Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11](CC#N)=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:22]([OH:25])(=[O:24])[CH3:23]>O>[C:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:23][C:22]([OH:25])=[O:24])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccc(C(=O)c2cccs2)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1ccc(C(=O)c2cccs2)cc1
Temperature: 0 °C

Procedure:
A mixture of 8.6 parts of 2-[p-(2-thenoyl)phenyl]acetonitrile, 18 parts of concentrated sulfuric acid, 10 parts of acetic acid and 10 parts of water is stirred and refluxed for one hour. The reaction mixture is cooled and poured onto 200 parts of ice-water. The product is extracted twice with 160 parts of ether. The combined extracts are washed with 100 parts of diluted sodium hydroxide solution and separated. The aqueous phase is acidified with concentrated hydrochloric acid solution, whereupon the product is separated as an oil. The latter is extracted with ether. The extract is dried and evaporated. The residue is triturated in petroleumether and the crude product is dissolved in chloroform. It is purified by column chromatography, using a mixture of chloroform and 5% of methanol. The pure fractions are collected and the solvent is evaporated. The residue is triturated in petroleumether and the solid product is crystallized from acetonitrile at -20° C, yielding 2-[p-(2-thenoyl)phenyl]acetic acid; mp. 126°-129° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][CH:45]([OH:48])[CH2:44][CH2:43]2)=[CH:38][C:32]=1[C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>>[CH3:36][N:35]([CH3:37])[C:33]([C:32]1[CH:38]=[C:39]([C@H:42]2[CH2:47][CH2:46][C@H:45]([OH:48])[CH2:44][CH2:43]2)[CH:40]=[CH:41][C:31]=1[NH:30][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1)=[O:34]
Reactant: CN(C)C(=O)c1cc(C2CCC(O)CC2)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)cc3C(=O)N(C)C)n2)c(OC)c1)OCC

Procedure:
The title compounds were prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (0.20 g, 0.45 mmol) and 2-amino-5-(4-hydroxycyclohexyl)-N,N-dimethylbenzamide (Compound 173A, 0.130 g, 0.496 mmol). The reaction mixture was partitioned between EtOAc and water and separated. The aqueous was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The compound was purified on an Isco Combiflash unit eluting with 0 to 5% MeOH in DCM to afford the individual trans and cis isomers. Cis: 1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.43 (s, 1H), 8.32 (s, 1H), 7.86 (d, J=8.34 Hz, 1H), 7.60 (d, J=7.83 Hz, 1H), 7.26 (dd, J=1.77, 8.59 Hz, 1H), 7.22 (d, J=2.02 Hz, 1H), 6.96 (t, J=1.89 Hz, 1H), 6.73 (d, J=7.83 Hz, 1H), 3.92-4.01 (m, 4H), 3.89 (br. s., 1H), 3.77 (s, 3H), 3.13-3.23 (m, 2H), 2.91 (d, J=15.16 Hz, 6H), 2.56 (t, J=11.87 Hz, 1H), 1.79-1.92 (m, 2H), 1.70-1.78 (m, 2H), 1.49-1.61 (m, 4H), 1.18 (t, J=7.07 Hz, 6H); MS (ES+): m/z: 681.2723 [MH+]. HPLC: tR=1.45 min (UPLC TOF MS: polar—3 min). Trans: 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 7.85 (d, J=8.84 Hz, 1H), 7.58 (d, J=8.08 Hz, 1H), 7.26 (dd, J=2.02, 8.34 Hz, 1H), 7.22 (d, J=2.02 Hz, 1H), 6.96 (s, 1H), 6.73 (d, J=7.83 Hz, 1H), 4.57 (d, J=4.55 Hz, 1H), 3.91-4.01 (m, 4H), 3.76 (s, 3H), 3.40-3.54 (m, 1H), 3.14-3.23 (m, 2H), 2.91 (d, J=18.95 Hz, 6H), 1.93 (d, J=9.35 Hz, 2H), 1.79 (d, J=12.38 Hz, 2H), 1.45-1.58 (m, 2H), 1.22-1.35 (m, 2H), 1.19 (t, J=7.07 Hz, 6H); MS (ES+): m/z: 680.2332 [MH+]. HPLC: tR=1.40 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH2:24]Br)[CH:17]=[CH:16][CH:15]=1.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([C:8]2=[O:11])[CH2:24][C:22]2[C:23]4[C:18]([CH:19]=[CH:20][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:4][CH:3]=1
Reactant: BrCc1cccc2cccc(CBr)c12
Reactant: O=C1CCc2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CC12Cc1cccc3cccc(c13)C2
Yield: 55.9 %

