Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.[F:20][C:21]([F:39])([F:38])[C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=[C:24]([NH2:37])[CH:23]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:39][C:21]([F:20])([F:38])[C:22]1[C:27]([C:9]2[CH:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:8]=2)=[CH:26][N:25]=[C:24]([NH2:37])[CH:23]=1
Reactant: Clc1cc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2cnc(N)cc2C(F)(F)F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1cc(C(F)(F)F)c(-c2cc(N3CCOCC3)nc(N3CCOCC3)n2)cn1
Temperature: 90 °C

Procedure:
Argon gas was bubbled through a heterogeneous mixture of 2,4-dimorpholino-6-chloropyrimidine (4.1 g, 14.3 mmol) and 4-(trifluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (16.5 g, 57.3 mmol) in 1,2-dimethoxyethane and 2M Na2CO3 (3:1) for 20 minutes. 1,1′-Bis(diphenylphosphino)ferrocene palladium(II) chloride (292 mg, 0.36 mmol) was added and the high pressure glass vessel containing the mixture was sealed. The reaction mixture was then heated at 90° C. for 15 hours, cooled and diluted with EtOAc (300 mL). The organic solution was washed with 300 mL of a mixture of water: Na2CO3(sat.):NH4OH(conc.)=5:4:1, then NH4Cl(sat), and brine (2×), dried over Na2SO4, filtered and concentrated. The crude material was purified by SiO2 chromatography (50-90% EtOAc/hexanes with 0.1% TEA) resulting in 5.62 g (95%) of 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine as an off-white solid. LCMS (m/z): 411.3 (MH+); 1H NMR (CDCl3): δ 8.27 (s, 1H), 6.78 (s, 1H), 5.97 (s, 1H), 4.77 (bs, 2H), 3.59-3.80 (m, 12H), 3.58-3.61 (m, 4H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CS(C)=O>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:3][CH:4]=2)=[N:12][N:11]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(F)cc2)o1
Reactant: C1CCNCC1
Solvent: CS(C)=O
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCCCC3)cc2)o1
Temperature: 170 °C
Reaction time: 5 h
Yield: 80.1 %

Procedure:
To a solution of 2-(4-fluoro-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.62 mmol) in DMSO (2 mL) was added piperidine (307 μL, 3.11 mmol) and the resulting mixture stirred for 5 h at 170° C. After cooling to ambient temperature the reaction mixture was extracted with aqueous hydrochloric acid (1 N, 20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with brine (half-saturated, 20 mL) and aqueous sodium carbonate (saturated, 20 mL). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=80:0:20 to 50:30:20) afforded the title compound (192 mg, 80%) as a white solid. MS: m/e=387.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH:11]=[CH:12][CH:13]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[NH2:24].C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:5]1[C:6]([C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH:11]=[CH:12][CH:13]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[C:21]([F:20])[CH:22]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Cl)ncc2Cl)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(F)c3)ncc2Cl)c1
Temperature: 200 °C
Yield: 32.9 %

Procedure:
N-(3-(2,5-dichloropyrimidin-4-yl)phenyl)acrylamide (50 mg, 0.170 mmol), 3-fluoro-4-morpholinoaniline (33.4 mg, 0.170 mmol) and Cs2CO3 (66.5 mg, 0.204 mmol) were dissolved in toluene (5 ml) in a sealable microwave compatible reaction tube, then Pd2(dba)3 (3.11 mg, 3.40 μmol) and X-phos (3.93 mg, 6.80 μmol) were added. The reaction tube was sealed and the reaction was heated under microwave irradiation (60 min, 200° C., 3 atm). The reaction was monitored by TLC and after completion of the reaction, the solvent was in vacuo. The compound was purified by column chromatography (10% CH3OH/CH2Cl2) to yield N-(3-(5-chloro-2-((3-fluoro-4-morpholinophenyl)amino)pyrimidin-4-yl)phenyl)acrylamide (26 mg, 0.056 mmol, 32.7% yield) as a solid. 1H NMR (400 MHz, CD3OD): δ 8.43 (s, 1H), 8.22 (s, 1H), 7.75 (d, 1H, J=7.2 Hz), 7.65-7.57 (m, 2H), 7.45 (t, 1H, J=8.0 Hz), 7.34 (m, 1H), 6.94 (t, 1H, J=9.2 Hz), 6.40 (m, 2H), 5.78 (dd, 1H, J=2.0 & 9.6 Hz), 3.80 (m, 4H), 2.98 (m, 4H). ESI-MS: m/z 454.1 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].Br[CH:29]([CH3:40])[C:30]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[F:39])=O>C(O)C>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:29]([CH3:40])=[C:30]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=4[F:39])[N:22]=3)[CH:21]=2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(-c2ccc(N)nc2)c1
Reactant: CC(Br)C(=O)c1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1c(-c2ccc(F)cc2F)nc2ccc(-c3cccc(CO[Si](C)(C)C(C)(C)C)c3)cn12
Temperature: 80 °C
Yield: 49.6 %

