Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13](O)=[O:14])=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[NH2:32][C@@H:33]([CH3:41])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([NH:32][C@@H:33]([CH3:41])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:14])=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:23])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(C3CC3)nc12)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of 2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (250 mg, 0.75 mmol) in DMF (6 mL) at room temperature was added triethylamine (0.52 mL, 3.75 mmol), (S)-tert-butyl 2-aminopropanoate hydrochloride (136 mg, 0.75 mmol) and PyBOP (429 mg, 0.83 mmol). The reaction mixture was stirred overnight then poured into EtOAc (50 mL) and washed with water (4×30 mL). The organic extracts were combined, dried (Na2SO4) and evaporated under reduced pressure. The crude residue was purified by SiO2 column chromatography (12 g, hexanes/EtOAc, 7:3 to 1:1) to give 285 mg (85%) of (S)-tert-butyl 2-(2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)propanoate as a viscous oil.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:12])[CH2:8][CH2:9][CH2:10][CH2:11][C:3]1=2.[O-:13][C:14]#[N:15].[K+]>O>[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH:12][C:14]([NH2:15])=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][C:3]1=2
Reactant: NC1CCCCc2sccc21
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NC1CCCCc2sccc21
Reaction time: 1 h

Procedure:
A mixture of 50 grams of 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-4-amine hydrochloride in 100 ml. of water is stirred at about 15° C. and a solution of 23.1 grams of potassium cyanate in 100 ml. of water is added dropwise. After completion of the addition, the mixture is warmed slowly to 70°-75° C. and held there for 1 hour. The mixture is cooled and the white solid is collected by filtration and washed with water. The solid is air-dried, pulverized, and washed with acetonitrile. Upon drying, this crude product is treated with hot acetone whereby there is obtained 5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-ylurea, m.p. 217° C. dec.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[NH:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:18]([C:22](O)=[O:23])[CH:19]([CH3:21])[CH3:20].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl>ClCCl>[NH2:16][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12][N:11]([C:22](=[O:23])[C@H:18]([NH:17][C:25](=[O:26])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:19]([CH3:21])[CH3:20])[CH2:10][C:9]1([CH3:14])[CH3:15]
Reactant: CC1(C)CNCCC1(N)c1ccc(Cl)cc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(N)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A mixture of 4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-amine (488 mg, 2.044 mmol), Boc-D-Val-OH (444 mg, 2.044 mmol), HOBT (626 mg, 4.09 mmol), and triethylamine (1.140 mL, 8.18 mmol) in dichloromethane (5 mL) was treated with EDC (784 mg, 4.09 mmol), and the mixture was stirred overnight at room temperature. The mixture was concentrated in-vacuo, and the residue was taken up in ethyl acetate. The organic phase was washed 3× with WATER, 3× with sat. sodium carbonate, and 1× with sat sodium chloride, dried over sodium sulfate, and concentrated in-vacuo. The residue was purified over silica gel, eluting with ethyl acetate/hexanes (25%-50%-100% EtOAc) to yield the title compound (845 mg, 1.929 mmol, 94% yield) as a colorless glass. MS (ESI+)=438.36, M+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:15]#[C:16][Br:17]>C(OCC)C>[Br-:17].[CH3:1]/[N+:2](=[CH:10]\[CH:11]=[CH:12]\[CH:13]=[CH:14]\[N:15]([CH3:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)/[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#CBr
Reactant: c1ccncc1
Reactant: CNc1ccccc1
Solvent: CCOCC
Product: CN(/C=C/C=C/C=[N+](\C)c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a solution of N-methylaniline (30 g, 140 mmol) and pyridine (11.2 g, 140 mmol) in diethylether (100 ml) at 0° C., was added a solution of cyanogen bromide (14.8 g, 140 mmol) in ether (40 ml) dropwise. The mixture was warmed to 20° C. and within 15 minutes a red oil began to separate. Exothermic (30° C.) crystallization ensued and the red solid mass was left to stand at room temperature overnight. The crystalline mass was filtered and washed with cold ether under N2 and the hygroscopic salt was used in the next step without further purification. Yield: 47.7 g (95%).
