Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][S:6]([CH2:9][CH:10]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]([O:13]CC1C=CC=CC=1)=[O:12])(=[O:8])=[O:7])[CH3:2]>C(O)C.[Pd]>[CH2:28]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][S:6]([CH2:9][CH:10]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]([OH:13])=[O:12])(=[O:8])=[O:7])[CH3:29]
Reactant: CCN(CC)CCS(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)CCS(=O)(=O)CC(Cc1ccccc1)C(=O)O

Procedure:
The title compound of Step 16 (167 mg, 0.4 mmol) is debenzylated in ethanol with 5 psi H2 at room temperature for 1.5 hours using 4% Pd/C catalyst. After filtering, the solvent is stripped off to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)=[CH:4][CH:3]=1.[C:17]1([C:23]2[N:27]=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([N:31]2[CH2:32][CH2:33][N:28]([C:26]3[S:25][N:24]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:27]=3)[CH2:29][CH2:30]2)=[O:16])=[CH:4][CH:3]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cn1
Yield: 32.3 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl (6-aminopyridin-3-yl)carbamate (210 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by high performance liquid chromatography (YMC HPLC Column eluted with 10% to 100% Liquid A; Liquid A: a 0.1% solution of trifluoroacetic acid in acetonitrile; Liquid B: an aqueous 0.1% trifluoroacetic acid solution) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 90.8 mg (32.3%) of the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH:12]([C:14]([OH:16])=O)[CH3:13])=[C:6]([CH:10]=1)C(O)=O.[C:17](OC(=O)C)(=[O:19])[CH3:18].C([O-])(=O)C.[Na+]>>[Br:1][C:2]1[CH:10]=[CH:6][C:5]2[O:11][C:12]([CH3:13])=[C:14]([O:16][C:17](=[O:19])[CH3:18])[C:4]=2[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(Oc1ccc(Br)cc1C(=O)O)C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)Oc1c(C)oc2ccc(Br)cc12
Temperature: 150 °C
Yield: 65 %

Procedure:
A mixture of 5-bromo-2-(1-carboxy-ethoxy)-benzoic acid (31.2 g, 108 mmol), acetic anhydride (216 mL) and anhydrous sodium acetate (21.8 g, 266 mmol) is heated under reflux (150° C.) for 4 h. After cooling to room temperature the reaction mixture is carefully quenched with ice-cold water (500 mL). A white precipitate is formed which is collected by suction filtration, thoroughly washed with water and dried in vacuo at 45° C. to afford the title compound as a white powder (19.0 g, 70.6 mmol, 65%). MS (ES+): 269 (M(C11H979BrO3)+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=4)=[O:21])=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH:11]=O)[N:6]2[N:5]=[CH:4][N:3]=1.[F:33][C:34]([F:38])([F:37])[CH2:35][NH2:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=4)=[O:21])=[CH:15][CH:14]=3)[CH:9]=[C:10]([CH2:11][NH:36][CH2:35][C:34]([F:38])([F:37])[F:33])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(C=O)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Reactant: NCC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Nc1ncnn2c(CNCC(F)(F)F)cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)n4)cc3)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 36.4 %

Procedure:
To a suspension of N-[4-(4-amino-7-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[6-(trifluoromethyl)pyridin-2-yl]urea (5.0 mg, 0.011 mmol) in 1,2-dichloroethane (2 mL) was added 2,2,2-trifluoroethylamine (11.2 mg, 0.11 mmol), followed by sodium triacetoxyborohydride (24.0 mg, 0.11 mg). The mixture was stirred at rt under nitrogen for 4 d. The solvent was evaporated under reduced pressure. The residue was dissolved in DMF and purified by HPLC using a gradient of 20-90% MeCN in water to yield 2.1 mg (35%) of the title compound. 1H-NMR (DMSO-d6) 9.95 (bs, 1 H), 9.79 (bs, 1 H), 8.05-7.99 (m, 2 H), 7.90 (s, 1 H), 7.57 (d, J=8.6, 2 H), 7.50 (dd, J=6.4, 1.7, Hz, 1 H), 7.40 (d, J=8.6 Hz, 2 H), 6.66 (s, 1 H), 4.07 (d, J=6.8 Hz, 2 H), 3.30-3.23 (m, 2 H), 2.92-2.85 (m, 1 H); MS [M+H]+=525.1; LCMS RT=2.91 min.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]([OH:22])=O)[CH:16]=3)[O:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1[C:33]2[O:32][C:31]([C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:30][C:29](=[O:39])[C:28]=2[CH:27]=[CH:26][CH:25]=1>>[O:39]=[C:29]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:23][C:20]([C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[O:11][CH:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:19][CH2:18]4)=[O:22])[C:33]=2[O:32][C:31]([C:34]2[NH:38][N:37]=[N:36][N:35]=2)=[CH:30]1.[CH3:10][OH:11]
Reactant: O=C(O)c1ccc2c(c1)CCC(CCCc1ccccc1)O2
Reactant: Nc1cccc2c(=O)cc(-c3nnn[nH]3)oc12
Product: CO
Product: O=C(Nc1cccc2c(=O)cc(-c3nnn[nH]3)oc12)c1ccc2c(c1)CCC(CCCc1ccccc1)O2
Yield: 65 %