Procedure:
300 mg of 5-[3-(tert-butyldimethylsilanyloxymethyl)phenyl]pyridin-2-ylamine dissolved in 5 ml of ethanol are placed in a screw reactor. 200 mg of sodium hydrogen carbonate and 470 mg of 2-bromo-1-(2,4-difluorophenyl)propan-1-one are added thereto. The reactor is closed and heated at 80° C. for 20 h. After cooling, the reaction mixture is concentrated under reduced pressure. The residue obtained is purified by silica gel chromatography, elution being carried out with a heptane/ethyl acetate mixture. 220 mg of compound are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][C@H:14]([CH3:18])[CH2:13]1)=[CH:8][C:7]2=[O:19].C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC.Cl>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:29]([C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][C@H:14]([CH3:18])[CH2:13]1)=[CH:8][C:7]2=[O:19])(=[O:31])[CH3:30]
Reactant: COC(=O)c1cc(Br)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(C(C)=O)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Methyl 8-bromo-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (1.45 g, 3.79 mmol), bis(triphenylphosphine) palladium(II) chloride (0.107 g, 0.15 mmol) and tributyl(1-ethoxyvinyl)stannane (1.346 mL, 3.98 mmol) in 1,4-dioxane (20 mL) were degassed, purged with argon and heated to 90° C. for 4 hrs. After cooling to RT, HCl 2N (1.9 mL, 3.79 mmol) was added and the mixture was left to stir for 1 h. The reaction mixture was concentrated, suspended in water, neutralised with NaHCO3 and extracted with DCM. The combined organic phases were washed with water, brine, dried over magnesium sulfate and concentrated. The crude product was triturated with n-heptane, filtered and retriturated with ether, filtered and dried to give methyl 8-acetyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (1.15 g, 88%) as a grey solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6](I)[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: OCc1cc(I)c(O)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)C#Cc1cc(CO)nc(Cl)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
C2 (13.9 g, 48.6 mmol) is combined with trimethylsilylacetylene (9.6 mL, 68 mmol), bis(triphenylphosphine)palladium dichloride (1.02 g, 1.46 mmol) and cuprous iodide (139 mg, 0.73 mmol) in 80 mL CHCl3/40 mL THF under N2. TEA (21 mL, 151 mmol) is added, and the reaction is stirred 3 h at rt and is diluted with 200 mL CHCl3. The mixture is washed with 2×150 mL 5% HCl and the combined aqueous layers are extracted with 2×50 mL CHCl3. The combined organic layer is washed with 100 mL 50% saturated NaCl, is dried over anhydrous MgSO4, and is concentrated in vacuo to an amber oil. The crude material is chromatographed over 350 g silica gel (230–400 mesh), eluting with 35% EtOAc/hexane. The fractions with the desired compound are combined and concentrated to afford 2-chloro-6-(hydroxymethyl)-4-[(trimethylsilyl)ethynyl]-3-pyridinol (C3) as a golden solid (92% yield). MS (EI) for C11H14ClNO2Si, m/z: 255(M)+.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19])=[CH:3][CH:2]=1.[CH3:28][NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:11]3[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=[C:8]2[N:29]([CH3:28])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][CH2:38][CH2:39]2)=[CH:3][CH:2]=1
Reactant: COC(=O)C=Cc1ccccc1N=C=Nc1ccc(-c2ccccc2)cc1
Reactant: CNCCCCCN1CCCC1
Product: COC(=O)CC1c2ccccc2N=C(N(C)CCCCCN2CCCC2)N1c1ccc(-c2ccccc2)cc1

