Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:24][CH2:23][C:13]3([O:18][CH2:17][C:16](=[O:19])[N:15]([CH:20]4[CH2:22][CH2:21]4)[CH2:14]3)[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:42]=[C:41]3[C:36]([CH:37]=[CH:38][CH:39]=[N:40]3)=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:20]1([N:15]2[CH2:14][C:13]3([CH2:23][CH2:24][N:10]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:33]5[CH:42]=[C:41]6[C:36]([CH:37]=[CH:38][CH:39]=[N:40]6)=[CH:35][CH:34]=5)=[CH:3][CH:4]=4)[CH3:9])[CH2:11][CH2:12]3)[O:18][CH2:17][C:16]2=[O:19])[CH2:22][CH2:21]1
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Reactant: CC(c1ccc(Br)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(c1ccc(-c2ccc3cccnc3c2)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Yield: 19.8 %

Procedure:
A solution of 9-[1-(4-bromophenyl)ethyl]-4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (0.297 mmol) in 1,4-dioxane (1.5 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.329 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.015 mmol) and 2M aq potassium carbonate (0.892 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture was irradiated in a Biotage Initiator Microwave at 150° C. for 20 min. The resulting black mixture was diluted with water (50 mL) and extracted three times with dichloromethane. The combined organic layers were treated with Silicycle Si-thiol (20 mg), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (4-10% methanol/dichloromethane) and then by reverse phase HPLC (5-35% acetonitrile with 0.1% TFA/water with 0.1% TFA). Fractions containing the desired product were combined and the pH of the resulting mixture was adjusted to ˜11 with 30% w/v ammonium hydroxide solution. This mixture was concentrated to a minimal volume in vacuo and was then extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Lyophilization of the resulting semi-solid from water yielded the title compound as a white solid (26 mg, 18%). MS(ES)+ m/e 442.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH2:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.[CH2:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:18]=[CH2:19]>CN(C=O)C>[CH:11]1([CH2:10][O:9][C:4]2[CH:3]=[C:2](/[CH:19]=[CH:18]/[CH2:17][NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=CCNC(=O)C(F)(F)F
Reactant: Fc1cc(Br)cc(OCC2CCCCC2)c1
Solvent: CN(C)C=O
Product: O=C(NC/C=C/c1cc(F)cc(OCC2CCCCC2)c1)C(F)(F)F

Procedure:
Coupling of 1-bromo-3-(cyclohexylmethoxy)-5-fluorobenzene with N-allyl-2,2,2-trifluoroacetamide following the method used in Example 10 except DMF was used as solvent gave (E)-N-(3-(3-(cyclohexylmethoxy)-5-fluorophenyl)allyl)-2,2,2-trifluoroacetamide as a white solid. Yield (0.44 g, 64%): 1H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, CDCl3) δ 9.68 (t, J=4.0 Hz, 1H), 6.79-6.86 (m, 2H), 6.65 (dt, J=10.8, 2.0 Hz, 1H), 6.45 (d, J=15.6 Hz, 1H), 6.31 (dt, J=16.0, 5.6 Hz, 1H), 3.95 (t, J=4.8 Hz, 2H), 3.77 (d, J=5.6 Hz, 2H), 1.58-1.80 (m, 6H), 1.10-1.28 (m, 3H), 0.90-1.06 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]([CH3:14])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>>[CH3:14][C:5]1[S:4][C:3]([CH2:2][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[N:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1sc(CCl)nc1-c1ccccc1
Product: Cc1sc(COc2ccc(C=O)cc2)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 45, 2-chloromethyl-5-methyl-4-phenylthiazole was allowed to react with p-hydroxybenzaldehyde to give 4-(5-methyl-4-phenyl-2-thiazolylmethoxy)benzaldehyde. Recrystallization from ethyl acetate--isopropyl ether gave colorless prisms, m.p.81°-82° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][C:8]2[S:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)(=O)C>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([CH2:7][C:8]2[S:12][C:11]([CH2:13][OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cc2ccc(C=O)s2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(Cc2ccc(CO)s2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
To a solution of 5-(5-methyl-thiophen-2-ylmethyl)-thiophene-2-carbaldehyde described in Preparation Example 66 (790 mg, 3.56 mmol) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (41 mg, 1.06 mmol), and the mixture was stirred at room temperature for 10 minutes. Water and ethyl acetate were added to the reaction mixture, which was then partitioned, the organic layer was filtered with a glass filter lined with silica gel, the filtrate was evaporated in vacuo, and the title compound (640 mg, 2.86 mmol, 80.3%) was obtained as a light brown oil.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([CH2:17][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: C1COCCN1
Reactant: CCCCN1CCN(C(=O)c2ccc(C=O)cc2)CC1
Product: CCCCN1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1

