Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[CH:5]=[C:6]([CH3:8])[N:7]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: OB(O)c1ccnc(Cl)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)pyrimidine (example A.12) (0.27 g, 1.0 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.21 g, 1.3 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.175 g, 50%). MS (ISP) 350.4 [(M+H)+]; mp 147° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:41]([OH:43])=O)=[N:11][C:12]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C.[F:57][C:58]1[CH:63]=[CH:62][C:61]([C@H:64]([NH2:66])[CH3:65])=[CH:60][CH:59]=1>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([C:41]([NH:66][C@@H:64]([C:61]2[CH:62]=[CH:63][C:58]([F:57])=[CH:59][CH:60]=2)[CH3:65])=[O:43])=[N:11][C:12]([C:15]2[C:16]([N:35]([CH3:40])[S:36]([CH3:39])(=[O:37])=[O:38])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[C:20]([C:30](=[O:33])[NH:31][CH3:32])[C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)O)n3)cc12
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)N[C@H](C)c4ccc(F)cc4)n3)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinic acid (110 mg, 0.18 mmol) was suspended in THF (2 ml), cooled to 0° C., then 4-methylmorpholine (55.3 mg, 0.55 mmol) and ethylchloroformate (27.7 mg, 0.26 mmol) were added. The resulting mixture was stirred at 0° C. for 1 h, then (R)-1-(4-fluorophenyl)ethylamine was added. The reaction was warmed to RT and stirred for 1 h, then concentrated in vacuo. The resulting residue was purified using column chromatography (eluted with 0-5% MeOH/DCM) to provide (R)-3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-N-(1-(4-fluorophenyl)ethyl)picolinamide (100 mg, yield: 76%). MS (M+H)+: 724.
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[N:14][CH:15]=2)[CH:12]=1.[I:16]I>O.CCO>[F:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[N:14][C:15]=2[I:16])[CH:12]=1
Reactant: II
Reactant: Fc1ccc2cncn2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Fc1ccc2c(I)ncn2c1

Procedure:
To a solution of sodium bicarbonate (1.3 g, 15.4 mmol) in water (3.66 mL) was added 6-fluoroimidazo[1,5-a]pyridine (see Example 32, 560 mg, 4.11 mmol) in EtOH (7.31 mL) followed by iodine (1.46 g, 5.76 mmol) at room temperature. After 16 h another 800 mg of iodine was added. After a further 16 h the reaction mixture was quenched with sodium thiosulfate and diluted with ethyl acetate. The organic phase was washed with water and brine then dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography (silica, ethyl acetate/hexane gradient). The product contained minor impurities and was used without further purification. MS (M+H)+=262.9; 1H NMR (CDCl3) δ: 8.14 (s, 1H), 7.90 (m, 1H), 7.35 (m, 1H), 6.77 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[CH:4][CH:3]=1.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C.C([Li])CCC.Cl>O1CCCC1.O>[F:10][CH:9]([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([B:12]([OH:17])[OH:13])=[CH:3][CH:4]=1
Reactant: FC(F)Oc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-bromo-4-(difluoromethoxy)-benzene (1.18 g) and triisopropyl borate (1.34 ml) in tetra-hydrofuran (6 ml) was added dropwise n-butyl lithium (1.58 M hexane solution, 3.68 ml) at −78° C. over 10 minutes under argon atmosphere, then the reaction mixture was allowed to warm to room temperature. After being starred at room temperature for 3 hours, the mixture was cooled to 0° C., and thereto were added a 6 N aqueous hydrochloric acid solution and water. The resultant mixture was extracted with ethyl acetate (30 ml) twice, and the combined organic layer was washed with brine (10 ml), dried over sodium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residual solid was triturated with cold hexane to give the titled compound as a colorless solid. 1H-NMR (DMSO-d6) δ 7.12 (d, J=8.4 Hz, 2H), 7.27 (t, J=74.1 Hz, 1H), 7.83 (d, J=8.6 Hz, 2H), 8.08 (br-s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH2:24])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(OCC(Cl)=O)(=O)C.N1C=CC=CC=1.[O:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][N:24]5[CH2:45][CH2:44][CH2:43][C:42]5=[O:41])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:12][CH2:13]2)=[CH:25][CH:26]=1
Reactant: NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Reactant: C1CCOC1
Agent: CC(=O)OCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg) obtained in Example 322-3), acetoxyacetyl chloride (64 mg), pyridine (3 ml) and tetrahydrofuran (5 ml) was stirred under ice cooling for 30 min. Then ice water and ethyl acetate were added to the reaction mixtures. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the resulting residue were added methanol (10 ml) and potassium carbonate (100 mg) followed by stirring for 30 min. Then ice water and ethyl acetate were added to the reaction mixtures. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/ethanol system) to give the title compound (140 mg) as white scales (yield: 80%).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][C:18]3[N:19]=[C:20](Br)[S:21][C:22]=3[CH3:23])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.[CH3:26][CH2:27]O>C1COCC1.O>[CH:9]([C:26]1[CH:27]=[CH:7][C:6]([C:20]2[S:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[C@H:6]([CH2:5][C:4]([OH:3])=[O:25])[CH2:7][CH2:8]4)[N:19]=2)=[CH:5][CH:4]=1)([CH3:10])[CH3:8]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(Br)sc3C)ccc21
Reactant: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1sc(-c2ccc(C(C)C)cc2)nc1CCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Reaction time: 24 h
Yield: 66 %