Procedure:
-nitrocinnamic acid (7) is reacted with methanol under acid catalyst to give methyl 2-nitrocinnamate (8), of which the nitro group is reduced preferably with SnCl22H2O to provide methyl 2-aminocinnamate (9). The compound (9) is reacted with triphenylphosphine, preferably in the presence of hexachloroethane and triethylamine to give methyl 3-[2-(triphenylphosphineimino)phenyl]acrylate (10). The compound (10) is reacted with 4-biphenylyl isocyanate in a suitable solvent to give methyl 3-[2-(4-biphenylyliminomethyleneamino)phenyl]acrylate (11). Then, the compound (11) is reacted with N-methyl-N-[5-(pyrrolidin-1-yl)pentyl]amine (6) obtained according to the above Reaction Scheme 1 in a suitable solvent to give 3-(4-biphenylyl)-2-[N-methyl-N-(5-pyrrolidin-1-ylpentyl)amino]-4-methoxycarbonylmethyl-3,4-dihydroquinazoline (12). This compound (12) is hydrolyzed preferably using LiOH/H2O to provide compound (13), which is reacted with benzylamine, preferably in the presence of 1-hydroxybenzotriazole (HOBT) and 1-[3-(dimethylamine)propyl]-3-ethylcarbodiimide hydrochloric acid (EDC) to give 4-(N-benzylacetamino)-3-(4-biphenylyl)-2- [N-(5-pyrrolidin-1-ylpentyl)-N-methylamino]-3,4-dihydroquinazoline (14).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11](Cl)=[O:12].Cl>C(Cl)Cl>[CH2:1]([NH:5][C:11]([C:7]1[O:6][CH:10]=[CH:9][CH:8]=1)=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: ClCCl
Product: CCCCNC(=O)c1ccco1
Temperature: 0 °C
Yield: 88.5 %

Procedure:
To a solution of n-butylamine (99 mL, 1.0 mol) in CH2Cl2 (300 mL) was added 2-furoyl chloride (33.0 mL, 0.335 mol) dropwise at 0-5° C. with stirring. The reaction mixture was stirred for additional 2 h at 0-5° C. and overnight at room temperature. The solution was poured into a mixture of wet-ice (200 g) and 37% HCl (50 mL). After separation, the organic layer was washed with 2×200 mL water, dried over Na2SO4 and filtered. Removal of solvent provided the title compound (49.59 g, 88.6% yield) as a white solid, m.p.=43.8° C. (Rf=0.53 on a silica gel plate using EtOAc as an eluant). This product was used without further purification.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([N:18]([C:29]1[C:41]2[CH:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1)[C@H:19]([C:25]([O:27][CH3:28])=[O:26])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:48](OS(C(F)(F)F)(=O)=O)[CH3:49]>C1COCC1>[CH2:48]([CH:20]([C:21]([O:23][CH3:24])=[O:22])[C@@H:19]([C:25]([O:27][CH3:28])=[O:26])[N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:29]1[C:41]2[CH:40]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1)[CH3:49]
Reactant: COC(=O)C[C@@H](C(=O)OC)N(Cc1ccccc1)c1cccc2c1C(c1ccccc1)c1ccccc1-2
Reactant: CCOS(=O)(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(C(=O)OC)[C@@H](C(=O)OC)N(Cc1ccccc1)c1cccc2c1C(c1ccccc1)c1ccccc1-2
Temperature: -74 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 8.65 ml (5.2 mmol) KHMDS (0.6M solution in toluene) in 50 ml dry THF was added 1.96 g (4.0 mmol) of dimethyl N-benzyl-N-(9-phenylfluorenyl)-aspartate of Example 3 dissolved in 8 ml THF drop by drop at -74° C. under N2. The pale yellow solution was stirred at -74° C. for 45 minutes then 568 μl (4.4 mmol) EtOTf were added neat at once at -76° C. After 10 minutes the reaction was quenched with 3 ml MeOH and partitioned between 40 ml 1M H3PO4 and 50 ml Et2O. The water layer was extracted with 40 ml Et2O and the combined organic layers were dried (MgSO4) and evaporated. The residue was purified by flash-chromatography (Kieselgel, Hexane/EtAc 8:1) to yield a mixture of dimethyl 3-ethyl N-benzyl-N-(9-phenylfluorenyl)-aspartate (20:1 mixture of diastereomers). The diastereomers were separated by MPLC (Kieselgel, Hexane/EtOAc 15:1) to yield the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[F:18][C:19]1[CH:20]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([CH:27]=1)[C:24](O)=[O:25]>>[CH:8]1([NH:7][C:5]([C:4]2[CH:11]=[CH:12][C:13]([C:14]([F:15])([F:16])[F:17])=[C:2]([NH:1][C:24](=[O:25])[C:23]3[CH:27]=[C:19]([F:18])[CH:20]=[CH:21][C:22]=3[N+:28]([O-:30])=[O:29])[CH:3]=2)=[O:6])[CH2:9][CH2:10]1
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: Nc1cc(C(=O)NC2CC2)ccc1C(F)(F)F
Product: O=C(NC1CC1)c1ccc(C(F)(F)F)c(NC(=O)c2cc(F)ccc2[N+](=O)[O-])c1