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:43])[O:21][NH:22][C:23](=[O:42])[C@@H:24]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)=[O:31])[CH2:25][C:26]([NH2:28])=[O:27])[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:63]1[C:71]2[C:66](=[CH:67][CH:68]=[C:69]([S:72](Cl)(=[O:74])=[O:73])[CH:70]=2)[CH:65]=[N:64]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:1]([C@H:8]([NH:19][C:20](=[O:43])[O:21][NH:22][C:23](=[O:42])[C@@H:24]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1)=[O:31])[CH2:25][C:26]([NH2:28])=[O:27])[C@H:9]([OH:18])[CH2:10][N:11]([O:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)[S:72]([C:69]1[CH:70]=[C:71]2[C:66]([CH:65]=[N:64][NH:63]2)=[CH:67][CH:68]=1)(=[O:74])=[O:73])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)NOC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCC1
Reactant: O=S(=O)(Cl)c1ccc2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)NOC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCC1)S(=O)(=O)c1ccc2cn[nH]c2c1
Reaction time: 24 h

Procedure:
(2S)-4-Amino-4-oxo-2-[(2-quinolinylcarbonyl)-amino]butanamido N-(1S,2R)-1-benzyl-3-[(cyclopentyloxy)-aminol-2-hydroxypropylcarbamate (Step 1, Example 51), (44 mg, 0.0825 mmol), 1-trityl-1H-indazole-6-sulfonyl chloride (38 mg, 0.0825 mmol), and anhydrous diisopropylethylamine (0.05 mL, 0.280 mmol) were combined in anhydrous tetrahydrofuran (3 mL) in a 25 mL round bottomed flask under nitrogen. The reaction was stirred for 24 hours and concentrated in vacuc. Ethyl acetate (30 mL) and water (10 mL) were added and the layers were separated. The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuc. The compound was deprotected as described in Example 57 and purified by preparative silica gel TLC using 90:10 chloroform: methanol as an eluent to provide the desired product as a white film (9 mg, 0.013 mmol, 15%). 1HNMR (d6-DMSO) 6:8.84 (d, J=8.5 Hz, 1H), 8.61 (d, J=8.5 Hz, 1H), 8.31-6.95 (m, 13H), 5.24 (d, J=6.6 Hz, 1H), 4.81-4.72 (m, 2H), 3.97 (bs, 1H), 3.68 (bs, 1H), 3.40-1.20 (m, 15H). MS(ES): 714 (M+1), 712 (M-1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=2)=[CH:12][N:11]=1.[H-].[Na+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=2)=[CH:12][N:11]=1
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(O)c(F)c3F)nc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCCCCCCCC)c(F)c3F)nc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A solution of 2.4 mmol of 2-(2,3-difluoro-4-hydroxyphenyl)-5-(6-octyloxypyridin-3-yl)pyrimidine in 10 ml of DMF is added dropwise at room temperature and under a protective gas to a suspension of 2.7 mmol of sodium hydride (80 percent in mineral oil) in 5 ml of dry DMF. The mixture is stirred for a further 30 minutes, and 2.7 mmol of 1-bromooctane, dissolved in 10 ml of DMF, are then added slowly. The reaction mixture is stirred at room temperature for 20 hours and introduced into 100 ml of ice/water, the mixture is extracted a number of times with dichloromethane, and the combined organic extracts are washed with sat. sodium chloride solution and dried using magnesium sulfate. After the solvent has been removed in vacuo, the crude product is chromatographed on silica gel 60 using dichloromethane/ethyl acetate 20:1 (v/v) as eluent and recrystallized from acetonitrile, giving 0.77 g (61%) of colorless crystals, X 89 S3 73.5 SC 164 SA 167 I.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.C[O:28][B:29](OC)[O:30]C.[Cl-].[NH4+]>O1CCCC1.O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([B:29]([OH:30])[OH:28])=[CH:3][CH:4]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc(COc2ccccn2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(COc2ccccn2)cc1
Reaction time: 0.75 h
Yield: 25.7 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-[(4-bromobenzyl)oxy]pyridine (50 g, 190 mmol) in tetrahydrofuran (200 mL) was cooled to −78° C. and a 2.6M n-butyllithium hexane solution (88 mL, 228 mmol) was added thereto dropwise. After stirring for 45 minutes, trimethoxy borane (29.6 g, 285 mmol) was added thereto dropwise at the same temperature. After 30 minutes, a saturated aqueous solution of ammonium chloride and water were added thereto for quenching, and the solution was extracted with ethyl acetate. After the organic layer was washed with a mixture of saturated aqueous solution of ammonium chloride and saturated sodium chloride water and dried over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure. To the residue was added acetonitrile (200 mL), followed by suspending and stirring at 70° C. for 30 minutes, then, cooled, and stirred overnight at 4° C. The precipitated solid was filtered, so as to obtain the title compound (11.2 g) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:26](=[O:28])[CH3:27]
Reactant: c1ccc(CNCCCSc2ccncc2)nc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(CCCSc1ccncc1)Cc1ccccn1
Yield: 85.6 %

Procedure:
To a solution of 1.62 g (6.24 mmol) of 4-[3-(N-2-pyridylmethylamino)propylthio]pyridine and 1.10 ml (7.80 mmol) of triethylamine in 10 ml of methylene chloride, 0.51 ml (7.80 mmol) of acetyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate/methanol=10:1) to obtain 1.61 g of the desired compound (yield: 85.6%, yellow oil).