Procedure:
To a solution of Example 174 (305 mg, 0.657 mmol) in a mixture of THF (8 mL), water (8 mL), and EtOH (4 mL), was added LiON (63 mg, 2.63 mmol). The reaction mixture was vigorously stirred for 24 hours, diluted with water (20 mL), and washed with Et2O (10 mL). The aqueous phase was then acidified to pH ˜1 using 1 N HCl, and then extracted with CH2Cl2 (4×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography (95:5 CH2Cl2/MeOH) to afford product (189 mg, 66%) as a white solid. (C26H29NO3S): LC-MS, RT 3.95 min., M+H 436.4; 1H NMR (CDCl3): δ 1.25 (s, 3H), 1.28 (s, 3H), 1.70-1.82 (m, 1H), 2.32-2.43 (m, 2H), 2.45 (s, 3H), 2.74-2.98 (m, 4H), 3.18 (t, 2H), 3.47-3.54 (m, 1H), 4.28 (t, 2H), 6.72 (dd, 1H), 6.78 (s, 1H), 7.08 (d, 1H), 7.51 (AB quartet, 4H).
Reaction SMILES: [CH:1]1([C:4]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[C:5]=2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([CH3:23])=[C:16]([C:20](O)=[O:21])[N:17]([CH3:19])[N:18]=3)=[CH:10][C:9]=2[CH3:24])[CH2:3][CH2:2]1.O1CCCC1.C(Cl)(=O)C([Cl:44])=O>CN(C)C=O>[CH:1]1([C:4]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[C:5]=2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([CH3:23])=[C:16]([C:20]([Cl:44])=[O:21])[N:17]([CH3:19])[N:18]=3)=[CH:10][C:9]=2[CH3:24])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(-c2nn(C)c(C(=O)O)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(-c2nn(C)c(C(=O)Cl)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Reaction time: 2 h

Procedure:
At room temperature, to the mixture of 5-{4-[2-Cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-2,4-dimethyl-2H-pyrazole-3-carboxylic acid (described in Reference Preparation example 116) and tetrahydrofuran 50 ml was added oxalyl dichloride 0.5 g and N,N-dimethylformamide 0.1 ml. The mixture was stirred for two hours and concentrated under reduced pressure to give 5-{4-[2-Cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-2,4-dim ethyl-2H-pyrazole-3-carbonylchloride 1.3 g.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([CH2:22][CH:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)O)[N:6]=1)([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH3:21][C:18]([C:9]1[C:10]([OH:11])=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[N:6]=[C:7]([CH:22]=[CH:23][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[N:8]=1)([CH3:19])[CH3:20]
Reactant: COCCOCOc1c(C(C)(C)C)nc(CC(O)c2cccnc2)nc1C(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc(C=Cc2cccnc2)nc(C(C)(C)C)c1O
Temperature: 190 °C
Yield: 49.8 %

Procedure:
A mixture of 4,6-bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-α-(3 -pyridinyl)-2-pyrimidineethanol (350 mg), sodium acetate (10 g) and acetic anhydride (7 mL) in toluene (100 mL) is heated at reflux for 8 hours. The reaction mixture is cooled and the solvent is evaporated. Dichlorobenzene (30 mL) is added and the reaction mixture is heated at 190° C. for 30 minutes. The reaction mixture is cooled and partitioned between ethyl acetate and water. The aqueous layer is adjusted to pH 4 with 1N HCl. The organic layer is collected and evaporated. Purification of the residue by flash chromatography (silica, 1:1 ethyl acetate/hexane) followed by recrystallization from hexane gives pure 4,6-bis(1,1-dimethylethyl)-2-[[2-(3-pyridinyl)]ethenyl]-5-pyrimidinol (130 mg, 40%); mp 150°-151° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[N+:9]([C:6]1[C:7]([NH2:8])=[C:2]([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH:3]=[N:4][CH:5]=1)([O-:11])=[O:10]
Reactant: OB(O)c1cccnc1
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1c(-c2cccnc2)cncc1[N+](=O)[O-]
Yield: 88.8 %