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 1 which is concerned with the preparation of starting materials, 3-amino-N-cyclopropyl-4-(trifluoromethyl)benzamide was reacted with 5-fluoro-2-nitrobenzoic acid to give N-[5-[(cyclopropylamino)carbonyl]-2-(trifluoromethyl)phenyl]-5-fluoro-2-nitrobenzamide; Mass Spectrum: M−H+ 410.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[O:11]([CH2:18][CH:19]([OH:28])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[O:11]([CH2:18][C:19]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:28])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC(COc1ccccc1)COc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(COc1ccccc1)COc1ccccc1
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
A solution of 0.44 ml (6.2 mmol) of dimethylsulfoxide in 25 ml of dichloromethane was cooled under inert atmosphere to -63° C., treated with 2.3 ml (4.6 mmol) of oxalyl chloride (2M in dichloromethane), and stirred for 15 min. A solution of 0.75 g (3.1 mmol) of the resultant compound of Example 4 in 10 ml of dichloromethane was subsequently added, the solution was stirred for 30 min, and 1.73 ml (12.4 mmol) of triethylamine was added. After stirring for an additional 15 min, the solution was quenched with 10% aqueous citric acid, poured into a mixture of 1:1 ether:hexane and 10% citric acid, extracted with ether, washed with aqueous brine, dried over MgSO4, and concentrated to a yellow oil. Purification by flash chromatography using 20% ethyl acetate in hexane gave 0.62 g (83%) of the desired compound as a white, crystalline solid, m.p. 55°-57° C. 1H NMR (CDCl3) δ4.89 (s, 4H), 6.92 (m, 4H), 7.02 (m, 2H), 7.30 (m, 4H). Mass spectrum (M+NH4)+ =260.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][C@H:15]3[C@H:19]([OH:20])[CH2:18][NH:17][CH2:16]3)=[O:13])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:24]1[CH:33]=[N:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1.C(O)CCC.O>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][C@H:15]3[C@H:19]([OH:20])[CH2:18][N:17]([C:24]4[CH:33]=[N:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)[CH2:16]3)=[O:13])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H]1CNC[C@H]1O)c1ccc(-c2cccc(F)c2)nc1
Reactant: Clc1cnc2ccccc2n1
Solvent: CCCCO
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CN(c2cnc3ccccc3n2)C[C@H]1O)c1ccc(-c2cccc(F)c2)nc1
Temperature: 90 °C
Yield: 79 %

