Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:13]([O:14][CH3:15])=[CH:12][C:10]([NH2:11])=[C:9]([Cl:16])[CH:8]=1.C([Li])CCC.CN(C)[CH:24]=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[NH2:11][C:10]1[C:9]([Cl:16])=[CH:8][C:7]([CH:24]=[O:25])=[C:13]([O:14][CH3:15])[CH:12]=1
Reactant: COc1cc(N)c(Cl)cc1Br
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
Isopropylmagnesium chloride (2M in tetrahydrofuran, 23 ml, 46 mmol) (commercially available, for example, from Aldrich) was added over 5 minutes to a stirred solution of 4-bromo-2-chloro-5-methoxyaniline (Step A) (10 g, 42 mmol) in tetrahydrofuran (70 ml) at −10° C. The resulting solution was allowed to warm to 0° C. over 50 minutes to give a thick slurry, then cooled to −25° C. and n-butyllithium (1.6M in hexanes, 90 ml, 144 mmol) was added over 20 minutes followed by tetrahydrofuran (20 ml). The solution was warmed to −10° C. over 30 minutes and then N,N-dimethylformamide (16 ml, 207 mmol) was added over 5 minutes and the resulting thick slurry was warmed to 0° C. over 20 minutes. A solution of citric acid (22 g, 105 mmol) in water (50 ml) was added cautiously over 15 minutes keeping reaction at <10° C. The slurry was aged at 20° C. for 30 minutes then filtered under vacuum. The cake was washed with water (100 ml) and then dried under vacuum at 40° C. for 16 hours to give 4-amino-5-chloro-2-methoxybenzaldehyde (6.1 g, 80% th) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[NH:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].P(Cl)(Cl)(Cl)=O.CN(C)[CH:23]=[O:24]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([OH:14])=[C:12]([CH:23]=[O:24])[C:11]([CH3:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CN(C)C=O
Reactant: Cc1cc(=O)n(-c2ccc(C)c(C)c2)[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-n2nc(C)c(C=O)c2O)cc1C
Temperature: 100 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
1.86 g (9.16 mmol) of 1-(3,4-dimethylphenyl)-3-methyl-3-pyrazolin-5-one was dissolved in 3.6 ml of dry dimethylformamide, and 1.02 ml (11.0 mmol) of phosphorus oxychloride was added gradually under cooling with ice at 20° C. or below. After the addition, the mixture was heated at 100° C. for 2 hours, cooled to room temperature and poured into 30 ml of ice-cold water. Then, the mixture was washed with 10 ml of water and 10 ml of dimethylformamide. The mixed solution was stirred for 18 hours, and the precipitated solid was collected by filtration, washed with 20 ml of water and dried to obtain 1.03 g of the desired product as a pale brown solid (yield 49%).
Reaction SMILES: [CH3:1][C:2]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH2:6][OH:7])[C:3](O)=[O:4].C([O-])([O-])(OC)CC>>[CH3:1][C:2]1([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:6][O:7][C:3]1=[O:4]
Reactant: CC(C)(C)CC(C)(CO)C(=O)O
Agent: CCC([O-])([O-])OC
Product: CC(C)(C)CC1(C)COC1=O

