Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:28])[F:27])=[N:19]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:32][C:33](=O)[CH2:34][C:35]1[NH:39][CH:38]=[N:37][N:36]=1)C.[C-]#N.[Na+].CS(C)=O>CCOC(C)=O>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:27])[F:28])=[N:19]3)[CH2:11][CH2:12][N:13]1[C:33](=[O:32])[CH2:34][C:35]1[NH:36][N:37]=[CH:38][N:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1nnc[nH]1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCN(C(=O)Cc3ncn[nH]3)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Temperature: 25 °C
Yield: 0.7 %

Procedure:
A solution of (S)-5-(3-benzylpiperazin-1-yl)-8-methoxy-2-(trifluoromethyl)quinoline (Example 65, Compound 153) (100.0 mg, 0.25 mmol), (4H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester (83 mg, 0.50 mmol), sodium cyanide (24 mg, 0.50 mmol), and DMSO (2 mL). The reaction mixture was heated in a heat block at 100 C for 24 h then cooled to room temperature, diluted with EtOAc, and washed with water followed by brine. The organic portion was dried over MgSO4, filtered, evaporated and purified by silica gel flash chromatography to afford product as a colorless solid (0.9 mg, 0.7%). LC/MS (Method B) 3.32 min, [m/z=510.9].
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1>C(O)C.O.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 60.1 %

Procedure:
A mixture of 2.00 g (6.6 mmole) of 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 1.655 g (12.08 mmole) of 4-amino-benzoic acid and 200 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then concentrated under reduced pressure. The solid was washed with water and then purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (92:8:0.3) to give 1.600 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-11).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:5]=[CH:4][N:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][N:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[S:25]([CH3:24])(=[O:27])=[O:26])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(-c2cccc(CNCCc3ccncc3)c2)n1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N(CCc1ccncc1)Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 20 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 403.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11].[N+:19]([O-])([O:21]C(C)C)=[O:20]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[OH:6][C:7]1[C:8]([N+:19]([O-:21])=[O:20])=[C:9]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:10]([O:12][CH3:13])=[O:11]
Reactant: CC(C)O[N+](=O)[O-]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(O)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Sulfuric acid (3.0 mL, 56 mmol) was added dropwise over 2 min to a solution of methyl 3-hydroxy-4-methoxybenzoate (3.64 g, 20 mmol), tetrabutylammonium hydrogensulfate (340 mg, 1.0 mmol), isopropyl nitrate (5.0 mL, 50 mmol), and dichloromethane (40 mL) at 0° C. The reaction was allowed to warm to rt, maintained for 45 min, and then quenched with ice water (100 mL). This mixture was extracted with dichloromethane (250 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (4:1→3:7; hexanes:ethyl acetate) to give methyl 3-hydroxy-4-methoxy-2-nitrobenzoate: MS (ESI): 228.4.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH2:21](Br)[CH:22]=[CH2:23].C1CCN2C(=NCCC2)CC1>ClCCl.CCOC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:18])[C:15]([O:17][CH2:23][CH:22]=[CH2:21])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(I)cc21
Reactant: C=CCBr
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=CCOc1cc2c(cc1I)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 2 h
Yield: 69.8 %

