Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[OH:2][CH2:3][CH2:4][CH2:5][N+:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[CH:8][CH:7]=1.[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:24]1[C:36]2[CH:35]=[CH:34][C:33]([CH:37]=O)=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2.N1CCCCC1>C(O)C>[Br-:1].[OH:2][CH2:3][CH2:4][CH2:5][N+:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](/[CH:16]=[CH:37]/[C:33]2[CH:34]=[CH:35][C:36]3[N:24]([CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH3:17])[C:25]4[C:30]([C:31]=3[CH:32]=2)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:8][CH:7]=1
Reactant: Cc1cc[n+](CCCO)c2ccccc12
Reactant: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Agent: [Br-]
Solvent: CCO
Solvent: C1CCNCC1
Product: COCCOCCn1c2ccccc2c2cc(/C=C/c3cc[n+](CCCO)c4ccccc34)ccc21
Temperature: 25 °C
Yield: 41 %

Procedure:
A solution mixture of 7 (0.17 g, 0.6 mmol), 3a (0.24 g, 0.8 mmol) and piperidine (0.1 mL) in ethanol (40 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed. The residue was purified by precipitation from methanol and ethyl acetate to afford SLOH-Pr (0.14 g) in 41% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J=6.8 Hz, 1H), 9.15 (d, J=8.4 Hz, 1H), 8.88 (s, 1H), 8.51 (d, J=6.8 Hz, 1H), 8.45 (d, J=16 Hz, 1H), 8.37 (d, J=16 Hz, 1H), 8.28-8.24 (m, 2H), 8.13 (d, J=8.4 Hz, 1H), 8.05 (t, J=8.0 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.31 (t, J=7.2 Hz, 1H), 5.01 (t, J=7.2 Hz, 2H), 4.86 (t, J=5.2 Hz, 1H), 4.63 (t, J=4.8 Hz, 2H), 3.84 (t, J=5.2 Hz, 2H), 3.55 (tr, J=5.2 Hz, 2H), 3.47 (t, J=5.6 Hz, 2H), 3.31 (t, J=4.8 Hz, 2H), 3.11 (s, 3H), 2.13 (t, J=6.0 Hz, 2H). 13C NMR (400 MHz, DMSO-d6) δ 153.3, 147.3, 145.1, 142.2, 140.9, 137.9, 135.0, 128.8, 127.4, 126.8, 126.7, 126.5, 126.4, 122.8, 122.2, 121.8, 120.4, 119.9, 119.0, 116.3, 115.2, 110.5, 110.4, 71.3, 69.8, 68.9, 58.1, 57.6, 54.2, 42.9, 32.0. HRMS (MALDI-TOF) m/z Calcd for C31H33N2O3 481.2485. Found 481.2458 [M]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][CH3:11])=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([C@H:18]2[CH2:20][C@H:19]2[CH2:21][CH2:22][OH:23])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:10]([O:9][CH2:8][C:5]1[CH:4]=[N:3][C:2]([N:12]2[CH2:17][CH2:16][CH:15]([C@H:18]3[CH2:20][C@H:19]3[CH2:21][CH2:22][OH:23])[CH2:14][CH2:13]2)=[N:7][CH:6]=1)[CH3:11]
Reactant: CCOCc1cnc(Cl)nc1
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
In a 250 ml RBF 2-chloro-5-(ethoxymethyl)pyrimidine (280 mg, 1.622 mmol) and 2-[(1S,2R)-2-(piperidin-4-yl)cyclopropyl]ethanol (334 mg, 1.622 mmol) were dissolved in DMF (1622 μl). Cesium carbonate (1586 mg, 4.87 mmol) was added and the mixture stirred at 70° C. overnight. The mixture was diluted with 4:1 water:brine (200 ml), extracted with EtOAc (3×100 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vacuo. The mixture was purified on a 100 g Biotage HP-SiO2 cartridge using a gradient eluant of 0-100% EtOAc:hexanes to afford the title compound. LC/MS (m/z): 306 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[NH:17][N:18]=[CH:19][CH:20]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:20]=[CH:19][N:18]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:17]=2)=[N:13][C:12]=1[CH3:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCc1ccccn1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1nc(-c2ccn(CCc3ccccn3)n2)sc1C(=O)NCc1ccccc1
Temperature: 90 °C
Yield: 42.1 %

