Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[OH:14])[CH:2]=[CH2:3]>CCO.[Pd]>[CH2:1]([C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[CH:6][C:5]=1[OH:14])[CH2:2][CH3:3]
Reactant: C=CCc1cc(C(F)(F)F)ccc1O
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude 2-allyl-4-(trifluoromethyl)phenol from Example 90 was dissolved in EtOH (5 mL), 10% Pd/C (20 mg) was added, and the mixture was stirred under an atmosphere of hydrogen at rt for 2 h. The catalyst was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (EtOAc/hexane (v/v) 1:10). This gave 91 mg (45% over 2 steps) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.00 (t, 3H), 1.68 (m, 2H), 2.61 (t, 2H), 5.14 (br, 1H), 6.80 (d, 1H), 7.32 (d, 1H), 7.36 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[C:11]([F:29])=[C:12]([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[C:24]([CH:26]([F:28])[F:27])[CH:25]=2)[C:21]#[N:22])[C:13]([Cl:16])=[CH:14][CH:15]=1.[Br:30][C:31]1[N:32]=[CH:33][NH:34][C:35]=1[C:36](O)=[O:37].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Br:30][C:31]1[N:32]=[CH:33][NH:34][C:35]=1[C:36]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][C:18]2[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[C:20]([C:21]#[N:22])[CH:19]=2)[C:11]=1[F:29])=[O:37]
Reactant: N#Cc1cc(Oc2c(Cl)ccc(CN)c2F)cc(C(F)F)c1
Reactant: O=C(O)c1[nH]cnc1Br
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Br)c2F)cc(C(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(difluoromethyl)benzonitrile trifluoroacetate (90 mg, 0.204 mmol), 4-bromo-1H-imidazole-5-carboxylic acid (39.0 mg, 0.204 mmol) and HOBT (31.3 mg, 0.204 mmol) in DMF (3 ml) was added EDC (39.1 mg, 0.204 mmol) and the reaction mixture was stirred at RT for 30 minutes. The crude material was purified via reverse phase HPLC to give the title compound (56 mg, 55% yield). 1H NMR (DMSO-d6) δ ppm 8.42 (br. s., 1H) 7.85 (s, 1H) 7.79 (s, 1H) 7.72 (s, 1H) 7.47-7.58 (m, 2H) 7.38 (t, 1H) 7.07 (t, 1H) 4.51 (d, 2H). LC-MS (ES+) m/z 499.00 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.Br[C:21]1[C:22](=[O:29])[N:23]([CH3:28])[N:24]=[C:25]([Cl:27])[CH:26]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:27][C:25]1[CH:26]=[C:21]([NH:1][C:2]2[N:7]=[CH:6][C:5]([C@@H:8]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]3)=[CH:4][CH:3]=2)[C:22](=[O:29])[N:23]([CH3:28])[N:24]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(N)nc2)C1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(Nc2ccc([C@@H]3CCN(C(=O)OC(C)(C)C)C3)cn2)c1=O
Temperature: 100 °C
Yield: 96 %

Procedure:
(S)-tert-Butyl 3-(6-aminopyridin-3-yl)pyrrolidine-1-carboxylate (307 mg, 1.17 mmol, Eq: 1.00) and 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (313 mg, 1.4 mmol, Eq: 1.20) were combined with 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (101 mg, 175 μmol, eq: 0.15), cesium carbonate (1.14 g, 3.5 mmol, eq: 3) and tris(dibenzylideneacetone)dipalladium(0) (53.4 mg, 58.3 μmol, Eq: 0.05) in dioxane (8.0 ml). The solution was degassed with Ar. The reaction mixture heated at 100° C. for 18 h. The solution was cooled to room temperature and diluted with 100 ml DCM. The organic layer was washed with water, and then dried over MgSO4. Concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 50% to 100% EtOAc/Hex gradient) to give (S)-tert-butyl 3-(6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)pyrrolidine-1-carboxylate (456 mg, 96%). LC/MS-ESI observed [M+H]+ 405.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]1[O:21][C@H:20]1[CH2:22][OH:23]>CC(C)=O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:19][C@@H:20]([OH:21])[CH2:22][OH:23])=[CH:10][CH:11]=1
Reactant: OC[C@H]1CO1
Reactant: OCCCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCCCc1ccc(OC[C@@H](O)CO)cc1