Procedure:
A solution of 3-bromo-5-nitropyridin-4-amine (XIII) (6 g, 26 mmol), pyridin-3-ylboronic acid (3.54 g, 29 mmol), 1 N Na2CO3 solution (78 ml) and 1,4-dioxane (150 mL) was degassed with argon thrice. Pd(PPh3)2Cl2 (927 mg, 5 mmol %) was added to the reaction and the solution was refluxed for 15 h until TLC showed the reaction was complete. The reaction was passed through a pad of Celite and then concentrated under reduced pressure. The reaction mixture was concentrated and the residue was taken up in ethyl acetate. The organic extract was washed with water, dried and concentrated under vacuum. The crude product was purified on a silica gel column (100% EtOAc→2:98 MeOH:DCM) to give 5-nitro-3,3′-bipyridin-4-amine (XIV) as a yellow solid (5 g, 23.1 mmol, 87% yield). 1H NMR (CDCl3, 400 MHz), δ ppm 9.31 (s, 1H), 8.80-8.79 (m, 1H), 8.70 (s, 1H), 8.23 (s, 1H), 7.80-7.73 (m, 1H), 7.52-7.48 (m, 1H). ESIMS found C10H8N4O2 m/z 216.95 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.O>[CH2:17]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a stirring solution of 1-(4-hydroxyphenyl)ethanone (5 g, 36 mmol) in Acetonitrile 50 mL was added potassium carbonate (9.9 g, 72 mmol) and benzyl bromide (7.5 g, 44 mmol) and stirred at RT for overnight, reaction mass was diluted with water and extracted with ethyl acetate, organic layer was given water and brine washes, dried over Na2SO4, evaporation under reduced pressure yields titled compound as white solid (7 g Yield: 84.1%): 1H NMR (300 MHz, CDCl3): δ 7.85-7.88 (d, 2H), 7.25-7.37 (m, 5H), 6.92-6.95 (d, 2H), 5.06 (s, 2H), 2.48 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.[CH2:35]([NH:37][C:38](=[O:51])[C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[CH:41][CH:40]=1)[CH3:36]>>[CH2:35]([NH:37][C:38](=[O:51])[C:39]1[CH:40]=[CH:41][C:42]([N:45]2[CH2:46][CH2:47][N:48]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:49][CH2:50]2)=[CH:43][CH:44]=1)[CH3:36]
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Temperature: 90 °C

Procedure:
To a suspension of (S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (800 mg, 3.43 mmol) was added (cyanomethyl)trimethylphosphonium iodide (1000 mg, 4.12 mmol) and DIEA (1797 μl, 10.29 mmol) and N-ethyl-4-(piperazin-1-yl)benzamide (800 mg, 3.43 mmol)). The vial was heated to 90° C. for 16 hours. The crude reaction was cooled to RT and filtered. The resulting solid were collected and suspended in EtOH (24 mL), heated to reflux, then cooled to RT and filtered. The resulting material was rinsed with EtOH to give a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([C:18]([C:22]1[CH:27]=[CH:26][C:25](O)=[C:24]([O:29][CH3:30])[CH:23]=1)([OH:21])[CH2:19][CH3:20])[CH3:17]>N1C=CC=CC=1>[CH2:16]([C:18]([C:22]1[CH:27]=[CH:26][C:25]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[C:24]([O:29][CH3:30])[CH:23]=1)([OH:21])[CH2:19][CH3:20])[CH3:17]
Reactant: CCC(O)(CC)c1ccc(O)c(OC)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CCC(O)(CC)c1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Trifluoromethanesulfonic anhydride (0.8 mL, 4.76 mmol) was added to a solution of 4-(1-ethyl-1-hydroxy-propyl)-2-methoxy-phenol (Example 176-(3); 1.0 g, 4.76 mmol) in pyridine (4 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The reaction solution was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid aqueous solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane only to hexane:ethyl acetate=1:1) to give trifluoromethanesulfonic acid 4-(1-ethyl-1-hydroxy-propyl)-2-methoxy-phenyl ester (1.51 g, 93%). Trifluoroacetic acid (0.1 mL) was added to a mixture of trifluoromethanesulfonic acid 4-(1-ethyl-1-hydroxy-propyl)-2-methoxy-phenyl ester (100 mg, 0.292 mmol) with o-cresol (68.2 mg, 585 mmol) at room temperature, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. Then, the resulting residue was purified by silica gel chromatography (hexane only to hexane:ethyl acetate=4:1) to give the title compound (0.12 g, 95%).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH:26]=O)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[C:31]1([CH:37]2[CH2:41][CH2:40][CH2:39][NH:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:38]5[CH2:39][CH2:40][CH2:41][CH:37]5[C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Reactant: c1ccc(C2CCCN2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5c5ccccc5)c4)cc23)CC1
Yield: 22.1 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL) was added 2-phenylpyrrolidine (147 mg, 1.0 mmol). The reaction mixture was then reacted in a microwave at 120° C. for 10 min. Sodium triacetoxyborohydride (220 mg, 1.0 mmol) was then added and the reaction was reacted at room temperature overnight. It was then purified by Gilson Preparatory HPLC to give 14.0 mg of the title compound (22%).
Reaction SMILES: F[C:2]1[C:3]([C:17]([F:20])([F:19])[F:18])=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C-:21]#[N:22].[Na+].C1OCCOCCOCCOCCOCCOC1.Cl>CN(C)C=O>[CH2:14]([N:11]1[CH2:12][CH2:13][CH:8]([C:4]2[C:3]([C:17]([F:20])([F:19])[F:18])=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:21]#[N:22])[CH2:9][CH2:10]1)[CH2:15][CH3:16]
Reactant: CCCN1CCC(c2cccc(F)c2C(F)(F)F)CC1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1CCC(c2cccc(C#N)c2C(F)(F)F)CC1