Procedure:
A solution of N-trifluoroacetyl-7-hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (30 mg, 0.075 mmol) in dichloromethane (2 mL) was treated with allyl bromide (18 mg, 0.15 mmol), DBU (23 mg, 0.15 mmol) and stirred 2 hours at 20 C. to The product mixture was diluted with EtOAc (10 mL), washed with 5% aqueous HCl (5 mL), brine (5 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 23 mg of a clear oil. MS calculated for C16H17F3INO2+H: 440, observed: 440.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([I:15])[N:12]=[C:11]1[CH2:16][CH2:17][CH3:18])(C)(C)C.[ClH:20].O1CCOCC1>C(Cl)Cl>[I:15][C:13]1[N:12]=[C:11]([CH2:16][CH2:17][CH3:18])[N:10]([CH2:9][CH2:8][NH2:7])[CH:14]=1.[ClH:20]
Reactant: CCCc1nc(I)cn1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCc1nc(I)cn1CCN
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of [2-(4-iodo-2-propyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (6.110 g; 16.111 mmol) in DCM (100 ml) was added slowly 4N HCl in dioxane (80.5 ml; 322 mmol; 20 eq.). The resulting suspension was stirred at 0° C. for 15 min., and then at rt for 2 h. The volatiles were removed under reduced pressure, then under HV. The product 2-(4-iodo-2-propyl-imidazol-1-yl)-ethylamine was obtained as a colorless solid (5.620 g; 100%; presence of 2 eq. of HCl). LC-MS: tR=0.24 min.; [M+H]+=279.96 g/mol.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH2:27][C:28]([O:30]CC)=[O:29].[OH-].[Na+].Cl>CO>[OH:1][CH:2]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][CH:18]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCCCCCCOc1ccc(COc2cccc3c2CC(CC(=O)OCC)C3O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCOc1ccc(COc2cccc3c2CC(CC(=O)O)C3O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
In 10 ml of methanol was dissolved 380 mg of ethyl 1-hydroxy-4-(p-heptyloxybenzyloxy)-2-indaneacetate obtained in Example 100 and, 2.5 ml of a 5% sodium hydroxide solution was added thereto followed by stirring at room temperature for 8 hours The system was rendered acidic with 20% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed subsequently with water and then a saturated saline aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystalline residue was recrystallized from ethyl acetate-hexane to obtain 230 mg of 1-hydroxy-4-(p-heptyloxybenzyloxy)-2-indaneacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][CH:20]([OH:22])[CH3:21])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])=[N:7][C:6]=2[CH:17]=1.CO.O>CC(C)=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][C:20](=[O:22])[CH3:21])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])=[N:7][C:6]=2[CH:17]=1
Reactant: CC(O)CCc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(=O)CCc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12
Reaction time: 2.5 h
Yield: 65.8 %

Procedure:
7.54 ml of Kiliani solution (30.2 mmol of 0) was added over 6 minutes to a solution of 8.80 g (26.2 mmol) of 5-chloro-2-(2-chlorophenyl)-7-(3-hydroxybutyl)-benzoxazole in 90 ml of acetone at −5° to 0° C. After 2.5 hours, 5 ml of methanol and 50 ml of water was added. The acetone was removed in vacuo, the solid suspended, collected, washed with 0.1 N sulfuric acid until colorless and water and dried to give 8.68 g of crude product, which was dissolved in 35 ml of dichloromethane and filtered through 260 g of silica gel. A first fraction of 100 mg was discarded then 5.94 g were recovered and crystallized from di-isopropyl ether to give 5.76 g (65.8%) of title compound, mp 109-10° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH:6]([C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)[CH2:7][C:8](=[O:21])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]=[C:17]([NH2:19])[N:16]=[C:15]([NH2:20])[CH:14]=1)C.[Li+].[OH-]>C1COCC1.O>[NH2:19][C:17]1[N:16]=[C:15]([NH2:20])[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][C:8](=[O:21])[CH2:7][CH:6]([C:22]2[CH:27]=[N:26][C:25]([CH3:28])=[N:24][CH:23]=2)[CH2:5][C:4]([OH:29])=[O:3])[N:18]=1
Reactant: CCOC(=O)CC(CC(=O)CCCCc1cc(N)nc(N)n1)c1cnc(C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncc(C(CC(=O)O)CC(=O)CCCCc2cc(N)nc(N)n2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The ester 15-6 (20 mg, 0.05 mmol) in THF (10 mL) and water (10 mL) was treated with 1 N LiOH (1.0 mL, 1.0 mmol). After stirring at room temperature for 1 hour, the solution was concentrated to 5 mL and purified by reverse phase HPLC (preppak C-18 column; water/acetonitrile/0.1% TFA gradient). After lyophilization, the title compound 15-7 (TFA salt) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:14].[C:15]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CC(=O)OCC>[Cl:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: Oc1ccc(S(F)(F)(F)(F)F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1ccc(S(F)(F)(F)(F)F)cc1Cl
Reaction time: 48 h
Yield: 93.1 %

