Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:19][CH3:20])=[C:6]([CH:8]2[C:14](=[O:15])[CH:13]3[CH2:16][CH2:17][CH:10]([CH:11]=[CH:12]3)[C:9]2=[O:18])[CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[C:24]([F:31])[CH:23]=1.[F-].[Cs+]>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[CH:4][C:5]([CH2:19][CH3:20])=[C:6]([CH:8]3[C:14](=[O:15])[CH:13]4[CH2:16][CH2:17][CH:10]([CH:11]=[CH:12]4)[C:9]3=[O:18])[CH:7]=2)=[C:24]([F:31])[CH:23]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: CCc1ccc(Br)cc1C1C(=O)C2C=CC(CC2)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: COCCOC
Product: CCc1ccc(-c2ccc(Cl)cc2F)cc1C1C(=O)C2C=CC(CC2)C1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 3-(5-bromo-2-ethylphenyl)bicyclo[3.2.2]non-6-ene-2,4-dione (0.180 g, 0.54 mmol) and 4-chloro-2-fluorophenylboronic acid (0.133 g, 0.76 mmol) in anhydrous dimethoxyethane (5 ml) is stirred at room temperature under an atmosphere of nitrogen. The reaction mixture is then evacuated and flushed with nitrogen (degassing cycle repeated 4 times). Cesium fluoride (0.246 g, 1.62 mmol) is added, and the suspension is stirred at room temperature for 45 minutes. Next [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (0.066 g, 0.081 mmol) is added in one portion, and the reaction mixture is heated at 80° C. for 21.5 hours. After cooling to room temperature the suspension is filtered through diatomaceous earth, then washed with 2M hydrochloric acid (20 ml) and dichloromethane (20 ml). The organic phase is separated, and the aqueous phase is extracted with dichloromethane (10 ml×2). All organics are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give a brown gum. The crude product is purified by flash column chromatography on silica gel (100% to 0% hexane/ethyl acetate eluant ratio), then further purified by preparative reverse-phase HPLC to afford 3-(4′-chloro-4-ethyl-2′-fluorobiphen-3-yl)bicyclo[3.2.2]non-6-ene-2,4-dione.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1.[C:15]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([NH:23][C:24]1[N:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1)=[O:22]>>[S:1]1[C:5]2[CH2:6][N:7]([C:30]([C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:16]4[C:15]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:22])=[N:29][CH:28]=3)=[O:31])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Reactant: c1ccc2c(c1)Cc1ccsc1CN2
Product: O=C(Nc1ccc(C(=O)N2Cc3sccc3Cc3ccccc32)cn1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 12, 9,10-dihydro-4H-thieno[2,3-c][1]benzazepine is reacted with 6-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][C:17](Cl)([Cl:21])[C:16](=[O:23])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[Cl-]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([Cl:21])=[C:16]([OH:23])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(n(Cc3ccccc3)c3ccccc23)CCC1(Cl)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Oc1c(Cl)ccc2c1c1ccccc1n2Cc1ccccc1
Temperature: 135 °C
Yield: 69.7 %

Procedure:
A mixture of 9-benzyl-3,3-dichloro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.225 g, 1.78 mmol), LiCl (0.225 g, 5.34 mmol), Li2CO3 (0.395 g, 5.34 mmol), and DMF (6 mL) is heated at 135° C. for 45 min. After cooling, the mixture is partitioned between ethyl ether and aq. ammonium chloride/brine and brine. The organic layer is dried over magnesium sulfate and concentrated to dryness. Chromatography on silica gel (40 mL) using ethyl acetate/hexane (10/90) gave 0.382 g of 9-benzyl-3-chloro-9H-carbazol-4-ol. 1H NMR (CDCl3) δ5.48, 6.14, 6.88, 7.11, 7.12, 7.24-7.36, 7.43, 8.37.