Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8]2[S:9][C:5]3[CH:4]=[C:3]([OH:2])[CH:20]=[CH:19][C:6]=3[N:7]=2)=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2nc3ccc(O)cc3s2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
Under N2, 23 (10.4 mmol) was dissolved in CH2Cl2 and, at −40° C., BBr3 (31.4 mmol) was slowly added. The mixture was then stirred 24 hours at room temperature. The reaction mixture was quenched with water and extracted with ethyl acetate (×3 100 ml). The organic layers were combined, dried over Na2SO4 and the solvent was removed via a rotary evaporator. The residue was purified by chromatography on silica gel using 7:3 hexane/ethyl acetate as the eluent to yield 1.53 g (53%) of 24 as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4](P(OCC)(OCC)=O)[O:5][CH3:6].[Li+].C[O-].[CH3:19][C:20]1[O:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][CH2:32][O:33][C:34]1[C:42]2[CH:41]=[CH:40][S:39][C:38]=2[C:37]([CH:43]=O)=[CH:36][CH:35]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])/[C:4](/[O:5][CH3:6])=[CH:43]/[C:37]1[C:38]2[S:39][CH:40]=[CH:41][C:42]=2[C:34]([O:33][CH2:32][CH2:31][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:24][C:20]=2[CH3:19])=[CH:35][CH:36]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c2sccc12
Reactant: CCOP(=O)(OCC)C(OC)C(=O)OC
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)/C(=C/c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)OC
Temperature: 75 °C
Yield: 56.9 %

Procedure:
A suspension of 6.07 g (20.2 mmol) of (diethoxyphosphoryl)-methoxy acetic acid methyl ester (H. Gross, Justus Liebigs Ann. Chem. 1967, 707, 35-43), 0.86 g of lithium methylat (21.6 mmol) and 5.00 g of 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-carbaldehyde (13.5 mmol) in 50 ml of DMF was heated for 21 h at 75° C. The suspension was cooled to 0° C., the solid filtered off and washed with 30 ml of cold (−15° C.) ethanol. The filter cake was dissolved in a mixture of 100 ml dichloromethane and 60 ml of water, the organic layer separated, dried over sodium sulfate and evaporated to dryness. Thereby, 3.45 g (55%) of the title compound with a purity of 91% (GC area) were obtained as white crystals.
Reaction SMILES: Cl[C:2]1[C:15]2[O:14][CH2:13][CH:12]3[N:7]([CH2:8][CH2:9][O:10][CH2:11]3)[C:6]=2[N:5]=[C:4]([Cl:16])[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(N(CC)CC)C>>[Cl:16][C:4]1[N:3]=[C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:15]2[O:14][CH2:13][CH:12]3[N:7]([C:6]=2[N:5]=1)[CH2:8][CH2:9][O:10][CH2:11]3
Reactant: Clc1nc(Cl)c2c(n1)N1CCOCC1CO2
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Product: Clc1nc(N2CCOCC2)c2c(n1)N1CCOCC1CO2
Temperature: 140 °C
Yield: 37.9 %

Procedure:
A mixture of 1,3-dichloro-5,6,8a,9-tetrahydro-8H-7,10-dioxa-2,4,4b-triaza-phenanthrene (100 mg, 0.38 mmol), morpholine (80 μL, 0.92 mmol) and triethylamine (70 μL, 0.50 mmol) in IMS (5 mL) was heated at 140° C. for 25 mins in a microwave reactor, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 10 to 15 to 25% ethyl acetate in pentane) affording 3-Chloro-1-morpholin-4-yl-5,6,8a,9-tetrahydro-8H-7,10-dioxa-2,4,4b-triaza-phenanthrene (45 mg, 38%). LCMS (method A): RT=2.92 min, [M+H]+=313. 1H NMR (400 MHz, CDCl3): δ 4.37 (1H, dd, J=13.2, 3.0 Hz), 4.19 (1H, dd, J=10.8, 3.3 Hz), 3.99 (1H, dd, J=11.1, 3.9 Hz), 3.88 (1H, dd, J=10.8, 3.2 Hz), 3.80 (dd, J=11.1, 8.4 Hz), 3.75 (4H, m), 3.66-3.53 (6H, m), 3.24 (1H, t, J=11.1 Hz), 3.00 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.O.[Sn](Cl)Cl.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[NH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
