Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]2[C:5]=1[CH:6]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[NH:8]2.[C:18](Cl)(=[O:26])[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH3:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]2[C:5]=1[CH:6]=[C:7]([C:14]([O:16][CH3:17])=[O:15])[N:8]2[C:18]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:26]
Reactant: COC(=O)c1cc2c(C)ccc(C)c2[nH]1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(C)ccc(C)c2n1C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
A suspension of 1.2 g (50 mmol) of 60% sodium hydride in 100 ml of anhydrous DMF was prepared. A solution of 9.2 g (45.3 mmol) of methyl 4,7-dimethylindole-2-carboxylate in 150 ml of anhydrous DMF was added dropwise thereto over a period of 1 hour. The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0° C. A solution of 6.25 ml (50.0 mmol) of phenyl chlorocarbonate in 20 ml of anhydrous DMF was added dropwise over a period of 30 minutes. The reaction mixture was stirred at room temperature for 15 hours and then added dropwise to 800 ml of ice water. The reaction mixture was extracted with 200 ml of ethyl acetate three times. The ethyl acetate layers were combined, washed with 300 ml of water twice and dried over anhydrous magnesium sulfate. After the ethyl acetate layers were distilled off under reduced pressure, the residue was recrystallized from acetone to provide 1.50 g of light yellow crystals. Yield: 10%
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:9]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1)#[N:2].[N:18]([Sn](CCCC)(CCCC)CCCC)=[N+:19]=[N-:20]>P(CC1C2N(C=C(C(O)=O)N=2)C=CC=1)(O)(O)=O>[NH:18]1[C:1]([CH2:3][C:4]2[N:9]3[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=[C:8]3[CH:7]=[CH:6][CH:5]=2)=[N:2][N:20]=[N:19]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCOC(=O)c1cn2c(CC#N)cccc2n1
Agent: O=C(O)c1cn2cccc(CP(=O)(O)O)c2n1
Product: CCOC(=O)c1cn2c(Cc3nnn[nH]3)cccc2n1
Temperature: 25 °C

Procedure:
The title material is prepared by heating the title product of Example 99 with azido tributylstannane at 80° C. for 72 h. After cooling to room temperature, the reaction is treated with methanolic HCl for 30 min., diluted with 4N HCl, washed with diethyl ether and concentrated to yield title material.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10]1[O:14][N:13]=[C:12]([CH2:15][NH2:16])[N:11]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH:30]=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CCOC(C)=O>C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][NH:16][CH2:15][C:12]2[N:11]=[C:10]([C:2]3[O:1][C:9]4[CH:8]=[CH:7][N:6]=[CH:5][C:4]=4[CH:3]=3)[O:14][N:13]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: NCc1noc(-c2cc3cnccc3o2)n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNCc2noc(-c3cc4cnccc4o3)n2)CC1
Reaction time: 72 h

Procedure:
A solution of C-(5-furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-yl)methylamine (Preparation 14, 50 mg, 0.23 mmol) and 4-formylpiperidine-1-carboxylic acid tert-butyl ester (59 mg, 0.27 mmol) in anhydrous CH2Cl2 (5 mL) was stirred for 45 min. Na(AcO)3BH (78 mg, 0.37 mmol) was added, then the mixture was stirred for 3 d. Standard aqueous work-up, followed by column chromatography (EtOAc), gave the title compound: RT=2.18 min; m/z (ES+)=414.1 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[N:14]3[N:15]=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:17]=[C:18]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:31][NH2:32]>C(O)CCC>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][C:8]([C:10]3[N:14]4[N:15]=[C:16]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:17]=[C:18]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]4=[N:12][CH:11]=3)=[CH:7][CH:6]=2)[NH:32][N:31]=1
Reactant: CC(C)CNc1cc(-c2ccccc2)nn2c(-c3ccc(C#N)c(F)c3)cnc12
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: CC(C)CNc1cc(-c2ccccc2)nn2c(-c3ccc4c(N)n[nH]c4c3)cnc12
Temperature: 120 °C
Yield: 53 %

