Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([NH:37][CH3:38])=[O:36])=[CH:33][CH:32]=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>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C:35](=[O:36])[NH:37][CH3:38])=[CH:39][CH:40]=3)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CNC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(NC(=O)c2cccc(-c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.8 %

Procedure:
A solution of 3-[7-(3,4-dimethoxy-phenylamino)-thiazolo[5,4-d]pyrimidin-5-yl]-benzoic acid (170 mg, 0.41 mmol) in 10 mL of DMF were added 4-amino-N-methyl-benzamide (81 mg, 0.54 mmol), HATU (205 mg, 0.54 mmol) and DIEA (79 mg, 0.61 mmol) at room temperature. Then the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated to give a solid as a crude product. It was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% TFA V/V) initially, and then proceed to 70% acetonitrile/30% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(4-(methylcarbamoyl)phenyl)benzamide (66 mg, 29.7%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.66 (s, 1H), 10.21 (s, 1H), 9.39 (s, 1H), 8.93 (s, 1H), 8.59 (d, 1H, J=7.2 Hz), 8.38-8.37 (m, 1H), 8.05 (d, 1H, J=8.7 Hz), 7.89-7.82 (m, 6H), 7.71-7.68 (m, 12H), 7.54-7.50 (m, 1H), 6.97 (d, 1H, J=8.7 Hz), 3.78 (s, 3H), 3.72 (s, 3H), 2.78 (d, 1H, J=3.9 Hz). LC-MS: 541.1 [M+H]+, tR=1.72 min. HPLC: 96.60% at 214 nm, 97.75% at 254 nm, tR=6.68 min.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[OH-].[NH4+:17]>>[NH2:17][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN1CCC(c2ccc(F)nc2)CC1=O
Reactant: [NH4+]
Agent: [OH-]
Product: CN1CCC(c2ccc(N)nc2)CC1=O
Temperature: 150 °C

Procedure:
To a steel bomb, (+/−)-4-(6-fluoropyridin-3-yl)-1-methylpiperidin-2-one (341 mg, 1.638 mmol) was added followed by addition of ammonium hydroxide solution (0.00 mmol)—remaining 40% head space. The reactor was heat at 150° C. for 20 hr (internal pressure built up to 100 psi upon heating). After cooling down, the reaction was completed. The whole solvent (transferred to a flask) was removed in vacuo. Toluene was added and co-evaporated to remove water. The crude product, (+/−)-4-(6-aminopyridin-3-yl)-1-methylpiperidin-2-one, was used for the next step without further purification (87%). LCMS (m/z): 206.1 (MH+), 0.24 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH2:20]([C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:25]=[CH:26][CH:27]=1)[CH3:21]
Reactant: CCc1cccc(N=C=O)c1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: CCc1cccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4cnccc34)cc2)c1

Procedure:
61 mg of pale yellow solid 3-{4-[3-(3-ethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 3-ethylphenyl isocyanate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:12]([OH:14])=O)#[N:8].[NH2:23][C:24]1[C:25]([Cl:34])=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C.Cl>ClCCl.C1COCC1.C1(C)C=CC=CC=1.CN(C=O)C>[Cl:34][C:25]1[C:24]([NH:23][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[C:9]([C:7]#[N:8])[CH:10]=2)=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: CC(C)COc1ccc(C(=O)O)cc1C#N
Reactant: COC(=O)c1cccc(N)c1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(NC(=O)c2ccc(OCC(C)C)c(C#N)c2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (889 mg, 7.0 mmol) was dropwise added to a solution of 3-cyano-4-isobutyloxybenzoic acid (767 mg, 3.5 mmol) in dichloromethane (10 mL) under cooling with ice. Subsequently, a catalytic amount of DMF was added. The mixture was then stirred for one hour at room temperature, heated under reflux for 3 hours, and placed under reduced pressure to distill the solvent off. Toluene was added to the residue and the solvent was distilled off under reduced pressure. THF (10 mL) was added to the residue. Further, a solution of methyl 3 amino-2-chlorobenzoate (497 mg, 2.68 mmol) and triethylamine (1.39 mL, 10 mmol) in THF (10 mL). The resulting mixture was stirred for 14 hours at room temperature, and toluene and aqueous 1M hydrochloric acid were added. The organic portion was taken out, washed with aqueous 1M hydrochloric acid and aqueous saturated sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and placed under reduced pressure to distill the solvent off.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]4[C:18](=[O:22])[CH2:19][CH2:20][CH2:21][CH:14]4[CH2:13]3)[CH2:9]2)C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:9][CH:10]([N:12]2[CH2:17][CH2:16][N:15]3[C:18](=[O:22])[CH2:19][CH2:20][CH2:21][CH:14]3[CH2:13]2)[CH2:11]1
Reactant: O=C1CCCC2CN(C3CN(C(c4ccccc4)c4ccccc4)C3)CCN12
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C1CCCC2CN(C3CNC3)CCN12
Temperature: 120 °C
Yield: 99.4 %