Procedure:
The resultant 2-methyl-2-neopentyl-3-hydroxypropionic acid (2.) was then reacted conventionally with methyl orthopropionate, followed by slow heating in the presence of Amberlyst® 15, then worked up to obtained the desired final product.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([NH:17]C(=O)C1C=CC=CC=1)=[S:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[Na+].CO>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([NH2:17])=[S:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(=S)Nc1ccccc1Oc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=S)Nc1ccccc1Oc1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Thus produced 1-(2-phenoxyphenyl)-3-benzoylthiourea was dissolved in a mixture of 10% aqueous sodium hydroxide (660 ml) and methanol (530 ml) at 50° C. The reaction mixture was stirred for 30 minutes at 50° C. and then cooled with ice to give crystals, which were separated by filtration, washed with water and dried to give 1-(2-phenoxyphenyl)thiourea. mp: 120°-124° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2([C:34]([F:37])([F:36])[F:35])[O:21][N:20]=[C:19]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C:27]3([CH2:33][NH:32][CH2:31]3)[O:26][CH2:25]4)[O:18]2)[CH:12]=[C:13]([Cl:16])[C:14]=1[F:15].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:67][S:68]([CH2:71][C:72](O)=[O:73])(=[O:70])=[O:69]>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([C:17]2([C:34]([F:36])([F:37])[F:35])[O:21][N:20]=[C:19]([C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[C:27]3([CH2:33][N:32]([C:72](=[O:73])[CH2:71][S:68]([CH3:67])(=[O:70])=[O:69])[CH2:31]3)[O:26][CH2:25]4)[O:18]2)[CH:12]=[C:13]([Cl:16])[C:14]=1[F:15]
Reactant: Fc1c(Cl)cc(C2(C(F)(F)F)ON=C(c3ccc4c(c3)COC43CNC3)O2)cc1Cl
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)CC(=O)N1CC2(C1)OCc1cc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)O3)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of trifluoroacetic acid salt of 5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-1,4,2-dioxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran](Preparation 45, 0.3 g, 0.648 mmol, 1 eq) in DMF (5 mL) was added triethyl amine (0.727 mL, 5.181mmol, 8 eq), followed by addition of EDC.HCl (0.185 g, 0.971 mmol, 1.5 eq), HOBt (0.087 g, 0.648 mmol, 1 eq) and methane sulfonyl acetic acid (0.178 g, 1.295 mmol, 2 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched by water (50 mL) and extracted with ethyl acetate (3×30 mL). Combined organic phase was washed with saturated solution of LiCl solution (30 mL), brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown thick oil (0.48 g, crude). Crude was purified by combiflash using 40 g Redisep column. Desired compound was eluted in 52% ethyl acetate in hexane to afford title compound as off white solid (0.228 g, 60.35%). 1H NMR (400 MHz, CDCl3) δ: 3.19 (s, 3H), 3.86 (s, 2H), 4.35 (d, J=11.16 Hz, 1H), 4.45 (d, J=11.16 Hz, 1H), 4.67 (t, J=10.72 Hz, 2H), 5.19 (s, 2H), 7.63-7.66 (m, 3H), 7.70 (s, 1H), 7.89 (d, J=8.08 Hz, 1H). (m/z): 580.9 (M−H), HPLC Purity: 95.78%.
Reaction SMILES: CI.[CH2:3]([C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([N+:13]([O-:15])=[O:14])[C:7]=1[OH:16])[CH:4]=[CH2:5].[C:17](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:3]([C:6]1[C:7]([O:16][CH3:17])=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][C:11]=1[F:12])[CH:4]=[CH2:5]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(F)ccc([N+](=O)[O-])c1O
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: C=CCc1c(F)ccc([N+](=O)[O-])c1OC
Yield: 75.8 %

Procedure:
Methyl iodide (5.3 g, 37.9 mmol, 5 eq) was added to a solution of 2-allyl-3-fluoro-6-nitro-phenol (1.5 g, 7.5 mmol) and potassium carbonate (2.1 g, 15.1 mmol, 2 eq) in anhydrous acetonitrile (20 ml) and the reaction mixture was heated to reflux for 6 hr. The reaction mixture was filtered and washed with acetonitrile and the filtrate was concentrated to dryness to yield 2-allyl-1-fluoro-3-methoxy-4-nitro-benzene (1.2 g, 75%). The crude compound was used in the next stage without purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@H:16]3[C@@H:20]4[O:21]C(C)(C)[O:23][C@@H:19]4[C@@H:18]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH2:17]3)=[C:9]([NH:31][CH2:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:8]=2)[CH2:3]1.[CH:46]1[N:50]=[CH:49][N:48]([C:51](N2C=NC=C2)=[O:52])[CH:47]=1>C(Cl)Cl>[OH:21][C@@H:20]1[C@H:19]([OH:23])[C@@H:18]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH2:17][C@H:16]1[N:13]1[CH:12]=[N:11][C:10]2[C:14]1=[N:15][C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([NH:1][C:51]([N:48]3[CH:47]=[CH:46][N:50]=[CH:49]3)=[O:52])[CH2:3]1)=[N:8][C:9]=2[NH:31][CH2:32][CH:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Solvent: ClCCl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)n5ccnc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
A mixture comprising N-{(3aR,4S,6R,6aS)-6-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-4-yl}-propionamide (Intermediate M) (0.24 g, 394 μmol) and CDI (0.275 g, 1.7 mmol) in dry DCM (6 ml) is stirred at room temperature for 3 hours. The resulting solution is purified by chromatography on silica eluting with 100% DCM changing to 5% MeOH in DCM to afford the title compound as a yellow oil. The oil consists of the imidazole-urea intermediate together with variable amounts of the corresponding isocyanate and imidazole which are equally suitable as precursors to ureas.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>C(#N)C.CO>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[C:7]1([S:4]([CH2:3][CH2:2][NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(CCCl)c1ccccc1
Reactant: NCCN1CCCCC1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=S(=O)(CCNCCN1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.78 %