Procedure:
A solution of 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid benzylamide (0.1 g, 0.33 mmol) in dimethyl sulfoxide (5 mL) was treated with 2-(2-bromo-ethyl)-pyridine (0.089 g, 0.33 mmol) and potassium carbonate (0.140 g, 1.0 mmol), and the reaction mixture was heated to 90° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue, was purified by preparative thin layer chromatography over silica gel eluting with (5% methanol, 95% methylene chloride) to provide 4-methyl-2-[1-(2-pyridin-2-yl-ethyl)-1H-pyrazol-3-yl]-thiazole-5-carboxylic acid benzylamide (56 mg, 43% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=4.0 Hz, 1H), 7.50-7.57 (m, 1H), 7.29-7.42 (m, 5H), 7.21 (s, 1H), 7.12-7.19 (m, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.68 (s, 1H), 6.01 (bs, 1H), 4.62 (d, J=8.0 Hz, 2H), 4.61 (t, J=8.0 Hz, 2H), 3.36 (t, J=8.0 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=404.2; Rt=1.25 min; HRMS (M+H)+=404.15.
Reaction SMILES: OC(CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=O.CN1CCOCC1.ClC(OCC(C)C)=O.N[C:33]1[CH:34]=[C:35]([CH:44]=[CH:45][CH:46]=1)[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:37]>CN(C=O)C>[C:36]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)(=[O:37])[C:35]1[CH:44]=[CH:45][CH:46]=[CH:33][CH:34]=1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 112.6 %

Procedure:
The D-biotin (50 mg, 2.05 mmol) is solubilized in 23 ml of anhydrous DMF in the hot state. The mixture is cooled to 0° C. under argon, and then N-methylmorpholine (295 μl, 2.67 mmol) and isobutyl chloroformate (420 μl, 3.28 mmol) are successively added. The mixture is kept stirred for 30 min, and then 3-aminobenzophenone (605 mg, 3.07 mmol) and N-methylmorpholine (240 μl, 2.17 mmol) in 7 ml of DMF are added. The solution is maintained stirred at 0° C. for 2 h, and then evaporated to dryness. The residue is taken up in 1 ml of MeOH, and then 25 ml of water are added. The precipitate obtained is filtered, washed with water and then with ether to give 810 mg (93%) of crude product 1d. Recrystallization from the MeOH—H2O pair gives 1d (630 mg, 72%) in the form of a white powder.
Reaction SMILES: [CH:1]([CH:3]1[CH2:9][CH:8]2[CH:6]([CH2:7]2)[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:2].CC(=CC)C.[O-:22]Cl=O.[Na+]>CC(C)=O.O>[C:13]([O:12][C:10]([N:4]1[CH:3]([C:1]([OH:22])=[O:2])[CH2:9][CH:8]2[CH:6]([CH2:7]2)[CH2:5]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(C)OC(=O)N1CC2CC2CC1C=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CC2CC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a mixture of tert-butyl 4-formyl-3-azabicyclo[4.1.0]heptane-3-carboxylate (D16) (615 mg, 2.73 mmol) in acetone/water (30/20 ml) NaH2PO4.2H2O (426 mg, 2.73 mmol), 2-methyl-2-butene (1.3 ml, 12.28 mmol) and NaClO2 (864 mg, 9.55 mmol) were added and the reaction mixture was stirred at RT overnight. Solvents were evaporated in vacuo and the remaining residue was taken up into EtOAc (10 ml) and water (10 ml). Phases were separated and the aqueous layer was extracted with EtOAc (2×10 ml). The combined organic extracts after solvent evaporation afforded the title compound (D17) (0.5 g).
Reaction SMILES: [CH3:1][CH:2]([N:9]1[CH2:12][CH:11]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-:22].[K+].O>C(O)(C)(C)C>[CH3:1][CH:2]([N:9]1[CH2:10][CH:11]([O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH2:19])=[O:22])=[CH:20][CH:21]=2)[CH2:12]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(c1ccccc1)N1CC(Oc2ccc(C#N)cc2)C1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(c1ccccc1)N1CC(Oc2ccc(C(N)=O)cc2)C1

Procedure:
To 45.0 g. (0.16 mole) of 4-[1-(α-methylbenzyl)-3-azetidinyloxy]benzonitrile in 500 ml of t-butyl alcohol was added 45.0 g. of finely ground potassium hydroxide. The mixture was stirred and refluxed for 30 minutes. Ice and water were added and a thick white solid separated. The solid was recrystallized from toluene to give 30.0 g. (63%) of product melting at 174°-178° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.C(Cl)Cl>[CH3:13][O:12][CH:11]([O:14][CH3:15])[CH2:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: COC(Cn1cc([N+](=O)[O-])cn1)OC
Temperature: 85 °C

