Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1([CH3:22])[C:11]2[C:7](=[C:8]([CH3:19])[N:9]([CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=2[CH3:12])[C:6]([CH3:21])([CH3:20])[CH2:5]1)(=[O:3])[NH2:2].[OH-].[Na+]>>[C:1]([C:4]1([CH3:22])[C:11]2[C:7](=[C:8]([CH3:19])[N:9]([CH2:13][C:14]([OH:16])=[O:15])[C:10]=2[CH3:12])[C:6]([CH3:21])([CH3:20])[CH2:5]1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)Cn1c(C)c2c(c1C)C(C)(C(N)=O)CC2(C)C
Agent: [Na+]
Agent: [OH-]
Product: Cc1c2c(c(C)n1CC(=O)O)C(C)(C(N)=O)CC2(C)C

Procedure:
Reaction of the ethyl 4-carbamoyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-2-acetate described above in Example 1AC with alcoholic sodium hydroxide and isolation of the product from an acid or neutral medium affords 4-carbamoyl-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-2-acetic acid.
Reaction SMILES: C[C@@H]1N([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)[C@@H](C)COC1.Cl.Cl.C[N:24]1C2CCC1CC(N)C2>>[O:9]1[C:10]2=[CH:16][CH:15]=[CH:14][C:13]([C:17]([NH2:24])=[O:19])=[C:11]2[N:12]=[CH:8]1
Reactant: CN1C2CCC1CC(N)C2
Reactant: C[C@H]1COC[C@H](C)N1c1nc2c(C(=O)O)cccc2o1
Agent: Cl
Product: NC(=O)c1cccc2ocnc12

Procedure:
Following general procedure GP-C1, a mixture of 2-((3S,5S)-3,5-dimethylmorpholino)benzoxazole-4-carboxylic acid and 8-methyl-8-azabicyclo[3.2.1]octan-3-amine dihydrochloride were coupled to provide N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2-(3 S,5S)-3,5-dimethylmorpholino)benzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[C:7](Cl)(=[O:11])[O:8][CH2:9][CH3:10].[OH-].[K+]>C(OCC)C>[C:7](=[O:11])([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[O:8][CH2:9][CH3:10]
Reactant: CCOC(=O)Cl
Reactant: OCC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CCOC(=O)OCC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.7 %

Procedure:
In a flask (5-liter volume), 2,2,2-trifluoroethanol (800 g, 8.0 mol), ethyl chlorocarbonate (867 g, 8.0 mol) and diethyl ether (1000 ml) were charged. While the flask was cooled so that the reaction was carried out at -5° C. to 0 ° C., a 29.5% by weight aqueous solution of potassium hydroxide (1500 g) was added dropwise to the flask for 6 hours and the mixture was stirred for 12 hours at room temperature. The ether layer was separated, washed with water, dried and distilled to give ethyl 2,2,2-trifluoroethyl carbonate as a colorless liquid (960 g, yield 70%). The chemical structure of the produced compound was determined based on the IR and NMR absorbance spectra shown in FIG. 5 and FIG. 6 respectively and the mass spectrometry spectrum (M/e=172).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][O:9][C:10](Cl)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClCCl.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24].C(N(C(C)C)CC)(C)C>O1CCOCC1.O>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][O:9][C:10]([N:21]2[CH2:22][CH2:23][NH:18][C:19](=[O:24])[CH2:20]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CNCCN1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: O=C1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The 48.7% solution of p-nitrobenzyloxycarbonyl chloride in 1,4-Dioxane (10.7 mL) was added to the dichloromethane (110 mL) solution of piperazin-2-one (2.21 g) and diisopropylethylamine (4.6 mL) at 0° C. and stirred for 0.5 h at 0° C. Water (300 mL) was added to the reaction mixture, and extracted with dichloromethane (3×100 mL). The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduce pressure. The residue was applied to silica gel column chromatography, eluted with CHCl3-methanol (30:1), and the title compound was obtained as white solid (7.1 g, quant.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([N+:18]([O-])=O)[C:10]=1[NH:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](O)C>C(O)=O.[Fe]>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH3:21])[CH:12]=[N:18][C:13]=2[CH:14]=[C:15]([Br:17])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Reactant: CCO
Agent: [Fe]
Solvent: O=CO
Product: Cn1cnc2cc(Br)cc(OCc3ccccc3)c21
Temperature: 90 °C