Procedure:
A mixture of 40.94 g (0.20 mole) of [(2-chloroethyl)sulfonyl]benzene, 27.85 g (0.217 mole) of N-(2-aminoethyl)piperidine and 28.0 g (0.277 mole) of triethylamine in 800 ml of acetonitrile was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was dissolved in methanol, a solution of 2 equivalents of maleic acid in methanol was added, and the product crystallized from the solution at room temperatue to give 64.35 g (60.78%) of title compound as a white crystalline solid, mp 154°-155.5° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]1[C:22]([C:23]#[N:24])=[C:21](CBr)[NH:20][C:19]2=[N:27][NH:28][CH:29]=[C:18]12.O.[CH3:31]N(C=O)C>>[ClH:10].[ClH:10].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]1[C:22]([C:23]#[N:24])=[C:21]([CH2:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][CH:5]2[CH3:31])[NH:20][C:19]2=[N:27][NH:28][CH:29]=[C:18]12
Reactant: N#CC1=C(CBr)Nc2n[nH]cc2C1c1ccccc1Cl
Reactant: CN1CCNCC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC1CNCCN1CC1=C(C#N)C(c2ccccc2Cl)c2c[nH]nc2N1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(2-Chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)-methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine was prepared from ethyl t-butyldimethylsilyloxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. To a solution of 4-(2-chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (10 g) in tetrahydrofuran (100 ml) was added a THF solution (24.9 ml) of 1.0 M tetrabutylammonium fluoride and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate (200 ml), and the resulting mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (5.46 g) as a white solid. To a solution of 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (1.0 g) and carbon tetrabromide (1.27 g) in methylene chloride (35 ml) was added triphenylphosphine (1.0 g) under ice-cooling and the mixture was stirred under ice-cooling for 4 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.45 g) as a pale-yellow solid. To a suspension of sodium hydride (25 mg) in DMF (3 ml) was added 1-methylpiperazine (69 μl) and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added a solution of 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (200 mg) in DMF (3 ml) under ice-cooling and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:ethyl acetate-methanol (4:1)). The obtained oil was treated with hydrogen chloride-methanol to give the title compound (87 mg) as white crystals.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Cl:16]N1C(=O)CCC1=O.O>CN(C=O)C>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][C:14]=2[Cl:16])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: [N-]=[N+]=Nc1ccc(-c2csc(N)n2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(-c2nc(N)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-azidophenyl)thiazol-2-amine (1.18 g, 5.43 mmol) in DMF (18 mL) at 0° C. was added 1-chloropyrrolidine-2,5-dione (0.746 g, 5.59 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was poured into water (100 mL). The precipitate that formed was collected by filtration, washed with water, and dried under high vacuum to give 4-(4-azidophenyl)-5-chlorothiazol-2-amine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[S:18][C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:16][CH:15]=1)CCC.C(Cl)Cl.C1(C)C=CC=CC=1>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.O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:14]2[S:18][C:17]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:16][CH:15]=2)[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(-c2cccnc2)s1
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cnc(-c3cccnc3)s2)n1
Temperature: 110 °C
Reaction time: 36 h
Yield: 34.8 %

