Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([NH:12][C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:9]=[CH:8][N:7]=1.C=O.[C:22](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([CH3:22])[CH2:14]2)[N:9]=[CH:8][N:7]=1
Reactant: CC(C)(C)CCNc1cc(N[C@@H]2CCNC2)ncn1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC[C@@H](Nc2cc(NCCC(C)(C)C)ncn2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35 %

Procedure:
A suspension of the compound of example 7 (38 mg, 0.144 mmol) in THF (1.5 mL) containing aqueous formaldehyde (11 μL, 0.144 mmol, 37% in water) and acetic acid (8.3 μL, 0.144 mmol) was treated with sodium triacetoxyborohydride (37 mg, 0.173 mmol) and stirred at ambient temperature for 10 min. The reaction mixture was applied directly to SCX resin, eluting non-basic compounds with MeOH and the basic compounds with 1 N ammonia in MeOH. The basic washings were concentrated in vacuo and purified by flash column chromatography on silica gel eluting with DCM:MeOH:0.880 ammonia (1:0:0 changing to 40:10:1, by volume) further purification on reverse phase silica eluting with water:acetonitrile (1:0 changing to 19:1 by volume) gave the title compound as a white solid (14 mg, 35%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:10][CH:11]=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C.C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1>>[OH:10][C:11]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Nc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccccc2c1O

