CH2:11][CH2:10]1)=[O:7])(C)(C)C.[Cl:24][C:25]1[C:29]([Cl:30])=[C:28](C)[NH:27][C:26]=1[C:32](NC1CCN(C2SC(C#N)=C(O)N=2)CC1)=O>>[Cl:30][C:29]1[C:25]([Cl:24])=[C:26]([CH3:32])[NH:27][C:28]=1[C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[O:19][C:18]([C:20]([O:22][CH3:23])=[O:21])=[N:17][N:16]=2)[CH2:13][CH2:14]1)=[O:7]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3nc(O)c(C#N)s3)CC2)c(Cl)c1Cl
Reactant: COC(=O)c1nnc(N2CCC(NC(=O)OC(C)(C)C)CC2)o1
Product: COC(=O)c1nnc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)o1

Procedure:
The title compound was synthesized by an analogous method to Example 42 by coupling methyl 5-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1,3,4-oxadiazole-2-carboxylate (Intermediate 160) with 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3). De-BOC and coupling should be separate steps.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([CH3:11])[C:3]=1[C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH:20](OCC)(OCC)[O:21][CH2:22][CH3:23]>C(OC(=O)C)(=O)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([CH3:11])[C:3]=1[C:12]([C:13](=[CH:20][O:21][CH2:22][CH3:23])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)c1c(C)c(F)c(F)c(F)c1F
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A solution of 8.1 g (29.1 mmol) of ethyl 3-(2,3,4,5-tetrafluoro-6-methylphenyl)-β-oxopropanoate, 7.2 g (43.3 mmol) of triethyl orthoformate, and 70 ml of acetic anhydride was refluxed for 3.5 hours. The solution was cooled to room temperature and concentrated under high vacuum to give 9.1 g of the title compound. The product was used as is in the next step.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[C:24]([O:28][C:29]([N-:31][S:32](N1C=CC(=[N+](C)C)C=C1)(=[O:34])=[O:33])=[O:30])([CH3:27])([CH3:26])[CH3:25]>C(#N)C.C(OCC)(=O)C>[C:24]([O:28][C:29]([NH:31][S:32]([NH:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1)(=[O:34])=[O:33])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](N)C1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NS(=O)(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a solution of tert-butyl (6R,7S)-6-amino-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (300 mg) in acetonitrile (5 mL) was added N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide (375 mg) prepared by the method described in Organic Letters, 3 (14), 2241-2243 (2001), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (200 mg).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([O:13]CC)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[NH2:2].[OH-].[Li+]>CCO.O>[C:1]([CH:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)C(c1ccccc1)N1CCC(C(N)=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=O)C1CCN(C(C(=O)O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
Ethyl 2-(4-carbamoylpiperidin-1-yl)-2-phenylacetate (202 mg, 0.69 mmol) was dissolved in a mixture EtOH (4.6 ml) and water (2.3 ml), and lithium hydroxide (50.0 mg, 2.09 mmol) was added. The reaction was stirred at room temperature overnight. LiOH (33.3 mg, 1.39 mmol) was added in two portions in the following two days. EtOH was evaporated and 1N HCl was added dropwise to the aqueous solution till pH 6-7. The solution was evaporated and the residue was purified by flash chromatography (DCM/MeOH=7/3 to 6/4) to obtain 2-(4-carbamoylpiperidin-1-yl)-2-phenylacetic acid (155 mg, 85% yield) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]([CH3:23])[C:8]2[N:13]=[C:12]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[N:16]=[CH:15]3)[CH:11]=[CH:10][N:9]=2)[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[C:33]1([S:39]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([N:7]([CH3:23])[C:8]3[N:13]=[C:12]([N:14]4[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[N:16]=[CH:15]4)[CH:11]=[CH:10][N:9]=3)[CH2:2]2)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCCN(S(=O)(=O)c2ccccc2)C1
Reaction time: 1 h
Yield: 48 %

