Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[O-:5])[CH3:2].[OH:7][C:8]1[C:9]([Cl:21])=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br>>[CH2:1]([NH:3][C:4](=[O:5])[O-:6])[CH3:2].[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][O:7][C:8]1[C:9]([Cl:21])=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1
Reactant: CC1c2cc(Cl)c(O)cc2C2CNCC12
Reactant: Fc1ccccc1CBr
Agent: CCNC(=O)[O-]
Product: CC1c2cc(Cl)c(OCc3ccccc3F)cc2C2CNCC12

Procedure:
The subtitle compound was prepared by the method of Example 6, Step A utilizing N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 5, Step A) and 2-fluorobenzyl bromide. The crude product was obtained without further purification. MS calculated for C22H23ClFNO3+H: 404, observed: 404.
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[N:6]=[C:7]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[OH-:26].[K+]>CCO>[C:14]1([C:7]2[N:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[C:5]([C:3]([OH:26])=[O:4])[N:6]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: O=C(c1nc(-c2cccc3ccccc23)n2ccccc12)C(F)(F)F
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1nc(-c2cccc3ccccc23)n2ccccc12
Yield: 54.8 %

Procedure:
To a solution of 2,2,2-trifluoro-1-(3-naphthalen-1-yl-imidazo[1,5-a]pyridin-1-yl)-ethanone (260 mg, 0.76 mmol) in EtOH (10 mL) was added KOH (582 mg, 10.4 mmol) and the mixture was heated to reflux for 30 min. The mixture was allowed to cool and concentrated. The residue was dissolved in water (25 mL) and acidified to pH 3 with 2N HCl. The precipitate was filtered, dried and recrystallized from ethyl acetate to yield the title compound (120 mg, 55%). 8.30 (1H), 8.10 (2H), 7.78 (2H), 7.70 (1H), 7.59 (2H), 7.52 (1H), 7.02 (1H), 6.70 (1H); m/z (M+H)=289.24.
Reaction SMILES: [CH2:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Br:16])=[N:7][NH:6][C:5]1=[O:17])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][C:26]([O:28][CH3:29])=[O:27]>C(#N)C>[CH2:1]([N:4]1[C:5](=[O:17])[N:6]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[N:7]=[C:8]1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Br:16])[CH:2]=[CH2:3]
Reactant: COC(=O)CCl
Reactant: C=CCn1c(-c2ccc(Cl)cc2Br)n[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCn1c(-c2ccc(Cl)cc2Br)nn(CC(=O)OC)c1=O

Procedure:
Of the compound from Example 164A, 9.78 g (about 23.32 mmol, purity 75%) were dissolved in 75 ml of acetonitrile. Then 3.55 g (25.65 mmol) of potassium carbonate and 2.46 ml (27.98 mmol) of methyl chloroacetate were added. The mixture was stirred under reflux for 5 hours. After cooling, it was filtered with suction. The filtrate was concentrated a little on a rotary evaporator and then diluted with 30 ml of ethyl acetate and washed with 30 ml each of 1M hydrochloric acid and of saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. The residue was purified by chromatography on silica gel (elution: cyclohexane/ethyl acetate 2:1). This gave 7.1 g (79% of theory) of the title compound.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:12]([O:15][CH2:16]Cl)[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:12]([O:15][CH2:16][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])[CH2:13][CH3:14]
Reactant: COC(=O)c1ccccc1O
Reactant: CCCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOCOc1ccccc1C(=O)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.2 %