Procedure:
In step 1 of sequence A, an aniline, substituted by the appropriate R2 group or groups, is condensed with a dialkyl alkoxymethylenemalonate such as diethyl ethoxymethylenemalonate by heating at 120° to 150°C. The intermediate formed is condensed by heating at a temperature of 150° to 300°C. in a high boiling inert solvent such as diphenyl ether or mixtures of diphenyl ether and biphenyl (e.g. Dowtherm A) to give the ethyl 4-hydroxyquinoline-3-carboxylate product of step 1.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[C:14](=[O:15])[CH:8]([CH2:9][S:10][CH2:11]2)[CH2:7]1)=[O:5])C.O.[OH-].[Na+]>C1COCC1>[O:15]=[C:14]1[CH:8]2[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:13][CH:12]1[CH2:11][S:10][CH2:9]2
Reactant: CCOC(=O)C1CC2CSCC(C1)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CC2CSCC(C1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
To a solution of 9-oxo-3-thia-bicyclo[3.3.1]nonane-7-carboxylic acid ethyl ester (5 g, 22 mmol) in a THF (55 ml)/water (30 ml) mixture at 0° C. was added dropwise a 1N sodium hydroxide solution (24 ml, 24 mmol). The reaction mixture was stirred at room temperature overnight, then heated to 60° C. for 1 hour before THF was evaporated. The remaining aqueous layer was washed with ethyl acetate, acidified with 1N HCl, the resulting precipitate was filtered and dried to yield 9-oxo-3-thia-bicyclo[3.3.1]nonane-7-carboxylic acid (2.22 g) as a solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C[Al](C)C.[Cl:14][C:15]1[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([CH:22]2[CH2:24][CH:23]2[C:25](OCC)=O)[CH:16]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([C@@H:22]2[CH2:24][C@H:23]2[C:25]2[N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:9]=2)[CH:16]=1
Reactant: CCOC(=O)C1CC1c1cc(Cl)nc(C)n1
Reactant: CNc1ccccc1N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N1-methylbenzene-1,2-diamine (5.08 g, 41.5 mmol) in toluene (100 mL) was added a 2M solution of trimethylaluminum (22.85 ml, 45.7 mmol) in toluene dropwise over 2 h with periodic cooling in an ice bath to prevent an exotherm. After addition was complete, the resulting dark brown mixture was warmed to room temperature and stirred for 15 min. The mixture was re-cooled in an ice bath and a solution of 6-3 (5 g, 20.8 mmol) in toluene (20 mL) was added drop-wise over 2 h, after which the reaction was warmed to room temperature. After stirring for 18 h, the reaction was cooled in an ice bath and slowly quenched with water. The mixture was filtered through a pad of celite washing with ethyl acetate. The filtrate was repeatedly washed with saturated copper (II) sulfate solution until a yellow orange organic layer was obtained and no N1-methylbenzene-1,2-diamine was observed by LCMS. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product which was purified by silica gel chromatography (0-100% EtOAc/hexanes) to afford racemic 6-4. The racemic compound was further purified by preparative chiral SFC on a ChiralCel OJ-H column (3 cm id×25 cm length) eluting with 70% carbon dioxide/30% methanol with 0.1% triethylamine modifier in isocratic mode at 80 mL/min. The first eluting peak was identified as the desired R,R enantiomer (6-4) and was used in subsequent steps. 1H NMR (400 MHz, CDCl3) δ 7.71-7.66 (m, 1H), 7.31-7.23 (m, 3H), 7.19 (s, 1H), 3.83 (s, 3H), 2.86-2.79 (m, 2H), 2.67 (s, 3H), 1.96 (m, 2H); MS: m/z=299.2 (M+H).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH3:17][S:18][C:19]1[CH:20]=[C:21]([NH:25][CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([OH:29])=[O:28])[CH:22]=[CH:23][CH:24]=1.C1C=CC2N(O)N=NC=2C=1.[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48]([O:28][C:27](=[O:29])[CH:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([S:18][CH3:17])[CH:20]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:47]2
Reactant: CSc1cccc(NC(C(=O)O)c2ccccc2)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CSc1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
PS-DCC (602 mg, 0.80 mmol, loading: 1.33 mmol/g) is suspended in dry THF (15 mL). (3-Methylsulfanyl-phenylamino)-phenyl-acetic acid hydrochloride (I51) (124 mg, 0.40 mmol), HOBT (123 mg, 0.80 mmol), and (R)-quinuclidin-3-ol (153 mg, 1.20 mmol) are added and the suspension is shaken at RT overnight (16 hours). PS-DCC is filtered off, washed with THF and the filtrate is evaporated. The resulting residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer is recovered, dried over Na2SO4, filtered and evaporated to afford the title compound as a brown oil (153 mg, quantitative yield, mixture of diastereoisomers).
Reaction SMILES: [CH:1]1([O:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:5]C=C[CH2:2]1.C[N+]1([O-])CCOCC1.[O:26]1[CH2:31][CH2:30][O:29]CC1.O>O=[Os](=O)(=O)=O>[OH:26][C@H:31]1[C@@H:30]([OH:29])[CH2:2][CH:1]([O:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:5]1
Reactant: O=C1c2ccccc2C(=O)N1OC1CC=CC1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OC1C[C@@H](O)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
To a solution of 2-(cyclopent-3-enyloxy)isoindoline-1,3-dione (736 mg, 3.2 mmol) in dioxane —H2O (5.0 mL, 4:1) was added NMO (421 mg, 3.60 mmol) and OsO4 (1.0 mL mg, 0.32 mmol, 2.5 wt % in H2O) and the reaction mixture was stirred for 24 h at rt. Quenched with 10% aqueous Na2S2O3 solution and extracted with ethyl acetate. The combined organic layers washed with brine and dried over anhydrous Na2SO4. Filtered and concentrated to provide yellow oil, which was purified by flash chromatography (80% EtOAc-hexane) to yield 2-((3R,4S)-3,4-dihydroxycyclopentyloxy)isoindoline-1,3-dione (650 mg, 77%) as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.94-2.12 (m, 2H) 2.14-2.35 (m, 2H) 4.22-4.88 (m, 2H) 4.75-5.11 (m, 1H) 7.67-7.78 (m, 2H) 7.79-7.86 (m, 2H). MS (ES) [M+H] calculated for C13H14NO5, 264.08. found 264.20.
Reaction SMILES: [C:1]([C:3]1[CH:9]([C:10]#[N:11])[NH:8][C:7]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:5]([CH3:19])[N:4]=1)#[N:2].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.N1CCCCC1>>[C:1]([C:3]1[N:4]=[C:5]([CH3:19])[C:6](=[CH:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[C:7]([OH:18])([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:8][C:9]=1[C:10]#[N:11])#[N:2]
Reactant: CC1=CC(O)(c2ccccc2)NC(C#N)C(C#N)=N1
Reactant: COc1ccc(C=O)cc1
Solvent: C1CCNCC1
Product: COc1ccc(C=C2C(C)=NC(C#N)=C(C#N)NC2(O)c2ccccc2)cc1

