Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:17]=1[NH2:18]>C(O)CO>[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:17]=1[NH:18][C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5]
Reactant: C#CCNC(=O)c1cccnc1Cl
Reactant: COc1ccc(OC)c(N)c1
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1cc(OC)ccc1OC
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 2,5-dimethoxyaniline (9h, 153 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(2,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10h as pure product. To a solution of 2-(2,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10h, 150 mg, 0.48 mmol) and 1-(azidomethyl)-3-phenoxybenzene (119 mg, 0.53 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1h (201 mg, 78%); mp: 154-156° C.; 1H NMR (300 MHz, CDCl3) δ 10.71 (s, 1H), 8.34 (d, J=2.2 Hz, 1H), 8.32 (dd, J=3.0, 1.5 Hz, 1H), 7.76 (dd, J=2.2, 1.5 Hz, 1H), 7.54 (s, 2H), 7.32 (d, J=7.5 Hz, 2H), 7.28 (d, J=2.2 Hz, 1H), 7.18-7.06 (m, 2H), 6.97-6.84 (m, 5H), 6.76 (d, J=8.3 Hz 1H), 6.66-6.62 (m, 1H), 6.42-6.38 (m, 1H) 6.40 (dd, J=3.0 Hz, 1H), 5.45 (s, 2H), 4.66 (d, J=5.2 Hz, 2H), 3.90 (s, 3H), 3.79 (s, 3H); MS (ESI m/z): 537 [M+H]+. Yield: 78%
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[CH:24][C:7]=1[O:8][CH:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1(C)C=CC=CC=1.[O-2].[O-2].[O-2].[Ni+3].[Ni+3]>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:34]=[CH:33][S:32][CH:31]=2)=[CH:24][C:7]=1[O:8][CH:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C1=NCCO1)c1ccccc1C
Agent: [Ni+3]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1-c1ncco1)c1ccccc1C
Reaction time: 16 h
Yield: 15.6 %

Procedure:
A solution of ethyl (RS)-4-[2-(4,5-dihydrooxazol-2-yl)-5- (3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate (900 mg) and nickel peroxide (5.04 g) in toluene (50 mL) is stirred at 100° C. for 2 hours. The reaction is left at ambient temperature for 16 hours then filtered through a pad of hyflo and the filtrate concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (15:85 v/v). Fractions homogeneous in the required product are combined and evaporated to give ethyl (RS)-4-[2-(oxazol-2-yl)-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate (140 mg) and starting material (400 mg).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1>C1COCC1>[Br:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.1 eq of aqueous NaOH (1 M solution) was added to a solution of methyl 4-bromobenzoate in THF (0.5 M) and the reaction allowed to stir at RT overnight. THF was removed in vacuo and aqueous HCl (6M) was added dropwise to the basic solution at 0° C. to adjust the pH to pH 2. The resultant aqueous mixture was extracted with EtOAc (3×) and then the combined organics were washed with brine, dried over Na2SO4, filtered and the solvent evaporated in vacuo. The title compound was obtained in quantitative yield; MS (ES+) m/z 201 (M+H)+, m/z 203 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[CH3:10][N:11](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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]>[F:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[C:10]#[N:11]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(C#N)c(F)c1
Temperature: 130 °C
Yield: 65 %