Procedure:
To a solution of 2-(benzyloxy)-4-bromo-N-methyl-6-nitroaniline 2.50 (770 mg, 2.25 mmol) in ethanol (12 mL) and formic acid (15 mL) was added iron (630 mg, 11.27 mmol) and heated at 90° C. at 4 h and LCMS shows still lot of starting material present. 500 mg of iron was added and the mixture was heated at 90° C. overnight. The reaction mixture was concentrated, diluted with water and acidified to pH˜7 with sat'd NaHCO3 and then the aqueous layer was extracted with EtOAc (3×). Combined organic layer were then washed successively with water and brine and dried over anhydrous magnesium sulfate. The residue was purified by flash column chromatography (SiO2, 100% EtOAc) to give 7-(benzyloxy)-5-bromo-1-methyl-1H-benzo[d]imidazole 2.51.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:4][CH3:5].Cl.Cl[CH2:15][CH2:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1.C(OCC)C>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:15][CH2:16][C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[CH:8][CH:7]=1)[CH2:4][CH3:5]
Reactant: ClCCc1c[nH]cn1
Reactant: CCCc1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCc1ccc(OCCc2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
240 mg (60% in oil; 6 mmol) of sodium hydride are slowly added to a solution of 1.63 g (12 mmol) of 4-propylphenol in 10 ml of dimethylformamide and the mixture is stirred at room temperature for 1 hour. 200 mg (1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride and tetrabutylammonium iodide are added and the mixture is stirred at 80° C. for 3 days. The reaction mixture is cooled and 150 ml of diethyl ether are added. The precipitate is separated by filtration and the filtrate is evaporated under reduced pressure to give a residue which is purified by preparative high performance chromatography. The title compound is converted to the oxalate (from an ethanol/diethyl ether mixture), M.p.: 168°-171° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl)[CH2:2][CH3:3].[C-:13]#[N:14].[Na+].O.CCOCC>CS(C)=O>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][C:13]#[N:14])[CH2:2][CH3:3]
Reactant: [C-]#N
Reactant: CCCOc1ccccc1CCl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCCOc1ccccc1CC#N
Temperature: 50 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
A 2 liter flask was charged with 367 grams (1.90 moles, 1.0 ec.) of crude 2-propoxybenzyl chloride in 700 ml of DMSO. The reaction is cooled by a water bath and 102 grams of sodium cyanide (2.09 moles, 1.1 eq.) was added and allowed to warm to 50° C. After the exotherm was complete, the reaction was stirred at room temperature overnight then worked up with water, dilute acid and ether. Removal of the solvent was followed by distillation (120°-150° C. at 1 mm) and gave 180 grams (54% Yield) of a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.C([Li])CCC.CCCCCC.CON(C)[C:26]([C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][CH:32]=[CH:31]2)=[O:27]>C1COCC1.O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:26]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:27])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: CON(C)C(=O)c1ccc2ncccc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=O)c2ccc3ncccc3c2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-bromo-3,5-dimethoxy-benzene (2.7 g, 12 mmol) in THF (20 mL) was added a solution of n-butyllitium in hexane (4.5 mL, 2.5 N, 11 mmol) at −78° C. and kept for 20 min. To the mixture was added quinoline-6-carboxylic acid methoxy-methyl-amide (2.2 g, 10 mmol) at −78° C. After 2 h, water (30 mL) was added to the mixture, and the cold bath was removed. The mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers was washed with sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and slurry in ether gave (3,5-dimethoxy-phenyl)-quinolin-6-yl-methanone as a white solid (1.48 g, 50% crude yield). The sample was used in the next step without further purification. 1H NMR (CDCl3) δ 3.84 (s, 6H, 2CH3), 6.70-6.73 (m, 1H, Ar), 6.97 (d, J=2 Hz, 1H, Ar), 7.49 (dd, J=4, 8 Hz, 1H, Ar), 8.17-8.28 (m, 4H, Ar), 9.02-9.04 (m, 1H, Ar).
Reaction SMILES: I[C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[C:4]2[O:9][C:10]([C:12]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:13]=3[CH:14]=[N:15][N:16]=[CH:17]4)=[CH:11][C:3]=12.[Si]([O:29][CH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[N:37]2)[CH2:32][CH2:31]1)(C(C)(C)C)(C)C>>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:39]2[CH:38]=[N:37][N:36]([C@H:33]3[CH2:34][CH2:35][C@H:30]([OH:29])[CH2:31][CH2:32]3)[CH:40]=2)=[C:3]2[CH:11]=[C:10]([C:12]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:13]=3[CH:14]=[N:15][N:16]=[CH:17]4)[O:9][C:4]=12
Reactant: Nc1ncc(I)c2cc(-c3cccc4cnncc34)oc12
Reactant: CC1(C)OB(c2cnn(C3CCC(O[Si](C)(C)C(C)(C)C)CC3)c2)OC1(C)C
Product: Nc1ncc(-c2cnn([C@H]3CC[C@H](O)CC3)c2)c2cc(-c3cccc4cnncc34)oc12