Procedure:
Preparation according to Example 7: 4-[3-fluoro-2-(trifluoromethyl)phenyl]-1-propylpiperidine (0.81 g, 2.8 mmol), N,N-dimethylformamide (30 ml), sodium cyanide (0.5 g, 10 mmol) and 18-crown-6-ether (30 mg). Yield: 0.53 g (64%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 266-269° C. MS m/z (relative intensity, 70 eV) 296 (M+, 3), 268 (16), 267 (bp), 204 (3), 184 (3).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[CH2:5][CH2:6][CH:7]1[CH2:13][N:12]([CH3:14])[C:11](=[S:15])[C:10]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:9]=2[O:8]1>>[CH3:1][N:2]([CH3:3])[CH2:5][CH2:6][CH:7]1[CH2:13][N:12]([CH3:14])[C:11](=[S:15])[C:10]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:9]=2[O:8]1
Reactant: CN1CC(CCCl)Oc2ccc([N+](=O)[O-])cc2C1=S
Reactant: CNC
Product: CN(C)CCC1CN(C)C(=S)c2cc([N+](=O)[O-])ccc2O1
Reaction time: 144 h

Procedure:
To 50 ml of freshly collected dimethylamine was added 4.25 g (0.014 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-7-nitro-1,4-benzoxazepine-5(4H)-thione. The reaction flask was sealed tightly and allowed to stand at room temperature for 6 days. The dimethylamine was evaporated at room temperature. The solid residue was taken up in methylene chloride, washed twice with 1N hydroxide and once with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Approximately 0.8 g of the crude solid residue was triturated with isopropyl/ether to give the crystalline free base, m.p. 104°-109° C.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[F:11][C:12]([F:25])([F:24])[CH2:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[Cl:10][C:4]1[CH:3]=[C:2]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:13][C:12]([F:11])([F:24])[F:25])[CH:16]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: OB(O)c1cccc(OCC(F)(F)F)c1
Reactant: Nc1c(F)cc(Br)cc1Cl
Product: Nc1c(F)cc(-c2cccc(OCC(F)(F)F)c2)cc1Cl
Yield: 60.4 %

Procedure:
The title compound (85 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and 3-(2,2,2-trifluoroethoxy)phenylboronic acid (127 mg, 0.57 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.53-7.44 (m, 2H), 7.38-7.26 (m, 3H), 6.94 (d, J 7, 1H), 5.55 (s, 2H), 4.83 (q, J 8.9, 2H).
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[O:26][CH3:27].Cl>CN(C)C=O.O>[CH3:27][O:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23][N:12]1[CH:13]=[C:8]([C:6]2[N:7]=[C:3]([CH3:2])[S:4][CH:5]=2)[C:9](=[O:15])[NH:10][C:11]1=[O:14]
Reactant: COC(CCBr)OC
Reactant: Cc1nc(-c2c[nH]c(=O)[nH]c2=O)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2csc(C)n2)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.9 %

Procedure:
5-(2-methyl-1,3-thiazol-4-yl)-2,4(1H,3H)-pyrimidinedione hydrochloride (Prep20, 287 mg, 1.110 mmol) was dissolved in N,N-Dimethylformamide (DMF) (4 ml). K2CO3(460 mg, 3.33 mmol) were added and the reaction mixture stirred at room temperature for 1 h. 3-bromo-1,1-bis(methyloxy)propane (0.185 ml, 1.221 mmol) was added. The obtained mixture was then stirred at room temperature. After 4 days it was diluted with water, neutralized with HCl, and extracted by EtOAc. The organic phase was washed with water (3 times), brine, dried over Na2SO4, filtered and the solvent evaporated. The obtained crude was purified by preparative LC-MS. 58.5 mg of the title compound were isolated as a white solid.