Procedure:
Prepared from the product of Example 13 and morpholine.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]([CH3:34])([CH3:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH:15]2[CH2:19][N:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[C:17](=[O:31])[N:16]2[CH3:32])=[CH:8][CH:7]=1.[OH-].[Na+].Cl>CO>[CH3:33][C:4]([CH3:34])([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH:15]2[CH2:19][N:18]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:26]=3)[C:17](=[O:31])[N:16]2[CH3:32])=[CH:10][CH:11]=1)[C:3]([OH:35])=[O:2]
Reactant: COC(=O)C(C)(C)Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the ester obtained from Step A (66 mg, 0.13 mmol) in methanol (1.5 ml) is added 5N NaOH (0.3 ml, 1.5 mmol), and the mixture stirred for 20 hours at ambient temperature. The mixture is poured into 1N HCl (20 ml), then extracted with ethyl acetate (2×15 ml). The combined ethyl acetate extracts were washed with water, brine, dried (Na2SO4), and concentrated to a foam (62 mg, 97%.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[Mg+2].[O-]S(C(F)(F)F)(=O)=O.O.C1(C2O[C@@H]3CC4C=CC=CC=4[C@@H]3N=2)(C2O[C@@H]3CC4C=CC=CC=4[C@@H]3N=2)CC1.[CH3:46][O:47][C:48](=[O:66])/[C:49](/[N+:63]([O-:65])=[O:64])=[CH:50]\[C:51]1[C:56]([O:57][CH3:58])=[CH:55][C:54]([O:59][CH3:60])=[CH:53][C:52]=1[O:61][CH3:62].[C:67]([O:74][CH3:75])(=[O:73])[CH2:68][C:69]([O:71][CH3:72])=[O:70].CN1CCOCC1>CO.C(Cl)(Cl)Cl>[N+:63]([CH:49]([C:48]([O:47][CH3:46])=[O:66])[CH:50]([C:51]1[C:56]([O:57][CH3:58])=[CH:55][C:54]([O:59][CH3:60])=[CH:53][C:52]=1[O:61][CH3:62])[CH:68]([C:67]([O:74][CH3:75])=[O:73])[C:69]([O:71][CH3:72])=[O:70])([O-:65])=[O:64]
Reactant: COC(=O)CC(=O)OC
Reactant: COC(=O)/C(=C\c1c(OC)cc(OC)cc1OC)[N+](=O)[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Agent: c1ccc2c(c1)C[C@H]1OC(C3(C4=N[C@H]5c6ccccc6C[C@H]5O4)CC3)=N[C@@H]21
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)C(C(=O)OC)C(c1c(OC)cc(OC)cc1OC)C(C(=O)OC)[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 1 h

Procedure:
In a two-necked 500 mL round-bottomed flask maintained under nitrogen, chloroform (10 mL), magnesium triflate (0.161 g, 0.5 mmol) and water (0.036 mL, 2.0 mmol) were added. To this stirred solution, (3aS,3a′S,8aR,8a′R)-2,2′(cyclopropane-1,1-diyl)bis(8,8a-dihydro-3aH-indeno[1,2-d]oxazole) (bis(oxazoline)) (0.196 g, 0.55 mmol) was added and the reaction mixture stirred for 1 hour. At the end of 1 hour, chloroform (30 mL) and molecular sieves (2 g) were added and the mixture stirred for another 90 mins. (E)-Methyl-2-nitro-3-(2,4,6-trimethoxyphenyl)acrylate (3.1 g, 0.01 mol), dimethyl malonate (1.92 g, 0.014 mol) and N-methylmorpholine (0.06 g, 0.6 mmol) were added and the reaction mixture was stirred for 12 hours followed by heating at 40° C. for 4 hours. Petroleum ether (15 mL) was added to the reaction mixture, stirred for 10 mins. and the mixture filtered. The molecular sieves were washed with methyl-t-butyl ether and the combined organic layer was washed with 5% phosphoric acid (10 mL) and brine (15 mL). The organic layer was concentrated under reduced pressure to give an oil. The oil was dissolved in methanol (10 mL), cooled and filtered to give a white crystalline solid.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(C=CC(O)=CC=1)[OH:10].ClOC(C)(C)C.ClCl.Cl.C(Cl)C=C>>[CH2:1]1[O:10][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccc(O)cc1
Reactant: C=Cc1ccccc1
Agent: CC(C)(C)OCl
Agent: Cl
Agent: ClCl
Solvent: C=CCCl
Product: c1ccc(C2CO2)cc1
Reaction time: 3 h