Procedure:
To a solution of 4-nitro-1H-pyrazole (1.50 g, 13.27 mmol) in MeCN (30 mL), 2-bromo-1,1-dimethoxyethane (2.34 mL, 19.90 mmol) and Cs2CO3 (6.48 g, 19.90 mmol) was added. The resulting mixture was refluxed (85° C.) for 20 h, then the reaction mixture was allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM and the filtrate was concentrated in vacuo. The residue was partitioned between water and DCM, then the aq. layer was extracted with DCM (2×) and the comb. org. layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 1-(2,2-dimethoxyethyl)-4-nitro-1H-pyrazole as a yellow oil which was used in the next step without further purification. LC-MS conditions B: tR=0.50 min, [M+H]+=no ionization.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:14])=[O:7]
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Reactant: NCCCN1CCOCC1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCCCN2CCOCC2)c1
Temperature: 25 °C
Yield: 20.6 %

Procedure:
3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid (200 mg, 0.59 mmol) and N-(aminopropyl)morpholine (0.17 ml, 1.18 mmol) in DMF 3.0 mL was added EDC (168.7 mg, 0.88 mmol), HOBt (118.9 mg, 0.88 mmol) and DIPEA (0.15 ml, 0.88 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=15:1) to give 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-(3-morpholine-4-yl-propyl)-benzamide as a yellow solid (56.7 mg, 20% yield).
Reaction SMILES: Cl[C:2]1[CH:14]=[C:6]2[N:7]([CH:11]3[CH2:13][CH2:12]3)[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:15])[N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH2:34][OH:35])[CH:20]=[CH:21][C:22]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1>>[CH:11]1([N:7]2[CH2:8][CH2:9][CH2:10][N:5]3[C:4](=[O:15])[N:3]=[C:2]([O:35][CH2:34][C:19]4[CH:20]=[CH:21][C:22]([O:23][C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=5)=[C:17]([F:16])[CH:18]=4)[CH:14]=[C:6]23)[CH2:13][CH2:12]1
Reactant: O=c1nc(Cl)cc2n1CCCN2C1CC1
Reactant: OCc1ccc(Oc2cccc(C(F)(F)F)c2)c(F)c1
Product: O=c1nc(OCc2ccc(Oc3cccc(C(F)(F)F)c3)c(F)c2)cc2n1CCCN2C1CC1

Procedure:
The title compound was prepared by a procedure similar to that described for E2 starting from 8-chloro-1-cyclopropyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (3-fluoro-4-(3-(trifluoromethyl)phenoxy)phenyl) methanol.
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:17])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH:18]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19]1.CCOCC>C1COCC1>[CH:11]1([CH2:10][CH2:9][C:8]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(CCC1CCCCC1)Sc1ccccn1
Reactant: Br[Mg]C1CCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CCC1CCCCC1)C1CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
3-Cyclohexyl-thiopropionic acid S-pyridin-2-yl ester (1.43 g, 5.74 mmol) from Step 1 above was dissolved in dry THF (28 mL) and cooled to −78° C. A solution of cyclopentylmagnesium bromide in Et2O (2.0 M, 3.01 mL, 6.02 mmol) was added dropwise. After stirring 1 h, the cooling bath was removed. The reaction mixture was quenched with 1N HCl and extracted with EtOAc (100 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (1% EtOAc in hexanes) to give the product (0.99 g, 83%) as clear oil. 1H NMR (CDCl3) δ: 0.82-1.84 (m, 21H), 2.42-2.47 (m, 2H), 2.82-2.92 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-].O>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC1CN(Cc2ccccc2)CCC1O
Yield: 68.7 %