Procedure:
To a stirred solution of 2-[(piperidin-3-yl)-methylamino]-4-[benzimidazol-1-yl]pyrimidine (20 mg, 0.065 mmol, 1 eq) in THF (1 mL) at 0° C. was added diisopropylethylamine (0.023 mL, 0.13 mmol, 2 eq) followed by addition of benzenesulfonylchloride (0.009 mL, 0.071 mmol, 1.1 eq) via syringe. Removed the cooling bath and let stir for 1 h. Quenched the reaction with saturated aqueous NaHCO3 and extracted 3× with CH2Cl2. Combined the organic extracts, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (eluted with 2:1 hexanes/acetone) to give 14 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 1.1-1.2 (1H, m), 1.6-1.9 (4H, m), 2.12 (1H, m), 2.42 (1H, t, J=10 Hz), 2.57 (1H, t, J=10 Hz), 3.4-3.6 (2H, m), 3.63 (1H, d, J=8.5 Hz), 5.6 (1H, br s), 6.84 (1H, d, J=5.5 Hz), 7.3-7.8 (7H, m), 7.88 (1H, d, J=7 Hz), 8.18 (1H, d, J=7 Hz), 8.41 (1H, d, J=5.5 Hz), 8.62 (1H, s). Mass spectrum (CI) 449.1 (M+1).
Reaction SMILES: [C:1]([C:9]1[CH:24]=[CH:23][C:12]([CH:13]=[CH:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:26]1[CH:27]=[C:28]([O:34][CH3:35])[C:29]([O:32][CH3:33])=[CH:30][CH:31]=1>>[C:1]([C:9]1[CH:24]=[CH:23][C:12](/[C:13](/[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)=[CH:14]\[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)cc1OC
Reactant: O=C(c1ccccc1)c1ccc(C=CC(=O)N2CCOCC2)cc1
Product: COc1ccc(/C(=C/C(=O)N2CCOCC2)c2ccc(C(=O)c3ccccc3)cc2)cc1OC

Procedure:
This compound was obtained analogous to Example 23 by reacting 4-benzoylcinnamic acid morpholide and 4-bromoveratrole.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][NH:6][CH:7]=1.[O:15]1CCC[CH2:16]1.C=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[OH:15][CH2:16][N:6]1[CH:7]=[C:3]([C:2]([F:1])([F:13])[F:14])[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5]1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1c[nH]cc1C(F)(F)F
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1cn(CO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
207 mg of 4-trifluoromethyl-3-ethoxycarbonyl-1H-pyrole, 5 ml of tetrahydrofuran and 5 ml of formaldehyde 36% in water were mixed. 0.2 ml of tetrabutylammonium hydroxide 10% in water was added to the mixture at room temperature, followed by stirring at room temperature for 10 minutes. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain crude product of 1-hydroxymethyl-4-trifluoromethyl-3-ethoxycarbonyl-1H-pyrole.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[NH:9]1[CH:13]=[N:12][C:11]([S:14]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:16])=[O:15])=[N:10]1.Cl>N1C=CC=CC=1>[CH:18]1([CH2:17][S:14]([C:11]2[N:12]=[CH:13][N:9]([C:4]([N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:5])[N:10]=2)(=[O:16])=[O:15])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=S(=O)(CC1CCCC1)c1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1cnc(S(=O)(=O)CC2CCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
Diethylcarbamoyl chloride (0.65 ml; 5.08 mmol) was added to cyclopentylmethyl 1,2,4-triazol-3-yl sulfone (1.00 g; 4.65 mmol) in dry pyridine (5 ml) under dry nitrogen, and the solution stirred at room temperature overnight. The resulting mixture was poured into 2M hydrochloric acid (20 ml) at 3° C. and the mixture extracted into ethyl acetate (3×30 ml). The extracts were combined, dried (Na2SO4), filtered and evaporated, to afford 3-(cyclopentylmethylsulfonyl)-N,N-diethyl-1,2,4-triazole-1-carboxamide (1.44 g; 99%) as white crystals, m.p. 77°-79° C., (Found, C: 49.82; H: 6.75; N: 17.96; S: 10.44. C13H22N4O3S requires C: 49.66; H: 7.05; N: 17.82; S: 10.20%) NMR - d(CDCl3 ; 60 MHz) 1.0-2.6 (15H, m), 3.3-3.8 (6H, m) and 9.0 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:31]([O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)[CH3:32]>CN(C1C=CN=CC=1)C>[CH2:31]([O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:18](=[O:19])[CH:17]([C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:37][CH:36]=1)[CH3:32]
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)cc1