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[CH3:28][C:29]1([CH3:44])[CH2:34][N:33]([CH3:35])[CH2:32][CH2:31][N:30]1[CH2:36][C:37]1[N:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:28][C:29]1([CH3:44])[CH2:34][N:33]([CH3:35])[CH2:32][CH2:31][N:30]1[CH2:36][C:37]1[N:42]=[CH:41][C:40]([NH:43][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=3[F:22])=[CH:14][CH:15]=2)=[O:5])=[CH:39][CH:38]=1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: CN1CCN(Cc2ccc(N)cn2)C(C)(C)C1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4(C)C)nc3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 6-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-3-ylamine (Step 114.1), 1.5 equiv of trimethyl aluminum, stirring the reaction mixture for 2 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 563.2 [M+H]+; tR=3.36 min (System 1); TLC: Rf=0.22 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: C(OO)(C)(C)C.[CH3:7][O:8][C:9]([C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10].[CH:17](=[O:20])[CH2:18][CH3:19]>O.OS(O)(=O)=O>[CH3:7][O:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:13][N:12]=1)=[O:10]
Reactant: COC(=O)c1cnccn1
Reactant: CCC=O
Agent: CC(C)(C)OO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(=O)c1cnc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
Tert-butyl hydroperoxide (70%, 1.0 ml, 7.25 mmol) and a solution of FeSO4.7H2O (3.02 g, 10.9 mmol) in water (8 ml) were added concurrently to a solution of methyl-2-pyrazine carboxylate (250 mg, 1.81 mmol) and propionaldehyde (0.78 ml, 0.9 mmol) in H2SO4 (0.75 ml) at 0 C. The reaction was allowed to warm to room temperature and was stirred for 2 hours. Solid Na2S2O5 was added (until starch/iodide test negative) and the mixture extracted with dichloromethane. Concentration in vacuo and flash column chromatography over silica gel in ethyl acetate:hexane (15:85) yielded methyl-5-propionyl-2-pyrazinecarboxylate as a pale yellow solid (106 mg). The methyl ester was treated with LiOH (25 mg, 0.6 mmol) in tetrahydrofuran (15 ml) and water (0.5 ml). After 2 hours at room temperature the mixture was acidified with HCl (2N). Work-up followed by concentration of the organic phase in vacuo gave the title compound (92 mg).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[C:15]2[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]([CH2:29][C@H:30]1[O:32][CH2:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:8]([CH2:31][C@H:30]([OH:32])[CH2:29][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:9]1[C:15]2[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(NCc1ccccc1)CCCC2
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1)C(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCCC2
Reaction time: 3 h
Yield: 66.2 %

Procedure:
Under nitrogen, to a solution of N-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)amine (187 mg) and (2S)-1-phenoxy-2,3-epoxypropane (100 mg) in dichloromethane (10 ml) was added ytterbium(III) trifluoromethanesulfonate (50 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford (2S)-1-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)amino]-3-phenoxy-2-propanol (190 mg).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][CH2:6][NH:7][C:8](=[O:16])[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)C.[OH-].[Na+]>CO.O>[N:13]1[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:17])=[O:3])=[O:16])=[CH:11][CH:12]=1
Reactant: CCOC(=O)CCNC(=O)Nc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCNC(=O)Nc1ccncc1
Yield: 77.4 %

Procedure:
A solution of 2 g (8.4 mmol) of 4-pyridylcarbamoyl-beta-alanine ethyl ester and 0.37 g (9.2 mmol) of sodium hydroxide in 50 ml of methanol and 0.1 ml of water is kept agitated for 24 hr at room temperature. After concentration to dryness, the resulting oily residue is taken up in 15 ml of water. After washing with 3 x 10 ml of dichloromethane, the aqueous phase is acidified with a 3 N hydrochloric acid solution until a pH close to 3 is obtained. The precipitate formed is filtered, washed with 10 ml of cold water and then dried 1.36 g (yield 95%) of 4-pyridylcarbamoyl-beta-alanine is obtained in the form of a solid having a melting point of 222° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[C:12](O)([CH3:15])([CH3:14])[CH3:13].S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][C:4]=1[OH:9]
Reactant: CC(C)(C)O