Procedure:
To a solution of methyl salicylate (0.637 g, 4.19 mmol) in N,N-dimethylformamide (8 ml) were added chloromethyl propyl ether (0.50 ml, 4.54 mmol) and potassium carbonate (0.755 g, 5.46 mmol), and the mixture was stirred at room temperature for 20 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 2-propoxymethoxybenzoate (0.414 g, 1.85 mmol, yield 44%). This was dissolved in methanol (5 ml), 1N-aqueous sodium hydroxide solution (5 ml) was added at room temperature, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure and neutralized with 5% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a carboxylic acid compound 2-propoxymethoxybenzoic acid (0.374 g, 1.78 mmol, yield 96%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[F:13][C:14]1[CH:27]=[CH:26][C:17]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1>C1COCC1.CCCCCC>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([OH:19])[CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)=[CH:26][CH:27]=1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Reactant: Cc1nnnn1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nnnc1CC(O)(c1ccccc1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of 1,5-dimethyltetrazole (29.25 g; 0.298 mole) in dry THF (400 mL) was cooled to -78° C. and treated with n-butyllithium (133 mL of a 2.5M solution in hexane; 0.3325 mole) over 30 minutes. The mixture was stirred at -78° C. for 30 minutes and treated with 4-fluorobenzophenone (50 g, 0.25 mole. The mixture was stirred at -78° C. for 30 minutes and allowed to warm up to 23° C. over 2 hours. The reaction was quenched with 2N HCl (100 mL) and the organic solvent was removed by evaporation. The residue was extracted with CHCl3 (2×100 mL) and the combined organic layers were dried (Na2SO4) and evaporated to afford a brown oil. Purification by chromatography using 20% EtOAc-hexane as eluent afforded the title compound as a white solid (46.3 g; 62%). m.p.=113°-114° C. (crystallized from EtOAc-hexane). MS (CI): m/e=299 for (M+H)+ ;
Reaction SMILES: C([Li])(C)(C)C.BrC1C(C)=CC(C)=CC=1C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[O:35].[Cl-].[NH4+]>CCCCC.C1COCC1>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2([OH:35])[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[O:17][CH3:16]
Reactant: COc1ccncc1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccncc1C1(O)C(=O)Nc2ccc(Cl)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 1.7 M solution of tert-butyllithium in pentane (43.4 mL) was added to THF (150 ml) at −78° C. 2-Bromomesitylene (5.4 mL) was added dropwise, keeping the temperature below −60° C., and the mixture stirred at −78° C. for 1 h. 4-Methoxypyridine (2.75 mL) was added dropwise at −78° C. and then the mixture was stirred at −30° C. to −20° C. for 3.5 h. The reaction mixture was re-cooled to −78° C. and a slurry of 5-chloroisatin (2.44 g) in THF (120 mL) was added portionwise, keeping the temperature below −65° C. The reaction mixture was stirred at −78° C. for 30 min. The reaction mixture was allowed to warm to −20° C. and then 10% aqueous ammonium chloride solution (75 mL) was added. After stirring for 10 min, the white solid was filtered off, washed with water (excess) and ethyl acetate (20 mL). Yield after drying in vacuo: 1.8 g (42%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]([CH2:16][CH3:17])[N:13]=[CH:14][CH:15]=3)=[CH:9][N:8]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[NH2:26][C:27]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:28]=1[C:29]([N:31]([CH3:33])[CH3:32])=[O:30].ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(#N)C>[NH2:26][C:27]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[N:12]([CH2:16][CH3:17])[N:13]=[CH:14][CH:15]=4)=[CH:9][N:8]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:5]3=[N:6][CH:7]=2)=[CH:34][C:28]=1[C:29](=[O:30])[N:31]([CH3:32])[CH3:33]
Reactant: CN(C)C(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: CCn1nccc1-c1cn(COC(=O)C(C)(C)C)c2ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCn1nccc1-c1cn(COC(=O)C(C)(C)C)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12

Procedure:
2,2-dimethyl-propionic acid 5-bromo-3-(2-ethyl-2H-pyrazol-3-yl)-pyrrolo[2,3-b]pyridin-1-ylmethyl ester, 2-amino-N,N-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide, [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) complex with dichloromethane, acetonitrile, 1M aqueous sodium carbonate solution, and tetrahydrofuran were combined in a microwave vial. The tube was placed in a microwave reactor and irradiated to 120° C. for 20 minutes. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0 to 100% [10% methanol in ethyl acetate] in hexanes) to give 2,2-dimethyl-propionic acid 5-(4-amino-3-dimethylcarbamoyl-phenyl)-3-(2-ethyl-2H-pyrazol-3-yl)-pyrrolo[2,3-b]pyridin-1-ylmethyl ester. MS: m/z 489.3 (M+H+).
Reaction SMILES: [C:1]1([CH:7]2[CH2:14][CH2:13][C:12](=O)[NH:11][C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2CC(=O)NC3C=CC=CC=3S2)C=CC=CC=1.[ClH:38].[CH3:39][N:40]([CH3:64])[CH2:41][CH2:42][N:43]([CH3:63])[C:44](N1C2C=CC=CC=2SC(C2C=CC=CC=2)CC1)=[O:45]>>[ClH:38].[CH3:39][N:40]([CH3:64])[CH2:41][CH2:42][N:43]([CH3:63])[C:44]([N:11]1[C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[S:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][CH2:13][CH2:12]1)=[O:45]
Reactant: CN(C)CCN(C)C(=O)N1CCC(c2ccccc2)Sc2ccccc21
Reactant: O=C1CCC(c2ccccc2)Sc2ccccc2N1
Agent: Cl
Agent: O=C1CC(c2ccccc2)Sc2ccccc2N1
Product: CN(C)CCN(C)C(=O)N1CCCC(c2ccccc2)Sc2ccccc21