Procedure:
In analogy to the procedure described in example 6, [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (example 5.1) was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 4-amino-benzoic acid ethyl ester (CAS Reg. No. 94-09-7) in the presence of DMAP to give the title compound as yellow oil. MS: m/e=520.4 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:22]([C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[F:19])=[O:23])=[CH:14][CH:13]=2)=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1nc2cc(Cl)c(-c3ccc(N)cc3)cc2o1
Reactant: O=C(Cl)c1ccccc1F
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc2cc(Cl)c(-c3ccc(NC(=O)c4ccccc4F)cc3)cc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.5 %

Procedure:
To a solution of 4-(5-chloro-2-methylbenzoxazol-6-yl)phenylamine (56) (23 mg, 0.089 mmol) and 2 mg DMAP in 2 ml DCM was added 2-fluorobenzoyl chloride (214.0.18 mmol) followed by addition of DIEA (78 μl). The resulting brown solution was stirred at r.t. for 3 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (200 μl) at r.t. for 2 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 19.5 mg 57 as off-white solid. (yield: 57.5%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[N:18]=[C:19](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:20][CH:21]=2)=[CH:11][CH:10]=1)(=O)=O.[NH:30]1[C:34]([C:35]([NH2:37])=[O:36])=[C:33]([C:38]([NH2:40])=[O:39])[N:32]=[CH:31]1>>[C:24]1(/[CH:23]=[CH:22]/[C:19]2[O:20][CH:21]=[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:30]4[C:34]([C:35]([NH2:37])=[O:36])=[C:33]([C:38]([NH2:40])=[O:39])[N:32]=[CH:31]4)=[CH:14][CH:13]=3)[N:18]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC(=O)c1nc[nH]c1C(N)=O
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: NC(=O)c1ncn(CCCc2ccc(OCc3coc(/C=C/c4ccccc4)n3)cc2)c1C(N)=O
Yield: 44 %

Procedure:
In substantially the same manner as in Working Example 25, 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate was allowed to react with 4,5-imidazoledicarboxamide to give 1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-4,5-imidazoledicarboxamide. The yield was 44%. Recrystallization from ethyl acetate gave colorless prisms, mp 194-195° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][C:6]=1[F:12])(=[O:4])=[O:3].[CH3:13][O:14][C:15]([C:17]1[CH:27]=[C:26]([OH:28])[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:13][O:14][C:15]([C:17]1[CH:27]=[C:26]([O:28][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[C:6]([F:12])[CH:7]=2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16]
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)c(F)c2)c2c(c1)OC(C)(C)C2
Temperature: 80 °C
Yield: 67.6 %

Procedure:
A mixture of 2,4-difluorophenyl methyl sulfone (865 mg, 4.50 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (1.00 g, 4.50 mmol), and Cs2CO3 (2.93 g, 9.00 mmol) in DMF (2 mL) was heated to 80° C. for 2.5 h, cooled to room temperature, quenched with H2O and extracted with 3× EtOAc. The organic layers were washed with 2×H2O, dried over Na2SO4 and concentrated. The residue was purified by Biotage column chromatography with 15%-40% EtOAc in hexanes to give a white solid (1.20 g, 68% yield). 1H NMR (400 MHz, CDCl3) δ 7.82-7.95 (m, 1 H) 7.21-7.34 (m, 2 H) 6.72-6.88 (m, 2 H) 3.90 (s, 3 H) 3.22 (s, 3 H) 2.90 (s, 2 H) 1.48 (s, 6 H); LCMS for C19H19FO6S m/z 395.00 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH3:31][S-:32].[Na+]>C1COCC1.CCOC(C)=O>[CH3:31][S:32][CH2:2][C:3]1[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: C[S-]
Reactant: CC[C@H](NC(=O)c1c(CBr)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1c(CSC)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reaction time: 1.5 h
Yield: 92.7 %