Procedure:
Following the process described in example 2 (point K), starting from 2-(3-phenylpropyl)-6-chromanecarboxylic acid and 8-amino-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran, the title compound was prepared as a white solid which decomposes at temperatures higher than 370° C. and which was purified by crystallization in methanol (65% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])[C:5]1=[O:29].C(N(C(C)C)CC)(C)C.Cl[C:40]([O:42][CH3:43])=[O:41].O>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])[C:5](=[O:29])[N:4]3[CH2:3][CH2:2][NH:1][C:40](=[O:41])[O:42][CH3:43])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: NCCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: COC(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)NCCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.0207 g, 0.052 mmol) and diisopropyl ethylamine (0.075 mL, 0.43 mmol) in DMF (2 mL) under nitrogen was treated with methyl chloroformate (0.0038 mL, 0.049 mmol) at ambient temperature. Water was added (2 mL) and the reaction was concentrated in vacuo. The resulting residue was purified by reversed phase HPLC to provide the title compound from pure fraction concentrated in vacuo as an off-white solid: 1H NMR (300 MHz, DMSO-D6) δ ppm 3.2 (m, 2 H), 3.4 (m, 5 H), 3.6 (m, 2 H), 4.1 (s, 2 H), 4.3 (t, J=6.3 Hz, 2 H), 4.9 (t, J=4.9 Hz, 1 H), 7.1 (t, J=8.9 Hz, 2 H), 7.3 (t, J=6.0 Hz, 1 H), 7.4 (m, 2 H), 8.1 (s, 1 H), 8.5 (s, 1 H), 10.4 (m, 1 H); ES+ MS: 459 (M+H+).
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].[CH:12]1(CC([Cl:21])=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH2:22]([O:24]CC)[CH3:23]>FC(F)(F)C(O)=O>[CH:12]1([CH:5]([N+:2]([CH3:3])([CH3:4])[CH3:1])[C:6]([C:22](=[O:24])[CH3:23])([CH2:7][C:8](=[O:10])[O-:9])[OH:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[Cl-:21]
Reactant: CCOCC
Reactant: O=C(Cl)CC1CCCCC1
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C(O)(CC(=O)[O-])C(C1CCCCC1)[N+](C)(C)C
Product: [Cl-]
Reaction time: 48 h

Procedure:
Carnitine chloride (2.97 g; 0.01 moles) was dissolved in trifluoro acetic acid (10 cc). To this solution was added cyclohexyl acetyl chloride (0.01 moles) prepared as previously disclosed and the resulting mixture was kept under stirring for 48 hours. Ethyl ether was then added and the resulting mixture was kept under stirring for 0.5 hours at 0° C. A precipitate was obtained, which was filtered off and dried under vacuum.
Reaction SMILES: [Br:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl>C(OCC)C>[CH3:16][S:17]([O:6][CH2:5][CH2:4][CH2:3][C:2]([Br:1])([F:8])[F:7])(=[O:19])=[O:18]
Reactant: OCCCC(F)(F)Br
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)OCCCC(F)(F)Br
Temperature: 0 °C