Procedure:
A mixture of 6-bromo-2,3-dihydro-1H-inden-1-one (400 mg, 1.9 mmol) and 1,8-bis(bromomethyl)naphthalene (596 mg, 1.9 mmol) in THF (20 mL) was added NaH (152 mg, 3.8 mmol) at room temperature, the mixture was heated under reflux for 2 h. The mixture was quenched with water, concentrated, then extracted with CH2Cl2, washed with brine, dried over Na2SO4 and concentrated to give 6-bromo-1′,3′-dihydrospiro[indene-2,2′-phenalen]-1(3H)-one (386 mg, 56%). 1H-NMR (CDCl3): 2.79 (d, 2H), 3.50 (d, 2H), 7.12 (m, 1H), 7.18 (m, 2H), 7.36 (m, 2H), 7.60 (m, 1H), 7.71 (m, 1H), 7.92 (m, 1H).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:13])[C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1.[CH3:15][OH:16].[ClH:17]>C(Cl)Cl.O1CCOCC1>[ClH:17].[F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:13])[C:11](=[NH:12])[O:16][CH3:15])[CH:7]=[CH:8][CH:9]=1
Reactant: CO
Reactant: N#CC(O)c1cccc(OC(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=N)C(O)c1cccc(OC(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 131A (1.83 g, 9.2 mmol) in anhydrous CH2Cl2 (30 mL) at 0° C. was added MeOH (2.24 mL) and 4.0 N HCl in dioxane (9.2 mL). The mixture was stirred at 0° C. for 30 min and then at rt for 4.0 h. Solvent was removed to give methyl 2-(3-(difluoromethoxy)-phenyl)-2-hydroxyacetimidate HCl salt. To this salt in CH2Cl2 (10 mL) was added H2O (10 mL). The mixture was stirred at rt for 30 min, then extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried and concentrated. The crude prouduct was purified by silica gel chromatography to give 131B (700 mg, 33% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.70 (s, 3H) 5.22 (s, 1H) 6.82 (t, J=74.04 Hz, 1H) 7.09 (dd, J=7.91, 2.20 Hz, 1H) 7.23 (s, 1H) 7.28-7.34 (m, 1H) 7.38 (t, J=7.91 Hz, 1H).
Reaction SMILES: [N:1](OCCCC)=O.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[CH3:18])([O-:10])=[O:9].CC(C)([O-])C.[K+].Cl>CN(C)C=O>[CH3:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[C:18]#[N:1]
Reactant: Cc1cccc([N+](=O)[O-])c1C
Reactant: CCCCON=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A solution of 16 g (150 mmol) of n-butyl nitrite (97%) and 7.7 g (50 mmol) of 3-nitro-o-xylene (97%) in 50 ml of dimethylformamide is cooled to from −5 to −10° C., and a solution of 11 g (100 mmol) of potassium tert-butoxide in 50 ml of dimethylformamide is added at this temperature, over a period of 1.5 hours. The reaction mixture is stirred at room temperature for another 6 days. For work-up, the mixture is poured onto ice-water and adjusted to pH 1 using hydrochloric acid, and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated. This gives 8.2 g of product. The 2-methyl-6-nitrobenzonitrile can be purified by silica gel chromatography using the mobile phase toluene. M.p.: 101-103° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]2[CH2:13][O:12]2)=[CH:5][CH:4]=1.S(=O)(=O)(O)[OH:15].CC(=O)C.C(=O)(O)[O-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH:11]([OH:15])[CH2:13][OH:12])=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(CCC2CO2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(CCC(O)CO)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 12 parts of 2-[2-(4-methoxyphenyl)-ethyl]oxirane in 1.8 parts of sulfuric acid and 160 parts of 2-propanone are added 100 parts of water. The whole is stirred for 2 days at room temperature. The reaction mixture is stirred with a sodium bicarbonate solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 1-[2-(4-methoxyphenyl)ethyl]-1,2-ethanediol as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=1[F:25]>CN(C=O)C.CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:25]
Reactant: COc1cc2ncnc(Nc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(N)cc3F)c2cc1OC
Reaction time: 3 h
Yield: 64.9 %