Procedure:
(+)-(2-[1-(Diphenylmethyl)azetidin-3-yl]octahydro-6H-pyrido[1,2-a]pyrazin-6-one (138 mg, 0.37 mmol) and ammonium formate (70 mg, 1.1 mmol) were dissolved in ethanol (3 mL). Palladium hydroxide on carbon (52 mg) was added and the reaction mixture was heated to 120° C. for 2 min using microwave single node heating. The catalyst was filtered off and the solvent was removed by evaporation. There was obtained 77 mg (100%) of the title compound. LCMS: m/z 210 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[N:14][CH:15]=[C:16]([C:17]([NH:19][C@@H:20]([CH3:24])[C:21]([OH:23])=O)=[O:18])[N:12]3[C@@:11]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:29][CH:28]=3)([CH3:25])[C:10]2=[O:40])[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C(O)=O.[NH:48]1[C:52]([C@@H:53]2[CH2:58][CH2:57][CH2:56][NH:55][CH2:54]2)=[N:51][N:50]=[N:49]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[C:10](=[O:40])[C@:11]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]4[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=4)=[CH:31][CH:32]=3)([CH3:25])[N:12]3[C:16]([C:17]([NH:19][C@@H:20]([CH3:24])[C:21](=[O:23])[N:55]4[CH2:56][CH2:57][CH2:58][C@@H:53]([C:52]5[NH:51][N:50]=[N:49][N:48]=5)[CH2:54]4)=[O:18])=[CH:15][N:14]=[C:13]23)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3ccc(F)cc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: C1CNC[C@H](c2nnn[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3ccc(F)cc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)N1CCC[C@@H](c2nnn[nH]2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.3 %

Procedure:
To a cold (0° C.) solution of (S)-2-{[(R)-7-(3,5-dichloro-phenyl)-5-(4′-fluoro-biphenyl-4-ylmethyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acid (0.12 g, 0.21 mmol) in DMF (1 mL) was added (R)-3-(1H-tetrazol-5-yl)-piperidine trifluoro-acetic acid salt (0.055 g, 0.21 mmol), HATU (0.093 mg, 0.25 mmol) and Et3N (0.059 mL, 0.41 mmol). The reaction was allowed to stir for 10 min and then HOAt (0.056 g, 0.41 mmol) was added. The mixture was allowed to warm to room temperature overnight. The crude reaction mixture was purified by reverse phase HPLC to give 35 mg of the title compound as a white solid, m/z 716.6 [M]+.
Reaction SMILES: [CH2:1]([CH:8]([S:13]([C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[CH2:30])=[CH:27][CH:26]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([CH:8]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH:30]=[CH:29][C:28]2[CH:31]=[CH:32][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(OC)cc1
Reactant: O=C(O)CC(Cc1ccccc1)S(=O)(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Product: O=C(O)CC(Cc1ccccc1)S(=O)(=O)c1ccc(C=Cc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 3-benzyl-3-(4-bromophenylsulfonyl)-propionic acid (250 mg), p-methoxystyrene (0.1 ml), diisopropylethylemine (0.25 ml), palladium acetate (5 mg) and tri(o-methylphenyl)phosphine (16 mg) was stirred overnight at 80° C. The reaction mixture was dissolved in methylene chloride and washed with aqueous citric acid. Solvent was removed from the methylene chloride solution, and the residue chromatographed on silica gel (preparative TLC, eluting with 10% methanol/methylene chloride), to afford 3-benzyl-3-(4-styrylphenylsulfonyl)-propionic acid (21 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:20])[CH2:12][NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:7][CH:6]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C1CCN2C(=NCCC2)CC1>>[CH3:18][CH:17]([S:14]([NH:13][CH2:12][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:10][CH:9]=1)[CH3:20])(=[O:16])=[O:15])[CH3:19]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(CCCN)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(CCCNS(C)(=O)=O)cc1
Yield: 23.9 %