Reaction SMILES: O[CH:2]([CH:5]1[CH2:9][S:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]1[C:16]([O:18][CH3:19])=[O:17])[CH:3]=[CH2:4].C[C:21](C)(C)[C:22]([O-:25])([O-])[O-:23].[C:28](O)(=O)CC>C1C=CC=CC=1>[C:16]([N:6]1[CH:5]([CH:2]=[CH:3][CH2:4][CH2:21][C:22]([O:25][CH3:28])=[O:23])[CH2:9][S:8][CH:7]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O:18][CH3:19])=[O:17]
Reactant: CCC(=O)O
Reactant: CC(C)(C)C([O-])([O-])[O-]
Reactant: C=CC(O)C1CSC(c2ccccc2)N1C(=O)OC
Solvent: c1ccccc1
Product: COC(=O)CCC=CC1CSC(c2ccccc2)N1C(=O)OC
Yield: 95 %

Procedure:
A solution of 44.0 g. (0.1575 mol) of crude 4-(1-hydroxyprop-2-en-1yl)-3-carbomethoxy-2-phenylthiazolidine, 191.5 g. (1.570 mol) of trimethylorthoacetate and 100 ml. of a 20% solution of propionic acid in benzene in 2 L. of benzene was heated for 24 hours, at 92°-93° C. The vapors were condensed and collected in a Dean-stark moisture receiver. After cooling, the resulting yellow solution was washed with 100 ml. of a 2N solution of sodium carbonate, then 3 × 100 ml. of water. Drying with magnesium sulfate and evaporation in vacuo gave 50.0 g. (95% yield) of crude methyl 5-(3-carbomethoxy-2-phenylthiazolidin-4-yl)-4-pentenoate. Gas chromatographic analysis showed a purity of 65-70%. If pure starting material is used instead in the process, no detectable impurities were detected in the final product.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:48]([N+:52]1[N:56]=[C:55]([CH3:57])[S:54][C:53]=1[CH3:58])[CH2:49][CH2:50][CH3:51]>>[CH2:48]([N:52]1[N:56]=[C:55]([CH3:57])[S:54]/[C:53]/1=[CH:58]\[C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[O:13])[CH2:49][CH2:50][CH3:51]
Reactant: O=C(O)c1cccc2ccccc12
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 1-naphthoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.87-0.93 (m, 3 H) 1.27-1.35 (m, 2 H) 1.69-1.78 (m, 2 H) 2.51 (s, 3 H) 4.16-4.20 (m, 2 H) 6.40 (s, 1 H) 7.49-7.59 (m, 3 H) 7.73-7.78 (m, 1 H) 7.94-8.01 (m, 2 H) 8.37-8.43 (m, 1 H); MS (ESI) m/z 325 (M+H)+.