Procedure:
5.50 g of 2-chloro-4-pentafluorosulfanylphenol, 7.89 g of K2CO3 and 4.05 g of CH3I were stirred at RT in 30 ml of anhydrous DMF for 2 hours and left to stand at RT for 2 days. The mixture was then diluted with 300 ml of EA and washed 3 times with 100 ml each time of water. Drying was effected with Na2SO4 and the solvent was removed under reduced pressure to obtain 5.40 g of a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[IH:32]>ClCCl>[IH:32].[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][N:20]1[C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=2[N:17]=[C:16]1[C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2Cc2ccccn2)CC1
Agent: I
Solvent: ClCCl
Product: O=C(c1nc2ccccc2n1Cc1ccccn1)C1CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(pyrid-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine (1.96 g, 4.7 mmol) and dichloromethane (150 mL). Cool to 0° C. using an ice bath. Add hydriodic acid (gas) until the solution is saturated and stir. After 30 minutes, again add hydriodic acid (gas) until the solution is saturated. After 2 hours, evaporate in vacuo to give, after drying, the title compound: mp 165-167° C.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([F:21])=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:11]=3[CH2:10][C:9](=[O:19])[C:8]=2[CH:20]=1>O.[OH-].[Na+].O1CCOCC1>[Cl:3][C:4]1[C:5]([F:21])=[CH:6][C:7]2[S:13][C:12]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:11]=3[CH2:10][CH:9]([OH:19])[C:8]=2[CH:20]=1
Reactant: O=C1Cc2ccc(F)cc2Sc2cc(F)c(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: OC1Cc2ccc(F)cc2Sc2cc(F)c(Cl)cc21

Procedure:
A solution of sodium borohydride (1.0 g) in water (3 ml) containing 2 drops of 20% sodium hydroxide solution was added dropwise to a stirred solution of the ketone from the preceding experiment (7.9 g) in dioxane (100 ml). The mixture was refluxed for 6 hours, the dioxane evaporated in vacuo and the residue mixed with water and extracted with benzene. Evaporation of the extract and crystallization of the residue from an ether-cyclohexane mixture yielded 6.0 g of the pure 8-chloro-3,7-difluoro-10-hydroxy-10,11-dihydrodibenzo(b,f)thiepine, m.p. 84°-86° C.
Reaction SMILES: [N:1]1[N:2]([C:10]2[N:33]=[CH:32][CH:31]=[CH:30][C:11]=2[C:12]([NH:14][CH:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]([OH:22])[C:17]([O:19]CC)=[O:18])=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[OH-].[Li+]>C1COCC1.O>[N:1]1[N:2]([C:10]2[N:33]=[CH:32][CH:31]=[CH:30][C:11]=2[C:12]([NH:14][CH:15]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:16]([OH:22])[C:17]([OH:19])=[O:18])=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2ccccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1cc2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a suspension of ethyl 3-[2-(2H-indazol-2-yl)nicotinamido]-2-hydroxy-4-phenylbutanoate (1.05 g, 2.362 mmol) in THF (50 ml) a solution of lithium hydroxide (100 mg) in water (5 ml) was added, and the mixture was stirred overnight at room temperature. The mixture was then concentrated in vacuo and, after addition of water (100 ml), acidified using 2 N HCl. The precipitate formed was filtered off and dried to give 895 mg of the title compound as an off-white solid.
Reaction SMILES: CC1C=CC=CC=1C.[Cl:9][C:10]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=1[NH2:12].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][C:22]=1[C:31]([F:34])([F:33])[F:32]>N1C=CC=CC=1>[Cl:9][C:10]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=1[NH:12][S:27]([C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:31]([F:34])([F:32])[F:33])[CH:23]=1)(=[O:29])=[O:28]
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c(Cl)c1
Temperature: 25 °C