Procedure:
Under N2, to a suspension of 1-bromo-2-fluoro-4-methyl-benzene (2.59 g, 13.7 mmol) and Zn(CN)2 (1.60 g, 13.7 mmol) in dry DMF (50 mL) was added 1,1′-bis(diphenylphosphino)ferrocene (DPPF) (0.0753 g, 0.136 mmol) and Pd2(dba)3 (dba=di(benzylidene)acetone) (0.0623 g, 0.0681 mmol). After the mixture was heated at 130° C. for 2 days, the solvent was removed by evaporation under vacuum, and saturated aqueous NaHCO3 (40 mL) was added. The aqueous suspension was extracted with CH2Cl2 (3×40 mL), and the extract was dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residual solid was purified by flash chromatography on silica gel (1:20 EtOAc/hexanes), affording 2-fluoro-4-methyl-benzonitrile as a pale yellow solid (1.21 g, 65%). 1H NMR (CDCl3) δ 2.43 (s, 3H), 7.01-7.07 (m, 2H), 7.48-7.52 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][N:12]([C@@H:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]([O:18]C(C)(C)C)=[O:17])[C:11]2=[O:27])[N:8]=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[CH3:1][O:2][CH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][N:12]([C@@H:15]([C:23]([CH3:25])([CH3:24])[CH3:26])[C:16]([OH:18])=[O:17])[C:11]2=[O:27])[N:8]=1
Reactant: COCc1nc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCc1nc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution containing the product from Example 6G (1.28 g, 3.2 mmol) in dichloromethane (10 mL) was treated with trifluoracetic acid (5 mL), stirred at 25° C. for 4 hours and concentrated. The residue was chromatographed on silica gel eluting with 0-5% methanol in dichloromethane to give the title compound (1.2 g) as the trifluoroacetic acid salt.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[C:17](=[O:20])([O-])[O-].[K+].[K+]>C(O)CCC>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:7][CH2:9][CH2:10][C:17](=[O:20])[C:6]3[CH:15]=[CH:16][C:3]([F:2])=[CH:4][CH:5]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCCCO
Product: O=C(CCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
A mixture of 13.9 g. (0.057 mole) of 4-(p-fluorobenzoyl)piperidine hydrochloride, 15.5 g. (0.063 mole) of 2-(p-fluorophenyl)-2-(ω-chloropropyl)-1,3-dioxolane, and 27.6 g. (0.2 mole) of potassium carbonate in 150 ml. of 1-butanol was refluxed 20 hours. The mixture was filtered, the filtrate concentrated, the oily residue dissolved in 50 ml. of an ether-methanol mixture and this solution stirred with 100 ml. of 3N HCl for one hour. The mixture was cooled, the layers separated, the aqueous layer basified and the basic mixture extracted with ether. The ethereal extracts were dried over anhydrous sodium sulfate, the mixture filtered and the filtrate treated with ethereal hydrogen chloride. The salt, which weighed 17.2 g. (74%), was recrystallized from an isopropanol-methanol mixture. The dried hydrochloride salt melted at 255°-257° C. The free base which was prepared by neutralization of a portion of the hydrochloride salt melted at 133°-135° C.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]([CH3:11])([CH3:10])[C:8]#[N:9])[CH2:2]2.[C:12]1([Li])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C(OCCCC)CCC.C1COCC1.CO>[CH:5]12[CH2:6][CH:1]1[CH2:2][N:3]([C:7]([CH3:11])([CH3:10])[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:9])[CH2:4]2
Reactant: [Li]c1ccccc1
Reactant: CC(C)(C#N)N1CC2CC2C1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCOCCCC
Product: CC(C)(C(N)c1ccccc1)N1CC2CC2C1
Yield: 44 %