Procedure:
A stirred solution of 4-bromo-4,4-difluorobutanol (0.57 g) in dry diethylether (5 cm3) was cooled to 0° C. Maintaining this temperature, triethylamine (1.7 cm3) was added. After ten minutes methanesulfonyl chloride (0.3 cm3) was added and the mixture stirred for a further hour at 0° C. The reaction mixture was poured into 2M hydrochloric acid (2 cm3) and diethylether (20 cm3). The organic phase was separated, washed with saturated brine, then passed through a plug of silica gel eluting with further diethylether. The diethylether fractions were evaporated under reduced pressure to give a light yellow oil (0.705 g). 1H NMR: δ 2.04-2.18(2H,m); 2.46-2.64(2H,m); 3.04(3H,s); 4.32(2H,t).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Clc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(Oc2ccccn2)cc1
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
To a stirred solution of 4-bromophenol (200 mg) in DMF (3 mL) was added NaH (60% in oil, 46.2 mg) at room temperature. The mixture was stirred for 30 min, and 2-chloropyridine (131 mg) was added. The mixture was exposed to microwave irradiation at 230° C. for 1 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane). The product was crystallized from AcOEt/hexane to give the title compound (76 mg).
Reaction SMILES: [CH2:1](O)C.[Cl:4][C:5]1[CH:18]=[CH:17][C:16]2[CH:15]3[CH2:19][C:8]([C:21]([O:23][CH3:24])=[O:22])([C:9]4[C:14]3=[CH:13][CH:12]=[C:11]([OH:20])[CH:10]=4)[C:7]=2[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CI>C(OCC)C>[Cl:4][C:5]1[CH:18]=[CH:17][C:16]2[CH:15]3[CH2:19][C:8]([C:21]([O:23][CH3:24])=[O:22])([C:9]4[C:14]3=[CH:13][CH:12]=[C:11]([O:20][CH3:1])[CH:10]=4)[C:7]=2[CH:6]=1
Reactant: CCO
Reactant: COC(=O)C12CC(c3ccc(O)cc31)c1ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Product: COC(=O)C12CC(c3ccc(Cl)cc31)c1ccc(OC)cc12
Yield: 90 %

Procedure:
To an ethanol solution of methyl 2-chloro-7-hydroxy-9,10-dihydro-9,10-methano-9-anthracenecarboxylate (described in example 90a) was added potassium carbonate and methyl iodide. The suspension was heated to reflux, cooled and diluted with diethyl ether, filtered to remove salts, and concentrated to a solid. The title compound was formed in 90% yield. TLC analysis (Rf 0.40, 20% ethyl acetate in hexane). MS (CI, CH4) m/z 315 (M+1,100), 343 (M+29,13), 301 (38), 287 (9), 279 (14), 265 (6), 255 (42).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH2:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33])[C:22]([OH:24])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C[CH2:35][O:36][C:37]([CH3:39])=[O:38]>CN(C=O)C>[CH3:35][O:36][C:37](=[O:38])[CH2:39][N:33]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26][CH2:25][C@H:21]([NH:20][C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[C:22]1=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1N)C(=O)O
Reactant: CCOC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reaction time: 18 h
Yield: 71 %

Procedure:
(3S)-2-Oxo-3-tert-Butoxycarbonylamino-1,3,4,5-tetrahydro-1H-1,5-benzodiazepine. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.54 g, 44.5 mmol) was added to a cooled (0° C.) solution of (2S)-2-tert-butoxycarbonylamino-3-(2-aminophenylamino)propionic acid (11.95 g, 40.5 mmol) in 100 ml of DMF and stirred for 18 h. The reaction was poured into 700 ml of EtOAc and washed four times with 100 ml of H2O. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give a brown solid that was purified by flash chromatography eluting with 3:7 EtOAc/hexane to give 8 g (71%) of the title compound: 1H NMR (CDCl3) δ 7.78 (1H, s), 7.02-6.95 (1H, m), 6.88-6.82 (1H, m), 6.82-6.78 (1H, m), 6.75-6.70 (1H, m), 5.8-5.7 (1H, d), 4.55-4.45 (1H, m), 3.95 (1H, s), 3.9-3.82 (1H, m), 3.48-3.40 (1H, m), 1.45 (9H, s).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[NH:11][C:12]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1.[CH2:22]([O:24][C:25]([CH:27]([CH3:31])[CH2:28][CH2:29]Br)=[O:26])[CH3:23].O>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]([CH3:31])[CH2:28][CH2:29][N:14]1[C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:12]=2[N:11]=[C:10]1[CH2:9][O:8][C:7]1[CH:20]=[CH:21][C:4]([Cl:3])=[CH:5][CH:6]=1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C(C)CCBr
Reactant: Cc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)CCn1c(COc2ccc(Cl)cc2)nc2c(C)cccc21
Temperature: 25 °C
Yield: 109.2 %