Procedure:
In a 400 ml flask, 200 ml of o-xylene, 1 ml of pyridine and 1.7 g (0.01 mole) of 2-chloro-4-nitroaniline were charged. While stirring the contents at room temperature, 2.8 g (0.01 mole) of 4-chloro-3-trifluoromethylbenzenesulfonylchloride was added dropwise at room temperature over 30 minutes. Thereafter, the reaction mixture was heated and stirred for 10 hours under reflux (140°-145° C.). After cooling the reaction mixture to room temperature, it was thoroughly washed first with dilute hydrochloric acid and then with water. Subsequent to its dehydration with anhydrous sodium sulfate, o-xylene was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent: benzene) to isolate the intended Compound 3. m.p. 156°-158° C., yield 2.3 g (55%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[S:33]([CH3:37])=[N:34][C:35]#[N:36])[CH2:5][NH:6][C:7]([C:9]1[C:14](=[O:15])[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[C:12]([CH3:26])[N:11]([CH:27]([CH3:29])[CH3:28])[CH:10]=1)=[O:8].C(O)(=[O:40])C.[Mn]([O-])(=O)(=O)=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[S:33]([CH3:37])(=[N:34][C:35]#[N:36])=[O:40])[CH2:5][NH:6][C:7]([C:9]1[C:14](=[O:15])[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[C:12]([CH3:26])[N:11]([CH:27]([CH3:29])[CH3:28])[CH:10]=1)=[O:8]
Reactant: CC(=O)O
Reactant: Cc1cc(CNC(=O)c2cn(C(C)C)c(C)c(-c3cccc(C(F)(F)F)c3)c2=O)ccc1S(C)=NC#N
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(CNC(=O)c2cn(C(C)C)c(C)c(-c3cccc(C(F)(F)F)c3)c2=O)ccc1S(C)(=O)=NC#N

Procedure:
A solution of 1-isopropyl-6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid 3-methyl-4-(N-cyano-S-methylsulfinimidoyl)-benzylamide (preparation 66d, 25 mg, 47 μmol) and acetic acid (3 μL, 50 μmol) in acetonitrile (0.2 mL) is added to a solution of potassium permanganate (8 mg, 50 μmol) in acetonitrile (0.15 mL) and water (0.15 mL). After 3 h another portion of potassium permanganate (8 mg, 50 μmol) is added and the mixture is heated at reflux. After 2 h saturated aqueous sodium thiosulfate solution is added, and the mixture is extracted twice with dichloromethane. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by preparative reversed phase HPLC (Xbridge, gradient of acetonitrile in water, 0.1% TFA). Yield: 2 mg (8% of theory); ESI mass spectrum: [M+H]+=545; r.t. HPLC: 0.61 min (X012_S01).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[Cl:10])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NNc1ccc(F)cn1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (for reference procedure see WO 2010/022076, which is incorporated herein by reference; 1.0 g, 7.87 mmol) and 2-chloro-benzoyl chloride (1 mL, 7.87 mmol) in DCM (50 mL) was added dropwise DIPEA (2.74 mL, 15.75 mmol). The reaction mixture was stirred at RT for 1 h then washed with water. The organic layer was dried through a phase separator and then concentrated in vacuo to afford the title compound (1.95 g, 93%) as a brown solid. LCMS (Method 3): Rt 2.82 min, m/z 266 [MH+].
Reaction SMILES: CC([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Br:17])=O.C([O-])([O-])=O.[K+].[K+].Cl>>[SH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Br:17]
Reactant: CC(=O)SCCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: SCCCCCCCCCCCCBr

