Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:29]([CH3:33])([C:30](=[S:32])[NH2:31])[C:28](=[O:34])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[N:9]=2)[N:7]=1.Br[CH:36]([CH3:40])[C:37](=O)[CH3:38]>C(O)C>[NH2:1][C:2]1[C:3]2[C:29]([C:30]3[S:32][C:36]([CH3:40])=[C:37]([CH3:38])[N:31]=3)([CH3:33])[C:28](=[O:34])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:22])[F:23])[N:9]=2)[N:7]=1
Reactant: CC(=O)C(C)Br
Reactant: CC1(C(N)=S)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Solvent: CCO
Product: Cc1nc(C2(C)C(=O)Nc3nc(-c4nn(CCC(F)(F)C(F)(F)F)c5cc(Cl)ccc45)nc(N)c32)sc1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of the intermediate from Step A above (11 mg, 0.021 mmol) in ethanol (423 μl), was added 3-bromo-2-butanone (32.0 mg, 0.212 mmol). The mixture was stirred at 80° C. overnight. The solvent was then removed in vacuo. The residue was purified by preparative TLC using hexanes/EtOAc (1/1) as the eluent to give the indicated compound. Chiral separation using SFC on a Chiralpak AD column provided both enantiomers of the title compound. 1H NMR (500 MHz, CH3OH-d4): δ 8.59 (d, J=8.7 Hz, 1H); 7.86 (s, 1H); 7.36 (d, J=8.7 Hz, 1H); 4.92-4.82 (m, 2H); 3.08-2.88 (m, 2H); 2.38 (s, 3H); 2.34 (s, 3H); 1.94 (s, 3H). m/z=572.0 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1.[C:13]1([C@H:19]2[O:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CS(C)=O.O>[OH:21][C@H:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:20][N:1]([CH2:20][C@H:19]([OH:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1
Reactant: c1ccc([C@@H]2CO2)cc1
Reactant: NCCCc1ccc(C(N)=O)s1
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(CCCN(C[C@H](O)c2ccccc2)C[C@H](O)c2ccccc2)s1

Procedure:
30 g of 5-(3-aminopropyl)-2-thiophenecarboxamide and 20.2 ml of (R)-phenylethylene oxide were stirred at 95° for 24 hours in 400 ml of dimethyl sulphoxide. After cooling, the mixture was diluted with 1.3 l of water and extracted three times with about 600 ml of methylene chloride. The methylene chloride solutions were washed twice with water, dried over sodium sulphate and evaporated in vacuo. Chromatography of the residue on silica gel with ether/methanol gave 21 g of 5-[3-[bis[(R)-β-hydroxyphenethyl]amino]propyl]-2-thiophenecarboxamide; UV: ε276 =9900; [α]D =-69° (c=0.1% in dioxan).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.F[C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([CH:39]=1)[C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:4]2[C:5]([N:24]([C:30]3[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([CH:39]=3)[C:35]([O:37][CH3:38])=[O:36])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:20])[NH:21][CH3:22])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 70 °C
Reaction time: 72 h
Yield: 83.3 %