Reaction SMILES: O=P(Cl)(Cl)Cl.C[N:7]([CH:9]=O)C.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[ClH:18].NO>O>[Cl:18][C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[C:9]#[N:7]
Reactant: O=C1CCCCC1
Reactant: CN(C)C=O
Reactant: Cl
Agent: NO
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: N#CC1=C(Cl)CCCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a stirring solution of POCl3 (15.20 mL, 163 mmol) at 0° C. was added DMF (13.40 mL, 173 mmol) drop-wise. Monitoring internal temperature, cyclohexanone (10.60 mL, 102 mmol) was slowly added, keeping the temperature between 35 and 40° C. Upon complete addition, the reaction was heated to 50° C. and hydroxylamine hydrochloride (40 g, 576 mmol) was added in eight portions, cooling when necessary to control the exothermic reaction. Upon completing this addition, ice was added to the reaction, followed by water (400 mL), and the mixture resumed stirring for 1 h. Filtration afforded the desired product as a brown solid (8.8 g). Some substrates may require an aqueous work-up/extraction procedure if water solubility is too high. EtOAc is generally a good solvent for this extraction. MS: No signal. 1H NMR (400 MHz, CDCl3 δ ppm 2.47-2.36 (m, 2H), 2.34-2.25 (m, 2H), 1.78-1.67 (m, 1H), 1.67-1.58 (m, 1H).
Reaction SMILES: [OH-].[Na+].[C:3]([CH:11]([CH2:17][C:18]#[CH:19])[C:12](OCC)=[O:13])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20][NH:21]O.Cl>O.CO.CCOCC>[CH3:20][N:21]1[C:12](=[O:13])[CH:11]([CH2:17][C:18]#[CH:19])[CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[O:10]1
Reactant: CNO
Reactant: C#CCC(C(=O)OCC)C(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: C#CCC1C(=O)N(C)OC1c1ccccc1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 34.5 %

Procedure:
A stirred solution of 0.28 g (7.0 mmol) of NaOH in 3 mL of water and 7 mL of methanol was cooled to -30° C. and and a solution of 1.42 g (6.2 mmol) of ethyl α-benzoyl-α-propargylacetate in 2 mL of methanol was added dropwise over 2 min. The mixture was stirred at -30° C. for 10 min and a precooled slurry of 0.54 g (13.5 mmol) of NaOH and 1.02 g (12.2 mmol) of N-methylhydroxylamine in 1.5 mL of water was added in one portion. After the mixture had been stirred at -30° C. for 2 h, a 2 mL portion of conc HCl was added and the mixture was heated at reflux for 1 h. The mixture was allowed to cool to room temperature, diluted-with 150 mL of ether, washed with 50 mL of water and 50 mL of saturated aqueous NaHCO3 and dried. Removal of the solvent on the rotovap left 1.09 g of an oil which was purified by flash chromatography on a column of 30 g of silica gel eluted successively with 100 mL portions of 20, 30, 40, 50, 60, 70 and 80% ether in hexanes to afford 0.46 g of 2-methyl-5-phenyl-4-propargylisoxazolin-3-one (Compound 1) as a white solid, m.p. 85°-87° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7].C(O)C.[CH3:14][NH:15][CH3:16]>>[CH3:14][N:15]([CH3:16])[C:3](=[O:2])[CH2:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: CNC
Reactant: COC(=O)CC(=O)C(C)C
Solvent: CCO
Product: CC(C)C(=O)CC(=O)N(C)C

Procedure:
0.69 mol (100 g) of 4-methyl-3-oxovaleric acid methyl ester and 309 ml 33% dimethylamine in ethanol (about 1.73 mol dimethylamine) were stirred in a pressure reactor for 2 hours at 110° C. After cooling, the solvents were distilled on a rotary evaporator. After drying, 93 g of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:6]([F:15])[C:5]([OH:16])=[C:4]([CH:17]=[O:18])[CH:3]=1.I[CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:6]([F:15])[C:5]([O:16][CH:20]([CH3:22])[CH3:21])=[C:4]([CH:17]=[O:18])[CH:3]=1
Reactant: CC(C)I
Reactant: O=Cc1cc(Br)c(-c2ccc(F)cc2)c(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1c(C=O)cc(Br)c(-c2ccc(F)cc2)c1F
Reaction time: 1 h
Yield: 74 %

Procedure:
A mixture of 6-bromo-2,4′-difluoro-3-hydroxybiphenyl-4-carbaldehyde (3.50 g), 2-iodopropane (5.70 g), potassium carbonate (3.09 g), and DMF (15 mL) was stirred at 50 C for 1 hour. The reaction mixture was poured to water, followed by extraction with ethyl acetate twice. The organic layer was separated, then washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.94 g)