Procedure:
To 4-(4-Hydroxy-butyl)-phenol (32.7 g, 197 mmol) in acetone (600 ml) is added potassium carbonate (40.8 g, 295 mmol) followed by (S)-glycidol (13.7 ml, 207 mmol). The mixture is heated at reflux overnight. Further potassium carbonate (20 g) is added, followed by (S)-glycidol (5 g) and the mixture is heated at reflux for 72 hours. The suspension is cooled, filtered and the filtrate concentrated in vacuo. The residue is partitioned between EtOAc (500 ml) and 5% citric acid solution (500 ml). The organics are separated, dried (MgSO4) and concentrated in vacuo to give (S)-3-[4-(4-Hydroxy-butyl)-phenoxy]-propane-1,2-diol as a brown oil; 1H NMR (CDCl3): 1.56-1.74 (4H, m), 2.20 (1H, t, J=2.46 Hz), 2.61 (2H, t, J=7.6 Hz), 3.68 (2H, t, J=6.2 Hz), 3.78 (1H, dd, J=5.4 and 11.5 Hz), 3.86 (1H, dd, J=3.9 and 11.5 Hz), 4.0-4.16 (3H, m), 6.85 (2H, d, J=8.6 Hz), 7.12 (2H, d, J=8.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([C:19](=[O:20])[CH2:18][Cl:17])[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(Nc2c(Cl)cccc2Cl)cc1
Product: Cc1ccc(N(C(=O)CCl)c2c(Cl)cccc2Cl)cc1

Procedure:
N-(2′,6′-Dichlorophenyl)-4-methylaniline (4.86 g) is reacted with chloroacetylchloride (3.92 g) at 90° C. for 2 h. After dilution with toluene, the mixture is washed with aqueous sodiumcarbonate twice, 40% aqu. sodium bisulfite and water. The organic phase is dried (MgSO4) and evaporated. The residue is recrystallised from ethanol (12 g) to obtain N-(2′,6′-Dichlorophenyl)-N-chloroacetyl (2.83 g), mp: 129.5-130° C.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:27]=[C:28]([NH:33]N)[CH:29]=[CH:30][C:31]=1[CH3:32]>>[F:25][C:26]1[CH:27]=[C:28]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=[CH:30][C:31]=1[CH3:32]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: Cc1ccc(NN)cc1F
Product: Cc1ccc(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)cc1F

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (3-fluoro-4-methyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=425.3 (M+H)+
Reaction SMILES: C[Mg]Br.[C:4]([C:7]1[CH:8]=[CH:9][C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:11]([CH:21]=1)[C:12]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:13])(=[O:6])[CH3:5].OS(O)(=O)=O.[C:35]([O-])(O)=O.[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:6][C:4]([C:7]1[CH:8]=[CH:9][C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:11]([CH:21]=1)[C:12]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:13])([CH3:35])[CH3:5]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Reactant: O=C([O-])O
Agent: C[Mg]Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Reaction time: 0.75 h

Procedure:
3M Methylmagnesium bromide (0.10 ml, 0.29 mmol) was added to a solution of 5-acetyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 72; 100 mg, 0.29 mmol) in tetrahydrofuran (3 ml) at 0° C. The solution was stirred for 45 minutes. Another 3 equivalents of 3M methylmagnesium bromide (300 ul) were added at 0° C. and solution was stirred for 18 hours. 1N H2SO4 (5 ml) was then added, the mixture was stirred for 3 minutes, then ethyl acetate (10 ml) was added. The acid layer was basified to pH 9 using saturated NaHCO3 solution. The organic layer was washed with saturated NaHCO3 solution (5 ml), dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by MDAP to give the title compound as a white solid. 61 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:14]([O:21][C:22]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[CH:34][C:23]=1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>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.C(OCC)(=O)C.O.COCCOC>[CH2:14]([O:21][C:22]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:35]=[CH:34][C:23]=1[C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Brc1ccccn1
Reactant: CC1(C)OB(c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(-c2ccccn2)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Water (1.1 mL), 2-bromopyridine (0.11 mL), sodium carbonate (0.21 g), and bis(triphenylphosphine)palladium(II) dichloride (14 mg) were added to a solution of ethylene glycol dimethyl ether (3.5 mL) of the obtained benzyl 2-(benzyloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, followed by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature, 2-bromopyridine (0.11 mL), sodium carbonate (0.21 g), and bis(triphenylphosphine)palladium(II) dichloride (14 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature, water and ethyl acetate were added thereto, and the insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 100-80% hexane/ethyl acetate] to obtain 0.18 g of benzyl 2-(benzyloxy)-4-(pyridin-2-yl)benzoate.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[CH3:19][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23].Cl[Si](C)(C)C.[Si:33]([O:40][CH2:41][CH2:42][CH:43]=O)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].Cl>C1COCC1>[Si:33]([O:40][CH2:41][CH2:42]/[CH:43]=[CH:19]\[P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])([C:36]([CH3:37])([CH3:38])[CH3:39])([CH3:35])[CH3:34]
Reactant: CCOP(C)(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C\CCO[Si](C)(C)C(C)(C)C)OCC
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 10.1 %