Procedure:
The title compound (393 mg, 44%) was prepared from 2-(3-azabicyclo[3.1.0]hex-3-yl)-2-methylpropanenitrile D15 (583 mg, 3.9 mmol), and phenyllithium in dibutylether (2.15 ml of a 2.0M solution; 4.3 mmol) in THF (7 ml), followed by reaction with sodium borohydride (445 mg, 11.7 mmol) in methanol (10 ml) in a similar manner to that described in D2. 1H NMR (CDCl3) δ: 0.38 (1H, m), 0.66 (1H, m), 0.74 (3H, s), 0.93 (3H, s), 1.30-1.40 (2H, m), 1.74 (2H, bs), 2.67 (2H, m), 2.91 (2H, t, J=8 Hz), 4.03 (1H, s), 7.20-7.30 (3H, m), 7.38 (2H, m).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]1[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[OH-].[Na+].OO>O1CCCC1.O>[CH2:1]([O:17][CH2:18][C@H:19]1[C@@H:24]([OH:25])[CH2:23][CH2:22][CH2:21][O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCC1OCCCC1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOC[C@@H]1OCCC[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.011 g of dl-2-hexadecyloxymethyltetrahydropyran-3-one (prepared as described in Preparation 3) were dissolved in 10 ml of tetrahydrofuran and cooled with ice. 12 ml of a 1M tetrahydrofuran solution containing L-selectride were added dropwise over 10 minutes, and the reaction mixture was then stirred at 0°-5° C. for 30 minutes and at room temperature for 60 minutes. The reaction mixture was then ice-cooled again, and 5 ml of a 10% w/v aqueous solution of sodium hydroxide were added at 5°-15° C. 5 ml of 30% hydrogen peroxide were added little by little at 15°-30° C. The mixture was stirred at room temperature for 2 hours, after which water was added, and the resulting mixture was separated. The water layer was extracted twice with diethyl ether. The organic layer and the extracts were combined, washed, dried and condensed by evaporation under reduced pressure. The residue, 2.84 g, was purified by chromatography using a silica gel Lobar C column. The fractions eluted with mixtures of ethyl acetate and hexane ranging from 1:4 to 1:3 by volume gave 2.381 g of the title compound as crystals, melting at 67.5°-68.5° C. (ethyl acetate).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17](O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:20])[CH3:1])=[CH:4][CH:5]=2)[N:18]=1
Reactant: CN(C)c1ccc(-c2nc(O)c3ccccc3n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CN(C)c1ccc(-c2nc(Cl)c3ccccc3n2)cc1
Temperature: 140 °C
Reaction time: 5 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-[4-(dimethylamino)phenyl]quinazolin-4-ol (2 g, 7.54 mmol, 1.00 equiv) in POCl3 (20 mL). The resulting solution was stirred for 5 h at 140° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 50 mL of dichloromethane. The resulting mixture was washed with 2×20 mL of saturation sodium bicarbonate solution and 1×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 2.0 g (93%) of 4-(4-chloroquinazolin-2-yl)-N,N-dimethylaniline as a red solid. MS (ESI) m/z 284 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]([CH2:45][CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][C@H:48]1[C:52]([O:54]C(C)(C)C)=[O:53])[C:3](=[O:44])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:43])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][C:13]=2[C:24]2[CH:29]=[C:28]([C:30](=[O:42])[NH:31][C@@H:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35][CH2:34][CH2:33]3)[CH:27]=[CH:26][N:25]=2)[CH:5]=1.C(O)(C(F)(F)F)=O>>[CH3:1][N:2]([CH2:45][CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][C@H:48]1[C:52]([OH:54])=[O:53])[C:3](=[O:44])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:43])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][C:13]=2[C:24]2[CH:29]=[C:28]([C:30](=[O:42])[NH:31][C@@H:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35][CH2:34][CH2:33]3)[CH:27]=[CH:26][N:25]=2)[CH:5]=1
Reactant: CN(CCN1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Product: CN(CCN1CCC[C@H]1C(=O)O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To (S)-tert-butyl 1-(2-(N-methyl-3-((4-(piperidin-1-yl)-2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzamido)ethyl)pyrrolidine-2-carboxylate (90 mg) was added TFA (5 mL). The mixture was stirred at room temperature for 6 h, concentrated and purified by column to give a yellow solid (75 mg, 90%).
Reaction SMILES: N1C=CN=C1[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:7].[CH:22]1([CH2:25][OH:26])[CH2:24][CH2:23]1>O1CCOCC1>[C:16]1([CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:26][CH2:25][CH:22]3[CH2:24][CH2:23]3)[CH2:14][CH2:13]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)c1ncc[nH]1
Reactant: OCC1CC1
Solvent: C1COCCO1
Product: O=C(NC1CCN(Cc2ccccc2)CC1)OCC1CC1