The mixture of 2-fluoro-4-nitrobenzonitrile (8.31 g, 50 mmol) and tin (II) chloride dihydrate (56.4 g, 250 mmol) in 250 mL of EtOAc was stirred at 25° C. overnight. LCMS (78109-084) indicated the reaction was completed. 25 mL of sat. K2CO3 was added to the reaction. The resulting mixture was stirred at room temperature for 2 h and was followed by addition of 100 g of solid K2CO3. The mixture was stirred at room temperature for 2 hours. Solid was removed by filtration and further washed with EtOAc (50 mL×2). The filtrate was concentrated to yield 6.81 g (100%) of 4-amino-2-fluorobenzonitrile as an off white solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.30 (s, 2H) 6.29-6.51 (m, 2H) 7.27-7.40 (m, 1H). MS (ESI) 137 (M+H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH:32]1([N:35]2[CH:39]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:37]=[N:36]2)[CH2:34][CH2:33]1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:38]3[CH:37]=[N:36][N:35]([CH:32]4[CH2:34][CH2:33]4)[CH:39]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2csc(-c3cnn(C4CC4)c3)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gave 235. 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.44 (s, 1H), 8.22 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 4.92-4.83 (m, 1H), 4.59-4.40 (m, 1H), 4.32 (dd, J=22.2, 15.0 Hz, 1H), 4.19-3.93 (m, 1H), 3.80 (dd, J=7.4, 3.7 Hz, 1H), 3.77 (s, 3H), 3.38-3.31 (m, 1H), 2.12-2.03 (m, 1H), 1.87-1.66 (m, 5H), 1.17-0.96 (m, 4H). LCMS (ES+) m/z 446 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(Cl)Cl.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To 1.3 g, 1.2 ml (10 mmol) of Dimethyl-1,3-dioxolane-4-methanol, 3.7 g (3.0 mmol, 3.0 eq) of 4-Dimethyl amino pyridine dried for one hour was added and dissolved with 100 mL of CH2Cl2. Thereafter, 2.3 g (12 mmol, 1.2 eq) of p-Toluenesulfonyl chloride was added, then, [the solution] was stirred for the first 30 minutes dipped in cold water at room temperature under argon atmosphere (colorless transparent). After stirring for 18 hours, the disappearance of the raw materials was checked by TLC, liquid separation was carried out with a separating funnel (organic solvent: CDCl3) and the oil layer was dried with anhydrous Na sulfate. An hour later, cotton plug-filtered and concentrated with an evaporator, [the solution] was the target compound was isolated by silica gel column chromatography (CHCl3→CHCl3:MeOH=100 to 10:1) to obtain an oily liquid (2) (pale yellow transparent to colorless transparent). The obtained liquid was dried overnight and an NMR measurement was carried out. (yield: 1.85 g, 8.3 mmol; yield 83%)
Reaction SMILES: N#N.[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][Si:8]([CH3:19])([CH3:18])[O:9][Si:10]([CH3:17])([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][OH:15].N1C=CC=CC=1.Cl[C:27]([O:29]C=C)=[O:28]>C(Cl)Cl.C(#N)C>[C:27](=[O:28])([OH:29])[O:15][CH:14]=[CH2:13].[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][Si:10]([CH3:17])([CH3:16])[O:9][Si:8]([CH3:18])([CH3:19])[CH2:7][CH2:6][CH2:5][CH2:4][OH:3]
Reactant: C=COC(=O)Cl
Agent: C[Si](C)(CCCCO)O[Si](C)(C)CCCCO
Agent: N#N
Solvent: CC#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=COC(=O)O
Reaction time: 4 h

Procedure:
A 500 ml 3-neck, round bottom flask equipped with a reflux condenser, a mechanocal stirrer, a thermometer, a dropping funnel and a N2 blanket, is charged with 69.5 g (0.25 mole) of 1,3-bis(4-hydroxybutyl) tetramethyl disiloxane (Silar Lab.), pyridine, 19.5 g and 300 ml of methylene chloride. The contents are cooled down to between 0 and 5 degrees C. by an ice bath. Through the dropping funnel 25.3 g (0.25 mole) of vinyl chloroformate in 50 ml of methylene chloride is added dropwise into the flask at a rate such that the temperature is maintained between 0 and 5 degrees C. The contents are then stirred for another 4 hours and then passed through a silica gel column. The eluents are condensed and injected in 6-8 gram portions into a reverse phase high performance liquid chromatography unit (Waters), using acetonitrile as solvent. Three fractions are collected. The major (center) fraction from each injection is collected and condensed to give 1,3-bis(4-hydroxybutyl)tetramethyl disiloxane monovinyl carbonate. The monovinyl carbonate product (34.8 g or 0.1 mole) is charged into a flask as already described, along with 8.0 g of pyridine, 50 mg of hydroquinone and 200 ml of chloroform. The contents are cooled down to between 0 and 5 degrees C. Through a dropping funnel, 10.5 g (0.1 mole) of methacryloyl chloride in 50 ml of chloroform is added into the flask at such a rate that the temperature is maintained between 0 and 5 degrees C. The contents are stirred continuously for 4 hours and then passed through a silica gel column. The contents are then condensed and distilled under reduced pressure to give the named product. Hydroquinone (50 mg) is added into the named product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH3:8][O:9][CH:10]([CH3:12])[O-].