Procedure:
To a solution of 46 mg (119 μmol) 2-fluoro-4-[8-(isobutylamino)-6-phenylimidazo[1,2-b]pyridazin-3-yl]benzonitrile which was prepared according to intermediate example 11a in 2.5 mL n-butanol were added 232 μL hydrazine hydrate and the mixture was heated at 120° C. overnight. The precipitate was filtered, washed with 2-propanol and dried to give 26.5 mg (53%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:31][CH2:32][CH:33]=[C:34]1[C:40]2[CH:41]=[CH:42][CH:43]=[N:44][C:39]=2[CH2:38][O:37][C:36]2[CH:45]=[CH:46][C:47]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:48][C:35]1=2>C(O)(C)C>[CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[CH:6]1[CH2:10][CH2:9][N:8]([CH2:31][CH2:32][CH:33]=[C:34]2[C:40]3[CH:41]=[CH:42][CH:43]=[N:44][C:39]=3[CH2:38][O:37][C:36]3[CH:45]=[CH:46][C:47]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:48][C:35]2=3)[CH2:7]1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCNC1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1

Procedure:
To a solution of [(4-Chloro-benzyl)-pyrrolidin-3-yl-amino]-acetic acid methyl ester (188 mg, 0.67 mmol) in isopropanol (5 mL) was added 2,6-lutidine (186 uL, 1.6 mmol), and a catalytic amount of potassium iodide. The resultant solution was heated at 80° C. and to it was added 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (149 mg, 0.4 mmol) portionwise over 0.5 h. The reaction solution was heated overnight then partitioned between water and ethyl acetate. The product was purified on SiO2 (ethyl acetate:Methanol:triethylamine 95:4.5:0.4) and isolated as a film. LCMS (retention time=1.84, ES+; 576); 1H NMR (CD3OD): δ 8.46 (1H,d), 7.76 (1H, d), 7.45 (2H, m), 7.23 (5H, m), 6.74 (1H, d), 6.15 (1H, m), 3.72 (2H, m), 3.60 (4H, s), 3.30 (6H, m), 2.78 (4H, m), 2.42 (2H, m), 2.05 (1H, m), 1.82 (1H, m), 1.50 (6H, s).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:26](=[O:30])[CH2:27][CH2:28][CH3:29])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N[C@@H]1CCc2cccc(N3CCN(C)CC3)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (300 mg, 1.2 mmol) and triethylamine (260 μL, 1.8 mmol) in methylene chloride (50 mL) was added dropwise butyryl chloride (140 μL, 1.3 mmol) in methylene chloride (10 mL). After the addition the reaction was allowed to stir at ambient temperature for 1 h and then washed with a dilute aqueous sodium hydrogen carbonate solution. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:4:0.5) as the eluent. Yield: 330 mg (86%) of the title compound as white crystals: mp 131-132° C.; [α]21D +24° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 315 (39, M+).
Reaction SMILES: C(=N[OH:9])C1C=CC=CC=1.[H-].[Na+].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:26]([C:33]#[N:34])([CH3:32])[C:27]([O:29]CC)=O)=[C:17]([C:19]#[C:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=1>CN(C=O)C.O1CCOCC1>[Cl:12][C:13]1[CH:18]=[C:17]2[C:16](=[CH:15][CH:14]=1)[C:26]([C:33]#[N:34])([CH3:32])[C:27](=[O:29])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]2[OH:9]
Reactant: CCOC(=O)C#Cc1cc(Cl)ccc1C(C)(C#N)C(=O)OCC
Reactant: ON=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C#N)C1=O
Reaction time: 0.5 h