Procedure:
By substituting an equivalent amount of 3,4-dihydro-2-phenyl-2H-1,6-benzothiazocin-5(6H)-one for the 2,3-dihydro-2-phenyl-1,5-benzothiazepin-4-one in part (A) of Example 1 and carrying out the procedure of the Example, there is obtained N-(2-dimethylaminoethyl)-N-methyl-2phenyl-1,2,3,4,5,6-hexahydro-1,6-benzothiazocine-6-carboxamide hydrochloride.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[C:7]([N:10]=[C:11]=[O:12])([CH3:9])[CH3:8])([CH3:3])=[CH2:2].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>ClCCl>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:11]([NH:10][C:7]([C:6]2[CH:13]=[CH:14][CH:15]=[C:4]([C:1]([CH3:3])=[CH2:2])[CH:5]=2)([CH3:9])[CH3:8])=[O:12])=[CH:19][CH:18]=1
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Reactant: Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: C=C(C)c1cccc(C(C)(C)NC(=O)Nc2ccc(Cl)cc2)c1
Yield: 110.3 %

Procedure:
To a solution of 3-isopropenyl α, α-dimethylbenzyl isocyanate 2 (473 mg, 2.35 mmol) in dichloromethane (6 mL) at 0° C. was added 4-chloroaniline (300 mg, 2.35 mmol) in dichloromethane (3 mL). The reaction was stirred until complete consumption of starting materials. The precipitated product was collected by filtration and washed with dichloromethane to give 5b (852 mg, 80%). mp 234-236° C. Yield 80%; 1H NMR (DMSO-d6, 400 MHz) δ 1.58 (s, 6H), 2.08 (s, 3H), 5.06 (s, 1H), 5.36 (s, 1H), 6.64 (s, 1H), 7.20 (d, J=6.4 Hz, 2H), 7.23-7.32 (m, 5H), 7.47 (s, 1H), 8.55 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 22.24, 30.30, 55.0, 113.06, 119.50, 122.35, 123.69, 124.86, 124.95, 128.65, 129.09, 140.11, 140.73, 143.60, 148.95, 154.53; ESI-HRMS for C9H22N2OCl (M+H)+ calcd. 329.1421. found 329.1418.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:11]=3[C:12]([NH2:20])=[N:13][N:14]4[CH3:19])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29](O)=[O:30])[CH:25]=[CH:26][CH:27]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:19][N:14]1[C:15]2[C:11](=[C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[N:1]([C:29](=[O:30])[CH2:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:2][CH2:3]4)[CH:18]=[CH:17][CH:16]=2)[C:12]([NH2:20])=[N:13]1
Reactant: Cn1nc(N)c2c(-c3ccc4c(c3)CCN4)cccc21
Reactant: Cc1cccc(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4cccc5c4c(N)nn5C)ccc32)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 106.2 %