[Na+].C[O:15]C(O)C>C(Cl)(Cl)(Cl)Cl>[CH3:8][O:9][CH2:10][CH2:12][O:15][CH2:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1
Reactant: BrCc1ccsc1
Reactant: COC(C)O
Reactant: COC(C)[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COCCOCc1ccsc1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of 3(bromomethyl)thiophene (6.2 g, 0.035 mol) in carbon tetrachloride (25 ml) was added to a solution of sodium methoxyethoxide (8.9 g, 0.09 mol) in methoxyethanol (90 ml) and the mixture was heated under reflux for 2 hours. After cooling to room temperature, the solvent mixture was removed under reduced pressure and the resultant oil was dissolved in dichloromethane (100 ml), extracted with distilled water (2×100 ml) and dried over potassium carbonate. After removal of the solvent, the crude oil was distilled under reduced pressure to yield 3-(methoxyethoxymethyl)thiophene (3.0 g, 50%), B.p. 100°-101° C./10 mm Hg. (Found: C, 55.0; H, 6.3; S, 17.6. Calculated for C8H12O2S: C, 55.8; H, 7.0; S, 18.6%); EI m/e Intensity (%): 172 (5, M+), 97 (12, C4H3S.CH2); δH(CDCl3): 7.05-7.24 (3H, m), 4.53 (2H, s), 3.54 (4H, m) and 3.34 (3H, s); δC(CDCl3): 59.6, 67.0, 69.7, 72.5, 123.4, 126.5, 127.9, 140.0 ppm.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[N:8][O:9][CH2:10][CH2:11][OH:12])=[C:5]([CH3:13])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][N:2]1[C:6]([CH:7]=[N:8][O:9][CH2:10][CH2:11][O:12][C:21]2[CH:53]=[CH:52][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]3=[O:51])=[CH:23][CH:22]=2)=[C:5]([CH3:13])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1nc(-c2ccccc2)n(C)c1C=NOCCO
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(-c2ccccc2)n(C)c1C=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Yield: 73.4 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 420 mg of 2-(1,4-dimethyl-2-phenylimidazol-5-ylmethyleneaminooxy)ethanol (prepared as described in Preparation 24), 580 mg of 5-(4-hydroxy-benzyl)-3-tritylthiazolidine-2,4-dione, 425 mg of triphenylphosphine and 282 mg of diethyl azodicarboxylate, 646 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: Br[CH:2]([CH2:15][CH2:16][CH2:17][CH2:18]Br)[C:3]([O:5][CH:6]([CH3:14])[C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4].[Na+].[I-].C(N(CC)CC)C.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([N:36]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:2]1[C:3]([O:5][C@@H:6]([CH3:14])[C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(OC(=O)C(Br)CCCCBr)C(=O)N1CCCC1
Reactant: NCc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](OC(=O)C1CCCCN1Cc1ccccc1)C(=O)N1CCCC1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
To 1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2,6-dibromohexanoate (295 mg, 0.75 mmol), NaI (225 mg, 1.5 mmol) and tetrahydrofuran (4 mL) were added. The mixture was stirred at 40° C. for 1.5 hours. Next, triethylamine (84 mg, 0.83 mmol), benzylamine (97 mg, 0.90 mmol) and tetrahydrofuran (4 mL) were added thereto. The mixture was stirred at 20° C. for 15 hours. It was confirmed with NMR analysis of the reaction solution that the conversion ration was 83% and the diastereo ratio calculated from the NMR analysis was 79:21.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C:11]([CH3:28])([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.C(=O)([O-])[O-].[Na+].[Na+].[CH:43]1([N:46]2[CH:51]=[CH:50][C:49](I)=[CH:48][C:47]2=[O:53])[CH2:45][CH2:44]1>COCCOC.CCO.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>[CH:43]1([N:46]2[CH:51]=[CH:50][C:49]([C:16]3[CH:15]=[CH:14][C:13]([C:11]([N:7]4[CH2:6][CH2:5][C:4]([CH2:3][C:2]([OH:1])([CH3:36])[CH3:35])([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[O:9][C:8]4=[O:10])([CH3:12])[CH3:28])=[CH:18][CH:17]=3)=[CH:48][C:47]2=[O:53])[CH2:45][CH2:44]1
