Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC(Br)C.C[Si](Cl)(C)C.[CH2:10]([O:12][C:13](=[O:16])[CH2:14]Br)C.[O:17]=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:20][CH2:19]1>C1COCC1.[Zn]>[OH:17][C:18]1([CH2:14][C:13]([O:12][CH3:10])=[O:16])[CH2:19][CH2:20][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:22][CH2:23]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)CBr
Agent: CC(Br)Br
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)CC1(O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a round-bottom flask containing Zn dust (2.3 g, 36 mmol) was added dibromoethane (585 mg, 3.11 mmol). The resulting mixture was warmed to 60° C. and allowed to cool for 1 min. This heating-cooling process was repeated three more times, and then the flask was allowed to cool for an additional 3 min. Trimethylsilylchloride (456 mg, 4.2 mmol) in THF (5 mL) was added, followed by addition of ethyl-2-bromoacetate (2 g, 12 mmol) in THF (8 mL). The reaction was warmed to 60° C. for an additional two hours until a dark grey suspension was obtained. The mixture was cooled to room temperature; benzyl 4-oxopiperidine-1-carboxylate (1.9 g, 8.2 mmol) in THF (20 mL) was then added. The resulting mixture was stirred for 3 days, and then quenched with water. The solid was filtered off, and the aqueous was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. Purification by a standard method gave the desired product. 1H NMR (CHLOROFORM-d) δ: 7.33-7.43 (m, 5H), 5.14 (s, 2H), 3.89-4.05 (m, 2H), 3.68-3.79 (m, 3H), 3.22-3.36 (m, 2H), 2.49 (s, 2H), 2.19 (s, 1H), 1.71 (d, J=12.6 Hz, 2H), 1.53 (dd, J=12.5, 4.2 Hz, 2H). LCMS (m/z): 308.1 (M+1)+
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[O:8][N:7]=[C:6]([CH3:9])[CH:5]=1.[CH:10]1C=C(OC(OC2N=CC=CC=2)=S)N=CC=1.[NH:26]([C:28](=[O:49])[C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([C@H:38]2[CH2:43][CH2:42][C@H:41]([CH2:44][C:45]([O:47]C)=[O:46])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1)=[O:30])[NH2:27].CCN=C=NCCCN(C)C>C1COCC1.CN(C=O)C>[CH3:9][C:6]1[CH:5]=[C:4]([NH:3][C:10]2[O:49][C:28]([C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([C@H:38]4[CH2:43][CH2:42][C@H:41]([CH2:44][C:45]([OH:47])=[O:46])[CH2:40][CH2:39]4)=[CH:34][CH:33]=3)=[O:30])=[N:26][N:27]=2)[O:8][N:7]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Reactant: Cc1cc(N)on1
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nnc(C(=O)Nc3ccc([C@H]4CC[C@H](CC(=O)O)CC4)cc3)o2)on1
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (50 mg of a 60% dispersion in mineral oil, 1.25 mmol) was added to a stirred solution of 5-amino-3-methylisoxazole in THF. After 5 minutes di-2-pyridyl thionocarbonate (290 mg, 1.25 mmol) was added. Stirring was continued for a further 10 minutes then methyl [trans-4-(4-{[hydrazino(oxo)acetyl]amino}phenyl)cyclo-hexyl]acetate (Intermediate 43) (333 mg, 1.00 mmol) was added followed by DMF (5 mL). The mixture heated to 85° C. for 15 minutes then EDAC (240 mg, 1.25 mmol) was added. After a further 1 h at 85° C. volatile material was removed by evaporation and the residue was redissolved in MeOH (5 mL), THF (2.5 mL) and NaOH (3 mL of a 2M aqueous solution) and stirred for 16 h. The reaction mixture was concentrated under reduced pressure then redissolved in water (10 mL) and acidified with HCl (2M aqueous solution) to ca pH 5. The resulting precipitate was centrifuged, washed with water, dried under reduced pressure and triturated with ether to give the title compound (83 mg, 20%) as a solid; 1H NMR δ 1.02-1.20 (m, 2H), 1.36-1.54 (m, 2H), 1.65-1.88 (m, 5H), 2.13 (d, 2H), 2.24 (s, 3H), 2.39-2.48 (m, 1H), 6.10 (s, 1H), 7.24 (d, 2H), 7.69 (d, 2H), 11.00 (s, 1H), 12.11 (s, 1H); MS m/e MH+ 426.