Procedure:
Scheme Vc, step C: {2-[4-(3-aminopropyl)phenyl]propyl}[(methylethyl)sulfonyl]amine (0.5 g, 1.67 mmol), methanesulfonyl chloride (0.15 mL, 1.84 mmol) and DBU (0.29 mL, 1.93 mmol) were combined and sulfonylation was carried out in a manner analogous to the procedure described in example 2 to provide the final title compound, [(methylethyl)sulfonyl][2-(4-{3-[(methylsulfonyl)amino]propyl}phenyl)propyl]amine, (0.15 g, 24%) as a white crystalline solid. Electron spray M.S. 377 (M*+H). Analysis for C16H28N2O4S2:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](O)(=[O:5])=[O:4].[NH2:9][C:10]1[S:11][C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[N:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]([F:8])([F:7])[S:3]([NH:9][C:10]1[S:11][C:12]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[N:14]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: Cc1ccc(-c2nc(N)sc2-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nc(NS(=O)(=O)C(F)(F)F)sc2-c2ccccc2)cc1
Yield: 37.4 %

Procedure:
15.9 g of anhydrous trifluoromethanesulfonic acid was slowly dropped into a solution of 5.0 g of 2-amino-4-(4-methylphenyl)-5-phenylthiazole and 5.2 ml of triethylamine in chloroform under stirring in a nitrogen atmosphere at -20° to -15° C., and the resulting mixture was stirred as such for 2 hours. Then the reaction mixture was successively washed with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and water in this order and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the reaction product was separated with a silica gel column by using chloroform/ethyl acetate as a developer. The crystals thus obtained were recrystallized from n-hexane/isopropyl ether/ethyl acetate to give 2.8 g of 2-trifluoromethanesulfonylamino-4-(4-methylphenyl)-5-phenylthiazole. The melting point of this product was from 186.5° to 188.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]([N+:17]([O-:19])=[O:18])[CH2:15][CH2:14][C:13](=[O:20])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([BH-](C(CC)C)C(CC)C)(CC)C.[K+].P([O-])([O-])([O-])=O>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]([N+:17]([O-:19])=[O:18])[CH2:15][CH2:14][CH:13]([OH:20])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(=O)CCC2[N+](=O)[O-])cc1OC
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2CC(O)CCC2[N+](=O)[O-])cc1OC
Temperature: 78 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere 16.76 g of (3RS,4SR)-3-(3,4-dimethoxyphenyl)-4-nitrocyclohexanone (compound F2) are dissolved in 300 ml of tetrahydrofurane, the solution is cooled to 78° C., and 75 ml of 1 M solution of potassium tri-sec-butylborohydride in tetrahydrofurane is added dropwise. After stirring for further 1 h, a mixture consisting of 30% hydrogeneperoxide solution and phosphate buffer solution is added. Stirring is continued for further 10 min, the reaction mixture is diluted with 400 ml of ethyl acetate and the aqueous layer is extracted with ethyl acetate, the combined organic phases are concentrated to give a foam, which is purified by chromatography on silica gel using a mixture of petroleum ether/ethyl acetate in the ratio 1/1 to furnish 10.18 g (60% of theory) of the title compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11]C(=O)C2C=CC=CC=2)[O:8][C@@H:7]([N:20]2[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]2=[O:22])[C@H:6]1[F:28])(=O)C.C([O-])(=O)C.[Na+].[Br:34]Br>C(O)(=O)C>[F:28][C@H:6]1[C@H:5]([OH:4])[C@@H:9]([CH2:10][OH:11])[O:8][C@H:7]1[N:20]1[CH:27]=[C:26]([Br:34])[C:24](=[O:25])[NH:23][C:21]1=[O:22]
Reactant: BrBr
Reactant: CC(=O)O[C@H]1[C@H](F)[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)cc1Br
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a solution of 1-(3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)uracil (500 mg) and sodium acetate (100 mg) in 5 ml of glacial acetic acid is added a solution of bromine (240 mg) in 1 ml of glacial acetic acid. After 30 minutes at room temperature, the solvent is removed by evaporation in vacuo. Traces of acetic acid is removed by several co-evaporation with toluene. The residue is dissolved in saturated methanolic ammonia (50 ml) and the mixture is kept standing at room temperature for 2 days. The solvent is removed by evaporation in vacuo and the residue is crystallized from water to give 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-bromouracil (325 mg), m.p. 214°-216°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]2[C:36](=[O:37])O[C:33](=[O:34])[C:32]2=[CH:38][CH:39]=1>C(O)(=O)C>[F:28][C:29]1[CH:30]=[C:31]2[C:36](=[O:37])[N:1]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4([C:21]5[CH:22]=[CH:23][C:24]([N:27]6[C:36](=[O:37])[C:31]7=[CH:30][C:29]([F:28])=[CH:39][CH:38]=[C:32]7[C:33]6=[O:34])=[CH:25][CH:26]=5)[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=5[C:15]5[C:20]4=[CH:19][CH:18]=[CH:17][CH:16]=5)=[CH:6][CH:7]=3)[C:33](=[O:34])[C:32]2=[CH:38][CH:39]=1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: Nc1ccc(C2(c3ccc(N)cc3)c3ccccc3-c3ccccc32)cc1
Solvent: CC(=O)O
Product: O=C1c2ccc(F)cc2C(=O)N1c1ccc(C2(c3ccc(N4C(=O)c5ccc(F)cc5C4=O)cc3)c3ccccc3-c3ccccc32)cc1