Procedure:
A mixture of 55.0 g (123 mmol) of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide, 36.7 g (184 mmol) of methyl 5-fluoro-2-nitrobenzoate, and 39.1 g (369 mmol) of sodium carbonate in 400 mL of DMF was heated to 70° C. with vigorous stirring. After 72 hours LCMS indicated nearly complete reaction. The mixture was cooled to RT, diluted with 300 mL of EtOAc, and filtered through a bed of celite to remove solids. The filter cake was washed with EtOAc until the filtrate ran colorless which gave a total filtrate volume of 1.2 L. The filtrate was transferred to a separatory funnel, partitioned with 1.4 L of 5% aqueous NaCl, and the phases separated. The aqueous solution was extracted with two additional 300 mL portions of EtOAc. The combined EtOAc solutions were washed with 95% aqueous NaCl (2×), saturated aqueous NaCl (1×), dried over sodium sulfate and concentrated to approximately 200 mL by rotary evaporation. At this point a solid began to crystallize. The suspension was diluted with 200 mL of DCM and the suspension stirred overnight. The suspension was then cooled in an ice water bath for 2 hours and the solid collected by vacuum filtration. The filter cake was washed twice with cold 1:1 EtOAc/DCM, suction air dried for 30 minutes and then dried in vacuo overnight to afford 59.6 g (83%) of methyl 5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nitrobenzoate as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (q, J=4.42 Hz, 1H) 8.13 (d, J=9.07 Hz, 1H) 8.08 (s, 1H) 7.93-8.01 (m, 2H) 7.57 (d, J=2.63 Hz, 1H) 7.53 (dd, J=9.07, 2.73 Hz, 1H) 7.38-7.46 (m, 2H) 7.29 (s, 1H) 3.83 (s, 3H) 3.60 (s, 3H) 2.85 (d, J=4.59 Hz, 3H) 1.87-2.04 (m, 1H) 0.87 (m, 2H) 0.73 (m, 1H) 0.46 (m, 1H). LCMS (ESI): 582 (M+H+).
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[C:1]([C:9](=[CH:14][N:15]([CH3:17])[CH3:16])[C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
Following the method of Toche et al. (Org. Prep. Proc. Intl. 1998, 39, 367), a mixture of 5.0 g (34.4 mmol) benzoylacetonitrile and 9.2 ml (69.0 mmol) N,N-dimethylformamide dimethyl acetal was stirred for 1 hour at room temperature. The reaction mixture was then concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was dried with sodium sulfate. Concentration in vacuo afforded 6.9 g (100%) 2-benzoyl-3-dimethylaminoacrylonitrile as a yellow oil which was used in the next step without further purification. ES-MS m/e (%):223 (M+Na+, 40), 201 (M+H+, 100).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]([OH:8])[CH3:7])[N:3]=[N:2]1.N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])[CH3:16]>C(Cl)Cl>[Si:18]([O:8][CH:6]([C:4]1[N:3]=[N:2][NH:1][CH:5]=1)[CH3:7])([C:15]([CH3:17])([CH3:16])[CH3:14])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(O)c1c[nH]nn1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1c[nH]nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
To a solution of 1-(1H-1,2,3-triazol-4-yl)ethanol (50.2 mmol) and imidazole (5.13 mg, 75 mmol) in DCM (50 ml) 0° C. was added TBDPSCl (14.6 mL, 55.2 mmol). After stirring at room temperature overnight the mixture was filtered through a celite pad and then concentrated to dryness. The resulting residue was dissolved in EtOAc, washed with water, brine, dried with sodium sulfate and concentrated. Purification of the crude residue via silica gel chromatography (EtOAc-Heptane, 5-25%) afforded the title compound (8.16 g, 46%) as a yellow oil. LCMS: Rt=1.09 min, m/z=352.1 (M+1) Method 2m_acidic. 1H NMR (400 MHz, CDCl3) δ ppm 7.71 (d, J=6.5 Hz, 2H) 7.64-7.54 (m, 3H) 7.49-7.28 (m, 6H) 5.14 (q, J=6.3 Hz, 1H) 1.46 (dd, J=6.3, 3.0 Hz, 3H) 1.08 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[F:13][C:14]1([F:32])[CH2:19][CH2:18][C:17]([CH2:30][NH2:31])([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[F:32][C:14]1([F:13])[CH2:15][CH2:16][C:17]([CH2:30][NH:31][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=2[CH3:12])([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Reactant: COc1cccc(C(=O)O)c1C
Product: COc1cccc(C(=O)NCC2(c3ccc(C(F)(F)F)nc3)CCC(F)(F)CC2)c1C