Procedure:
To a clear solution of 4-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-indazol-3-amine (200 mg, 0.76 mmol, 1 equiv), (3-methylphenyl)acetic acid (114 mg, 0.76 mmol, 1 equiv), and DIEA (145 uL, 0.83 mmol, 1.1 equiv) in 4 mL of DCM was added at rt in one portion solid HATU (316 mg, 0.83 mmol, 1.1 equiv). The mixture as stirred at rt for 20 h. LCMS showed conversion complete. The suspension was filtered. The filtrate was absorbed onto a dryload cartridge. Purification was done on an SF25-24 g silica gel cartridge using gradient elution of 1% EtOAc in hexane to 100% EtOAc. The product eluted in the 100% EtOAc as a broad but well-defined peak. Concentration in vacuo gave a white foam (320 mg). LCMS showed it was only 84% pure with a major impurity at 11%. This material was dissolved in EtOAc (75 mL), and washed with water (25 mL) and brine (15 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo. LCMS showed the impurities still present. The material was dissolved in EtOAc (1 mL) with some material still sticked to the wall of the 100 mL recovery flask, to which was added 3 mL of MTBE. The mixture turned cloudy initially, and was immersed in a water bath at (40° C.). The cloudiness disappeared and then solids began to form on the walls. A spatula was used to scratch the flask. The mixture was then cooled to room temperature and the suspension was filtered. The solids (light tan colored) was washed with MTBE (2 mL). Both LCMS and NMR showed this lot was quite pure. The solid was dried under vacuum at 65° C. for 16 h to give 210 mg as tan-colored solids. LC-MS (ES) m/z=397 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.31 (s, 3H), 3.23 (t, J=8.3 Hz, 2H), 3.78 (s, 3H), 3.83 (s, 2H), 4.23 (t, J=8.6 Hz, 2H), 4.38 (s, 2H), 6.78 (d, J=5.8 Hz, 1H), 7.05-7.15 (m, 13H), 7.20-7.26 (m, 2H), 7.28-7.38 (m, 3H), 8.16 (d, J=8.3 Hz, 1H).
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:3]([OH:5])=[O:4])=[CH:7][CH:8]=1
Reactant: O=C(O)C(Br)c1ccc(Cl)cc1
Reactant: C1CCNCC1
Solvent: CC#N
Product: O=C(O)C(c1ccc(Cl)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.4 %

Procedure:
2-Bromo-2-(4-chlorophenyl)acetic acid (300 mg, 1.20 mmol), piperidine (125 μl, 1.26 mmol) and TEA (503 μl, 3.61 mmol) were dissolved in acetonitrile (6 ml). The resulting reaction was stirred at room temperature for 48 hours. Acetonitrile was evaporated, the residue was triturated with acetonitrile/petroleum ether (9/1) and filtered by suction filtration to collect 2-(4-chlorophenyl)-2-(piperidin-1-yl)acetic acid (190 mg, 62.3% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[Cl:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH:24]=[CH:23][C:22]([NH2:25])=[N:21]2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH:24]=[CH:23][C:22]([NH:25][CH:10]3[CH2:11][CH2:12][N:7]([C:5]4[S:4][N:3]=[C:2]([CH3:1])[N:6]=4)[CH2:8][CH2:9]3)=[N:21]2)=[CH:17][CH:16]=1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1ccn(Cc2ccc(Cl)cc2)n1
Product: Cc1nsc(N2CCC(Nc3ccn(Cc4ccc(Cl)cc4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(4-chloro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a white solid (yield=70%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[CH:5]=[C:4]([N+:11]([O-])=O)[C:3]=1[CH2:14][C:15]([OH:17])=[O:16].C(N(CC)CC)C>CO.[Pd]>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[CH:5]=[C:4]([NH2:11])[C:3]=1[CH2:14][C:15]([OH:17])=[O:16]
Reactant: COc1cc([N+](=O)[O-])c(CC(=O)O)c(Cl)c1O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cc(N)c(CC(=O)O)c(Cl)c1O
Reaction time: 3 h
Yield: 139 %

Procedure:
To 2-chloro-3-hydroxy-4-methoxy-6-nitrophenylacetic acid (52 g) in methanol (600 ml) was added triethylamine (56 ml) and 10% palladium on carbon (4 g). The mixture was hydrogenated for 3 hours at 1.4 bar, filtered, evaporated and the residue crystallised to give the triethylamine salt of 2-chloro-3-hydroxy-4-methoxy-6-aminophenylacetic acid (64 g); NMR (DMSO-d6 /CD3COD/CF3COOD) 1.17(t,9H); 3.05(s,6H); 3.54(s,2H); 3.73(s,3H); 6.4(s,1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C1COCC1>[O:36]1[CH2:37][CH2:38][CH:33]([NH:32][C:16]2[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=2)[CH2:34][CH2:35]1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NC1CCOCC1
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC2CCOCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 18 h