Procedure:
A solution of benzaldehyde oxime (0.16 g, 1.3 mmol) in DMF (3 mL) was added dropwise to a stirred suspension of 60% NaH (0.033 mL, 1.3 mmol) in dry 1,4-dioxane (5 mL) under a nitrogen atmosphere at room temperature. After 30 minutes, a solution of ethyl 3-(5-chloro-2-(2-cyano-1-ethoxy-1-oxopropan-2-yl)phenyl)propiolate (0.445 g, 1.3 mmol) in DMF (3 mL) was added dropwise. The reaction was monitored by LC-MS and, when complete, the solvent was removed. The residual brown oil was dissolved in DCM (50 mL), water (30 mL), and AcOH (2 mL). The layers were separated, and the aqueous layer was extracted with DCM (3×30 mL). The combined organic layers were dried with MgSO4 and concentrated in vacuo. The crude residue was purified using silica flash chromatography with a gradient of 10-50% EtOAc/hexanes. MS m/e=306 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[N:19]1([CH2:25][CH2:26][O:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[Cl-].[Cl-].[Cl-].[Al+3].C(S)C>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[C:32]([C:31]2[CH:35]=[CH:36][C:28]([O:27][CH2:26][CH2:25][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:29][CH:30]=2)=[O:33])=[CH:4][CH:3]=1
Reactant: COc1ccc2cc(-c3ccc(F)cc3)sc2c1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCCl
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(F)cc2)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product from Example 17, Step 1 (83 mg, 0.32 mmol) and 4-(2-Piperidin-1-yl-ethoxy)-benzoyl chloride (1.39 mL, 0.39 mmol) in 3.3 mL of 1,2-dichloroethane was added, in two portions, aluminum trichloride (322 mg, 2.4 mmol) and the reaction was heated at reflux for 1 hr. At this time the coupling was complete and demethylation was carried out cooling the reaction to room temperature, adding ethanethiol (0.10 mL, 1.41 mmol) dropwise and stirring at room temperature for a further 1.5 hrs. The reaction was quenched with saturated sodium bicarbonate solution and extracted twice with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was chromatographed on silica gel using 1% MeOH:methylene chloride to 3% MeOH:methylene chloride as the gradient eluant to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]1[O:14][CH2:13][CH2:12][O:11]1.[C:15]([N:19]1[C@H:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][O:21][C:20]1=[O:30])(=[O:18])[CH:16]=[CH2:17].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:11]1[CH2:12][CH2:13][O:14][CH:10]1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1/[CH:17]=[CH:16]/[C:15]([N:19]1[C@H:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][O:21][C:20]1=[O:30])=[O:18]
Reactant: COc1ccc(Br)c(C2OCCO2)c1
Reactant: C=CC(=O)N1C(=O)OC[C@H]1c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: COc1ccc(/C=C/C(=O)N2C(=O)OC[C@H]2c2ccccc2)c(C2OCCO2)c1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A mixture of Compound 20 (2.6 g, 10.0 mmol), (R)-3-acryloyl-4-phenyloxazolidin-2-one (2.2 g, 10.0 mmol), tri-o-tolyl phosphine (0.30 g, 1.0 mmol) and palladium acetate (0.11 g, 0.5 mmol) in triethylamine (35 mL) under argon was stirred under reflux for 90 min. The resulting reaction mixture was cooled to room temperature and concentrated in vacuo. The residue obtained was purified by flash column chromatography (hexanes/ethyl acetate 95:5 to 60:40) to give Compound 21 (3.2 g, 81%) as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=15.5 Hz, 1H), 7.81 (d, J=15.5 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.41-7.30 (m, 5H), 7.17 (d, J=3.0 Hz, 1H), 6.91 (dd, J=8.5, 3.0 Hz, 1H), 6.01 (s, 1H), 5.54 (dd, J=9.0, 3.5 Hz, 1H), 4.73 (t, J=9.0 Hz, 1H), 4.30 (dd, J=9.0, 4.0 Hz, 1H), 4.32-4.28 (m, 2H), 4.13-4.10 (m, 2H), 3.85 (s, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:6]=2[NH2:7])[CH2:3][CH2:2]1.CO[C:23](OC)(OC)[CH3:24]>CO>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[C:9]1[CH:10]=[CH:11][C:5]2[N:4]([CH:1]3[CH2:2][CH2:3]3)[C:23]([CH3:24])=[N:7][C:6]=2[CH:8]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CC1
Reactant: COC(C)(OC)OC
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.6 %