Procedure:
From 3-methoxy-2-methylbenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=443.2, tR (minutes, Method D)=0.78
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.[OH:12][C:13]([CH3:46])([CH3:45])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH3:23])[CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.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>[OH:12][C:13]([CH3:45])([CH3:46])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:25]=[CH:26][C:27]([C:2]3[CH:3]=[N:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=3)=[CH:28][CH:29]=2)[CH3:23])[CH2:17][CH2:16]1
Reactant: CC(C)(O)c1ncc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: C[C@@H](c1ccc(-c2cnc(C(C)(C)O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To a solution of 2-(5-bromopyrimidin-2-yl)propan-2-ol (30 mg, 0.14 mmol) in DME (6 mL) was added Pd(PPh3)4 (10 mg, 0.01 mmol) under nitrogen. The mixture was stirred at room temperature for 1 h. (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (60 mg, 0.125 mmol) in EtOH (2 mL) was added, followed by addition of satd aq NaHCO3 (2 mL). The mixture was stirred at 100° C. for 2 h, quenched with water, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(2-(2-hydroxypropan-2-yl)pyrimidin-5-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (17 mg, yield 25.12%). LC-MS Method 2 tR=1.00 min, m/z=490; 1H NMR (CD3OD): δ0.95 (s, 3H), 1.27 (s, 3H), 1.57 (d, 3H), 1.61 (s, 6H), 2.22 (s, 2H), 2.25 (m, 1H), 2.50 (m, 2H), 3.06 (m, 1H), 5.61 (m, 1H), 7.10 (m, 2H), 7.34 (m, 5H), 7.45 (m, 2H), 8.92 (s, 2H).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:8](=[O:9])[O:7][CH2:6][C:5]=12.CN(C)C(=O)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20]>CCO>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:8]([C:4]2[C:5]([CH2:6][OH:7])=[N:1][O:2][N:3]=2)=[O:9])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=C1OCc2nonc21
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CCO
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CO
Temperature: 80 °C
Yield: 74.1 %

Procedure:
4H,6H-Furo[3,4-c][1,2,5]oxadiazol-4-one (2.00 g, 0.0159 mol) was dissolved in EtOH (80 mL) and N,N-dimethylacetamide (10 mL) and then 3-chloro-4-fluoroaniline (2.5 g, 0.017 mol) was added as a solid. The reaction was heated at 80° C. overnight. The crude reaction mixture was concentrated in vacuo. The oil was extracted twice with EtOAc and washed with water. The organic was dried over Na2SO4 and concentrated. The crude residue was purified by flash column chromatography eluting with EtOAc:Hexane (1:1) to yield the desired product (3.2 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ: 11.30 (s, 1H), 8.30 (dd, J=7.0, 2.7 Hz, 1H), 7.69 (ddd, J=9.1, 4.4, 2.6 Hz, 1H) 7.45 (dd, J=9.1, 9.1 Hz, 1H), 4.86 (d=5.8 Hz, 2H), 5.78 (t, 5.8 Hz, 1H); MF═C10H7ClFN3O3; LCMS calculated for C10H8ClFN3O3(M+H)+: m/z=272.024.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:11]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:11]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=4[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)c1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCc2cccc([N+](=O)[O-])c2)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6,7,8-tetrahydro-4-(3-nitrobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]([F:22])([F:21])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][C:16]([CH2:19]O)=[N:15]2)=[CH:10][CH:9]=1>CCOCC>[Br:2][CH2:19][C:16]1[CH:17]=[CH:18][N:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]([F:22])([F:21])[F:5])=[CH:9][CH:10]=2)[N:15]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccn(-c2ccc(OC(F)(F)F)cc2)n1
Solvent: CCOCC
Product: FC(F)(F)Oc1ccc(-n2ccc(CBr)n2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.3 %