Procedure:
The reaction given in the above example was repeated with styrene in the presence of 0.1 g. of hydroquinone stabilizer. The styrene charged was 49.3 cc (44.8 g., 430 mmole). The t-butyl hypochlorite charged was 48.0 cc (45.0 g., 408 meq. active chlorine), and the total reaction time was three hours. A trace of hydrochloric acid was found in the aqueous product layer. The product pattern in the organic layer was similar to that observed in the allyl chloride reaction. Saponification, as in Example 5, of the organic layer produced styrene oxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=O)[CH2:24][S:25][C:26]#[N:27])=[CH:19][CH:18]=1>C(O)C.O1CCOCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]=[C:26]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[S:25][CH:24]=2)=[CH:19][CH:18]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: N#CSCC(=O)c1ccc(Cl)cc1
Solvent: CCO
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(-c3ccc(Cl)cc3)cs2)ccc1-n1cnc(C)c1
Temperature: 25 °C

Procedure:
A solution of 51 mg (0.25 mmol) 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and of 53 mg (0.25 mmol) 1-(4-chloro-phenyl)-2-thiocyanato-ethanone in ethanol (1.25 ml) and dioxane (1.25 ml) was refluxed over night. After cooling to room temperature the solvent was evaporated under vacuo and the residue was purified on silica gel with methylene chloride/methanol 19/1 yielding 35 mg (35%) [4-(4-chloro-phenyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a yellow solid. MS ISP (m/e): 397.1/399.1 (100/50) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.54 (s, 1H), 7.96 (d, 2H), 7.86 (s, 1H), 7.68 (s, 1H), 7.50 (d, 2H), 7.48 (s, 1H), 7.31 (d, 1H), 7.22 (d, 1H), 7.06 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[C:4]([F:12])[CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl.Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][S:21]([CH3:20])(=[O:23])=[O:22])([CH3:10])[CH3:9])=[C:4]([F:12])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(N)c1ccc(Br)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NS(C)(=O)=O)c1ccc(Br)cc1F
Reaction time: 16 h
Yield: 56.7 %

Procedure:
To 1-(4-bromo-2-fluoro-phenyl)-1-methyl-ethylamine (1.2 g, 5.4 mmol) and triethylamine (900 μL, 6.5 mmol) in dichloromethane (10 mL) at room temperature was added methanesulfonyl chloride (500 μL, 6.5 mmol). The solution was stirred 16 h, diluted in 1N HCl(aq) and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, then saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to an off-white solid. Flash chromatography (SiO2, 40% ethyl acetate/hexane) gave a white solid (950 mg, 57%). 1H NMR (300 MHz, CDCl3): δ ppm 1.76 (s, 6 H) 2.74 (s, 3 H) 4.88 (s, 1 H) 7.24 (d, J=1.51 Hz, 1 H) 7.27-7.30 (m, 2 H)
Reaction SMILES: [O:1]=[C:2]([CH2:20][CH2:21][C:22]1C=CC=[CH:24][CH:23]=1)/[CH:3]=[CH:4]/[CH:5]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][S:6]1.O=C(CCCCC)/C=C/C1N(CCCCCCC(O)=O)C(=O)CS1>>[OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])/[CH:3]=[CH:4]/[CH:5]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][S:6]1
Reactant: O=C(O)CCCCCCN1C(=O)CSC1/C=C/C(=O)CCc1ccccc1
Agent: CCCCCC(=O)/C=C/C1SCC(=O)N1CCCCCCC(=O)O
Product: CCCCCC(O)/C=C/C1SCC(=O)N1CCCCCCC(=O)O