Procedure:
To a vial was added trans-6-(3-fluorophenyl)-N-[4-hydroxypyrrolidin-3-yl]nicotinamide (40 mg, 0.12 mmol 2-chloroquinoxaline (29.2 mg, 0.18 mmol), n-butanol, water and triethylamine (0.3 mL of each). The reaction mixture was heated to 90° C. overnight and then cooled to room temperature and the solvent removed. The residue was taken up in DMSO and purified by RP-HPLC to give the desired product, trans-6-(3-fluorophenyl)-N-[4-hydroxy-1-quinoxalin-2-ylpyrrolidin-3-yl]nicotinamide (40 mg, 79%). HRMS (M+H) expected 430.1679, observed 430.1793
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C:12]1[C:13]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39]C(C)(C)C)=[O:38])=[CH:33][CH:32]=2)=[CH:14][CH:15]=[C:16]([C:18]2[S:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[N:22]=2)[CH:17]=1)=[O:11]>C(Cl)Cl>[CH3:8][O:9][C:10]([C:12]1[C:13]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][CH:32]=2)=[CH:14][CH:15]=[C:16]([C:18]2[S:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[N:22]=2)[CH:17]=1)=[O:11]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
Trifluoroacetic acid (8.3 mL, 108 mmol) was added to a solution of 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 4′-tert-butyl ester 2-methyl ester (which may be prepared as described for Intermediate 7; 5.8 g, 10.7 mmol) in CH2Cl2 (25 mL) at 0-5° C. The mixture was allowed to warm to room temperature and stir for 3 h. The resulting solution was concentrated under a stream of nitrogen and then dried under high vacuum to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (5.1 g, 98%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.08 (br s, 1H), ppm 8.49 (s, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 8.30 (d, J=8.0 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 8.02 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.3 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5](O)=[O:6].B.C1COCC1.O>C1COCC1>[OH:6][CH2:5][C:4]1[CH:8]=[CH:9][C:10]([I:11])=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)c1ccc(I)c(O)c1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(I)c(O)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a solution of 3-hydroxy-4-iodobenzoic acid (20.9 g, 79.3 mmol) in anhydrous THF (160 mL) was added 1 M borane THF solution (240 mL, 240 mmol) by small portions, and the mixture was stirred at 60° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with diisopropyl ether and hexane to give the title compound (17.4 g, yield 88%) as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:8][C:7](=[O:16])[CH2:6][O:5]1)(=[O:3])[CH3:2].[O:17]1CCC[CH2:18]1.C=O>C(N(CC)CC)C>[C:1]([N:4]1[CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:8]([CH2:18][OH:17])[C:7](=[O:16])[CH2:6][O:5]1)(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(=O)N1OCC(=O)NC1c1ccccc1
Agent: C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1OCC(=O)N(CO)C1c1ccccc1
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 1.1 g. (5 mmoles) of 2-acetyl-3-phenyl-tetrahydro-1,2,4-oxadiazin-5-one in 10 ml. of tetrahydrofurane 1 ml. of triethyl amine and 0.4 ml. of a 37% aqueous formaldehyde solution are added. The mixture is allowed to stand at room temperature overnight and is then evaporated to dryness. The residue is triturated with diethyl ether and the product is isolated by filtration. 1.16 g. (93%) of 2-acetyl-3-phenyl-4-hydroxymethyl-tetrahydro-1,2,4-oxadiazin-5-one are obtained, melting at 123° to 126° C. RfA =0.5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH:12]=[C:11](OCC2C=CC=CC=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1>>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:10]=[C:11]([C:35]2[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=[C:33]([F:32])[CH:34]=2)[CH:12]=[C:13]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:17])=[O:18])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield from 2-(3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (prepared in Example 26, step (c)) under the conditions described in Example 26, step (d-f)) using 3-fluoro-5-trifluoromethylphenylboronic acid in step (d).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][C:10]1[C:11]([N+:19]([O-])=O)=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14].[OH-].[NH4+]>O>[Cl:9][C:10]1[C:11]([NH2:19])=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: Nc1c(Cl)cccc1C(=O)O
Reaction time: 0.33 h

Procedure:
Sodium dithionite (104.4 g, 0.6 m) in water (400 ml) was added in portions to a slurry of 3-chloro-2-nitrobenzoic acid (30 g, 0.15 m) in water (200 ml) containing concentrated ammonium hydroxide solution (10 ml). After stirring an additional 20 minutes the mixture was filtered, acidified to pH 3-4 with concentrated hydrochloric acid and filtered again. The filtrate was saturated with sodium chloride and extracted with ether. Drying and concentration of the extract gave a white powder which was combined with the precipitates above. The crude product was used without further purification.