Procedure:
A sealed tube was charged with 2,6-dibromopyridine (269 mg, 1.13 mmol), 3-(5-tributylstannanyl-thiazol-2-yl)-pyridine (511 mg, 1.13 mmol), Pd(PPh3)4 (131 mg, 0.11 mmol), [1,1-Bis(diphenylphosphino)ferrocene]palladium(II) chloride. CH2Cl2 (20 mg, 0.024 mmol) and anhydrous and degassed toluene (5 ml) and heated to 110° C. with stirring for 36 h. The cooled reaction mixture was treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2 using combiflash Companion®, eluting with cyclohexane/ethyl acetate to afford the title compound as a white solid (125 mg, 35%). 1H NMR (DMSO-d6, 300 MHz): δ=9.21 (d, J=1.7 Hz, 1H), 8.72 (s, 1H), 8.70 (m, 1H), 8.39 (m, 1H), 8.14 (d, J=7.8 Hz, 1H), 7.88 (dd, J=8.0; 7.8 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.57 (m, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33](=[O:35])[CH3:34])=[N:31][CH:32]=2)=[CH:23][CH:22]=1>C1COCC1>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)([OH:35])[CH3:34])=[N:31][CH:32]=2)=[CH:25][CH:26]=1
Reactant: Ic1ccncc1
Reactant: COc1ccc(-c2ccc(C(C)=O)nc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(-c2ccc(C(C)(O)c3ccncc3)nc2)cc1
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To cooled (−78° C.) 4-iodopyridine (270 mg, 1.3 mmol) [Albrecht, et al., US Patent Application Publication No. 2009/0318436] in THF (15 mL) was added slowly 1.6 M n-BuLi in hexane (1.65 mL, 2.6 mmol). Stirring was continued for an additional 30 minutes at the same temperature, followed by the addition of a THF (5 mL) solution of 1-(5-(4-methoxyphenyl)pyridin-2-yl)ethanone (300 mg, 1.3 mmol). After stirring for 2 hours at the same temperature, the reaction mixture was quenched with saturated aqueous NH4Cl solution (10 mL). The aqueous layer was extracted with ethylacetate (2×150 mL). The combined organic layers were washed with brine (20 mL). Finally, the organic phase was dried over Na2SO4 and concentrated under reduced pressure to give crude product. The crude product was purified by flash chromatography (silica gel 60-120μ) using 20% ethyl acetate and hexane as eluent to afford racemic 1-(5-(4-methoxyphenyl)pyridin-2-yl)-1-(pyridin-4-yl)ethanol as an off-white solid (135 mg, 33% yield) in 99.6% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.74 (d, 1H), 8.45 (dd, 2H), 7.98 (dd, 1H), 7.68 (d, 1H), 7.62 (d, 2H), 7.48 (dd, 2H), 7.02 (d, 2H), 6.15 (s, 1H), 3.78 (s, 3H), 1.88 (s, 3H); LC-MS m/z calculated for [M+H]+ 307.14. found 307.3.
Reaction SMILES: C(#N)C.[NH2:4][C:5]1[CH:6]=[C:7]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:24])=[C:20](Cl)[N:21]=3)[C:16](=[O:25])[C:15]([C:26]([OH:28])=[O:27])=[CH:14]2)[C:8]([F:12])=[CH:9][C:10]=1[F:11].Cl.Cl.[NH2:31][CH:32]1[CH2:35][NH:34][CH2:33]1>C(N(CC)CC)C>[NH2:31][CH:32]1[CH2:35][N:34]([C:20]2[N:21]=[C:22]3[C:17]([C:16](=[O:25])[C:15]([C:26]([OH:28])=[O:27])=[CH:14][N:13]3[C:7]3[C:8]([F:12])=[CH:9][C:10]([F:11])=[C:5]([NH2:4])[CH:6]=3)=[CH:18][C:19]=2[F:24])[CH2:33]1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1F
Reactant: NC1CNC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)nc32)c(F)cc1F
Temperature: 80 °C
Reaction time: 15 h
Yield: 91.2 %