Procedure:
A sodium hydride solution (60% in oil, 810 mg, 20.3 mmol) was washed with hexanes (2×50 ml) and then diluted with N,N-dimethylformamide (100 ml). At room temperature, under a nitrogen atmosphere, 2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (5 g, 18.3 mmol) was then added in one portion. The resulting mixture was then stirred at room temperature for thirty minutes, and then 3-(ethoxycarbonyl)butyl bromide (4.25 g, 20.3 mmol) in N,N-dimethylformamide (10 ml) was added dropwise. Upon completion of this addition, the reaction mixture was stirred for about six hours at a temperature of 70-80° C. The reaction mixture was then cooled to room temperature, poured into water (500 ml), and then extracted with ethyl acetate (500 ml). The organic fraction was washed once with water (500 ml) and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 8.01 grams of a dark oil. The crude material was further purified by flash silica gel chromatography, eluting with a gradient solvent of methylene chloride to 3:1 methylene chloride:ethyl acetate. The fractions containing the desired title product were combined and concentrated in vacuo to yield 7.21 grams (98%) of a viscous yellow oil.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](O)(=[O:22])[CH2:18][C:19](O)=[O:20]>C(OC(=O)C)(=O)C>[C:11]1([N:10]2[C:19](=[O:20])[CH2:18][C:17](=[O:22])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]2=[O:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=C(Nc1ccccc1)Nc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(=O)N(c2ccccc2)C(=O)N1c1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
Acetic anhydride (290 ml) was added to 1,3-diphenylurea 18 (148 g), malonic acid 4 (81.6 g) was added under a nitrogen atmosphere, and the mixture was stirred at 90° C. for 3 hrs. The mixture was stirred at 100° C. for 1.5 hrs and allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure. Ethanol (500 ml) was added to the residue, and the mixture was stirred at 90° C. When the mixture was cooled to 40° C., the crystals were collected by filtration, washed with ethanol and dried to give 1,3-diphenyl-pyrimidine-2,4,6-trione 19 (78.0 g, yield 40%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C@:13]([CH3:19])([C:16](O)=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[N:35]1C=CC=CC=1.[NH4+].[OH-].O>C(OCC)(=O)C.O>[C:16]([C@@:13]1([CH3:19])[CH2:14][CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)(=[O:17])[NH2:35]
Reactant: C[C@]1(C(=O)O)CCN(C(=O)OCc2ccccc2)C1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@]1(C(N)=O)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a mixture of (S)-1-(benzyloxycarbonyl)-3-methylpyrrolidine-3-carboxylic acid (32.87 g, 124.8 mmol), Boc2O (29.97 g, 137.3 mmol) in ethyl acetate (200 mL) was added pyridine (12.62 mL, 156.1 mmol) and the reaction mixture was stirred at ambient temperature for 3 hours. A solution of 28-30% w/w NH4OH/water (21.79 mL, 162.3 mmol) was added. The reaction was stirred at ambient temperature for 5 hours. Water (50 mL) was added. The organic layer was separated, washed with 1N HCl (50 mL) and brine, dried and concentrated under reduced pressure to give (S)-benzyl 3-carbamoyl-3-methylpyrrolidine-1-carboxylate (31.30 g, 119.3 mmol, 95.6% yield) as an oil.
Reaction SMILES: Br[C:2](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:27]([O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)[CH3:28].O>C1(C)C=CC=CC=1.C(O)C.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>[CH2:27]([O:29][C:30]1[CH:35]=[C:34]([C:5]2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=[C:3]([CH:2]=[C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12]3=[O:20])[CH:4]=2)[CH:33]=[CH:32][CH:31]=1)[CH3:28]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: COc1ccc(C(Br)=C2C(=O)Nc3ccccc32)cc1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOc1cccc(-c2cc(C=C3C(=O)Nc4ccccc43)ccc2OC)c1
Reaction time: 12 h
Yield: 397.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) was added to a solution of 3-(bromo-4-methoxy-benzylidene)-1,3-dihydroindol-2-one (0.2 g, 0.61 mmol) in toluene (1 ml) and ethanol (1 ml), followed by addition of 2M aqueous sodium carbonate (1.2 ml, 2.4 mmol). To this mixture was added 3-ethoxyphenylboronic acid (0.11 g, 0.67 mmol), and the mixture was held at 100° C. in a sealed tube for 12 hours. The reaction mixture was added to water (40 ml) and extracted with ethyl acetate (75 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate and concentrated. The resulting solid was triturated with dichloromethane/hexanes to afford 0.9 g (39%) of 3-(3′-ethoxy-6-methoxy-biphenyl-3-ylmethylene)-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][N:46]=[C:45]([CH3:49])[CH:44]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:50][C:37]1[CH:38]=[C:39]([C:43]2[CH:48]=[CH:47][N:46]=[C:45]([CH3:49])[CH:44]=2)[CH:40]=[C:41]([CH3:42])[C:36]=1[C:19]1[CH:20]=[CH:21][C:22]([F:24])=[C:23]2[C:18]=1[CH2:17][CH2:16][C@H:15]2[O:14][C:12]1[CH:11]=[CH:10][C:9]2[C@H:5]([CH2:4][C:3]([OH:34])=[O:2])[CH2:6][O:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cc(C)c(Br)c(C)c2)ccn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: Cc1cc(-c2cc(C)c(-c3ccc(F)c4c3CC[C@H]4Oc3ccc4c(c3)OC[C@H]4CC(=O)O)c(C)c2)ccn1