Procedure:
Alternations to the referenced procedure include the substitution of S-12-(2,5-dihydroxyphenyl)dodecyl ethanethioate with CH3(CO)S(CH2)12Br and K2CO3 for concentrated HCl, the reaction time was reduced from 12 h to 5 h and the product was purified by sublimation (−20° C. cold finger, 0.5 mmHg, 70° C. oil bath). Yield; 3.47 g, 12.32 mmol, 89%; 1H NMR (400.09 MHz, CDCl3) δ (ppm); 3.40 (t, 2H, 3JH—H=7.2 Hz, BrCH2), 2.51 (dt, 2H, 3JH—H=7.2 Hz, HSCH2), 1.84 (quintet, 2H, 3JH—H=7.2 Hz, BrCH2CH2), 1.60 (quintet, 2H, 3JH—H=7.2 Hz, HSCH2CH2), 1.44-1.26 (m, 17H, CH2 and SH t, 3JH—H=7.6 Hz). 13C NMR (100.60 MHz, CDCl3) δ (ppm); 45.14, 34.01, 32.80, 32.61, 29.45, 29.03, 28.85, 28.72, 28.33, 28.14, 26.84, 24.62.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:29])[CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:16][CH2:15]3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[BH4-].[Na+]>>[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([CH:12]([OH:29])[CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:28])[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:16][CH2:15]3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(CN1CCC(NC(=O)c2ccccc2)CC1)c1ccc2c(c1)CCCC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: O=C(NC1CCN(CC(O)c2ccc3c(c2)CCCC3)CC1)c1ccccc1

Procedure:
The title compound as its hydrochloride, m.p. 253° C. (decomp.), was prepared by reduction of the free base of the compound obtained in Example 56 using sodium borohydride. The procedure is that described in Example 53. (Found: C, 69.7; H, 7.5; N, 6.6. C24H30N2O2.HCl requires C, 69.5; H, 7.5; N, 6.75%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].Cl.[NH2:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:32]([O:34]C)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Li+].[OH-]>>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH:27][CH2:28][C:29]3[CH:30]=[C:31]([CH:36]=[CH:37][C:38]=3[O:39][CH3:40])[C:32]([OH:34])=[O:33])=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2]
Reactant: COC(=O)c1ccc(OC)c(CN)c1
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cc(C(=O)O)ccc3OC)cn2)C1

Procedure:
(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4-methoxybenzoic acid was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid and methyl 3-(aminomethyl)-4-methoxybenzoate hydrochloride using Amidation Method 1 (HATU) and Ester Hydrolysis Method 1 (LiOH). 1H NMR (300 MHz, DMSO-d6) δ 12.6 (s, 1H), 8.78 (app s, 3H), 7.89 (dd, 1H), 7.76 (m, 1H), 7.10 (d, 1H), 7.05 (d, 1H), 6.89 (m, 3H), 4.45 (d, 2H), 4.38 (m, 1H), 4.18 (d, 1H), 3.91 (m, 8H), 2.05 (m, 1H), 1.88 (m, 2H), 1.52 (m, 1H), 1.21 (t, 3H). MS (ES+) 507.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH3:22])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([F:23])[CH:3]=1.Cl.[NH2:25][OH:26].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH3:22])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:25]\[OH:26])=[C:4]([F:23])[CH:3]=1
Reactant: NO
Reactant: CCCC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCC(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1F

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-2-fluoro-phenyl)-hexanoyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=395.1 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:57]1[CH:62]=[C:61](B(O)O)[CH:60]=[N:59][CH:58]=1>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[C:15]([C:61]4[CH:62]=[N:57][CH:58]=[N:59][CH:60]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1cncnc1
Reactant: O=C1C(Br)=C(c2ccc(C(F)(F)F)cc2)c2ccc(OCCN3CCOCC3)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2cncnc2)=C(c2ccc(C(F)(F)F)cc2)c2ccc(OCCN3CCOCC3)cc21
Yield: 25 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 6-(2-morpholinoethoxy)-2-bromo-3-(4-(trifluoromethyl)phenyl)-1H-inden-1-one obtained in Step 6 of Example 32 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 5-pyrimidinylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (25%).