Reactant: CC(C)(O)CC1(c2ccccc2)CCN(C(C)(C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Reactant: O=c1cc(I)ccn1C1CC1
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: COCCOC
Solvent: O
Solvent: CCO
Product: CC(C)(O)CC1(c2ccccc2)CCN(C(C)(C)c2ccc(-c3ccn(C4CC4)c(=O)c3)cc2)C(=O)O1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 112.2 %

Procedure:
To a solution of 6-(2-Hydroxy-2-methyl-propyl)-3-{1-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one (50 mg, 151.5 μmol) in DME (10 mL) were added a solution of sodium carbonate (64.5 mg, 609 μmol) in EtOH (2 mL) and water (1 mL), 1-cyclopropyl-4-iodo-1H-pyridin-2-one (19 mg, 73 μmol) and Pd(PPh3)4(7.5 mg, 6 μmol) successively under nitrogen. The reaction mixture was stirred at 100° C. for 2.5 h and then concentrated under vacuum. The residue was dissolved in water, extracted with EtOAc (5 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by preparative prep HPLC to afford 3-{1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-1-methyl-ethyl}-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (41 mg, 71%). 1H NMR (CDCl3) δ 7.45-7.25 (m, 8H), 7.12-7.10 (d, 2H), 6.75 (s, 1H), 6.40 (d, 1H), 3.39-3.29 (m, 2H), 2.90-2.83 (m, 1H), 2.39-2.21 (m, 4H), 1.67 (d, 3H), 1.50 (s, 3H), 1.16-1.12 (m, 5H), 1.02 (s, 3H), 0.92-0.87 (m, 2H); LC-MS Method 2 tR=1.10 min, m/z=501.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:19][CH3:20])=[CH:11][C:12]([I:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>C(OCC)(=O)C.CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]([O:19][CH3:20])=[CH:11][C:12]([I:18])=[C:13]([C:14]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:16])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: COc1cc(I)c(C(=O)O)cc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(I)c(C(=O)N2CCCCC2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 5-benzyloxy-2-iodo-4-methoxybenzoic acid (reference example 5-2) (1.92 g), piperidine (0.74 mL) and N,N-dimethylforamide (12 mL) was added 1-hydroxybenzotriazole (676 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.44 g) at room temperature. The mixture was stirred at room temperature for 6 hours. After addition of ethyl acetate, the mixture was poured into 2 mol/L hydrochloric acid. The organic layer was washed with water, an aqueous solution of sodium bicarbonate, and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The mixture of the residue, aminopropylsilicagel and dichloromethane was stirred for 30 minutes. Insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (2.13 g).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][CH:16]([N:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[C:15]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1.[OH-].[K+].I[CH2:36][CH2:37][CH3:38]>CS(C)=O.C(OCC)C.O>[F:32][C:2]([F:1])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][CH:16]([N:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[C:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:36][CH2:37][CH3:38])=[CH:26][CH:25]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)N(C)C1CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(O)cc1
Reactant: CCCI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(OC(F)(F)F)cc3)CC2N(C)C(=O)OC)cc1
Temperature: 50 °C

Procedure:
To 1.0 g (2.2 mmole) of N-(4-trifluoromethoxyphenyl)-3-(4-hydroxyphenyl)-4-(N-methyl-N-(methoxycarbonyl)amino)-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 297) dissolved in 7.5 ml of dimethylsulfoxide was added 0.35 g (2.8 mmole) of 45% aqueous potassium hydroxide and 1.02 g (6.0 mmole) of 1-iodopropane. The mixture was warmed to 50° C. for 30 minutes and diluted with diethyl ether and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and chromatographed over silica gel using hexane and diethyl ether to yield the title compound, a white solid, mp 153°-155° C.