Procedure:
PBr3 (0.312 mL, 3.32 mmol) was added to a solution of alcohol 67 (0.858 g, 3.32 mmol) in ether (15 mL) at 0° C. The mixture was stirred at room temperature for 17 h, then cooled to 0° C., quenched with ice, and partitioned between CH2Cl2 and water. Column chromatography of the organic portion on silica gel (eluting with CH2Cl2) gave 3-(bromomethyl)-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole (68) (0.952 g, 89%) as a white solid: mp 71-73° C.; 1H NMR (CDCl3) δ 7.84 (d, J=2.5 Hz, 1H), 7.69 (d, J=9.1 Hz, 2H), 7.31 (d, J=9.1 Hz, 2H), 6.54 (d, J=2.5 Hz, 1H), 4.56 (s, 2H). APCI MS m/z 321, 323 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:19]([NH2:21])=[O:20])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:8]=1)=[N+]=[N-].CO.[Cl-].[NH4+]>[Zn].O1CCCC1>[NH2:1][C:4]1[S:5][C:6]([C:19]([NH2:21])=[O:20])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[N:8]=1
Reactant: [N-]=[N+]=Nc1nc(-c2cccc(C(F)(F)F)c2)c(C(N)=O)s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1sc(N)nc1-c1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 102.9 %

Procedure:
To a solution of 0.9035 g (2.884 mmole) of 2-azido-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide, 27 mL of methanol and 27 mL of tetrahydrofuran, was added 1.91 g (29.21 mg-atom) of zinc and 3.82 g (71.42 mmole) of ammonium chloride. The mixture was stirred vigorously for 1 hour, and then filtered through Diatomaceous earth, washing the filter pad with methanol and tetrahydrofuran. The filtrate was concentrated under reduced pressure, diluted with 350 mL of ethyl acetate and washed three times with 100 mL of water, twice with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 0.8527 g of 2-amino-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (V.48).
Reaction SMILES: [CH2:1]([C:9]1[C:10](=O)[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O=P(Cl)(Cl)[Cl:33].C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:33][C:10]1[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCCOc1ccc(-c2ccc(CCCCCCCC)c(=O)[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCCCOc1ccc(-c2ccc(CCCCCCCC)c(Cl)n2)cc1

Procedure:
0.32 g (0.8 mmol) of 3-octyl-6-(4-octyloxyphenyl)-1H-2-pyridone are heated together with 15 ml of phosphorus oxytrichloride in a sealed tube at 200° C. for 3 hours. The reaction mixture is poured onto ice water, and the resulting mixture is made basic with sodium carbonate. Extraction of the aqueous phase with methylene chloride, washing of the organic phase with sodium chloride solution, drying over sodium sulfate, filtration, removal of the solvent by distillation and chromatography (silica gel, 8:2 hexane/ethyl acetate) give 0.22 g of 2-chloro-3-octyl-6-(4-octyloxyphenyl)pyridine. ##STR15##
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][C:18]([O:20]CC)=O)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.O.[NH2:24][NH2:25]>C(O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][C:18]([NH:24][NH2:25])=[O:20])=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: CCOC(=O)CCc1ccc2c(cnn2C2CCCCO2)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CCc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 80 °C
Yield: 99.5 %

Procedure:
To a stirred solution of ethyl 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanoate (0.59 g, 1.951 mmol) in ethanol (5 mL) was added hydrazine hydrate (0.306 mL, 9.76 mmol) and the reaction was heated at 80° C. overnight. The solid which formed was filtered and dried to afford 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl) propanehydrazide (0.56 g, 82%), used without further purification. 1HNMR: 400 MHz, DMSO-d6: δ 1.58-1.59 (m, 2H), 1.92-1.96 (m, 1H), 1.97-2021.00 (m, 1H), 2.34-2.42 (m, 3H), 2.90-2.92 (m, 2H), 3.72-3.76 (m, 1H), 3.86-3.89 (m, 1H), 4.14 (s, 4H), 5.79-5.79 (m, 1H), 7.25-7.26 (m, 1H), 7.54 (s, 1H), 7.62 (d, J=8.80 Hz, 1H), 8.01 (s, 1H), 8.94 (s, 2H). LCMS: RT 0.64 min; LCMS (ES-API), m/z 205 (M-THP).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:11][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13].[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:12]([O:14][CH:15]([CH3:16])[CH3:17])=[O:13]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1c(F)cccc1NC(=O)OC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(C(=O)OC(C)C)c1cccc(F)c1C(=O)OC
Reaction time: 1 h
Yield: 68 %