Procedure:
To 200 ml of acetonitrile were added 3.7 g of 1-(3-amino-4,6-difluorophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 2.18 g of 3-aminoazetidine dihydrochloride, and 6.06 g of triethylamine. The solution was stirred at 80° C. for 15 hours. The reaction solution was cooled whereupon the precipitated solid was collected by filtration and washed with ethanol and isopropyl ether to give 3.7 g of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.C1COCC1.[Pd]>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH:16]=1
Reactant: c1ccc(COc2ccc(-c3cccnc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1ccc(-c2cccnc2)cc1
Yield: 92.9 %

Procedure:
3-(4-Benzyloxy-phenyl)-pyridine (1.15 g, 4.4 mmol) in EtOH/THF (10 mL/25 mL) was treated with 10% Pd on carbon (1.5 g) over period of 48 h at rt under H 2 balloon. Reaction mixture was filtered through Celite and concentrated to obtain the product (700 mg, 93%).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[N:26][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:36])=[CH:28][CH:29]=3)[S:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH3:37])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[N:26]=[CH:25][C:24]([C:20]2[S:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:6]([OH:38])=[O:5])=[C:10]([CH3:37])[CH:11]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: Cc1cc(OCCc2nc(-c3ccc(-c4ccccc4F)nc3)sc2C)ccc1CCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1cc(OCCc2nc(-c3ccc(-c4ccccc4F)nc3)sc2C)ccc1CCC(=O)O
Reaction time: 2 h

Procedure:
To a solution of 3-[4-(2-{2-[6-(2-Fluoro-phenyl)-pyridin-3-yl]-5-methyl-thiazol-4-yl}-ethoxy)-2-methyl-phenyl]-propionic acid tert-butyl ester (130 mg) in methylene chloride (1 mL) is added TFA (0.8 mL) and two drops of water. The mixture is stirred for 2 h, and concentrated and purified by reversed phase HPLC (water-acetonitrile with 0.1% TFA) yield 120 mg of product. MS (ES): 477.2(M++1).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])(=[O:5])[CH3:4].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>C(OCC)(=O)C.CN(C)C=O>[CH2:23]([N:6]([C:7]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])[C:3](=[O:5])[CH3:4])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)Nc1cc(Oc2ccccc2)ccc1C(=O)O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1ccccc1)c1cc(Oc2ccccc2)ccc1C(=O)O
Reaction time: 0.5 h

Procedure:
60% Sodium hydride 30 mg was added to N,N-dimethylformamide 2.0 mL solution of 2-(acetamido)-4-phenoxybenzoic acid 0.10 g at room temperature, and it was stirred at same temperature for 30 minutes. Benzyl bromide 0.092 mL was added to the reaction mixture at room temperature, and it was stirred at same temperature for 2 hours and 30 minutes. 60% Sodium hydride 15 mg was added to the reaction mixture at room temperature, and it was stirred at same temperature for 30 minutes. Benzyl bromide 0.022 mL was added to the reaction mixture at room temperature, and it was stirred at same temperature for 1 hour and 30 minutes. 1.0 mol/L Hydrochloric acid and ethyl acetate were added to the reaction mixture. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate:acetic acid=40:10:1] to give 2-(N-benzylacetamido)-4-phenoxybenzoic acid 0.10 g of colorless oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:14]=1[CH:27]([CH3:29])[CH3:28])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+]>CC(O)=O>[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]([N+:1]([O-:4])=[O:2])=[CH:15][C:14]=1[CH:27]([CH3:29])[CH3:28])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc([N+](=O)[O-])c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 75 °C
Yield: 35 %

Procedure:
HNO3 (1.11 ml, 13.7 mmol) was added to a suspension of 2,4-bis-benzyloxy-1-isopropyl-benzene (3.8 g, 11.44 mmol) in AcOH (46 ml) and the reaction was heated to 70-80° C. for 40 minutes. The solution was cooled down to 0° C. and neutralized with aq. NaHCO3. The organic phase was extracted with AcOEt and the solvent was removed under reduced pressure. The crude reaction mixture was purified by flash chromatography (PE/AcOEt:95/5 to 90/10) and the title compound was obtained as a yellow solid.