Procedure:
The title compound was prepared from 4-iodo-2-(phthalazin-5-yl)furo[2,3-c]pyridin-7-amine and 1-[4-(tert-butyldimethylsilanyloxy)-cyclohexyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole by a procedure analogous to Example 365, Step F. 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 1H), 9.80 (d, J=1.26 Hz, 1H), 8.65 (d, J=7.33 Hz, 1H), 8.25-8.35 (m, 2H), 8.20 (t, J=7.80 Hz, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 6.54 (br s, 2H), 4.68 (d, J=4.29 Hz, 1H), 4.18 (tt, J=3.73, 11.43 Hz, 1H), 3.48-3.59 (m, 1H), 2.07 (br d, J=12.10 Hz, 2H), 1.81-2.01 (m, 4H), 1.31-1.44 (m, 2H); MS (ESI): 427.01 [M+H]+; HPLC tR=2.38 min (ZQ3: polar—5 min).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])[CH:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[O:9])[CH2:3][CH2:2]1.C=O.[C:34](O)(=O)C.CO[BH-](OC)OC.[Na+]>O1CCCC1.CO>[CH3:34][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])[CH:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[O:9])[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: CCNC(=O)Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CCNCC3)c2)ccn1
Agent: C=O
Agent: CO[BH-](OC)OC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCNC(=O)Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CCN(C)CC3)c2)ccn1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
5-(2-(3-Ethylureido)pyridin-4-yloxy)indole-1-carboxylic acid piperidin-4-ylamide (36 mg, 0.085 mmol, Example 181) was dissolved in tetrahydrofuran (2.0 ml) and methanol (1.0 ml); and a 37% aqueous formaldehyde solution (0.036 ml, 0.43 mmol) and acetic acid (0.0098 ml, 0.17 mmol) were added thereto. While stirring at room temperature, sodium trimethoxyborohydride (27 mg, 0.13 mmol) was added; and the reaction mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate; and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure; the obtained crystals were suspended in diethyl ether, filtered off, washed with diethyl ether, and dried to yield the title compound (25 mg, 0.057 mmol, 67%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].[C:18]1(C)C=CC=C[CH:19]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)=[CH2:19]
Reactant: Cc1ccccc1
Reactant: O=C1CCc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=Cc1ccc2c(c1)CCC2=O
Temperature: 25 °C
Yield: 48 %