Procedure:
Add a solution of 2-Isopropoxycarbonylamino-6-fluor-benzoic acid methyl ester (3.0 g, 11.76 mmol) in DMF (43 mL) to a suspension of sodium hydride 60% dispersion mineral oil (471 mg, 11.76 mmol) in DMF (43 mL) at 0° C. under an atmosphere of nitrogen and allow to reach room temperature over 1 h. Add ethyl 4-bromobutyrate (2.5 mL, 17.64 mmol) and stir at room temperature for 14 h. Dilute with ethyl acetate, wash with 1M HCl, water and brine. Dry the organic layer over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to provide the title compound (2.96, 68%). MS (ES+): 370 (M+H).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[N:6]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:35]=[N:36][C:37]([NH2:40])=[N:38][CH:39]=3)=[N:32][CH:33]=2)O1>>[NH2:40][C:37]1[N:38]=[CH:39][C:34]([C:31]2[N:32]=[CH:33][C:28]([C:2]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=3[O:4][C:5]3[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[N:6]=3)=[CH:29][CH:30]=2)=[CH:35][N:36]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Reactant: Nc1nccc(Oc2cc(C(F)(F)F)ccc2Br)n1
Product: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3Oc3ccnc(N)n3)cn2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(2-bromo-5-(trifluoromethyl)phenoxy)pyrimidin-2-amine and 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H14F3N7O, 425.12; m/z found, 426.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.89 (s, 2H), 8.67 (dd, J=2.3, 0.8, 1H), 7.99 (d, J=5.6, 1H), 7.95 (dd, J=8.3, 2.3, 1H), 7.81 (dd, J=8.2, 0.9, 1H), 7.76-7.69 (m, 2H), 7.59 (s, 1H), 6.18 (d, J=5.8, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=2)[N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][N:11]([C:17]1[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=3)[N:18]=1)[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc3cc([N+](=O)[O-])ccc3n1)C2

Procedure:
Was prepared according to method A from 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 2-chloro-6-nitroquinoline. Decomp.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>C(#N)C>[CH3:25][O:24][C:22](=[O:23])[CH2:21][N:17]1[CH2:16][CH2:15][N:14]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:19][CH2:18]1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60 %

Procedure:
Potassium carbonate (3.4 g, 25 mmol) was added to a mixture of N-Boc-piperazine (3.0 g, 16 mmol) in acetonitrile (20 mL). Methyl bromoacetate (1.5 mL, 16 mmol) was added to the mixture. Reaction stirred at room temperature for 1.5 hours. Mixture was filtered over celite. Filtrate was concentrated in vacuo. Residue was treated with diethyl ether (10 mL), filtered and concentrated in vacuo. Bulb to bulb distillation (165° C. at 700 mtorr) gave the title compound as clear colorless oil in 60% yield. MS m/e (M+H)+=259.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]([NH2:16])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:27][C:28]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:29]=1[C:30](Cl)=[O:31].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH:7]([NH:16][C:30](=[O:31])[C:29]1[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:28]=1[CH3:27])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([I:15])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(N)Cc1ccc(I)cc1
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)c(C(=O)NC(Cc2ccc(I)cc2)C(=O)OC(C)(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
1.5 g (4.32 mmol) of (1) and 2.9 ml (17.3 mmol) of DIPEA were dissolved in 15 ml of DCM and cooled to 0° C. 1.73 g (9.51 mmol) of 2,4,6-trimethylbenzoyl chloride were added and the solution was stirred at room temperature for 3 h. The solution was poured into saturated NaHCO3 and the aqueous layer was extracted with ethyl acetate. The organic layer was extracted with saturated NaHCO3, brine and dried over Na2SO4. The solvent was removed at the evaporator. The product was purified by column chromatography on silica gel using ethyl acetate/hexane to give 1.83 g of (2).