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(O)c(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
A mixture of 2-trifluoromethylphenol (25 g., 0.15 moles), tert-butyl alcohol (12 g., 0.16 mole), trifluoroacetic acid (100 ml.) and 96% sulfuric acid (2ml.) is stirred at about 20°C for 48 hours. The mixture then is evaporated as far as possible under reduced pressure at 35°-40°C. The residue is dissolved in benzene (500 ml.) and the solution is washed with water, saturated NaHCO3 solution and saturated salt brine and dried over anhydrous Mg SO4. The dried solution is again evaporated under reduced pressure and the temperature is finally raised to 140°-150°C under 65 mm. pressure to remove unchanged 2-trifluoromethylphenol. The residue is distilled at 65 mm. after collecting a small fore-run (75% unchanged starting phenol and 25% product), 2-trifluoromethyl-4-tert-butylphenol (13.6 g) is collected at 120°- 132°C as a pale pink oil that is 98% pure by gas liquid chromatography analysis and can be used directly in the next step.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]2[CH2:24][CH:23]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH:22]3[CH2:21]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35]>C(Cl)Cl>[ClH:35].[NH:27]1[CH2:26][CH2:25][CH:23]2[CH2:24][N:20]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:13]=3[N:12]=[CH:11][C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])=[CH:19]4)[CH2:21][CH:22]12
Reactant: CC(C)(C)OC(=O)N1CCC2CN(c3cccc4cc(S(=O)(=O)c5ccccc5)cnc34)CC21
Agent: Cl
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)c1cnc2c(N3CC4CCNC4C3)cccc2c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl 5-(3-(phenylsulfonyl)quinolin-8-yl)hexahydropyrrolo[2,3-c]pyrrole-1(2H)-carboxylate (92 mg, 0.19 mmol) in CH2Cl2 (5 ml) was treated with hydrochloric acid (4M in dioxane, 2 ml) at 0° C. and then stirred at 50° C. for 16 h. After concentration, the product was washed with EtOAc and dried in vacuo to give the title compound (80 mg, 100% as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][CH3:4].[CH:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[C:24]([CH:29]([OH:32])[CH2:30][NH2:31])[CH:23]=1>>[CH3:1][C:2]([C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]2[CH2:16][CH2:17][CH:18]([NH:31][CH2:30][CH:29]([C:24]3[CH:25]=[C:26]([OH:28])[CH:27]=[CH:22][CH:23]=3)[OH:32])[CH2:19][CH2:20]2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)([CH3:5])[CH2:3][CH3:4]
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)N2CCC(=O)CC2)cc1
Reactant: NCC(O)c1cccc(O)c1
Product: CCC(C)(C)c1ccc(S(=O)(=O)N2CCC(NCC(O)c3cccc(O)c3)CC2)cc1

Procedure:
The title compound was prepared from 4-(1,1-dimethyl-propyl)-benzenesulfonyl-piperidin-4-one and norphenylephrine according to the reductive amination procedure of Intermediate 21 as an off-white solid; 1H NMR (DMSO) δ 0.60 (t, J=7.32 Hz, 3H), 1.28 (s, 6H), 1.60-1.68 (m, 2H), 1.77-1.91 (m, 2H), 2.27-2.45 (m, 4H), 2.51-2.56 (m, 2H), 2.56-2.59 (m, 2H), 3.42-3.47 (m, 2H), 4.42-4.44 (m, 2H), 5.18 (bs, 1H), 6.57-6.60 (m, 1H), 6.67-6.71 (m, 2H), 7.05 (t, J=7.74 Hz, 1H), 7.58 (d, J=8.61 Hz, 2H), 7.65 (d, J=8.58 Hz, 2H) 9.25 (s, 1H); MS (ES) m/z 446.9 (MH+); HRMS for C24H34N2O4S: 447.2323
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].O.O.Cl[Sn]Cl.CO.C([O-])(O)=O.[Na+]>CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(N)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
2-Bromo-1-methoxy-4-nitrobenzene (2.50 g, 10.8 mmol), SnCl2.2H2O (12.2 g, 53.9 mmol), and MeOH (30 mL) were combined and allowed to stir for 3 h at ambient temperature. To the mixture was added H2O (100 mL) and EtOAc (100 mL) resulting in the formation of a thick emulsion. To this was added sat. aq. NaHCO3 (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×30 mL). The organics were combined and dried over MgSO4 before being filtered. Concentration of the filtrate in vacuo gave 2.02 g of an off-white solid. This material was used without further purification.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH3:11])[C:6]=2[C:5]([Br:12])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.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>[Br:12][C:5]1[C:6]2[N:10]([CH3:11])[CH:9]=[CH:8][C:7]=2[C:2]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:14]([Cl:13])[CH:15]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cn1ccc2c(Br)ncc(Br)c21