Procedure:
In the presence of a catalytic amount of HCl (4N=4 mol/l), 1 mol of diaminomaleonitrile was reacted with 1 mol of benzoylacetone in a solvent (benzene) at 45° C. for 6 hours to give 2,3-dicyano-5-hydroxy-5-phenyl-7-methyl-4H-1,4-diazepine (compound 1a). The diazepine compound (1a) thus obtained was reacted with 4-methoxybenzaldehyde in the presence of piperidine to give the object compound 2,3-dicyano-5-hydroxy-5-phenyl-6-(4-methoxyphenylmethylidene)-7-methyl-4H-1,4-diazepine (compound 1).
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]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.[C:53]([O:57][C:58]([N:60]1[C:64]([CH3:66])([CH3:65])[CH2:63][CH2:62][C@H:61]1[C@H:67]([C:71]1[CH:76]=[CH:75][CH:74]=[C:73]([Cl:77])[CH:72]=1)[C:68](O)=[O:69])=[O:59])([CH3:56])([CH3:55])[CH3:54]>C(Cl)Cl>[Cl:77][C:73]1[CH:72]=[C:71]([C@@H:67]([C@H:61]2[N:60]([C:58]([O:57][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:59])[C:64]([CH3:66])([CH3:65])[CH2:63][CH2:62]2)[C:68]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:69])[CH:76]=[CH:75][CH:74]=1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2cccc(Cl)c2)CCC1(C)C
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4cccc(Cl)c4)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
(5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.0661 g, 0.215 mmol), HATU (0.0744 g, 0.196 mmol), and DIEA (d 0.742; 0.0341 mL, 0.196 mmol) were added to a solution of (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(3-chlorophenyl)acetic acid (0.072 g, 0.196 mmol, see Example B, Step 3) in DCM (25 mL). The reaction was stirred overnight at room temperature. The reaction was partitioned between water (20 mL) and DCM (50 mL), and the layers were separated. The organics were washed with water (2×10 mL). The aqueous portion was back extracted with DCM (25 mL), dried (MgSO4), concentrated to an oil and purified by flash chromatography (5% MeOH/DCM) to give (S)-tert-butyl 5-((S)-1-(3-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.090 g, 0.154 mmol, 78.7% yield). LC/MS=3.79 minutes, (APCI+) m/z=584 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[S:28]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=1)([CH3:27])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)CCc1ccc(CCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1ccc(CCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
With a 4.82 g (18.3 mmols) portion of t-butyl 3-[4-(3-hydroxypropyl)phenyl]propionate were admixed 5.09 ml (36.6 mmols) of triethylamine, 2.84 ml (36.6 mmols) of methanesulfonyl chloride and 50 ml of methylene chloride. The mixture was stirred at room temperature for 12 hours, concentrated and then diluted with benzene. The benzene layer was washed with saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated, giving 6.29 g (yield 100%) of t-butyl 3-[4-(3-mesyloxypropyl)phenyl]propionate in the form of an oil. This product was used for the subsequent reaction without purification.
Reaction SMILES: [C:1](=[N:4][C:5]1[C:10]([CH2:11][CH3:12])=[CH:9][C:8]([CH2:13][C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[C:17]([N:22]=[C:23]([CH3:25])[CH3:24])=[C:16]([CH2:26][CH3:27])[CH:15]=2)=[CH:7][C:6]=1[CH2:28][CH3:29])([CH3:3])[CH3:2].C(O)C>[Pt].C(OCC)(=O)C>[CH:23]([NH:22][C:17]1[C:16]([CH2:26][CH3:27])=[CH:15][C:14]([CH2:13][C:8]2[CH:7]=[C:6]([CH2:28][CH3:29])[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[C:10]([CH2:11][CH3:12])[CH:9]=2)=[CH:19][C:18]=1[CH2:20][CH3:21])([CH3:24])[CH3:25]
Reactant: CCc1cc(Cc2cc(CC)c(N=C(C)C)c(CC)c2)cc(CC)c1N=C(C)C
Agent: [Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cc(Cc2cc(CC)c(NC(C)C)c(CC)c2)cc(CC)c1NC(C)C
Reaction time: 1.2 h
Yield: 70 %

Procedure:
N,N′-diisopropylidene-4,4′-methylenebis(2,6-diethylbenzeneamine) (2.6 g) and Pt(S)/C (0.35 g) were added to a mixture of ethanol (20 g) and ethyl acetate (20 g) in an autoclave. The closed autoclave was purged 3 times with 125 psig (9.63×105 Pa) of H2 at 22° C. to remove traces of air. The mixture was kept at 22° C. and 0-125 psi (0 to 8.62×105 Pa) of H2 for 1.2 hours, forming the corresponding N,N′-diisopropyl-4,4′-methylenebis(2,6-diethylbenzeneamine) in 70% yield, with 25% of the diimine underhydrogenated. Conversion of the diimine was 95%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH2:12][CH3:13])=[CH:5][C:4]=1B(O)O)[CH3:2].FC(F)(F)S(O[C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:32])[CH2:30][CH3:31])=[CH:25][C:24]=1[CH2:33][CH3:34])(=O)=O>>[CH2:12]([O:11][CH2:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:32])[CH2:30][CH3:31])=[CH:25][C:24]=2[CH2:33][CH3:34])[CH:5]=1)[CH3:13]
Reactant: CCOCOc1ccc(CC)c(B(O)O)c1
Reactant: CCC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(CC)c1
Product: CCOCOc1ccc(CC)c(-c2ccc(C(=O)CC)cc2CC)c1