Procedure:
(6,7-Dimethoxy-quinazolin-4-yl)-(2-fluoro-4-nitro-phenyl)-amine (673 mg, 1.95 mmol) was dissolved in a combination of DMF (20 ml) and MeOH (20 ml), to which was added 10% Pd/C (227 mg). The mixture was shaken under an atmosphere of H2 on a Parr hydrogenator at 40 psi for 3 hrs. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. The resulting residue was triturated in EtOAc/Et2O. The resulting solids were filtered, washed with Et2O, and dried under vacuum to give N1-(6,7-dimethoxy-quinazolin-4-yl)-2-fluoro-benzene-1,4-diamine (398 mg, 65%) which was used in the next reaction without further purification. 1H-NMR (400 MHz, DMSO): 10.80 (br s, 1H), 10.30 (br s, 1H), 8.63 (s, 1H), 8.15 (s, 1H), 7.33 (s, 1H), 7.15 (m, 1H), 6.45 (m, 1H), 3.96 (s, 6H). LC/MS Calcd for [M+H]+ 315.1. found 315.4.
Reaction SMILES: NCC1C=C(NC([O:17][CH2:18][CH2:19][C:20]2C=C[C:23](C(NC3C=C4C(=CC=3)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C4)C(O)=O)=[CH:22][C:21]=2C)=O)C=CC=1S(CC)(=O)=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:90]([OH:96])([C:92](F)(F)F)=[O:91]>>[OH:91][CH:90]1[C:92]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:17])[O:96]1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)OCCc2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc1CN
Reactant: O=C(O)C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Product: O=C1OC(O)c2ccccc21
Yield: 35 %

Procedure:
Using a procedure analogous to that used to prepare Example 28, 31D (400 mg, 0.51 mmol) was cyclized with PyBOP instead of BOP, deprotected with TFA, and purified by reverse phase HPLC to give Example 31 (100 mg, 35%) as a tan solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.09-1.24 (m, 3 H) 2.27 (s, 2 H) 2.49 (s, 2 H) 2.67-2.88 (m, 1 H) 3.05-3.17 (m, 1 H) 3.22-3.28 (m, 2 H) 4.05 (d, J=9.89 Hz, 0.5 H) 4.13-4.25 (m, 0.5 H) 4.29-4.39 (m, 1 H) 5.01-5.12 (m, 2 H) 5.14-5.18 (m, J=3.30 Hz, 1 H) 6.43 (none, 1 H) 6.68 (d, J=2.75 Hz, 1 H) 6.70-6.78 (m, J=5.50 Hz, 1 H) 6.78-6.86 (m, 1 H) 6.92-7.16 (m, 2.5 H) 7.21 (m, 0.5 H) 7.44 (m, 0.5 H) 7.51 (s, 0.5 H) 7.65-7.74 (m, 1 H) 7.90-8.02 (m, 1 H) 8.76-8.92 (m, J=6.05 Hz, 1 H). MS (ESI) m/z 574.18 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]1([O:31][C:32]2[N:37]=[CH:36][C:35]([C:38]([OH:40])=O)=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.[F:50][C:51]([F:64])([F:63])[C:52]1[NH:53][C:54]2[C:59]([CH:60]=1)=[CH:58][C:57]([CH2:61][NH2:62])=[CH:56][CH:55]=2>CN(C=O)C>[O:31]([C:32]1[N:37]=[CH:36][C:35]([C:38]([NH:62][CH2:61][C:57]2[CH:58]=[C:59]3[C:54](=[CH:55][CH:56]=2)[NH:53][C:52]([C:51]([F:64])([F:50])[F:63])=[CH:60]3)=[O:40])=[CH:34][CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)nc1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1ccc(Oc2ccccc2)nc1
Reaction time: 24 h
Yield: 16.7 %

Procedure:
To a stirred solution of HATU (121 mg, 0.319 mmol) in DMF (1 ml) was added 6-(phenyloxy)-3-pyridinecarboxylic acid (Maybridge; 51.5 mg, 0.239 mmol) in DMF (0.5 ml), followed by DIPEA (0.084 ml, 0.479 mmol) and finally {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 4, 40 mg, 0.160 mmol) in DMF (1 ml). The solution was stirred for 24 hrs. DMF was removed using a rotary evaporator followed by addition of DCM and sodium bicarbonate solution. The mixture was poured through a phase separation cartridge, the organic layer evaporated to dryness and purified using MDAP to give the title compound as a white solid (11 mg);
Reaction SMILES: C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([S:50]([N:53]([CH2:62][CH2:63][C:64]([O:66][CH3:67])=[O:65])[C:54]3([C:59]([OH:61])=O)[CH2:58][CH2:57][CH2:56][CH2:55]3)(=[O:52])=[O:51])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1.Cl.[CH2:69]([O:76][NH2:77])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>CN(C)C=O>[CH3:67][O:66][C:64](=[O:65])[CH2:63][CH2:62][N:53]([C:54]1([C:59](=[O:61])[NH:77][O:76][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH2:55][CH2:56][CH2:57][CH2:58]1)[S:50]([C:47]1[CH:48]=[CH:49][C:44]([C:41]2[CH:40]=[CH:39][C:38]([F:37])=[CH:43][CH:42]=2)=[CH:45][CH:46]=1)(=[O:51])=[O:52]
Reactant: COC(=O)CCN(C1(C(=O)O)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: NOCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCN(C1(C(=O)NOCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 4 h
Yield: 85.7 %