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1ccc2c(Nc3cccc(Cl)c3)ncc(Br)c21
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A mixture of 4,7-dibromo-1-methyl-1H-pyrrolo[3,2-c]pyridine (290 mg), 3-chloroaniline (153 mg), cesium carbonate (652 mg), tris(dibenzylidineacetone)dipalladium(0) (10 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6 mg) in dioxan (5 ml) was heated at reflux under nitrogen overnight. A further addition of tris(dibenzylidineacetone)dipalladium(0) (10 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6 mg) was made and the mixture refluxed for 4 hrs, then a repeat addition made and reflux continued for 2 hrs. The mixture was diluted with ethyl acetate (5 ml), filtered through Celite using ethylacetate and evaporate. The residue was dissolved in ethyl acetate and passed through silica gel eluting with ethyl acetate and evaporated. Purification of the residue by chromatography on Biotage, eluting with isohexane/dichloromethane 1:1, and evaporation gave the title compound (199 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5](O)=[O:6].C(C1NC=CN=1)([C:15]1[NH:16]C=CN=1)=O.Cl.CN.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH3:12])[C:5]([NH:16][CH3:15])=[O:6]
Reactant: CNc1ccc(C(=O)O)cc1Cl
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(NC)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-chloro-4-fluorobenzonitrile (1.0 g), methylamine (16 mL of a 2 M solution in methanol) and diisopropylethylamine was reacted in the microwave at 120° C. for 15 min. The mixture was then partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with brine (30 mL), dried (MgSO4) and reduced in vacuo to give 3-chloro-4-methylamino-benzonitrile. A suspension of 3-chloro-4-methylamino-benzonitrile (900 mg) in 2 M aqueous sodium hydroxide solution (30 mL) was heated at reflux for 3 h. After cooling to room temperature, the solution was acidified with 2 M aqueous hydrochloric acid and the resulting solid collected by filtration and air-dried to give 3-chloro-4-methylamino-benzoic acid. To a solution of 3-chloro-4-methylamino-benzoic acid (860 mg) in DMF (20 mL) was added carbonyl diimidazole (630 mg) and the reaction stirred at room temperature for 1 h. Then, methylamine hydrochloride (262 mg) and triethylamine (1.62 mL) were added and the reaction stirred at room temperature for 16 h. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with brine (3×40 mL), dried (MgSO4), reduced in vacuo and purified on silica to give 3-chloro-N-methyl-4-methylamino-benzamide.
Reaction SMILES: [O:1]=[C:2]([CH3:34])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[C:8]([NH:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([NH:21][C:22]([C:24]4[CH:29]=[N:28][CH:27]=[C:26]([CH3:30])[N:25]=4)=[O:23])([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:9].[CH3:35][Mg+].[Br-]>C1COCC1.CCOCC>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[C:8]([NH:10][C:11]12[CH2:18][CH:17]3[CH2:16][CH:15]([CH2:14][C:13]([NH:21][C:22]([C:24]4[CH:29]=[N:28][CH:27]=[C:26]([CH3:30])[N:25]=4)=[O:23])([CH2:19]3)[CH2:12]1)[CH2:20]2)=[O:9]
Reactant: C[Mg+]
Reactant: CC(=O)COc1cccc(C(=O)NC23CC4CC(C2)CC(NC(=O)c2cncc(C)n2)(C4)C3)c1
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cncc(C(=O)NC23CC4CC(CC(NC(=O)c5cccc(OCC(C)(C)O)c5)(C4)C2)C3)n1

Procedure:
Reaction of 6-methyl-pyrazine-2-carboxylic acid {3-[3-(2-oxo-propoxy)-benzoyl-amino]-adamantan-1-yl}-amide with MeMgBr in THF or ether at 0° C. could yield the title compound, 6-methyl-pyrazine-2-carboxylic acid {3-[3-(2-hydroxy-2-methylpropoxy)-benzoylamino]-adamantan-1-yl}-amide.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:34]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:33])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:29][CH:30]([F:32])[F:31])[C:13]=2[N:14]2[CH2:20][CH2:19][CH2:18][C@@H:17]([N:21]([CH3:28])C(=O)C(F)(F)F)[CH2:16][CH2:15]2)[N:6]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:44]=1B(O)O>>[NH2:34][C:4]1[S:3][C:2]([C:44]2[CH:45]=[C:46]([CH3:49])[CH:47]=[CH:48][C:43]=2[F:42])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH2:29][CH:30]([F:31])[F:32])[C:13]=1[N:14]1[CH2:20][CH2:19][CH2:18][C@H:17]([NH:21][CH3:28])[CH2:16][CH2:15]1)=[O:33]
Reactant: CN(C(=O)C(F)(F)F)[C@@H]1CCCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2CC(F)F)CC1
Reactant: Cc1ccc(F)c(B(O)O)c1
Product: CN[C@H]1CCCN(c2c(NC(=O)c3nc(-c4cc(C)ccc4F)sc3N)cnn2CC(F)F)CC1

Procedure:
Following the procedure for Example 108, (R)-tert-butyl 2-bromo-4-(1-(2,2-difluoroethyl)-5-(4-(2,2,2-trifluoro-N-methylacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (80 mg, 0.12 mmol) and 2-fluoro-5-methylbenzeneboronic acid (30 mg, 0.20 mmol) were reacted to give 119 as the mono formate salt as a pale pink solid (11 mg, 19% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 8.56 (s, 1H), 8.08 (dd, J=7.3, 2.2 Hz, 1H), 7.60 (s, 1H), 7.26-7.20 (m, 1H), 7.12 (dd, J=11.4, 8.4 Hz, 1H), 6.41-6.08 (m, 1H), 4.54-4.43 (m, 2H), 3.40-3.33 (m, 3H), 3.32-3.24 (m, 2H), 2.64 (s, 3H), 2.41 (s, 3H), 2.33-1.94 (m, 3H), 1.91-1.76 (m, 3H). LCMS (ES+) m/z 508 (M+1).
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH:27]=[O:28])[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:31]([Mg]Br)[CH3:32].[Cl-].[NH4+]>O1CCCC1>[C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH:27]([OH:28])[CH2:31][CH3:32])[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2noc(C3(C=O)CC3)c2-c2ccccc2)cc1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)C1(c2onc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2-c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropanecarbaldehyde, which may be produced as in Example 172 (20.38 g) in 300 mL tetrahydrofuran under an N2 atmosphere is cooled to 0° C. Ethylmagnesium bromide (53.4 mL, 1.0 M/methyl tert-butyl ether) is added over approximately 15 minutes. The reaction is stirred at 0° C. for 1 hour, 10 minutes. Saturated ammonium chloride (˜600 mL) is added and the product is extracted into ethyl acetate two times. The combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude material is purified by column chromatography (15% followed by 20% ethyl acetate/hexane) to obtain a viscous oil that partially solidified under house vacuum. The material is dried in a 50° C. vacuum oven for approximately 1 hour to give (±)-1-(1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropyl)-propan-1-ol as a waxy off-white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H]4CCCNC4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.ClC1C=C2C(C3N=C(N[C@H:43]4[CH2:48][CH2:47][CH2:46][NH:45][CH2:44]4)C(F)=CN=3)=CNC2=NC=1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH3:82][C:83]1([C:86](O)=[O:87])[CH2:85][CH2:84]1>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][CH:44]4[CH2:43][CH2:48][CH2:47][CH2:46][N:45]4[CH:84]4[C:83]([CH:86]=[O:87])([CH3:82])[CH2:85]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: CC1(C(=O)O)CC1
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1(C=O)CC1N1CCCCC1Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F

Procedure:
To a solution of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine hydrochloride, 5b, (0.04 g, 0.10 mmol) in CH2Cl2 (1.4 mL) and DMF (0.3 mL) was added N,N-diisopropyl-N-ethylamine (0.3 mL, 1.72 mmol), followed by 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (0.02 g, 0.12 mmol), 1-hydroxybenzotriazole hydrate (0.02 g, 0.12 mmol) and 1-methylcyclopropane-1-carboxylic acid (0.01 g, 0.12 mmol). The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H2O/acetonitrile) to afford the desired product, 445.