Procedure:
In a manner similar to that of Example 1(g), by reacting 2 g (8.9 mmol) of 2-ethyl-5-ethoxymethoxyphenylboronic acid with 2.1 g (6.9 mmol) of 2-ethyl-4-propionylphenyl 1,1,1-trifluoromethanesulfonate, a black oil is obtained, which is used without further purification for the rest of the synthesis.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>ClC(Cl)Cl>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:2][CH2:3]1
Reactant: CCOC(=O)Cl
Reactant: OCC1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(CO)CC1
Reaction time: 2 h
Yield: 70 %

Procedure:
To a stirred mixture of 67 parts of 4-piperidinemethanol, 61 parts of N,N-diethylethanamine and 750 parts of trichloromethane there were added dropwise 64.5 parts of ethyl chloroformate. Stirring was continued for 2 hours at reflux temperature. After cooling, the reaction mixture was washed with water, dried, filtered and evaporated, yielding 75 parts (70%) of ethyl 4-(hydroxymethyl)-1-piperidinecarboxylate (interm. 50).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][CH2:9][C:10]2[CH:11]=[C:12]3[CH:18]=[C:17]([C:19]([OH:21])=O)[O:16][C:13]3=[N:14][CH:15]=2)=[CH:5][CH:4]=1.[Br:24][C:25]1[C:26]([NH2:31])=[N:27][CH:28]=[CH:29][CH:30]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.CN(C)C(Cl)=[N+](C)C>CN(C=O)C>[Br:24][C:25]1[C:26]([NH:31][C:19]([C:17]2[O:16][C:13]3=[N:14][CH:15]=[C:10]([CH2:9][O:8][CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=4)[CH:11]=[C:12]3[CH:18]=2)=[O:21])=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ncccc1Br
Reactant: COc1ccc(COCc2cnc3oc(C(=O)O)cc3c2)cc1
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc(COCc2cnc3oc(C(=O)Nc4ncccc4Br)cc3c2)cc1
Temperature: 70 °C

Procedure:
In an oven-dried sealed tube, a mixture of 5-(((4-methoxybenzyl)-oxy)methyl)furo[2,3-b]pyridine-2-carboxylic acid (2.0 g, 6.4 mmol), 3-bromo-2-amino pyridine (3.31 g, 19.2 mmol), N-methyl morpholine (1.93 g, 19.2 mmol) and N,N,N′,N′-tetramethylchloroformamidinium hexafluorophosphate (3.58 g, 12.8 mmol) in DMF (20 mL) was heated to 70° C. for 5 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 40% ethyl acetate in petroleum ether to give the title compound. MS: m/z=468.5 (M+1).
Reaction SMILES: [CH:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])=[O:21])=[N:18][CH:19]=1)=O.[Cl:30][C:31]1[CH:36]=[C:35]([NH2:37])[CH:34]=[CH:33][C:32]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1.C(C1C(OC)=CC(C(F)(F)F)=CC=1C1C=CC(C(NCCC(OCC)=O)=O)=NC=1)=O.ClC1C=C(N)C=CC=1C1C=CC(C(F)(F)F)=CC=1>>[Cl:30][C:31]1[CH:36]=[C:35]([NH:37][CH2:1][C:3]2[C:8]([OH:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=2[C:14]2[CH:15]=[CH:16][C:17]([C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:21])=[N:18][CH:19]=2)[CH:34]=[CH:33][C:32]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)c(Cl)c1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(O)c2C=O)cn1
Agent: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(OC)c2C=O)cn1
Agent: Nc1ccc(-c2ccc(C(F)(F)F)cc2)c(Cl)c1
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(O)c2CNc2ccc(-c3ccc(Cl)cc3)c(Cl)c2)cn1

Procedure:
The title compound was prepared as described in Example 159 substituting ethyl 3-(5-(2-formyl-3-hydroxy-5-(trifluoromethyl)phenyl)picolinamido)propanoate and 2,4′-dichloro-[1,1′-biphenyl]-4-amine for ethyl 3-(5-(2-formyl-3-methoxy-5-(trifluoromethyl)phenyl)picolinamido)propanoate and 2-chloro-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-amine, respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10].[CH2:21](O)[CH2:22][OH:23].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C(OCC)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:21][CH2:22][OH:23])(=[O:10])=[O:11]
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(O)c1
Reactant: OCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCO)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 67.7 %