Procedure:
To a solution of n-butyllithium in hexane (38.9 ml, 2.7M, 105 mmol) stirred at -20° C. under dry nitrogen was added a solution of diisopropylamine (11.5 g, 114 mmol) in dry THF (70 ml). The solution was cooled to -70° C. before a solution of diethyl methylphosphonate (7.6 g, 50 mmol) in dry THF (10 ml) was added dropwise. A solution of chlorotrimethylsilane (5.8 g, 53 mmol) in dry THF (15 ml) was then added dropwise, maintaining the internal temperature below -60° C. The resulting solution was stirred at -70° C. for 15 min. then warmed to -20° C. before a solution of 3-(t-butyldimethylsilyloxy)propanal (approx. 46 mmol) in dry THF (10 ml) was added dropwise. The solution was then stirred at room temperature for 1.5 hr. The reaction mixture was neutralized by addition of 2M hydrochloric acid and extracted with ether (250 ml). The organic phase was dried (magnesium sulphate), filtered and the solvent removed. The residual oil was purified by column chromatography on silica gel eluting with hexane-acetone (5:1, 3:1) to afford diethyl (Z)-4-(t-butyldimethylsilyloxy)but-1-enylphosphonate as a colourless liquid (1.5 g, 9%); νmax (film) 2940, 1625, 1390, 1245, 1095, 1055, 1030 and 950 cm-1 ; δH (CDCl3) 0.05 (6H, s, SiCH3), 0.87 (9H, s, C(CH3)3), 1.30 (6H, t, J 7 Hz, CH3), 2.83 (2H, m, CH2), 3.73 (2H, t, J 7 Hz, CH2OSi), 4.10 (4H, qu, J 7 Hz, CH2O ), 5.70 (1H, dd, J 14 Hz and 20 Hz, PCH=CH), 6.70 (1H, ddt, J 7 Hz, 14 Hz and 54 Hz, PCH=CH) (Found: MH+ 323.1808. C14
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10](=[O:26])[N:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][NH:15][CH2:14]2)[CH3:12])[CH2:5][CH2:4]1.[CH3:29][C:30]1[N:35]=[N:34][C:33]([N:36]2[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1>>[F:28][C:2]([F:1])([F:27])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10](=[O:26])[N:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][N:15]([C:42]([CH:39]3[CH2:38][CH2:37][N:36]([C:33]4[N:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=4)[CH2:41][CH2:40]3)=[O:43])[CH2:14]2)[CH3:12])[CH2:5][CH2:4]1
Reactant: Cc1ccc(N2CCC(C(=O)O)CC2)nn1
Reactant: CN(C(=O)OC1CCC(C(F)(F)F)CC1)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Product: Cc1ccc(N2CCC(C(=O)N3C[C@@H](N(C)C(=O)OC4CCC(C(F)(F)F)CC4)[C@H](c4ccc(Cl)c(Cl)c4)C3)CC2)nn1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound {(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(6-methyl-pyridazin-3-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-trifluoromethyl-cyclohexyl ester was prepared from [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-trifluoromethyl-cyclohexyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-(6-methyl-pyridazin-3-yl)-piperidine-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 642.4 [M]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[O:1]=[CH:2][C@H:3]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl [(1R)-2-hydroxy-1-phenylethyl]carbamate (200 mg, 0.844 mmol) in CH2Cl2 (20 mL) at 0° C. was added Dess-Martin periodinane (447 mg, 1.05 mmol). The reaction was stirred at 0° C. for 15 minutes and then at room temperature for 30 minutes. The reaction was then diluted with EtOAc (75 mL) and washed rapidly with 10% K2CO3 (2×30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue on a short column of silica gel with 50% EtOAc/hexanes gave tert-butyl [(1R)-2-oxo-1-phenylethyl]carbamate. 1H NMR (CDCl3, 600 MHz) (a major and a minor conformer observed). Data for major conformer given) δ 9.53 (s, 1H), 7.29-740 (m, 5H), 5.80 (bs, 1H), 5.31 (m, 1H), 1.42 (s, 91-1). This material was used immediately in the following reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>C(#N)C.C(N(CC)CC)C>[CH3:32][N:33]([O:34][CH3:35])[C:7]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:10]=1)=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CON(C)C(=O)c1cncc(Br)c1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a suspension of 5-bromonicotinic acid (5.0 g) and N-hydroxysuccinimide (4.27 g) in acetonitrile (60 ml) was added 1-ethyl-3—(3′-dimethylaminopropyl)carbodiimide hydrochloride (7.12 g) at room temperature, and the mixture was stirred for 30 minutes. To the reaction mixture were added N,O-dimethyl-hydroxylamine hydrochloride (2.66 g) and triethylamine (10 ml), and the mixture was stirred for 64 hours and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=2:1) to give N-methyl-N-methoxy-5-bromopyridine-3-carboxamide (3.71 g) as pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1>C(Cl)Cl>[N+:14]([C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1)([O-:16])=[O:15]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cccnc1N1CCNCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
Anhydrous piperazine (60 g) was dissolved in methylene chloride (400 ml) and then, 2-chloro-3-nitropyridine (40 g) was added slowly at 10~20° C. and the mixture was stirred at 20° C. for 2 hours. After completion of the reaction, the reaction mixture was washed with water (300 ml) three times and the separated organic layers were concentrated under reduced pressure. The precipitate was washed with water and small amount of ethanol and dried in vacuo to give 46 g (yield: 87.5%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:29])[C:12]3[CH:26]=[C:25]([CH2:27]Cl)[S:24][C:13]=3[N:14]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:32][CH:33]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:34]1[CH2:38][CH2:37][CH2:36][NH:35]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:29])[C:12]3[CH:26]=[C:25]([CH2:27][N:35]4[CH2:36][CH2:37][CH2:38][C@@H:34]4[C@@H:33]([OH:32])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[S:24][C:13]=3[N:14]([CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH:15]=2)=[O:9])=[CH:30][CH:31]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn(CCN2CCOCC2)c2sc(CCl)cc2c1=O
Reactant: OC(c1ccccc1)C1CCCN1
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCN2CCOCC2)c2sc(CN3CCC[C@@H]3[C@@H](O)c3ccccc3)cc2c1=O