Procedure:
The methyl ester of the title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(4-bromo-3,5-dimethyl-phenyl)-2-methyl-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. Saponification of the methyl ester following a procedure analogous to that described for Example 4 gives the title compound; if the title compound does not precipitate from the aqueous solution, the crude title compound is purified by HPLC. LC (method 9): tR=0.95 min; Mass spectrum (ESI+): m/z=524 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([NH:26][S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH:9]=1.ClCCl.[OH-].[NH4+:36]>C(OCC)(=O)C.CN(C)C=O>[Br:7][C:8]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])=[CH:15][C:11]([C:12]([NH2:36])=[O:13])=[C:10]([NH:26][S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH:9]=1
Reactant: [NH4+]
Reactant: CCS(=O)(=O)Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
Oxalyl chloride (0.046 mL, 0.54 mmol) was added dropwise to a suspension of Example 324d (214 mg, 0.49 mmol) and dichloromethane (2.2 mL). 1 Drop dimethylformamide was added and the reaction mixture was stirred at ambient temperature for 2 hours. The solvent was evaporated and the residue was dried (in-vacuo). The resulting acid chloride was suspended in tetrahydrofuran (1.0 mL) and was cooled to 0° C. as ammonium hydroxide (0.65 mL, 4.7 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours. Ethyl acetate was added and the solution was washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 1-8% methanol/dichloromethane gradient) to afford the title compound (176 mg, 82% yield).
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[O:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=2[OH:35])[CH2:24][CH2:23]1>C(#N)C>[F:21][C:32]1[CH:33]=[C:28]([CH:25]2[CH2:24][CH2:23][O:22][CH2:27][CH2:26]2)[C:29]([OH:35])=[CH:30][C:31]=1[OH:34]
Reactant: Oc1ccc(C2CCOCC2)c(O)c1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: Oc1cc(O)c(C2CCOCC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.2 %

Procedure:
3.65 g of N-fluoro-N′-(chloromethyl)triethylenediamine bis(tetrafluoroborate) are added to a solution of 2 g of 4-(tetrahydropyran-4-yl)benzene-1,3-diol (Example 1) in 20 ml of acetonitrile at 0° C. The reaction mixture is stirred for 16 hours at ambient temperature. The reaction mixture is extracted with ethyl acetate, and the organic phases are washed and then dried over sodium sulphate. The residue is chromatographed on silica gel (9/1 heptane/ethyl acetate). 200 mg of 4-fluoro-6-(tetrahydropyran-4-yl)benzene-1,3-diol are obtained. Yield=10%.