Reaction SMILES: [CH2:1]([CH:3]1[C:7](=[O:8])[N:6]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:5][C:4]1([C:18]([O:20]C)=[O:19])[CH3:17])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([CH:3]1[C:7](=[O:8])[N:6]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:5][C:4]1([C:18]([OH:20])=[O:19])[CH3:17])[CH3:2]
Reactant: CCC1C(=O)N([C@H](C)c2ccccc2)CC1(C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC1C(=O)N([C@H](C)c2ccccc2)CC1(C)C(=O)O
Temperature: 60 °C
Reaction time: 5.5 h

Procedure:
To a solution of the methyl 4-ethyl-3-methyl-5-oxo-1-[(R)-1-phenylethyl]pyrrolidin-3-yl-carboxylate (stereoisomer A) produced in Reference Example 32 (10.63 g, 36.7 mmol) in tetrahydrofuran (330 mL) and methanol (110 mL), 2N aqueous solution of sodium hydroxide (110 mL, 220 mmol) was added at room temperature, and the mixture was stirred in an oil bath at 60° C. for 5.5 hours. The reaction mixture was concentrated under reduced pressure, and after adding concentrated hydrochloric acid to the concentrate in an ice bath for acidification, the mixture was extracted with chloroform (300 mL+2×100 mL). The organic layers were combined, and dried with anhydrous sodium sulfate. After removing the dessicating agent by filtration, the solvent was removed by distillation under reduced pressure to obtain 11.46 g (quantitative) of the crude title compound as a pale brown solid. The crude product was used in the subsequent reaction with no further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH:14]([NH2:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>C(Cl)Cl.O.C(N(CC)CC)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:27][CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 68.7 h
Yield: 98.7 %

Procedure:
2-Nitrobenzenesulfonyl chloride (2.50 g) was added to a methylene chloride solution (30 ml) containing benzhydrylamine (1.87 g) and triethylamine (1.58 g) under ice cooling, followed by stirring for 3.3 hours under ice cooling and for 68.7 hours at room temperature. Water (40 ml), 6 N hydrochloric acid (2 ml) and methylene chloride (10 ml) were added to the reaction mixture, followed by extraction and solution separation, and the aqueous layer was extracted again with methylene chloride (10 ml). The resulting extract was dried over sodium sulfate, filtered, concentrated and further dissolved again in ethyl acetate (70 ml), followed by washing with water (20 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and dried under vacuum to obtain N-(2-nitrobenzenesulfonyl)benzhydrylamine (3.71 g; yield: 98.7%).