Procedure:
A solution of 4-imidazolylcarbonylamino-1-phenylmethylpiperidine (10 g, 0.035 mol), from Preparation 2, in dioxane (100 mL) was added to cyclopropanemethanol (2.42 g, 0.035 mol), then heated overnight at 80°-100° C. with stirring. The reaction mixture was allowed to return to room temperature and the dioxane evaporated under reduced pressure, and the residue was flash-chromatographed using ethyl acetate/heptane (50:50) as eluent. 9.5 g of cyclopropylmethyl (1-phenylmethyl-4-piperidyl)carbamate, m.p. 70°-72° C., was recovered and used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH2:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[K+]>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].CN(C=O)C>[CH3:23][N:22]([CH3:24])[S:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:10]2[CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]([C:29]4[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=4)[CH:3]=[C:4]3[C:12](=[O:13])[C:11]=2[CH:14]=1)(=[O:21])=[O:20]
Reactant: CN(C)S(=O)(=O)Cc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)Cc1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
1-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N,N-dimethylmethanesulfonamide (1.44 g, 3.97 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H pyrazole (1.239 g, 5.95 mmol), tri-t-butylphosphonium tetrafluoroborate (0.104 g, 0.357 mmol), Pd2(dba)3 (0.145 g, 0.159 mmol), and potassium fluoride (0.761 g, 13.10 mmol) were combined as solids and then placed under a nitrogen atmosphere. DMF (39.7 ml) was added and the resulting suspension was heated to 130° C. and left to stir for 1 h. Then, the reaction was cooled to room temperature and partitioned between saturated aqueous sodium hydrogen carbonate (250 mL) and dichloromethane (250 mL). The organic layer was dried over anhydrous Na2 SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (EtOAc+10% MeOH/Hexanes gradient) to afford the title compound as a yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 9.21 (d, 1H); 8.54 (d, 1H); 8.47 (s, 1H); 8.19 (s, 1H); 8.14 (s, 1H); 7.81 (m, 2H); 7.40 (d, 1H); 7.32 (d, 1H); 4.63 (s, 2H); 3.88 (s, 3H); 2.74 (s, 6H). LRMS (APCI) calculated for C21H21N4O3S [M+H]+, 409.1; found 409.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].S([O-])(O)=O.[Na+].CN(C)C(=O)C.[CH3:28][C:29]1[NH:30][CH:31]=[C:32]([CH3:36])[C:33]=1[CH:34]=O>O>[CH3:28][C:29]1[NH:30][CH:31]=[C:32]([CH3:36])[C:33]=1[C:34]1[NH:1][C:2]2[CH:3]=[C:4]([C:5](=[O:6])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[CH:14][C:15]=2[N:16]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: Cc1c[nH]c(C)c1C=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c[nH]c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.9 %

Procedure:
3,4-Diaminobenzophenone (1.48 g) and sodium hydrogensulfite (0.87 g) were added to N,N-dimethylacetamide (5 ml) at 130° C., and stirred for 5 minutes. 2,4-Dimethyl-3-formyl-pyrrole (1.03 g) was added and stirred at 130° C. for 8 hours. The reaction mixture was cooled to room temperature and stirred, and after addition of water to reaction mixture, precipitate was collected by filtration, and dried in vacuo to afford 2-(2,4-dimethyl-pyrrol-3-yl)-5-benzoylbenzimidazole (1.78 g, 81%) as a brown solid.
Reaction SMILES: B([O-])([O-])[O-].[Na+].[Cl-].[NH2:7][C@H:8]([C:13]([NH:15][C@H:16]([C:21]([NH2:23])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]>>[NH2:7][C@H:8]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:8]([C:13]([NH2:15])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:22])[CH2:17][CH:18]([CH3:19])[CH3:20])=[O:14])[CH2:9][C:10]1[CH:11]=[CH:21][CH:16]=[CH:17][CH:12]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CC(C)C)C(N)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.3 %

Procedure:
2 ml 0.05 borate buffer, pH 9, containing 0.2M NaCl, 2 mMMal-Phe-OMe, 50 mM H-Leu-Leu-NH2 and 12 μM trypsinogen are agitated at 25° C. under pH control. The reaction is stopped as described in Example 1a. After 24 hours, the yield, analytically determined with HPLC, is 61% of theory. A parallel batch resulted, after 48 hours, in a yield of 60.3% of theory.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[C:31]1[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: CC(C)(C)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1