Procedure:
Analogous to the procedures described in Example 2, N-(4-chlorobenzyl)-2-(chloromethyl)-7-(2-morpholin-4-ylethyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 23) is treated with 2-(hydroxy(phenyl)methyl)pyrrolidine (Preparation 2) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:14])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:35])[NH2:14])=[CH:8]2
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=O)[nH]c12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=S)[nH]c12
Temperature: 55 °C
Reaction time: 3 h
Yield: 151.5 %

Procedure:
A mixture of 7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxamide (0.73 g) and Lawesson's reagent (0.49 g) in tetrahydrofuran (30 mL) was stirred at 55° C. for 3 h. The reaction mixture was concentrated to give a light yellow oil, which was crystallized from ethyl acetate-hexane to give the title compound (691 mg, 91%) as light yellow prisms. MS 375 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH2:19]S(C(F)(F)F)(=O)=O)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:30](#[N:33])[CH:31]=C>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH:19]=[CH:31][C:30]#[N:33])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(Cc1c[nH]c2c(CS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Reactant: C=CC#N
Product: CC(C)(Cc1c[nH]c2c(C=CC#N)cccc12)NC(=O)OC(C)(C)C

Procedure:
{2-[7-(2-Cyano-vinyl)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester is prepared from [1,1-dimethyl-2-(7-trifluoromethanesulfonylmethyl-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester and acrylonitrile as described for the preparation of Amine 23 (85%). FDMS m/e=339.2 (M++1).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[CH3:20][C:21]1[CH:22]=[C:23]([C:28]2[C:29]([C:34](O)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]>>[CH3:20][C:21]1[CH:22]=[C:23]([C:28]2[C:29]([C:34]([N:3]3[CH2:4][C@H:5]4[C@H:1]([CH2:6]4)[C@H:2]3[CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1C
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1ccc(-c2ccccc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)cc1C

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 3′,4′-Dimethyl-biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.40 min; [M+H]+=485.2.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>C(#N)C.O>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([N:2]2[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]2)=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: O=C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.4 %

Procedure:
To 4-piperidone hydrochloride (2.17 g, 16.0 mmol) in acetonitrile (20 ml) was added triethylamine (3.9 ml) and potassium carbonate (2.9 g, 21.0 mmol). After stirring for 20 min at room temperature, 1-fluoro-4-nitrobenzene (1 g, 7.09 mmol) was added and the reaction mixture was heated to reflux for 12 hr. The reaction mixture was then cooled and filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was dissolved in water, extracted with ethyl acetate, dried and evaporated to give 1-(4-nitro-phenyl)-piperidin-4-one (0.6 g, 38%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[CH3:26]>>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:24][C:25]=1[CH3:26]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: Cc1ccc(B(O)O)cc1F
Product: Cc1ccc(-c2cc(C#N)cc3cc4n(c23)CCCNC4=O)cc1F

Procedure:
The title compound, light grey solid (75 mg, 90%), MS (ISP) m/z=334.5 [(M+H)+], mp 250.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 3-fluoro-4-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).