Procedure:
To a stirred solution of 5-bromo-2,3-dihydro-1H-inden-1-one (5 g, 23.7 mmol) in toluene were added vinylboronic anhydride pyridine complex (8.55 g, 35.54 mmol), Pd(PPh3)4 (0.1 g, 0.094 mmol), K2CO3 (22.88 g, 165.83 mmol). The resultant reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to 25° C. and filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and washed with water and brine. The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (SiO2, 5% EtOAc in petroleum ether) afforded the title compound as a solid (1.8 g, 48%): 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=7.2 Hz, 1H), 7.49 (br s, 1H), 7.44 (d, J=7.2 Hz, 1H), 6.82 (m, 1H), 5.90 (d, J=7.4 Hz, 1H), 5.42 (d, J=6.4 Hz, 1H), 3.20 (m, 2H), 2.70 (m, 2H); ESIMS m/z 159.06 ([M+H]−).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:51]=[CH:50][NH:49][N:48]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:48]1[CH:47]=[CH:51][C:50]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[CH:3]=2)=[N:49]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc[nH]n3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 130 °C
Yield: 51.6 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (78 mg, 0.32 mmol), sodium carbonate (43 mg, 0.41 mmols) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.02 mmol) in 1.5 mL dimethylformamide under argon conditions. The mixture was heated at 130° C. overnight. The mixture was poured into water and was extracted twice with ethyl acetate. The organics were dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to give 39 mg (66% yield) of the title compound. Purity 100%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH:11]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([F:20])=[C:15](Br)[C:14]=2[O:22][CH3:23])[CH3:12])[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][CH:35]=[C:36]([CH:39]=2)[C:37]#[N:38])O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH:11]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([F:20])=[C:15]([C:32]3[CH:33]=[N:34][CH:35]=[C:36]([C:37]#[N:38])[CH:39]=3)[C:14]=2[O:22][CH3:23])[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: COc1c(C(C)Nc2ncnc(N)c2C#N)cc(Cl)c(F)c1Br
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C(C)Nc2ncnc(N)c2C#N)cc(Cl)c(F)c1-c1cncc(C#N)c1
Temperature: 90 °C
Yield: 37 %

Procedure:
Into a microwave vial was added 4-amino-6-{[1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]amino}pyrimidine-5-carbonitrile (8.0 mg, 0.020 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (5.51 mg, 0.0240 mmol), a solution of sodium carbonate (48 μL, 0.050 mmol) in water (48 μL), 1,4-dioxane (0.2 mL, 2 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol). The mixture was bubbled with N2 for 5 minutes and heated at 90° C. for 2 h. Purification by preparative LCMS (pH 10) gave the desired compound (37% yield). LCMS calculated for C20H16ClFN7O (M+H)+: m/z=424.1. found: 424.1.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:8]([NH:10][C@H:11]1[C@H:18]2[C@H:14]([CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:17]2)[CH2:13][CH2:12]1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].C(N(CC)C(C)C)(C)C.[C:39](Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>ClCCl>[CH3:41][C:40]([CH3:43])([CH3:42])[C:39]([N:2]([CH3:1])[C@H:3]([C:8]([NH:10][C@H:11]1[C@H:18]2[C@H:14]([CH2:15][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=3)[CH2:17]2)[CH2:13][CH2:12]1)=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6])=[O:44]
Reactant: CN[C@@H](CC(C)C)C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)N(C)C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N2-methyl-N1-{(3aS,4R,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide (38.9 mg, 0.095 mmol) from Example 166 in dichloromethane (0.5 mL) was added N,N-diisopropylethylamine (24.77 μL, 0.142 mmol) followed by pivaloyl chloride (12.79 μL, 0.104 mmol), and the resultant reaction mixture was stirred at room temperature overnight. The reaction was reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-4). The title compound was eluted with a gradient of 0% to 100% ethyl acetate/hexanes over 15 minutes: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.81 (d, J=7.4, 1H), 7.74 (s, 1H), 7.60-7.55 (m, 2H), 7.43 (dd, J=6.6, 14.3, 1H), 5.45 (dd, J=7.0, 8.7, 1H), 4.35-4.29 (m, 1H), 3.57 (d, J=13.5, 1H), 3.44 (d, J=13.5, 1H), 3.13 (s, 3H), 2.73 (dd, J=2.6, 8.9, 1H), 2.53-2.45 (m, 1H), 2.41 (ddd, J=2.7, 8.3, 12.0, 1H), 2.37-2.32 (m, 1H), 2.29 (dd, J=3.0, 9.0, 1H), 2.26-2.21 (m, 1H), 2.05 (dq, J=6.0, 12.0, 1H), 1.86-1.80 (m, 3H), 1.55 (ddd, J=6.9, 12.8, 19.6, 2H), 1.41-1.31 (m, 1H), 1.30 (s, 9H), 0.88 (d, J=6.7, 3H), 0.82 (d, J=6.6, 3H); MS (ESI+) m/z 496 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)[CH:6]=[CH:7][CH:8]=1.[C:17]1([CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:25]2[CH2:26][CH2:27][CH:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24]2)=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: COc1cccc(-c2oncc2C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2oncc2C(=O)N2CCC(c3ccccc3)C2)c1
Temperature: 25 °C

