Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH2:17][S:16][CH:15]3[N:12]([C:13](=[O:26])[CH:14]3[NH:18]C(OC(C)(C)C)=O)[C:11]=2[C:27]([O:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[CH:8][N:9]=1)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[C:1]([NH:4][C:5]1[S:6][C:7]([C:10]2[CH2:17][S:16][CH:15]3[N:12]([C:13](=[O:26])[CH:14]3[NH2:18])[C:11]=2[C:27]([O:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: CC(=O)Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)s1
Yield: 85.9 %

Procedure:
3-(2-Acetamidothiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4.6 g) is dissolved in acetonitrile (190 cc) at 35° C. and treated with a solution of p-toluenesulphonic acid (monohydrate) (2.9 g) in acetonitrile (20 cc) for 3 hours at 35° C., for 16 hours at 25° C. and then for a further 6 hours at 35° C. after the addition of p-toluenesulphonic acid (monohydrate) (0.95 g). The reaction mixture is partially concentrated under reduced pressure (30 mm Hg; 4 kPa) at 30° C. and then diluted with methylene chloride (200 cc) and a saturated solution of sodium bicarbonate (200 cc). The aqueous layer is extracted with methylene chloride (100 cc) and the combined organic solutions are washed with water (200 cc) and then dried and concentrated under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue is dried under reduced pressure (10 mm Hg; 1.3 kPa) at 25° C. This gives crude 3-(2-acetamidothiazol-5-yl)-7-amino-2-benzhydryloxycarbonyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (3.3 g) in the form of a beige powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[N+:14]([O-])=O)[CH3:2].Cl.[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[NH2:14])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)Nc1ccc(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Nc1ccc(OC)cc1N
Yield: 79.3 %

Procedure:
A solution of (4-methoxy-2-nitrophenyl)carbamic acid ethyl ester (7.3 g; 0.03 mol) in 95% EtOH (500 ml), was hydrogenated at room temperature and pressure in the presence of 10% aqueous HCl (13 ml) and 10% Pd/C (0.35 g). When the theoretical amount of hydrogen was taken up, the catalyst was filtered off and the solution was evaporated to dryness to give the title compound (5 g) after crystallization from Et2O/EtOH (85:15). The compound was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]1[CH2:16][C:17]([N:19]([CH:28]([CH3:30])[CH3:29])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:18].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:41][Si:42]([CH3:50])([CH3:49])[O:43][CH2:44][CH2:45][O:46][CH2:47]Cl>CN(C=O)C>[O:1]=[C:2]1[C:8](=[CH:47][O:46][CH2:45][CH2:44][O:43][Si:42]([CH3:50])([CH3:49])[CH3:41])[C:7](=[O:9])[N:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]1[CH2:16][C:17]([N:19]([CH:28]([CH3:30])[CH3:29])[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)=[O:18]
Reactant: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)CC2=O)C(C)C)cc1
Reactant: C[Si](C)(C)OCCOCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=COCCO[Si](C)(C)C)C2=O)C(C)C)cc1
Reaction time: 0.17 h

Procedure:
A solution of 2-(2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl)-N-isopropyl-N-(4-methoxyphenyl)acetamide (12p, 1.500 g) in anhydrous DMF (15 mL) under argon was cooled to 0-5° C. Sodium bis(trimethylsilyl)amide (0.6 M in toluene, 7.68 mL) was added via syringe followed 5 minutes later by chloromethyl 2-(trimethylsilyloxy)-1-ethyl ether (0.815 mL). After approximately 10 min., the reaction was quenched with glacial acetic acid and evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered and evaporated in vacuo. The crude product was purified on flash grade silica gel eluting with 2:5 ethyl acetate/hexane. Fractions containing the product were combined, evaporated in vacuo and dried under high vacuum to provide 2-[2,4-dioxo-5-phenyl-3-[2-(trimethylsilyloxy)-1-ethoxymethylene]-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide(12q, 1.236 g) as a foam. 1H NMR (400 MHz, CDCl3) 0.00 (s, 9H), 0.95 (m, 2H), 1.04 (d, J=6 Hz, 3H), 1.06 (d, J=6 Hz, 3H), 3.62 (m, 3H), 3.83 (s, 3H), 3.91 (d, J=2 Hz, 2H), 4.02 (dd, J=5,10Hz, 1H), 4.15 (dd, J=8,10Hz, 1H), 4.95 (m, 1H), 5.93 (d, J=6 Hz, 1H), 5.99 (d, J=6 Hz, 1H), 6.94 (m, 2H), 7.11 (m, 2H), 7.33 (m, 5H).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22](O)=[O:23])[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:4]=1[CH3:36])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:61]=[C:62]1[CH2:67][NH:66][CH2:65][CH2:64][NH:63]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C@@H:8]2[C:3]([C:1]#[N:2])=[C:4]([CH3:36])[N:5]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:6](=[O:25])[N:7]2[CH2:21][C:22](=[O:23])[N:66]2[CH2:65][CH2:64][NH:63][C:62](=[O:61])[CH2:67]2)=[C:10]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:11]=1)#[N:16]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: O=C1CNCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)N2CCNC(=O)C2)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 55.5 %