Procedure:
A solution of 3-(2-methoxyphenylsulfonyloxy)-5-methylphenol (245 mg, 0.83 mmol, prepared in step b of example 8), ethylene glycol (0.23 mL, 4.1 mmol), 1,1'-(azodicarbonyl)dipiperidine (420 mg, 1.66 mmol) and anhydrous tetrahydrofuran (6 mL) was cooled to 0° C. under nitrogen. Tri-n-butylphosphine (0.41 mL, 1.66 mmol) was added dropwise over 2.5 minutes. The mixture was stirred at 0° C. for 5 hours, then more 1,1'-(azodicarbonyl)dipiperidine (210 mg) and tri-n-butylphosphine (0.21 mL) were added. The reaction was stirred overnight at ambient temperature, then more 1,1'-(azodicarbonyl)dipiperidine (420 mg) and tri-n-butylphosphine (0.41 mL) were added. The mixture was stirred overnight at ambient temperature, then diethyl ether (50 mL) was added and the mixture was filtered. The filtrate was concentrated, and the residue was purified by flash column chromatography through silica gel (3:2 ethyl acetate/hexane) to give the title compound as a colorless oil (190 mg, 67%). 1H-NMR (300 MHz, CDCl3) δ 7.82 (dd, 1H, J=1.7, 7.9 Hz), 7.62 (ddd, 1H, J=1.8, 7.4, 8.4 Hz), 7.09 (dd, 1H, J=0.8, 8.4 Hz), 6.99-7.05 (m, 1H), 6.60-6.61 (m, 1H), 6.53-6.55 (m, 1H), 6.46-6.48 (m, 1H), 4.02 (s, 3H), 3.89-4.01 (m, 4H), 2.25 (d, 3H, J=0.6 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C16H18O6S: 361.1 (M+Na). Found: 360.6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24](=[O:30])[NH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24](=[O:30])[N:25]([C@H:11]([CH3:12])[C@:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:10])[CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[CH:26]=[N:27]2)=[CH:22][CH:21]=1
Reactant: O=c1[nH]cnc2cc(Cl)ccc12
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C[C@@H](n1cnc2cc(Cl)ccc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 80 °C

Procedure:
To a solution of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (2.46 g, 9.8 mmol, obtained as described in Tasaka et al., Chem.Pharm.Bull. 1993, 41, 1035-1042) in N-methylpyrrolidone (10 mL), 7-chloro-3H-quinazolin-4-one (1.77 g, 9.8 mol) and K2CO3 (1.35 g, 9.8 mmol) were added. The resulting solution was heated at 80° C. for 3 days. The mixture was cooled to room temperature, water was then added and the pH was adjusted to 7. The mixture was extracted with ethyl acetate (4×). The combined organic extracts were washed with water (4×), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to a reduced volume and was allowed to crystallize at 0° C. The resulting product was filtered, dried and dissolved in hot ethanol (10 mL/g). The insoluble material was filtered off, and the filtrate was then poured over cold water (120 mL/g of UR-9825) under stirring. The resulting precipitate was filtered and dried in vacuo (50° C.) to give the desired product as a white amorphous powder (3.1 g, 75%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:25])[F:26])=[CH:24][CH:23]=1
Reactant: Cc1ccccc1O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1OCc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Yield: 97.6 %

Procedure:
2-Methylphenol (12.53 g, 115.9 mmol) was dissolved in DMF (60 mL), and stirred at 0° C. To the solution was added K2CO3 (24.03 g, 173.9 mmol) and 4-trifluoromethylbenzyl bromide (23.08 g, 96.6 mmol), and the reaction was stirred at room temperature for 2 h. Water was added to the reaction, and the product was extracted with EtOAc twice. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo to give a crude residue. The crude residue was purified using silica gel column chromatography (hexane/EtOAc=30/1) to give 4.1 (25.1 g). 1H NMR (400 MHz) (CDCl3) δ 7.64 (2H, d, J=8.2 Hz); 7.56 (2H, d, J=8.2 Hz); 7.18-7.08 (2H, m); 6.90 (1H, t, J=7.2 Hz); 6.84 (1H, d, J=8.1 Hz); 5.14 (2H, s); 2.30 (3H, s).