Procedure:
5-(3-methoxyphenyl)-isoxazole-4-carboxylic acid (50.6 mg, 0.231 mmol), 3-phenylpyrrolidine (40 mg, 0.271 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (92.6 mg, 0.288 mmol) and diisopropylethylamine (49.7 mg, 0.384 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo (0.5-1.0 mL) and the residue was taken up in dichloromethane (1 mL), filtered and purified by normal-phase chromatography (20-50% EtOAc:petroleum ether). The combined fractions were partitioned between H2O/acetic acid (pH 4) and ethyl acetate. The organic fractions were washed with H2O/brine and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O3: 348.1474, found 348.1482.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][NH:13][C:12]3[N:16]=[CH:17][C:18](I)=[CH:19][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][N:29]=2)[CH2:24][CH2:23]1>>[C:1]1([S:7]([N:10]2[CH2:15][CH2:14][NH:13][C:12]3[N:16]=[CH:17][C:18]([C:31]4[CH:30]=[N:29][C:28]([N:25]5[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]5)=[CH:33][CH:32]=4)=[CH:19][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: O=S(=O)(c1ccccc1)N1CCNc2ncc(I)cc21
Product: CN1CCN(c2ccc(-c3cnc4c(c3)N(S(=O)(=O)c3ccccc3)CCN4)cn2)CC1
Yield: 72 %

Procedure:
1-Benzenesulfonyl-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (88 mg) was reacted with 1-Methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4A to give the title compound as a yellow foam (72% yield). M.p. (foam), LCMS: m/z=450-98 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.39 (s, 3H), 2.60 (t, J=5.0 Hz, 4H), 2.98-3.03 (m, 2H), 3.64 (t, J=5.0 Hz, 4H), 3.80 (t, J=5.0 Hz, 2H), 5.16 (bs, 1H), 6.73 (d, J=8.8 Hz, 1H), 7.40-7.45 (m, 2H), 7.51-7.54 (m, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.67 (dd, J=8.8 Hz, 2.5 Hz, 1H), 8.08 (s, 1H), 8.40 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH2:3][CH3:4])[CH3:2].C(O[Cl:18])(C)(C)C>C(Cl)(Cl)(Cl)Cl>[CH:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[C:10]([Cl:18])[CH:11]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Oc1ccc(O)cc1
Reactant: CC(C)(C)OCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(C)Oc1ccc(O)c(Cl)c1
Yield: 88.1 %

Procedure:
To a solution of 5.0 g of 4-sec-butoxyphenol in 50 ml of carbon tetrachloride, there was added dropwise 3.27 g of t-butylhypochlorite with vigorously stirring and ice-cooling. After completion of the addition, the reaction mixture was stirred at room temperature for 5 hours and concentrated, followed by addition of 200 ml of ethyl acetate. The obtained solution was washed with an agueous solution of 5% wt. sodium dicarbonate, dried and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 5.32 g of 4-sec-butoxy-2-chlorophenol. Yield. 88%. nD23.5 1.5312.