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][N:19]([CH3:21])[C:18](=[O:22])[N:17]([CH3:23])[CH2:16]2)=[CH:11][C:10]=1Br.[C:25]1(B(O)O)[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1>>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][N:19]([CH3:21])[C:18](=[O:22])[N:17]([CH3:23])[CH2:16]2)=[CH:11][C:10]=1[C:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: CN1CC(c2ccc(N)c(Br)c2)CN(C)C1=O
Reactant: OB(O)C1=CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(c2ccc(N)c(C3=CCCCC3)c2)CN(C)C1=O
Yield: 38 %

Procedure:
5-(4-Amino-3-bromo-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-one trifluoroacetic acid salt (as prepared in the previous step, 92 mg, 0.30 mmol) was reacted with cyclohex-1-enyl boronic acid (48.7 mg, 0.375 mmol) according to the Suzuki coupling procedure of Example 4, step (e) and purified on silica (2% MeOH-EtOAc) to afford the title compound (35 mg, 38%): Mass spectrum (ESI, m/z): Calcd. for C18H25N3O, 300.2 (M+H), found 300.3.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]([CH3:30])[CH3:29])[C:6]2[O:10][C:9]([C:11]3[CH:26]=[CH:25][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:27]=1)#[N:2].[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[CH2:31]([NH:38][C:39]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:15](=[O:16])[C:14]2[CH:13]=[CH:12][C:11]([C:9]3[O:10][C:6]4[C:5]([CH:28]([CH3:30])[CH3:29])=[CH:4][C:3]([C:1]#[N:2])=[CH:27][C:7]=4[N:8]=3)=[CH:26][CH:25]=2)[CH2:20][CH2:21]1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCNCC4)cc3)oc12
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(C(=O)NCc5ccccc5)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-(piperidin-4-ylmethyl)benzamide (30 mg, 0.075 mmol, INTERMEDIATE 15) in dichloromethane (1 ml) was added benzyl isocyanate (10 μl 0.081 mmol). The mixture was stirred for 2 h at room temperature, at which point LC/MS analysis showed a new peak at the desired molecular weight. The reaction mixture was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes. The resulting mixture was repurified by reverse-phase HPLC: Kromasil C18 21×100 mm column, eluting at 15 ml/min with 90% water (0.1% TFA) to 95% acetonitrile (0.1% TFA) over 10 min, hold for 2 min, then back to 90% water over 0.5 min, hold for 0.5 min, to provide the title compound (7.9 mg, 0.015 mmol, 19.79% yield). Mass spectrum (ESI) 536.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.32 (d, J=7.0 Hz, 2H), 7.94 (d, J=7.0 Hz, 2H), 7.93 (d, J=1.5 Hz, 1H), 7.52 (s, 1H), 7.27-7.35 (m, 4H), 6.55 (br s, 1H), 4.43 (s, 2H), 3.99 (br d, J=11.0 Hz, 2H), 3.47 (septet, J=5.5 Hz, 1H), 3.42 (t, J=5.5 Hz, 2H), 2.86 (br t, J=10.5 Hz, 2H), 2.73 (s, 3H), 1.90 (m, 1H), 1.81 (br d, J=10.0 Hz, 2H), 1.46 (d, J=5.5 Hz, 6H), 1.31 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21](O)=[O:22].FC1C=CC(C2(C3C=CC(F)=CC=3)CCCN(CC(O)=O)C2=O)=CC=1.[F:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2([C:61]3[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=3)[CH2:60][CH2:59][NH:58][CH2:57]2)=[CH:52][CH:51]=1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[F:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2([C:61]3[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=3)[CH2:60][CH2:59][N:58]([C:21](=[O:22])[CH2:20][N:3]3[CH2:4][CH2:5][CH2:6][C:7]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]3=[O:1])[CH2:57]2)=[CH:52][CH:51]=1
Reactant: Fc1ccc(C2(c3ccc(F)cc3)CCNC2)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid from Example 68E for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 3,3-bis(4-fluorophenyl)pyrrolidine from Example 203A for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.30 (d, J=4.4, 8H), 7.25-7.21 (m, 2H), 7.17-7.10 (m, 4H), 6.98-6.88 (m, 4H), 4.14-4.07 (m, 4H), 3.67-3.45 (m, 4H), 2.70-2.60 (m, 2H), 2.55 (t, J=6.7, 1H), 2.45 (t, J=6.8, 1H), 1.90-1.78 (m, 2H); MS (DCI) m/z 551.2 (M+H)+.