Procedure:
Diisopropylethylamine (4.3 mL, 24.6 mmole) and (benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate (11.0 grams, 24.9 mmole) were added sequentially to a solution of 1-[(4'-fluorobiphenyl-4-sulfonyl)-(2-methoxycarbonylethyl)-amino]cyclopentane-1-carboxylic acid (10.1 grams, 22.4 mmole) in N,N-dimethylformamide (170 mL). The mixture was stirred for 4 hours. Additional diisopropylethylamine (7.8 mL, 44.6 mmole) and O-benzylhydroxylamine hydrochloride (4.64 grams, 29.1 mmole) were then added and the resulting mixture was stirred at 60° C. for 16 hours. After concentration under vacuum, the residue was taken up in water and acidified with 1 N aqueous hydrogen chloride solution. The mixture was extracted with ethyl acetate and the extract was washed sequentially with water, saturated aqueous sodium bicarbonate solution and brine. The solution was dried over magnesium sulfate and concentrated to give a solid which upon trituration with 7:3:1 hexane/ethyl acetate/methylene chloride provided 3-[(1-benzyloxycarbamoylcyclopentyl)-(4'-fluorobiphenyl-4-sulfonyl)amino]propionic acid methyl ester as a white crystalline solid (10.65 grams, 86%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:12][C@H:13]([N:31]([C:33]([O:35]C(C)(C)C)=O)[CH3:32])[CH2:14][O:15][C:16](=[O:30])[NH:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[CH:19]=1)[CH2:8][CH:9]([F:11])[F:10])(C)(C)C.C(O)(C(F)(F)F)=O.[Cl:48][C:49]1[C:68]([F:69])=[CH:67][CH:66]=[CH:65][C:50]=1[CH2:51][NH:52]C(=O)OC1C=CC([N+]([O-])=O)=CC=1>C(Cl)Cl>[F:29][C:25]1[CH:24]=[C:23]([C:20]2[CH:19]=[C:18]([NH:17][C:16](=[O:30])[O:15][CH2:14][C@@H:13]([N:31]([CH3:32])[C:33]([NH:52][CH2:51][C:50]3[CH:65]=[CH:66][CH:67]=[C:68]([F:69])[C:49]=3[Cl:48])=[O:35])[CH2:12][NH:7][CH2:8][CH:9]([F:10])[F:11])[O:22][N:21]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(NCc1cccc(F)c1Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](COC(=O)Nc1cc(-c2cccc(F)c2)no1)CN(CC(F)F)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CNCC(F)F)COC(=O)Nc1cc(-c2cccc(F)c2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a solution of {(S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-[3-(3-fluoro-phenyl)-isoxazol-5-ylcarbamoyloxy]-propyl}-(2,2-difluoro-ethyl)-carbamic acid tert-butyl ester (291 mg, 0.62 mmol) in DCM (5 mL) was added TFA (1.0 mL). The mixture was stirred at RT for 1 h, concentrated, and dissolved in THF (10 mL). To the resulting solution were added 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate (220 mg, 0.68 mmol) and TEA (0.3 mL, 1.24 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. The solvent was removed and the resulting residue was purified on RP-HPLC using a mixture of acetonitrile and water to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-3-(2,2-difluoroethylamino)propyl 3-(3-fluorophenyl)isoxazol-5-ylcarbamate (135 mg, 39% for two steps) as white solid. LRMS (M+H+) m/z 559.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:22])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][Cl:20])=[CH:14][CH:13]=3)[C:6]=2[CH:21]=1.[C:23](Cl)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:25])[CH3:24])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][Cl:20])=[CH:16][CH:17]=3)[C:6]=2[CH:21]=1
Reactant: CC(=O)Cl
Reactant: CCc1nc2cc(N)c(Cl)cc2n1-c1ccc(CCCl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCc1nc2cc(NC(C)=O)c(Cl)cc2n1-c1ccc(CCCl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.4 %