Procedure:
To a stirring solution of 3-(bromomethyl)-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (8) (2.9 g, 6.32 mmol) in anhydrous THF (35 mL) under N2 was added sodium thiomethoxide (NaSMe, 880 mg, 12.64 mmol) and reaction stirred 1.5 h. It was then diluted with EtOAc; washed with aqueous 0.3 N NaOH, then H2O, then brine; dried over Na2SO4; filtered; and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-15% EtOAc/CH2Cl2) to give the desired product (2.5 g, 90% yield) as a solid. 1H NMR (300 MHz, CDCl3, 52° C.) δ 8.10 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.72-7.60 (m, 3H), 7.53-7.25 (m, 9H), 6.68 (d, J=7.8 Hz, 1H), 5.29 (q, J=7.6 Hz, 1H), 3.79 (q, J=13.7 Hz, 2H), 2.19-1.90 (m, 2H), 1.77 (s, 3H), 1.03 (t, J=7.4 Hz, 3H); LCMS: m/z 427 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:13][O:14][CH3:15])[C:9](OC)=[O:10].OC1C=CC=CC=1/[C:23](=[N:28]/OC)/C(OC)=O.CN.CO>O1CCCC1>[CH3:23][NH:28][C:9](=[O:10])[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])=[N:13][O:14][CH3:15]
Reactant: CON=C(C(=O)OC)c1ccccc1O
Reactant: CO/N=C(\C(=O)OC)c1ccccc1O
Agent: CN
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)C(=NOC)c1ccccc1O
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
0.5 g (0.0013 mol) of methyl 2-(2-hydroxyphenyl)-2-methoxyimino-acetate (in particular Example II-Id from process step 4; HPLC: 54.4% methyl Z-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=2.39 is disolved in 6 ml of tetrahydrofuran and cooled to 10° C. With cooling, methylamine is introduced. After about 30 minutes, 2 ml of methanol are added, the solution is saturated with methylamine and the mixture is allowed to stand at 10° C. overnight. The solvents are distilled off under reduced pressure and the residue is mixed with a mixture of 5 ml of 2 N hydrochloric acid and 5 ml of saturated sodium chloride solution and extracted three times with 10 ml of ethyl acetate each time. The organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure, giving 0.6 g of crude product. This crude product is chromatographed with a mixture of 7 parts of n-hexane and 3 parts of acetone on silica gel. This gives 0.4 g of product which, according to HPLC, contains 99.2% N-methyl-Z-2-(2-hydroxyphenyl)-2-methoxyiminoacetamide of log p=1.29.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([O:20][CH3:21])[CH:4]=1.[C-:22]#[N:23].[K+].C1OCCOCCOCCOCCOCCOC1.O>CN(C)C=O>[CH3:21][O:20][C:5]1[CH:4]=[C:3]([CH2:2][C:22]#[N:23])[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(CBr)c3o2)cc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cc3cc(OC)cc(CC#N)c3o2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of benzyl bromide 17 (0.640 g, 1.843 mmole) in 100 mL dimethylformamide was added pulverized potassium cyanide (0.186 g, 2.76 mmole) and 18-crown-6 ether (0.786 g, 2.965 mmole). After stirring at 80° C. for 2 hours, the reaction mixture was cooled and poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 9:1) to afford 0.529 g (98%) of acetonitrile 18 as a white solid: Mp=149-150° C.; 1H NMR (DMSO-d6) δ 7.87 (d, 2 H, J=8.8 Hz), 7.26 (s, 1 H), 7.12 (d, 1 H, J=2.4 Hz),), 7.10 (d, 2 H, J=8.7 Hz), 6.88 (d, 1 H, J=2.4 Hz), 4.42 (s, 2 H), 3.82 (s, 3 H), 3.81 (s, 3 H); MS 294 (M+H)+
Reaction SMILES: [OH:1][CH:2]([CH2:29][CH2:30][CH3:31])[C:3]#[C:4][C:5]1[C:6]([F:28])=[C:7]([F:27])[C:8]([F:26])=[C:9]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH:10]=1.[H][H]>[C].[Pd].C(O)C>[OH:1][CH:2]([CH2:29][CH2:30][CH3:31])[CH2:3][CH2:4][C:5]1[C:6]([F:28])=[C:7]([F:27])[C:8]([F:26])=[C:9]([C@H:11]2[CH2:12][CH2:13][C@H:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]3)[CH2:15][CH2:16]2)[CH:10]=1
Reactant: [H][H]
Reactant: CCCC(O)C#Cc1cc([C@H]2CC[C@H]([C@H]3CC[C@H](CCC)CC3)CC2)c(F)c(F)c1F
Agent: [Pd]
Solvent: CCO
Product: CCCC(O)CCc1cc([C@H]2CC[C@H]([C@H]3CC[C@H](CCC)CC3)CC2)c(F)c(F)c1F
Reaction time: 8 h