Reaction SMILES: O[CH2:2][N:3]1[CH2:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][C:4]1=[O:21].S(Cl)([Cl:24])=O>C1C=CC=CC=1>[Cl:24][CH2:2][N:3]1[CH2:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][C:4]1=[O:21]
Reactant: O=S(Cl)Cl
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)CN1CO
Solvent: c1ccccc1
Product: O=C1CCC(c2ccccc2)(c2ccccc2)CN1CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a stirred suspension of 28 g (0.1 mol) of the product of step (a) in 150 mL of benzene at 10° C. was added dropwise a solution of 16 mL (1.63 mol) of thionyl chloride in 150 mL of benzene. The mixture was allowed to warm to ambient temperature, stirred overnight and concentrated to dryness. Fresh benzene was added and the solution reconcentrated several more times to give 27 g of crude 1-(chloromethyl)-5,5-diphenyl-2-piperidinone as a white solid.
Reaction SMILES: [CH3:1][CH2:2]N(C(C)C)C(C)C.[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][C:13]([N:16](C)[C:17](=[O:22])[CH2:18][C:19]([OH:21])=O)=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Br:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[C:60]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[C:10]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:11]=[CH:12][C:13]([NH:16][C:17]([C:18]2([C:19]([N:65]3[CH2:64][CH2:63][N:62]([C:60](=[O:61])[C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=4[Br:53])[CH2:67][CH2:66]3)=[O:21])[CH2:2][CH2:1]2)=[O:22])=[CH:14][CH:15]=1
Reactant: CN(C(=O)CC(=O)O)c1ccc(-c2ccccc2)cc1
Reactant: O=C(c1ccccc1Br)N1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1Br)N1CCN(C(=O)C2(C(=O)Nc3ccc(-c4ccccc4)cc3)CC2)CC1
Reaction time: 0.03 h
Yield: 7.5 %

Procedure:
DIPEA (140 mg, 1.1 mmol) was added to a stirred solution of N-biphenyl-4-yl-N-methyl-malonamic acid (100 mg, 0.37 mmol) in DMF (2.0 mL) followed by HOBt (60 mg, 0.44 mmol) and EDCI.HCl (85 mg, 0.44 mmol). After 2 minutes of stirring, (2-bromo-phenyl)-piperazin-1-yl-methanone hydrochloride (136 mg, 0.44 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine and concentrated under reduced pressure to get the residue. Purification by column chromatography, (using silica gel 60-120, 100% EtOAc as eluent) to afford 14.8 mg (12.95%) of 1-[4-(2-bromo-benzoyl)-piperazine-1-carbonyl]-cyclopropanecarboxylic acid biphenyl-4-ylamide. LC/MS [M+H]+: 520.12, 89.73%. 1H NMR (300 MHz, CDCl3): δ 7.7-7.3 (m, 2H), 7.3-7.2 (m, 2H), 4.0-3.6 (m, 5H), 3.58-3.4 (m, 5H), 3.4-3.2 (m, 3H).
Reaction SMILES: [N:1]#[C:2][NH2:3].C(N(C(C)C)CC)(C)C.[CH3:13][S:14]([NH:17][C:18]1[N:23]=[CH:22][C:21]([N:24]=[C:25]=[N:26][CH:27]([CH3:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:20][CH:19]=1)(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[CH3:13][S:14]([NH:17][C:18]1[N:23]=[CH:22][C:21]([NH:24][C:25]([NH:26][CH:27]([CH3:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[N:3][C:2]#[N:1])=[CH:20][CH:19]=1)(=[O:15])=[O:16]
Reactant: N#CN
Reactant: CC(N=C=Nc1ccc(NS(C)(=O)=O)nc1)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(NC(=NC#N)Nc1ccc(NS(C)(=O)=O)nc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
Cyanamide (172 mg, 4.1 mmol) and diisopropylethylamine (711 μl, 4.1 mmol) were added to 1 ml of a solution of N-(6-methanesulfonylamino-3-pyridyl)-N'-(1,2,2-trimethylpropyl)carbodiimide (121 mg, 0.41 mmol) in chloroform and the mixture was stirred at room temperature for 16 hours. After an insoluble matter was removed by filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography [eluent: chloroform alone to chloroform:methanol=5:1 (v/v)] and subjected to recrystallization from chloroform-ether to obtain 97 mg of the intended product (yield: 72%).