Procedure:
The reaction was carried out under argon. 2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (50 mg, 96 μmol; Example 21) was initially charged in DMF (2 ml), HATU (183 mg, 482 μmol, 5 eq.) was added at 0° C. and the mixture was stirred for 20 min. 2-Oxopiperazine (48.3 mg, 482 μmol, 5 eq.) and N,N-diisopropylethylamine (62 mg, 482 μmol, 5 eq.) were then added, and the mixture was stirred at RT for 30 min until complete conversion had been achieved (HPLC control). The reaction mixture was then concentrated under reduced pressure and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (32 mg, 55% of theory).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][NH:18][CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][C:23]1[N:28]=[C:27]([CH:29]=O)[CH:26]=[CH:25][N:24]=1>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][N:18]([CH2:29][C:27]5[CH:26]=[CH:25][N:24]=[C:23]([CH3:22])[N:28]=5)[CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nccc(C=O)n1
Reactant: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1
Product: Cc1nccc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCCC4)c(=O)[nH]3)C2)n1

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-cyclopentyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 2-methylpyrimidine-4-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.60 (d, J=5.4 Hz, 1H), 8.03 (s, 1H), 7.24 (s, 1H), 5.18-5.10 (m, 1H), 3.97-3.94 (m, 1H), 3.72-3.68 (m, 1H), 3.40 (t, J=8.3 Hz, 1H), 3.15 (d, J=9.5 Hz, 1H), 2.89 (m, 1H), 2.73 (s, 3H), 2.68-2.63 (m, 1H), 2.53-2.47 (m, 1H), 2.15-1.89 (m, 7H), 1.74-1.65 (m, 2H), 1.21 (d, J=7.1 Hz, 3H). MS: (M+H m/z=394.1).
Reaction SMILES: [C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:45])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)Cl>[Br:45][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]2[N:8]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:9]=[N:10][N:11]=2)=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a nitrogen-saturated suspension of N-triphenylmethyl-5-[4′-methylbiphenyl-2-yl]tetrazole (10 g, 20.9 mmol) in DCM was added NBS (3.7 g, 20.9 mmol) and a catalytic amount of benzoyl peroxide (60 mg, 0.2 mmol). The mixture was stirred at reflux for 15 hours. After cooling to room temperature, the precipitate was filtered and the organic solution was concentrated in vacuo. Purification by silica gel chromatography (EtOAc/hexane) gave the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@H:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.[CH3:13][C:14]1[S:23][C:22]2[NH:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[N:18]=[C:17](N)[C:16]=2[CH:15]=1>CN1C(=O)CCC1.[Cl-].[Na+].O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[NH:8][CH2:9][CH2:10][N:11]([C:17]2[C:16]3[CH:15]=[C:14]([CH3:13])[S:23][C:22]=3[NH:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[N:18]=2)[CH2:12]1
Reactant: COCCCC[C@H]1CNCCN1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COCCCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1
Temperature: 211 °C