Procedure:
To a methanol (5 mL) solution of 2-(2-cyclopropylaminoanilin-5-yl)benzoxazole (see Working Example 53-1) (140 mg, 0.425 mmol) was added 1,1,1-trimethoxyethane (75 mg, 0.624 mmol), and this was stirred at room temperature for 6 hours. After the reaction was complete, this was concentrated, and the residue obtained was purified by silica gel column chromatography to yield the imidazole (63.5 mg, 42% yield).
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[O:11]=[CH:12][C:13]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:15]([OH:16])[CH:14]=1>CN(C=O)C.CCOCC>[CH:1]([O:16][C:15]1[CH:14]=[C:13]([CH:21]=[CH:20][C:17]=1[O:18][CH3:19])[CH:12]=[O:11])([CH3:3])[CH3:2]
Reactant: COc1ccc(C=O)cc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC(C)C
Temperature: 80 °C

Procedure:
Isopropyl bromide (19.0 mL, 200 mmol) was added to a suspension of K2CO3 (42.0 g, 302 mmol) and isovanillin (23 g, 151.3 mmol) in DMF (100 gmL) and the stirring slurry heated to 80° C. for 13 h. The reaction mixture was then cooled to room temperature, diluted with ether (200 mL) and washed with H2O (4×200 mL), dried (MgSO4) and concentrated under reduced pressure giving the title compound as a slightly tan oil (29.3 g, 100%) which required no further purification. The spectra of this material are identical with those previously reported (H. Ishii, I.-S. Chen and T. Ishikawa J. Chem. Soc., Perkin Trans. 1, 1987, 671.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH:42]3[CH2:44][CH2:43]3)=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH:42]3[CH2:43][CH2:44]3)=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K21) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow solid (325 mg, 78%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:19])=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)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.[CH2:60]([O:62][C:63](=[O:71])[CH2:64][C:65]1[N:66]=[C:67]([NH2:70])[S:68][CH:69]=1)[CH3:61]>C(Cl)Cl>[CH2:60]([O:62][C:63](=[O:71])[CH2:64][C:65]1[N:66]=[C:67]([NH:70][C:8](=[O:9])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:19])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[S:68][CH:69]=1)[CH3:61]
Reactant: O=C(Nc1ccc(C(CC2CCCC2)C(=O)O)cc1)c1cccnc1
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(NC(=O)c3cccnc3)cc2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 39.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-[(pyridine-3-carbonyl)-amino]-phenyl}-propionic acid (prepared in Example 10, 169 mg, 0.50 mmol) in methylene chloride (10 mL) at 25° C. was treated with triethylamine (0.21 mL, 1.3 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), and (2-amino-thiazol-4-yl)-acetic acid ethyl ester (140 mg, 0.75 mmol). The reaction mixture was stirred at 25° C. for 20 h. At this time, the reaction was diluted with methylene chloride (50 mL). This solution was washed with a 1N aqueous hydrochloric acid solution (1×15 mL), water (1×15 mL), and a saturated aqueous sodium chloride solution (2×25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 100% ethyl acetate) afforded [2-(3-cyclopentyl-2-{4-[(pyridine-3-carbonyl)-amino]-phenyl}-propionylamino)-thiazol-4-yl]-acetic acid ethyl ester (100.1 mg, 39.5%) as white solid: mp 195-200° C.; EI-HRMS m/e calcd for C27H30N4O4S (M+) 506.1987, found 506.1985.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11]>>[CH2:1]([O:8][C:14]([NH:13][S:10]([Cl:9])(=[O:12])=[O:11])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Product: O=C(NS(=O)(=O)Cl)OCc1ccccc1