Procedure:
To a solution of 6-chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylamine (step 6 of Example 110, 100 mg, 0.3 mmol) in pyridine (7 mL) was added dropwise acetyl chloride (0.03 mL, 0.33 mmol) under nitrogen atmosphere at 0° C., and the reaction mixture was stirred at room temperature for 1.5 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with 2N aqueous NaOH (30 mL), brine (30 mL), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:3) to afford 110 mg (98%) of the title compound as white solids: 1H-NMR (CDCl3) δ: 8.66 (1H, s), 7.56 (1H, br.s), 7.45 (2H, d, J=8.2 Hz), 7.29 (2H, d, J=8.2 Hz), 7.12 (1H, s), 3.82 (2H, t, J=7.1 Hz), 3.19 (2H, t, J=7.1 Hz), 2.77 (2H, q, J=7.6 Hz), 2.26 (3H, s), 1.34 (3H, t, J=7.6 Hz).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41].C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:37][O:38][CH2:39][C:40]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:34])([F:35])[F:36])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)=[O:41]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4ccc(N5CCNCC5)nc4)cnn23)c1
Reactant: COCC(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCN(c2ccc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-{3-[7-(6-piperazin-1-ylpyridin-3-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea (20.5 mg, 0.0413 mmol) HCl salt, methoxyacetyl chloride (5.66 μL, 0.0619 mmol) and N,N-diisopropylethylamine (40.0 μL, 0.230 mmol) in DMSO (0.5 mL) was stirred at RT for 1 h. The mixture was diluted with DMSO, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=569.2.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]23[CH2:24][CH2:23][CH2:22][CH:21]=[C:8]2[N:9]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[C:10](=[O:12])[NH:11]3)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C=O)C>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:8]12[CH2:21][CH2:22][CH2:23][CH2:24][C:7]1([CH2:6][C:5]1[CH:25]=[CH:26][C:2]([Br:1])=[CH:3][CH:4]=1)[NH:11][C:10](=[O:12])[N:9]2[C:13]1[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]([Cl:19])[CH:18]=1)[CH3:35]
Reactant: O=C1NC2(Cc3ccc(Br)cc3)CCCC=C2N1c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC12CCCCC1(Cc1ccc(Br)cc1)NC(=O)N2c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3a-(4-Bromo-benzyl)-1-(3,5-dichlorophenyl)-1,3,3a,4,5,6-hexahydro-benzimidazol-2-one (190 mg) (0.42 mmol) in DMF (5 ml) was carefully dropped on a suspension of NaH 60% (20.2 mg) (1.2 eq) in DMF (5 ml) at RT. The reaction mixture was stirred 1 h at RT, then ethyl bromoacetate (0.094 ml) (2.0 eq) was added. After one night at RT, the mixture was heated to 100° C. for 8 h, then the reaction mixture was poured on water and extracted with tBuOMe. The organic layer was washed with water, dried over Na2SO4 and concentrated. The residue was purified on SiO2 chromatography (eluent EtOAc/cyclohexane—1/10) to give [7a-(4-Bromo-benzyl)-3-(3,5-dichlorophenyl)-2-oxo-2,3,5,6,7,7a-hexahydro-benzimidazol-3a-yl]-acetic acid ethyl ester (30.2 mg) as a yellow oil. 1H NMR (CDCl3): 7.35 (2H, d), 7.10 (1H, m), 6.95 (2H, d), 6.8 (2H, m), 4.95 (1H, m), 4.45 (1H, d), 4.2 (2H, q), 3.7 (1H, d), 2.9 (1H, d), 2.8 (1H, d), 2.45-2.1 (2H, m), 2.0-1.8 (4H, m), 1.25 (3H, t).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[C:10]([OH:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[CH:42]=[CH:41][C:26]([O:27][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:32][C:33]=2[CH3:34])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:10]([O:20][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][C:29]3[N:30]=[C:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[O:32][C:33]=3[CH3:34])=[CH:41][CH:42]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccccc2)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CCC(=O)O)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.1 %

Procedure:
A mixture of ethyl 3-(1-benzyl-3-hydroxy-1H-pyrazol-4-yl)propionate (900 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.06 g), potassium carbonate (690 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtained colorless oil, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (5 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give 3-[1-benzyl-3-[-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]propionic acid (1.53 g, yield 89%). The crystals were recrystallized from acetone-hexane. melting point: 125–126° C.