Procedure:
This compound is prepared essentially by the method as described in Example 13, Step D, except that the 7-[2-(3oxo-5-phenyl-1-trans-pentenyl)-4-oxo-3-thiazolidinyl]heptanoic acid is replaced with 7-[2-(3-oxo-1-trans-octenyl)4-oxo-3-thiazolidinyl]heptanoic acid. Chromatographic purification of the product resulting this method on silica gel affords the title compound as a pale yellow, viscous oil.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9]([O:10]C(C2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:8][CH2:7][N:6]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].O>CO>[N:1]([CH2:4][C@@H:5]1[C@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@H]1CN=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a solution of the compound 4 (1.22 g) in methanol (20 mL), potassium carbonate (0.91 g) was added. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was added water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→4:1→3:1) to obtain the title compound (0.66 g) having the following physical properties.
Reaction SMILES: [OH-].[K+:2].[Cl:3][C:4]1[C:8]([Cl:9])=[C:7]([CH3:10])[NH:6][C:5]=1[C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][N:17]([C:20]2[S:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][N:24]=2)[CH2:16][C@@H:15]1[F:28])=[O:12].CC(C)=O>CO.CC(C)=O.O>[Cl:3][C:4]1[C:8]([Cl:9])=[C:7]([CH3:10])[NH:6][C:5]=1[C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][N:17]([C:20]2[S:21][C:22]([C:25]([O-:27])=[O:26])=[CH:23][N:24]=2)[CH2:16][C@@H:15]1[F:28])=[O:12].[K+:2]
Reactant: Cc1[nH]c(C(=O)N[C@@H]2CCN(c3ncc(C(=O)O)s3)C[C@@H]2F)c(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: Cc1[nH]c(C(=O)N[C@@H]2CCN(c3ncc(C(=O)[O-])s3)C[C@@H]2F)c(Cl)c1Cl
Reaction time: 1 h
Yield: 73.3 %

Procedure:
An aqueous solution of potassium hydroxide (0.1 M, 4.75 ml, 0.475 mmol) was added to a solution of 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-1,3-thiazole-5-carboxylic acid (Example 42, 200 mg, 0.475 mmol) in methanol (35 ml). The mixture was stirred for 1 h and then concentrated under reduced pressure to provide the crude salt (230 mg). The salt was dissolved in acetone/water (50 ml; 48:2) and acetone was added slowly to the stirred mixture until it became cloudy. Stirring was continued and more acetone was added very slowly over 20 min. The mixture was stored at 4° C. overnight. The solid was collected by filtration and air dried for 24 h to provide the salt (160 mg).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[N+:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23].C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>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.C(O)C>[CH3:8][C:7]1[C:2]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:22]([O-:24])=[O:23])[CH:30]=2)=[CH:3][C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 101.4 %

Procedure:
To N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide (400 mg, 0.99 mmol) was added (3-nitrophenyl)boronic acid (180 mg, 1.1 mmol) followed by toluene (8.2 mL), ethanol (1.1 mL), and K2CO3 (270 mg, 2.0 mmol in 1.1 mL water). The resulting mixture was degassed with N2, then tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) was added. The mixture was degassed again, then heated under reflux condenser and N2 atmosphere at 90° C. until LCMS and TLC indicated complete reaction, typically 16 hours. The reaction was then cooled to ambient temperature and transferred to a separatory funnel and partitioned between water and EtOAc. The phases were separated and the organic phase was washed with water, then saturated aqueous NaCl. The washed organic phase was then dried (MgSO4) and evaporated to dryness to leave the crude product, which was purified by column chromatography to give the product (402 mg, 102%). 1H NMR (400 MHz, CDCl3): δ 8.23 (m, 2H), 8.12 (s, 1H), 8.07 (d, 1H), 7.88 (bs, 1H), 7.82 (d, 1H), 7.6 (m, 4H), 7.32 (d, 1H), 2.27 (s, 3H). MS (EI) m/z=401 (M+H).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1=[O:31].C(N(C(C)C)CC)(C)C.C(O)(C(F)(F)F)=O>CN1C(=O)N(C)CCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[C:26](=[O:31])[CH2:27]3)[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: CN1CCNCC1=O
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCN(C)C1=O
Product: CN1CCN(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)CC1=O
Temperature: 25 °C