Procedure:
3-Bromo-7-tert-butylimidazo[1,2-α]pyrimidine was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 2′-fluoro-5′-(7-tert-butylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as an off-white powder: δH (360 MHz, CDCl3) 1.43 (9H, s), 7.05 (1H, d, J 7), 7.37-7.73 (6H, m), 7.81 (1H, s), 7.85 (1H, dd, J 8 and 1), 8.75 (1H, d, J 7); m/z (ES+) 371 (M++H).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:22]2[CH:21]=[N:20][N:19]([C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]3[CH:24]=[CH:25][CH:2]=[CH:3][CH:4]=3)[CH:23]=2)=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1ccc(C(c2ccccc2)(c2ccccc2)n2cccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51 %

Procedure:
To a suspension of 4-bromo-trityl-1H-pyrazole (0.7 g) in N,N-dimethylformamide (14 ml) was added 4-fluorophenylboronic acid (0.377 g), cesium carbonate (1.758 g), and tetrakis triphenylphosphine palladium (0.208 g). The resulting suspension was stirred at room temperature for 10 min. The irradiation of microwaves at 160° C. for 10 min was sufficient to complete a reaction in the suspension. The product was filtered through silica gel, diluted in ethyl acetate (30 ml) and washed with saturated ammonium chloride solution (30 ml) and then with brine (30 ml). The washed organic layer thus formed was dried over anhydrous magnesium sulfate and concentrated by evaporation in a vacuum. The residue thus obtained was separated using silica gel chromatography to produce 4-(4-fluorophenyl)-1-trityl-1H-pyrazole (yield 51%).
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:13]=1[CH2:14][O:15]C(=O)C)([CH3:11])[CH2:3][C@:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[Li].[OH-].[Na+].Cl.[CH2:28]1COC[CH2:29]1>CS(C)=O>[F:23][C:20]1[CH:21]=[CH:22][C:12]([C:2]([CH3:11])([CH3:1])[CH2:3][C@@:4]([C:7]([F:10])([F:8])[F:9])([OH:5])[CH2:6][C:28]#[CH:29])=[C:13]([CH2:14][OH:15])[CH:19]=1
Reactant: C1CCOC1
Reactant: CC(=O)OCc1cc(F)ccc1C(C)(C)C[C@]1(C(F)(F)F)CO1
Agent: Cl
Agent: [Li]
Agent: [Na+]
Solvent: CS(C)=O
Product: C#CC[C@](O)(CC(C)(C)c1ccc(F)cc1CO)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To 19.1 g (0.057 mol) of acetic acid 2-[1,1-dimethyl-2-((R)-2-trifluoromethyloxiranyl)ethyl]-5-fluorobenzyl ester in 450 mL of DMSO at 15° C. was added 481 mL (0.240 mol) lithium trimethylsilylacetylide (0.5 M in THF). The mixture was warmed to room temperature and stirred for 3 hours. The mixture was then cooled to 0° C. and 300 mL of 3N NaOH was added and the mixture was stirred for 1 hour. The mixture was neutralized by the addition of 400 mL of 3N HCl. The organic phase was removed and the aqueous layers were extracted four times with diethyl ether. The organic phases were washed with 300 mL of water and 300 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture was chromatographed on silica gel using 10-12% ethyl acetate/hexanes to afford 15 g (83%) of (S)-6-(4-fluoro-2-hydroxymethylphenyl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([OH:14])=O)=[CH:4][N:3]=1.C(Cl)(=O)C([Cl:18])=O>CN(C=O)C.ClCl>[F:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([Cl:18])=[O:14])=[CH:4][N:3]=1
Reactant: O=C(O)c1cnc(F)nc1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Agent: ClCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc(F)nc1C(F)(F)F
Yield: 75 %

Procedure:
The title compound was prepared as described in Example 25, but employing a solution of 2-fluoro-4-trifluoromethylpyrimidine-5-carboxylic acid (1.5 g, 7.1 mmol) and oxalyl chloride (1.0 g, 8 mmol), DMF (2 drops) in CH2 Cl2 (30 mL) resulted in a 75% yield (1.2 g); 1H NMR (CDCl3) δ 9.42 (s, 1H).