Procedure:
A mixture of 9,9-bis(4-aminophenyl )fluorene (17.4 g, 50 mmol), 4-fluorophthalic anhydride (18.3 g, 110 mmol), and 250 ml of acetic acid was stirred and heated under reflux for five hours and then stirred at ambient temperature overnight. A colorless precipitate formed which was filtered, washed twice with 150 ml of ethanol, washed twice with 100 ml of hexane, suction-dried for two hours, and then dried in a vacuum oven at 120° C. for 16 hours. The title compound was isolated as a colorless powder (29.2 g, 90.6% yield) that had melting point of 323.5°-326° C. and a 1H NMR spectrum (DMSO-d6) corresponding to δ8.02 (m, 4H), 7.86 (dd, 2H), 7.72 (m, 2H), 7.60 (d, 2H), 7.46 (t, 2H), and 7.35 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:16])[C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[CH:9][C:8]([CH3:14])=[C:7]([CH3:15])[CH:6]=2>O>[CH3:14][CH:8]1[CH:7]([CH3:15])[CH2:6][C:5]2[C:4](=[O:16])[C:3]([O:2][CH3:1])=[CH:12][C:11](=[O:13])[C:10]=2[CH2:9]1
Reactant: COC1=CC(=O)c2cc(C)c(C)cc2C1=O
Solvent: O
Product: COC1=CC(=O)C2=C(CC(C)C(C)C2)C1=O