Procedure:
A solution of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.20 g, 0.53 mmol), 1-methylpiperazin-2-one (0.21 g, 1.86 mmol) and diisopropylethylamine (0.19 mL, 1.06 mmol) in DMPU (2.0 mL) were heated at 135 C for 26 hr. Diisopropylethylamine (0.19 mL, 1.06 mmol) was added and the reaction heated at 135C for a further 24 hr. The reaction was cooled to room temperature, neutralized by the addition of TFA and purified by reverse phase HPLC. (Vydak C18, Gradient elution with Water:Acetonitrile 95:5 to 5:95 with 0.1% TFA at 30 mL/min over 15 mins). Lyophilization of the pure fractions afforded the title compound as an off white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[CH2:13][C@@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.O>[CH3:19][C:16]1([CH3:20])[O:15][C@H:14]([CH2:13][O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:18][O:17]1
Reactant: CC1(C)OC[C@@H](CCl)O1
Reactant: COC(=O)c1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OC[C@@H]2COC(C)(C)O2)c1
Temperature: 160 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
A mixture of methyl 3-hydroxybenzoate (10.0 g, 65.8 mmol), (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (13.0 g, 98.7 mmol) and K2CO3 (18.0 g, 132 mmol) in DMF (100 ml) was stirred for 18 h at 160° C. The mixture was diluted with water (150 mL) and adjusted to pH=6 by the addition of 3N HCl. The mixture was extracted with ethyl acetate (200 ml×3) and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (10% Ethyl acetate in petroleum ether) to give (R)-methyl 3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoate as a brown oil, (8.5 g, 49% yield).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]=[C:17]=[O:18])[C:11]=1[CH3:19].N([O-])=O.[Na+].Cl>O.CN(C)C=O>[CH3:19][C:11]1[C:10]([F:9])=[CH:15][CH:14]=[CH:13][C:12]=1[N:16]1[C:17](=[O:18])[NH:7][N:6]=[N:5]1
Reactant: Cc1c(F)cccc1N=C=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Al+3]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(F)cccc1-n1nn[nH]c1=O
Temperature: 0 °C
Yield: 95.1 %

Procedure:
Under ice-cooling, to N,N-dimethylformamide 250 mL was added anhydrous aluminum chloride 21.9 g and the resulting mixtures were stirred for fifteen minutes. Thereto was added sodium azide 10.7 g and the resulting mixtures were stirred for fifteen minutes and thereto was then added 1-fluoro-3-isocyanato-2-methylbenzene 22.5 g and the resulting mixtures were heated at 80° C. for three and a half hours. After cooling the mixtures, to a mixture of sodium nitrite 34 g, water 2 L and ice 500 g was added the reaction solutions with stirring. The mixtures were acidified with 10% hydrochloric acid and were extracted with ethyl acetate. The organic layers were washed with water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure to give 1-(2-methyl-3-fluorophenyl)-1,4-dihydrotetrazole-5-one 27.5 g.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13]1(B(O)O)[CH2:15][CH2:14]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].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>[CH:13]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:15][CH2:14]1
Reactant: COC(=O)c1c(F)cccc1Br
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(F)cccc1C1CC1
Yield: 98.8 %

Procedure:
Methyl 2-bromo-6-fluorobenzoate (2, 11.29 g, 48.5 mmol), cyclopropylboronic acid (6.24 g, 72.7 mmol), K3PO4 (30.85 g, 145.4 mmol) and Pd(PPh3)4 (2.80 g, 2.4 mmol) were mixed under argon in a degassed mixture of toluene and water (20:1, 160 mL). The resulting brown suspension was heated at reflux for 2.5 h, cooled, filtered through Celite, and evaporated. The residue was partitioned between ethyl acetate (150 mL) and brine (150 mL). The layers were separated and organic layer was dried over magnesium sulfate and evaporated. The oily residue was suspended in hexane and the solid was removed by filtration. Evaporation of the filtrate afforded the title compound (9.30 g, 47.9 mmol, 99%) as a light brown oil.