Procedure:
A solution (15 ml) of 3.98 g of 1-benzyl-3-methyl-4-piperidone in diethyl ether was added to a suspension (10 ml) of 0.78 g of aluminum lithium hydride in diethyl ether in an ice bath, and the solution was heated under ref lux for 3 hours. Water was added to the solution, and the solution was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous solution of hydrogen chloride. The solution was dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography, and from the fractions eluted with chloroform-methanol (19:1 v/v) was obtained 2.76 g of 1-benzyl-4-hydroxy-3-methylpiperidine, which was an oily product (yield: 69%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1([C:25]2[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[N:19]1([C:25]2[N:30]=[CH:29][C:28]([NH:31][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:27][CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCOCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (1.58 g, 6.14 mmol), 6-morpholin-4-yl-pyridin-3-ylamine (1.0 g, 5.58 mmol), N-hydroxybenzotriazole (1.27 g, 8.37 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.6 g, 8.37 mmol) in anhydrous dichloromethane (20 mL) was stirred at room temperature overnight. After the reaction was complete, solvent was evaporated. The resulted mixture was mixed with water and extracted twice with ethyl acetate. The organic layers were collected, combined, washed with brine, dried over sodium sulfate, and then concentrated to give a solid. The crude product was purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-100% ethyl acetate in hexane) to gave 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide (1.15 g, 50%) as an off-white solid. LCMS calcd for C20H17F3N4O3 (m/e) 418, obsd 419 (M+H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][S@:7]([CH2:9][CH2:10][CH3:11])=[O:8])[CH3:2].[O:12]1[CH2:14][C@@H:13]1[CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>C(O)(C)C>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][S@:7]([CH2:9][CH2:10][CH3:11])=[O:8])[CH2:14][C@@H:13]([OH:12])[CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)[CH3:2]
Reactant: CCC[S@](=O)CCCNCC
Reactant: N#Cc1ccc(OC[C@H]2CO2)cc1
Solvent: CC(C)O
Product: CCC[S@](=O)CCCN(CC)C[C@@H](O)COc1ccc(C#N)cc1
Yield: 102.4 %

Procedure:
A mixture of 3 g of ethyl (3-(S*)-propylsulfinyl)propylamine and 3.18 g of (R)-4-(oxiranylmethoxy)benzonitrile was refluxed for 16 h in 25 ml of isopropyl alcohol. After evaporation of the solvent, the crude product was dissolved in 2M hydrochloric acid, washed with ether, the solution brought to pH 11.5 with 2M sodium hydroxide and extracted with dichloromethane. Evaporation of the organic phase gave 6.11 g of an oil,
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[S:22][C:21]([C:23]([OH:25])=O)=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:19]=3[CH:32]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[N:36]1([CH2:35][CH2:34][NH:33][C:23]([C:21]2[S:22][C:18]3[CH:17]=[CH:16][C:15]([NH:14][S:11]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=4)(=[O:12])=[O:13])=[CH:32][C:19]=3[C:20]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3sc(C(=O)O)c(-c4ccccc4)c3c2)cc1
Reactant: NCCN1CCOCC1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3sc(C(=O)NCCN4CCOCC4)c(-c4ccccc4)c3c2)cc1
Yield: 14 %