Procedure:
A solution of 5,8-dihydro-6,7-dimethyl-2-methoxynaphthalene-1,4-diol (2.00 g, 9.08 mmol) in MeOH (250 mL) was hydrogenated over Pd/C (200 mg, 10%, Aldrich) at 30-40 psi for 24 h at rt in a Parr hydrogenator. The catalyst was removed by filtration (Celite) and the solvent removed in vacuo to yield a brown tacky solid (~2.2 g, ~100%). Analysis (1H NMR) showed the solid to be a mixture of reduced diol (90%) and 2-methoxy-6,7-dimethylnaphthalene-1,4-dione. Without purification, the mixture was dissolved in CHCl3 (100 mL) and the resulting solution vigorously stirred with a solution of NaIO4 (3.89 g, 18.2 mmol, Baker) in H2O (200 mL) for 30 min at rt. The layers were separated and the aqueous portion extracted with CHCl3 (1×30 mL). The combined organic portion was washed with saturated brine (1×30 mL), filtered through a cotton plug and the solution concentrated in vacuo to yield a brown concentrate. The concentrate was passed through a silica gel column (2.5×17 cm) with CHCl3 elution to give an initial yellow band, which contained the desired product. Solvent removal in vacuo yield a brown oil (1.3 g). This material was further purified on a silica gel column (2.5×25 cm) to yield an orange viscous oil from the initial band (787 mg, 39%, pure by TLC and 1H NMR, as a probable mixture of cis- and trans-isomers (85 to 15)); 1H NMR (CDCl3) δ0.88 (d, J=6.6 Hz, 6H), 1.90 (m, 2H), 2.20 (m, 2H), 2.50 (m, 2H), 3.79 (s, 3H), 5.85 (s, 1H). The minor isomer shows a doublet at 1.03, J=6.0 Hz.
Reaction SMILES: [CH:1](=[C:8]1[NH:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])[CH:16]=[CH2:17].[OH-].[K+].CN(C=O)C>C1(C)C=CC=CC=1>[CH:1](=[C:8]1[C:9](=[O:14])[N:10]([CH2:17][CH2:16][C:15]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[C:11](=[O:13])[NH:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2ccccc2)N1
Reactant: C=CC(=O)OCC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)COC(=O)CCN1C(=O)NC(=Cc2ccccc2)C1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
20 g (0.106 mol) of benzalhydantoin, 14.9 g (0.117 mol) of isobutyl acrylate and 1.2 g (0.02 mol) of potassium hydroxide were added to 150 ml of DMF, and the mixture was stirred at 110° C. for 2 hours. After cooling, the reaction solution was added with 300 ml of toluene and crystallized. The crystals were filtered out and dried to obtain 27.2 g of isobutyl 4-benzylidene-2,5-dioxo-1-imidazolidinepropionate (yield: 81%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>[OH-].[Na+]>[CH2:13]([O:12][C:10]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
L-Proline 5 (100 gms, 0.87 moles) was dissolved in 2N sodium hydroxide (430 mL) and cooled in an ice bath. A further 220 mL of 4N sodium hydroxide was added simultaneously with benzyl chloroformate (155 gms, 0.90 moles) over 2 hrs. The reaction was then allowed to warm to room temperature overnight.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:13][CH2:12][CH:9]2[CH2:11][CH2:10]2)[N:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1ccnc(NCC2CC2)n1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
In a microwave reaction vessel, slurry 2,4-dichloropyrimidine (1.0 g, 6.7 mmol), cyclopropylmethylamine (550 μL, 6.0 mmol), and diisopropylethylamine (2.35 mL, 13.4 mmol) in toluene (3 mL). Irradiate in microwave (300 watts) at 120° C. for 30 min. Cool to room temperature and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with hexane/EtOAc (4:1 to 3:7 over 30 min; 40 mL/min) to obtain the desired intermediate (157.5 mg, 15%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:10]2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[CH:29]([Mg]Br)([CH3:31])[CH3:30]>C1COCC1.CN1CCCC1=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[C:15]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([CH:29]([CH3:31])[CH3:30])=[CH:3][C:4]=2[C:25]([F:28])([F:27])[F:26])[N:10]=1)=[O:24]
Reactant: CC(C)[Mg]Br
Reactant: O=C(Nc1ccn(Cc2ccc(Cl)cc2C(F)(F)F)n1)c1c(F)cccc1F
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CC(C)c1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
To a solution of N-(1-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-2,6-difluorobenzamide (for a preparation see Example 80)(100 mg, 0.241 mmol) in a mixture of THF (0.9 ml) and N-methyl-2-pyrrolidone (0.1 ml) was added iron(III) acetylacetonate (17 mg, 0.048 mmol, Aldrich). The resulting red solution was stirred for 10 min and then treated with a solution of 15% isopropylmagnesium bromide in THF (1.2 ml, 0.60 mmol, Fluorochem) at ambient temperature. The solution was stirred at room temperature under nitrogen overnight. The reaction mixture was quenched with methanol (1 ml) and the solvent removed in vacuo. The residue was dissolved in 1:1 MeOH:DMSO (2 ml) and purified by MDAP (Method B) on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a yellow solid (26 mg); LCMS: (System 4) MH+=424, tRET=3.41 min.