Procedure:
Heat in a 211° C. oil bath, a stirring solution of (S)-2-(4-methoxybutyl)-piperazine 0.086 g, 0.49 mmol), and 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (0.114 g, 0.49 mmol) in NMP (1 mL) for 4 h. Cool to room temperature, dilute the solution with brine (15 mL) and extract with EtOAc (3×30 mL). Concentrate the organic layers under reduced pressure to a volume of 20 mL and wash with 75% brine (4×20 mL). Dry the organic layer over Na2SO4, and filter. Concentrate the mixture under reduced pressure and purify by silica gel chromatography eluting with 10% (33% 2 M NH3 in MeOH/64% EtOH)/CH2Cl2. Combine the purified fractions, concentrate under reduced pressure, azeotrope with CH2Cl2/hexanes and place under vacuum to give the title compound: brown solid (0.036 g), mass spectrum (m/e):385.08 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.Cl[C:10]1[N:11]=[N:12][C:13]([CH3:22])=[CH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:22][C:13]1[N:12]=[N:11][C:10]([O:1][CH2:2][C:3]2([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]2)=[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=1
Reactant: Cc1cc(-c2ccccc2)c(Cl)nn1
Reactant: OCC1(CO)CCC1
Product: Cc1cc(-c2ccccc2)c(OCC2(CO)CCC2)nn1

Procedure:
The title compound was prepared using the same experimental procedure as in example 25a from [1-(hydroxymethyl)cyclobutyl]methanol and 3-chloro-6-methyl-4-phenylpyridazine. 1H NMR (300 MHz, CDCl3) δ 7.58-7.25 (m, 6H), 4.64 (s, 2H), 3.59 (d, J=6 Hz, 2H), 3.05 (t, J=7 Hz, 1H), 2.63 (s, 3H), 2.00-1.73 (m, 6H). GC-MS m/z 285 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH:13]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([CH2:32][CH3:33])[CH:19]=3)[CH3:17])[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:34]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[CH3:29][C:27]([CH3:28])([CH3:30])[C:26](=[O:31])[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH:16]([CH:13]([C:11]2[O:12][C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:34][C:9]=3[CH:10]=2)[CH2:14][CH3:15])[CH3:17])=[CH:19][C:20]=1[CH2:32][CH3:33]
Reactant: CCc1cc(C(C)C(CC)c2cc3cc(C(=O)OC)ccc3o2)ccc1OCC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(C(C)C(CC)c2cc3cc(C(=O)O)ccc3o2)ccc1OCC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
A solution of 2-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-ethyl-phenyl]-ethylpropyl}-benzofuran-5-carboxylic acid methyl ester (1.64 g, 3.53 mmol) in methanol (5.0 mL) and THF (5.0 mL) is treated with NaOH (2.0 M, 10 mL). The resulting mixture is stirred at RT for 12 h. The mixture is concentrated and neutralized with HCl (5 N) until pH˜3, and extracted with EtOAc (3×30 mL). The organic layer is dried over Na2SO4, concentrated to afford the title compound (1.57 g, 99%).
Reaction SMILES: Cl.C([O:4][CH2:5][CH2:6][O:7][NH:8][C:9]([C:11]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:19]([F:30])[C:14]2[N:15]=[CH:16][N:17]([CH3:18])[C:13]=2[CH:12]=1)=[O:10])=C>C(O)C>[OH:4][CH2:5][CH2:6][O:7][NH:8][C:9]([C:11]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:19]([F:30])[C:14]2[N:15]=[CH:16][N:17]([CH3:18])[C:13]=2[CH:12]=1)=[O:10]
Reactant: C=COCCONC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Solvent: CCO
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCCO)cc21
Reaction time: 24 h
Yield: 102.4 %

Procedure:
Hydrochloric acid (14 mL, 1.0 M aqueous solution, 14 mmol) is added to a suspension of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide 29a (2.18 g, 4.50 mmol) in ethanol (50 mL) and the reaction mixture allowed to stir for 24 hours. The reaction mixture is concentrated to dryness by rotary evaporation and the solids partitioned between 3:1 ethyl acetate/tetrahydrofuran and saturated potassium carbonate. The aqueous phase is extracted with 3:1 ethyl acetate/tetrahydrofuran (3×), the combined organics dried (Na2SO4), and concentrated to provide 2.11 g (100%) 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide as an off-white solid. MS ESI (+) m/z 457, 459 (M+, Br pattern) detected. 1H NMR (400 MHz, MeOH-d4) δ 8.26 (s, 1H), 7.78 (s, 1H), 7.57 (d, 1H), 7.24 (dd, 1H), 6.40 (dd, 1H), 3.86 (s, 3H), 3.79 (m, 2H), 3.49 (m, 2H). 19F NMR (376 MHz, MeOH-d4) −133.68 (s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Br:25]Br>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:25][CH:9]([C:10](=[O:15])[C:11]([CH3:14])([CH3:12])[CH3:13])[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:18]
Reactant: BrBr
Reactant: CC(C)(C)C(=O)CC(c1ccc(Cl)cc1)S(=O)(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)C(Br)C(c1ccc(Cl)cc1)S(=O)(=O)c1ccccc1
Reaction time: 3 h
Yield: 95.4 %