Procedure:
The product of Example 48 (200 mg, 0.45 mmol) and 4-aminotetra-hydropyran (102 mg, 1 mmol) were combined in THF (10 mL) and stirred under Ar at 23° for 18 h. The solvents were removed in vacuo, and the residue was flash chromatographed with 0-15% EtOAc/CH2Cl2 Recrystallization from CH2Cl2/hexane gave the title compound as a light-yellow crystalline solid. mp 231-232°, LC MS m/z=467 (MH+) Retention time=2.27 min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])O.[Na+].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C(O)C>[CH2:25]([NH:32][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.19 mmol) in ethanol (5 mL) was added sodium hydrogen carbonate (195 mg, 2.32 mmol) and benzylamine (311 mg, 2.90 mmol), and this was heated to reflux with stirring for 4 hours. After the reaction was complete, it was cooled to room temperature and water was added. The precipitated crystals were filtered off, and after washing with water and ethanol the crystals were dried to yield the title compound (347 mg, 84% yield) as orange crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][C:9]1([C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(O)=O.O.[CH2:28]([CH:31](CO)CO)[CH2:29]C>C1(C)C=CC=CC=1>[CH2:29]([CH:5]1[CH2:4][O:3][CH:2]([CH2:7][CH2:8][C:9]2([C:15]3[CH:16]=[C:17]([F:23])[C:18]([F:22])=[C:19]([F:21])[CH:20]=3)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[O:1][CH2:6]1)[CH2:28][CH3:31]
Reactant: Fc1cc(C2(CCC3OCCCO3)CCCCC2)cc(F)c1F
Reactant: CCCC(CO)CO
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CCCC1COC(CCC2(c3cc(F)c(F)c(F)c3)CCCCC2)OC1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
1-(2-(1,3-Dioxane-2-yl)ethyl)cyclohexyl-3,4,5-trifluorobenzene 3.7 g (11 mmol) obtained in Example 8 and formic acid 25.0 g (540 mmol) were added to toluene 20 ml, and the mixture was refluxed with heating for 3 hours. The reactant was cooled to room temperature, water 100 ml was added, and the product was extracted with toluene. The extract was washed with water, a saturated sodium bicarbonate aqueous solution, and water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain crude 3-(4-(3,4,5-trifluorophenyl)cyclohexyl)propanal 3.5 g. The product and 2-propyl-1,3-propanediol 2.3 g (20 mmol) were dissolved in toluene 20 ml, PTS 0.5 g was added. The mixture was refluxed with heating for 3 hours while removing water formed with Dien-Stark. The reactant was washed with a saturated sodium bicarbonate aqueous solution, and then with saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized twice from ethanol to obtain 1-(2-(5-propyl-1,3-dioxane-2-yl)ethyl)cyclohexyl-3,4,5-trifluorobenzene 1.4 g (3.8 mmol). The yield was 34.5% from 1-(2-(1,3-dioxane-2-yl)ethyl)cyclohexyl-3,4,5-trifluorobenzene.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:15])=O>>[C:1]1([C:7]2([C:10]([Cl:15])=[O:12])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1(c2ccccc2)CC1
Product: O=C(Cl)C1(c2ccccc2)CC1
Temperature: 80 °C

Procedure:
1-Phenyl-cyclopropanecarboxylic acid (0.5 g, 3.1 mmol), was dissolved in thionyl chloride (10 eq, 0.031 mol, 3.68 g, 2.3 ml), and refluxed at 80° C. for 1.5 hours. Then excess of thionyl chloride was evaporated on the rotary evaporator which yielded a dark-yellowish liquid (1-phenyl-cyclopropanecarbonyl chloride A), which was then cooled to 0° C., under argon.
Reaction SMILES: FC1C=C(C=C(C(F)(F)F)C=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])C)=O.[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([O:41][C:42]([F:45])([F:44])[F:43])[CH:40]=1)[C:35]([OH:37])=O>>[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([O:41][C:42]([F:45])([F:44])[F:43])[CH:40]=1)[C:35]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:5])=[O:37]
Reactant: O=C(O)c1cc(Cl)cc(OC(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(Cl)cc(OC(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(4-fluoro-2-methoxyphenyl)-N-methylpyridin-3-amine (example 129, intermediate) and 3-chloro-5-(trifluoromethoxy)benzoic acid (228 mg, 947 μmol, CAS RN 433926-46-6) after a reaction time of 19.5 hours. The compound was purified by silica gel chromatography on a 10 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (47%). MS (ESI): m/z=455.08 [M+H]+.