Procedure:
According to Step 1, after reaction of 5-(4-tert-Butylbenzenesulfonylamino)-3-phenyl-1-benzothiophene-2-carboxylic acid (155 mg, 0.33 mmol) with N—(2-aminoethyl)-morpholine (0.046 mL, 0.35 mmol) followed by chromatographic purification (silica gel, dichloromethane/methanol (0-10% methanol)) and recrystallization from ethyl acetate/hexane, the desired compound is obtained at 14% yield (27 mg).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH2:9])[N:6]([CH3:10])[N:5]=2)[CH2:3][CH2:2]1.[F:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:20]=2)[CH:15]=[CH:14][C:13]=1[NH:31][C:32](=O)[O:33]C(C)=C.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:32]([NH:31][C:13]3[CH:14]=[CH:15][C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]5[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=5)[CH:20]=4)=[CH:17][C:12]=3[F:11])=[O:33])[N:6]([CH3:10])[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cn1nc(C2CC2)cc1N
Reactant: C=C(C)OC(=O)Nc1ccc(Oc2ccnc(-c3cnn(C)c3)c2)cc1F
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C5CC5)nn4C)c(F)c3)ccn2)cn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
To a solution of 3-cyclopropyl-1-methyl-1H-pyrazol-5-amine (60 mg, 0.434 mmol) in dioxane (1 mL) was added prop-1-en-2-yl 2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamate from Example 21 (0.16 g, 0.434 mmol), and DBU (6.61 mg, 0.043 mmol) and the mixture was stirred overnight at 70° C. The reaction was checked by LC-MS, solvent was removed and the residue was purified by silica gel column chromatography (EtOAc/hexane→CH2Cl2/MeOH). Pure fractions were combined and concentrated. The residue was dissolved in CH3CN:H2O (1:1, 2 mL) and lyophilized to obtain 1-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (26 mg, 13% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.92 (s, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.39 (d, J=6.0 Hz, 1H), 8.28 (s, 1H), 8.18 (t, J=9.6 Hz, 1H), 7.99 (s, 1H), 7.26 (m, 2H), 7.02 (m, 1H), 6.70 (dd, J=2.4, and 6.0 Hz, 1H), 3.87 (s, 3H), 3.59 (s, 3H), 1.76 (m, 1H), 0.80 (m, 2H), 0.59 (m, 2H); MS (ESI) m/z; 448.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][O:8][C@H:9]1[CH2:25][O:24][C:12]2=[CH:13][CH:14]=[C:15]3[C:19]([N:18]([CH2:20][C@H:21](O)[CH3:22])[N:17]=[CH:16]3)=[C:11]2[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:43]=[N+:44]=[N-:45].[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:26])[CH2:7][O:8][C@H:9]1[CH2:25][O:24][C:12]2=[CH:13][CH:14]=[C:15]3[C:19]([N:18]([CH2:20][C@@H:21]([N:43]=[N+:44]=[N-:45])[CH3:22])[N:17]=[CH:16]3)=[C:11]2[CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](O)Cn1ncc2ccc3c(c21)C[C@@H](OCC(=O)OC(C)(C)C)CO3
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc3c(c21)C[C@@H](OCC(=O)OC(C)(C)C)CO3)N=[N+]=[N-]
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
To a solution of the product from Step B (0.68 g, 1.88 mmol) and triethylamine (0.76 g, 1.04 mL, 7.51 mmol, 4.0 equiv.) in anhydrous THF (50 ml) at 0° C. was added methanesulfonic anhydride (0.59 g, 3.38 mmol, 1.8 equiv.). The mixture was stirred for 10 min and sodium azide (1.22 g, 18.8 mmol, 10 equiv.) was added. The solvent was removed by evaporation and anhydrous dimethyl sulfoxide (20 mL) was added. This mixture was heated at 95° C. for 3 h, cooled, poured into a saturated solution of sodium bicarbonate (80 mL), and extracted with ethyl acetate (3×60 mL). The combined extracts were dried (MgSO4), filtered, and evaporated to an oil, which was purified by chromatography (silica, 10% ethyl acetate in hexane) to give a solid (0.61 g, 84%): mp 77-78° C.; LC/MS (+ESI) m/z 388 (M+H).
Reaction SMILES: C(O[C:4]([CH:6]1[C:14](=[O:15])[C:13]2[CH:12]=[N:11][CH:10]=[CH:9][C:8]=2[C:7]1=[O:16])=[O:5])C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:25][C:4]([CH:6]2[C:14](=[O:15])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7]2=[O:16])=[O:5])[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1C(=O)c2ccncc2C1=O
Reactant: COc1cccc(N)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1cccc(NC(=O)C2C(=O)c3ccncc3C2=O)c1
Temperature: 25 °C

Procedure:
5,7-Dioxo-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid ethyl ester (18 g) (see, Robin D. Allan and Joyce Fong, Aust. J. Chem., Vol. 36, Pp. 1221-1226, 1983), m-anisidine (17.7 ml) and acetic acid (9 ml) were suspended in toluene (1,000 ml). This mixture was refluxed for 110 minutes under nitrogen. The mixture was cooled to room temperature and the precipitate (ppt) was collected with suction. The ppt was washed with toluene and dichloromethane and dried under reduced pressure to give a brown powder (21.6 g). ESI−MS: m/z 297 (MH+); 1H-NMR (DMSO-d6): δ3.74 (3H, s), 6.54 (1H, dd, J=8.5 Hz, J=2.5 Hz), 7.00 (1H, bd, J=8.5 Hz), 7.17 (1H, t, J=8.5 Hz), 7.42 (1H, t-like, J=ca 2.5 Hz), 7.73 (1H, d, 5 Hz), 8.71 (1H, s), 8.91 (1H, d, J=5 Hz), 10.65 (1H, brs).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[N:16]([CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN([CH:28]=[O:29])C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]3[N:16]([C:17]=2[CH:28]=[O:29])[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2cc3ccccn3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc3ccccn3c2C=O)cc1
Temperature: 55 °C
Reaction time: 0.67 h

Procedure:
A slurry of 20 g of 2-(4-methoxy phenyl) indolizine in 35 ml of DMF was added to a solution of 10 ml of phosphorus oxychloride in 30 ml of DMF at 10°-20° C. After the reaction solution was stirred at 40° for 40 min., it was added to 200 g of ice. 120 g of 25 percent sodium hydroxide solution was added and the resulting mixture was heated to 55° C., cooled, and filtered. The air-dried product weighed 23 g.