Procedure:
1-(4-Chlorophenyl)-4,4-dimethyl-1-phenylsulfonylpentan-3-one (5.0 g) was dissolved in a mixture of 100 ml of chloroform and 100 ml of acetic acid. To this solution, 2.2 g of bromine was added dropwise at 50° C. The mixture was kept at 50° C. for 3 hours and then washed with ice-water and an aqueous solution of sodium bicarbonate. The chloroform layer was evaporated and the solid residue was crystallized in a mixture of carbon tetrachloride and n-hexane. The crystals were collected by filtration and dried to give 5.8 g of the captioned compound. m.p. 167°-168° C.
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)[CH2:15][C:16]([CH3:18])=[O:17].[OH-].[Na+].Cl>O>[O:17]=[C:16]1[CH2:18][CH:10]([C:11]([OH:13])=[O:12])[CH2:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15]1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(O)C=CC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1C=C(c2ccccc2)CC(C(=O)O)C1

Procedure:
An 800 L still is charged with 53.9 kg (306 mol) of 3-benzoylacrylic acid. The 800 n still is charged with 41 kg (315 mol) of ethyl acetoacetate. The still is charged with 150 L of water. The agitator is started on the still. The still is charged with 56 kg (1475 mol) of 50% sodium hydroxide, followed by 20 L of water. The resulting solution is agitated, and the temperature of the contents is maintained at 45°-50° C. for 16 to 18 hours after the addition of the sodium hydroxide. The solution in the still is then refluxed for 20 to 24 hours (~100° C.). An 800 L reactor is charged with 140 L of water and 90.6 kg (1100 mol) of concentrated hydrochloric acid followed by 20 L of water, and the agitator is started. The reaction mixture in the still is cooled to 25°-40° C. The still is vented through the condenser to an atmospheric scrubber. The cooled solution in the still (25°-40° C.) is added to the diluted hydrochloric acid solution in the reactor at a rate of about 2-4 L/minute. The still is charged with 100 L of water, and this is transferred to the reactor. The resulting slurry in the reactor is agitated at 25°-40° C. for about 2 to 4 hours. The solid product in the reactor is filtered onto a centrifuge. The reactor is charged with 100 L water, and the water is directed to the cake on the centrifuge. The mother liquors and washes are discarded. The still is charged with 100 L water, the water is directed over the filter-cake, and the filtrate is discarded. The product wet cake from the centrifuge is returned to the still followed by 400 L of water, and the slurry is agitated for 2 to 4 hours. The solid product is filtered onto a centrifuge. The still and filter-cake are washed with 200 L of water. The filtrates are discarded. The water wet 5-oxo-3-phenyl-3-cyclohexenecarboxylic acid is transferred to a vacuum tray dryer and dried at 80°±5° C. for at least 24 hours using the best available vacuum to yield 62.5 kg of an off-white to pale yellow solid; mp 140°-160° C. (average of 2 determinations). The dry product is stored in plastic lined drums.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:14]=[C:13]([CH3:33])[N:12]=1.O>COCCOCCOC>[CH3:33][C:13]1[N:12]=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:14]=1
Reactant: Cc1cc(NCCOCCCc2cccnc2)c([N+](=O)[O-])c(Cl)n1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: Cc1cc(NCCOCCCc2cccnc2)c([N+](=O)[O-])c(Oc2ccccc2)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 129.4 %