Procedure:
To 20 g of 5-(3-hydroxy-1-hexynyl)-2,3,4-trifluoro-1-[trans-4-(trans-4-propylcyclohexyl) cyclohexyl]benzene which was dissolved into 80 mL of ethanol, 2 g of 5% palladium carbon (50% in water) was added, stirred for 6 hours at a hydrogen pressure of 0.5 MPa, and was then left to stand overnight. After palladium carbon was removed by filtration, the solvent was evaporated under a reduced pressure to obtain 10 g of 5-(3-hydroxy-1-hexyl)-2,3,4-trifluoro-1-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]benzene.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10](=O)[CH3:11])[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[NH2:23])([CH3:15])[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC>[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[N:23]=[C:10]([C:8]1[N:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][CH:7]=1)[CH3:11])([CH3:15])[CH3:14]
Reactant: Cc1cccc(C(C)C)c1N
Reactant: CC(=O)c1cccc(C(C)=O)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCO
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cccc2C(C)C)n1

Procedure:
1-(6-Acetyl-pyridin-2-yl)-ethanone 2 (35.54 g, 0.22 mol), 25.0 g (0.168 mol) of 2-Isopropyl-6-methyl-phenylamine 14, 350 ml of n-propanol, and a few crystals of p-toluenesulfonic acid were stirred at room temperature for 36 h in a 500 ml flask under a flow of the nitrogen. The resultant yellow precipitate was filtered and washed by 20 ml of methanol. It was then dried at 1-mm vacuum overnight. The yield of 1-{6-[1-(2-Isopropyl-6-methyl-phenylimino)-ethyl]pyridin-2-yl}-ethanone 15 was 13.35 g (27%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:37]([C:39]1[C:40]([N:49]2[CH2:54][CH2:53][CH:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:51][CH2:50]2)=[CH:41][C:42]([O:46][CH2:47][CH3:48])=[C:43]([CH:45]=1)[NH2:44])[CH3:38].Cl.O1CCOCC1.N>CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:43]3[CH:45]=[C:39]([CH2:37][CH3:38])[C:40]([N:49]4[CH2:50][CH2:51][CH:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:53][CH2:54]4)=[CH:41][C:42]=3[O:46][CH2:47][CH3:48])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(CC)cc1N
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: CCOc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(CC)cc1Nc1nccc(-c2c(-c3ccc(OCC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 58 %

Procedure:
In a microwave vial with septum cap, 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.148 g, 0.293 mmol) and 5-ethyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}aniline (0.104 g, 0.293 mmol) were taken up in 1,1,1-trifluoroethanol (1.5 mL) and 4M HCl in dioxane (0.147 mL, 0.587 mmol) was added. The vial was sealed and heated in the microwave at 180° C. for 40 min. Reaction was complete by MS, it was cooled to rt, neutralized with 7N ammonia in MeOH, and concentrated in vacuo onto silica gel and flash chromatographed. The desired fractions were combined and concentrated and the resulting solid was triturated with diethyl ether, filtered and air dried to give the title compound (0.14 g, 0.17 mmol, 58%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.70 (s, 1H), 9.29 (d, J=6.8 Hz, 1H), 8.34 (s, 1H), 8.23 (d, J=5.2 Hz, 1H), 8.03 (s, 1H), 7.61-7.79 (m, 2H), 7.55 (s, 1H), 7.29-7.48 (m, 2H), 7.08-7.28 (m, 3H), 6.89 (t, J=6.8 Hz, 1H), 6.76 (s, 1H), 6.56 (d, J=5.1 Hz, 1H), 4.23 (q, J=6.7 Hz, 2H), 4.03 (q, J=6.9 Hz, 2H), 3.07-3.20 (m, 2H), 2.84-3.04 (m, 5H), 2.60 (t, J=10.9 Hz, 2H), 2.51 (q, J=7.5 Hz, 2H), 1.75 (d, J=11.2 Hz, 2H), 1.60-1.70 (m, 2H), 1.35-1.55 (m, 4H), 1.15-1.36 (m, 5H), 1.05 (td, J=7.2, 1.9 Hz, 3H). MS (M+H, ES+) 824.