Procedure:
The procedure of Example 6 was followed scaling the reaction to 0.2 moles each of benzyl alcohol and chlorosulfonyl isocyanate to give benzyloxycarbonylsulfamoyl chloride.
Reaction SMILES: [Si]([O:18][C:19]1[CH:20]=[C:21]([C@:26]([NH:45][C:46]([NH:48][CH2:49][C:50]([F:53])([F:52])[F:51])=[O:47])([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[C:36]([C:41]([F:44])([F:43])[F:42])[CH:35]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=[C:23]([F:25])[CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(Cl)Cl>[F:40][C:37]1[CH:38]=[CH:39][C:34]([C@@:26]([NH:45][C:46]([NH:48][CH2:49][C:50]([F:51])([F:52])[F:53])=[O:47])([C:21]2[CH:20]=[C:19]([OH:18])[CH:24]=[C:23]([F:25])[CH:22]=2)[CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:35][C:36]=1[C:41]([F:44])([F:42])[F:43]
Reactant: CC(C)(C)[Si](Oc1cc(F)cc([C@](Cc2ccccc2)(NC(=O)NCC(F)(F)F)c2ccc(F)c(C(F)(F)F)c2)c1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)N[C@@](Cc1ccccc1)(c1cc(O)cc(F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78.9 %

Procedure:
To a solution of (R)-1-(1-(3-(tert-butyldiphenylsilyloxy)-5-fluorophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (85 mg, 0.11 mmol) in THF (1.5 mL) was added TBAF (1.0 M in THF, 0.12 mL, 0.12 mmol). The resulting mixture was stirred at room temperature for 45 min. The reaction was diluted with CH2Cl2 and washed with sat. NH4Cl, H2O and sat. NaCl, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give (R)-1-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-hydroxyphenyl)-2-phenylethyl)-3-(2,2,2-trifluoroethyl)urea (Example 254, 45 mg, yield 77%). LCMS: RT=2.0 min [M+H] 519.1 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.20-7.27 (3H, m), 7.09-7.18 (3H, m), 6.72 (1H, d, J=9.60 Hz), 6.66 (3H, d, J=7.07 Hz), 6.57 (1H, s), 3.73-3.78 (1H, m), 3.65-3.71 (1H, m), 3.63 (1H, d, J=8.59 Hz), 3.47-3.58 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:28]([NH2:30])([CH3:29])[C:27](=[O:31])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[N:9]=2)[N:7]=1.[CH:32]1([CH:35]=O)[CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:28]([NH:30][CH2:35][CH:32]3[CH2:34][CH2:33]3)([CH3:29])[C:27](=[O:31])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:22])([F:21])[F:23])[N:9]=2)[N:7]=1
Reactant: CC1(N)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC1(NCC2CC2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the intermediate from Step B (20 mg, 0.045 mmol) in MeOH (45.2 μl) and DCM (45.2 μl) was added cyclopropanecarbaldehyde (3.17 mg, 0.045 mmol) followed by sodium triacetoxyborohydride (28.7 mg, 0.136 mmol). The reaction was stirred for 3 h at room temperature and was quenched with aqueous NaHCO3. The solution was extracted with EtOAc. The organic layer was dried (sodium sulfate), concentrated in vacuo and purified by silica gel column chromatography to afford the title product as a white solid. 1H NMR (500 MHz, CHCl3-d): δ 9.20 (s, 1H); 8.77 (d, J=8.07 Hz, 1H); 8.56 (dd, J=4.53, 1.58 Hz, 1H); 7.13 (dd, J=8.08, 4.50 Hz, 1H); 5.55 (s, 2H); 4.95-4.88 (m, 3H); 2.88-2.74 (m, 2H); 2.27 (dd, J=11.46, 6.00 Hz, 1H); 2.20-1.94 (m, 1H); 1.54 (s, 3H); 0.87-0.80 (m, 1H); 0.48-0.37 (m, 2H); 0.05-0.00 (m, 2H). m/z=497.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:23]=[CH:22][N:21]=[C:20](O)[CH:19]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:27]>C(#N)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[CH:19]=[C:20]([Cl:27])[N:21]=[CH:22][N:23]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)ncn1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Clc1ccc(-c2nc3ccccn3c2Cc2cc(Cl)ncn2)cc1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a mixture of 360 mg of 6-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-4-ol (1.07 mmol, 1 eq) in 5 mL of ACN was added 0.98 mL of POCl3 (10.7 mmol. 10 eq). The mixture was heated to 65° C. and stirred for 1 h. The solution was then diluted with EtOAc, washed with NaHCO3, dried on MgSO4, filtered and concentrated (210 mg, 55%) m/e+=355 (M+H+).