Procedure:
The general method described in Part E of Example 80 was used with the following modifications. A solution of phenol (1.45 g, 15.4 mmol) in diglyme (10 mL) was added to a cooled mixture of the sodium hydride dispersion (0.59 g, 14.7 mmol) in diglyme (15 mL), and the addition flask was rinsed twice with diglyme (5 mL), which was added to the reaction. A solution of (2-chloro-6-methyl-3-nitropyridin-4-yl)-{2-[3-(pyridin-3-yl)propoxy]ethyl}amine (4.9 g, 14 mmol) was added, and the reaction was heated at 60° C. for 20 hours. Additional reagent prepared from phenol (0.50 g, 5.3 mmol) and 60% sodium hydride (0.21 g, 5.3 mmol) in diglyme was added, and the reaction was heated at 60° C. for 2.5 hours. The reaction was allowed to cool to room temperature and slowly added to 800 mL of water and stirred for one hour to form a bright yellow solid. The solid was isolated by filtration and washed with hexane (50 mL) to provide 7.4 g of (6-methyl-3-nitro-2-phenoxypyridin-4-yl)-{2-[3-(pyridin-3-yl)propoxy]ethyl}amine as a yellow solid contaminated with water.
Reaction SMILES: [Li].Br[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:13]1[CH2:16][C:15](=[O:17])[CH2:14]1>CCOCC.C1COCC1>[C:7]1([CH2:6][CH2:5][CH2:4][CH2:3][C:15]2([OH:17])[CH2:16][O:13][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1COC1
Reactant: BrCCCCc1ccccc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(CCCCc2ccccc2)COC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 34.9 %

Procedure:
Under argon atmosphere at −45° C., to a stirred mixture of Lithium in pellets (0.129 g, 18.7 mmol) suspended in dry Et2O (15 mL), 4-bromo-butylbenzene (1.5 g, 7.03 mmol) in dry Et2O (10 mL), was added dropwise. The reaction was left to stir at 0° C. for 3 h, then the mixture was transferred via a cannula to a solution of 3-oxetanone (0.4 g, 5.55 mmol) in dry THF (10 mL), previously cooled to −78° C. After 3 h at −78° C., the reaction mixture was quenched with a saturated NH4Cl solution, the organic solvents removed under reduced pressure. The crude mixture was then dissolved in CH2Cl2, dried over Na2SO4, concentrated to dryness and subjected to column chromatography using a Teledyne ISCO apparatus, eluting with Cy/TBME (from 100:0 to 70:30) to afford a pure compound (0.4 g, 35%) as colorless oil. 1H NMR (CDCl3): δ 1.41-1.55 (m, 2H), 1.65-1.78 (m, 2H), 1.84-1.94 (m, 2H), 2.62-2.73 (m, 2H), 4.52 (d, J=7.2 Hz, 2H), 4.58 (d, J=7.0 Hz, 2H), 7.21 (dd, J=5.4, 7.2 Hz, 3H), 7.27-7.34 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11](=[O:35])[NH:12][C@H:13]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:14][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:16])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[CH3:37][O-:38].[Na+].O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11](=[O:35])[NH:12][C@H:13]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:14][C@H:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:16])[N:8]=[C:7]([O:38][CH3:37])[N:6]=1)=[O:4]
Reactant: C[O-]
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(C(=O)OC)nc(Cl)n1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(C(=O)OC)nc(OC)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butylcarbamoyl)-2-chloro-pyrimidine-4-carboxylic acid methyl ester (74 mg, 0.145 mmol, from Example 42-1) in THF (5 mL) is added sodium methoxide (47 mg, 0.218 mmol) and the mixture is stirred at room temperature for 18 hours. Water is added and the mixture is extracted with EtOAc. The organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure to give 6-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butylcarbamoyl)-2-methoxy-pyrimidine-4-carboxylic acid methyl ester.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)#[CH:12].N>>[F:19][C:15]1[CH:14]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[N:8][CH:7]=[CH:6][N:5]=3)[CH:12]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: ON=C(Cl)c1cnccn1
Reactant: C#Cc1cccc(F)c1
Agent: N
Product: Fc1cccc(-c2cc(-c3cnccn3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 1-ethynyl-3-fluorobenzene (Aldrich, 60 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.19-7.33 (m, 1H), 7.48 (s, 1 H), 7.58 (td, J=8.1, 5.8 Hz, 1H), 7.69 (dt, J=9.6, 2.2 Hz, 1H), 7.77 (dt, J=8.0, 1.1 Hz, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.76 (dd, J=2.4, 1.7 Hz, 1H), 9.29 (d, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 242 (M+H)+.