Reaction SMILES: COC1C=CC(C(Cl)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:41][CH:42]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:46]([NH:45][C:43](=[O:44])[C:40]2[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=2)=[S:47])=[C:29]([F:34])[CH:28]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: COc1ccc(C(=O)Cl)cc1
Agent: COc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
4-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (71 mg, yield 88%).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[SH:5][C:6]1[NH:10][N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[N:7]=1>C[O-].[Na+]>[CH:11]([C:8]1[N:7]=[C:6]([S:5][CH2:3][C:2]#[CH:1])[NH:10][N:9]=1)([CH3:13])[CH3:12]
Reactant: C#CCBr
Reactant: CC(C)c1n[nH]c(S)n1
Agent: C[O-]
Agent: [Na+]
Product: C#CCSc1nc(C(C)C)n[nH]1

Procedure:
11.9 g. Prop-2-ynyl bromide was added to a solution of 14.3 g. 5-mercapto-3-isopropyl-1,2,4-triazole in sodium methoxide solution (2.3 g. sodium dissolved in 200 ml. methanol). Then the solution was boiled under reflux for 21/2 hours. The solvent was evaporated under reduced pressure from the steam bath and the residual solid triturated with 500 ml. cold water, filtered off and dried under vacuum to give 3-isopropyl-5-prop-2-ynylthio-1,2,4-triazole which was purified by recrystallisation in the presence of charcoal, from petroleum ether (boiling point 80°-100° C.). The melting point of the product was 91°-92° C.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[S:11][C:10]([Br:12])=[N:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=O)[CH:2]=[CH2:3].P(Cl)(Cl)(Cl)(Cl)Cl.Cl.O1CCOCC1.CO[CH:36](OC)[CH2:37][NH2:38]>ClCCl.O>[CH2:1]([N:4]1[CH:36]=[CH:37][N:38]=[C:5]1[C:7]1[S:11][C:10]([Br:12])=[N:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH:2]=[CH2:3]
Reactant: C=CCNC(=O)c1sc(Br)nc1-c1ccc(Cl)cc1Cl
Reactant: COC(CN)OC
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: C=CCn1ccnc1-c1sc(Br)nc1-c1ccc(Cl)cc1Cl
Temperature: 60 °C
Yield: 66.8 %

Procedure:
To a solution of N-Allyl-2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole-5-carboxamide (8.40 g, 21.4 mmol) in dichloromethane (200 mL) was added phosphorus pentachloride (5.05 g, 24.2 mmol) and 4M hydrochloric acid in dioxane (0.833 mL, 3.26 mmol), and the reaction was heated to 60° C. for 90 minutes under an atmosphere on nitrogen. The reaction was allowed to cool to room temperature and then aminoacetaldehyde dimethyl acetal (25.7 mL, 236 mmol) was added slowly through the condenser. The mixture was heated to 60° C. for 2 hours under an atmosphere on nitrogen. The mixture was cooled to room temperature, and water was added (200 mL). The layers were separated and the organic phase was washed with water again (2×200 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and washed with dichloromethane (200 mL). To this dichloromethane solution of the intermediate was added 4M hydrochloric acid in dioxane (17 mL, 65 mmol) and the solution was stirred at reflux for 16 hours. The solution was decanted (leaving behind an oily black residue on the flask) and then evaporated and diluted with ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted 3 more times with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (5.93 g, 67%). LCMS: (FA) ES+, 416. 1H NMR (400 MHz, d1-chloroform) δ: 7.45-7.42 (m, 1H), 7.25-7.19 (m, 2H), 7.16-7.14 (m, 1H), 6.93-6.90 (m, 1H), 5.55-5.44 (m, 1H), 5.13-5.08 (m, 1H), 5.95-4.88 (m, 1H), 4.19-4.15 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[C:3]([C:6]1[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12)=[N:4][OH:5].C[Si]([N:26]=[C:27]=[O:28])(C)C.N1C=CC=CC=1>C1COCC1>[C:27]([O:5][N:4]=[C:3]([C:6]1[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12)[CH:2]([CH3:21])[CH3:1])(=[O:28])[NH2:26]
Reactant: CC(C)C(=NO)c1c(-c2ccccc2)nn2ccccc12
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)C(=NOC(N)=O)c1c(-c2ccccc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 630 mg (2.24 mmol) of 2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one oxime in 2 ml of anhydrous THF was added 600 μl of trimethylsilyl isocyanate (85%) dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature overnight, followed by the addition of 500 μl pyridine and stirring for another 4 hours. The solvent was removed in vacuo, and the residue obtained was purified on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant to yield 482 mg (66.3%) of 2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one O-carbamoyl oxime. Compound 1017.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]2[N:22]([CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[N:19]=2)=[C:6]([C:8]#[C:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH:7]=1>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]2[N:22]([CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[N:19]=2)=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=2)[CH:7]=1
Reactant: N#Cc1ccc(C#Cc2cc(Cl)ccc2-c2nc3ccccc3n2CC2CCCCC2)cc1
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(CCc2cc(Cl)ccc2-c2nc3ccccc3n2CC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
To a solution of 4-[5-chloro-2-(1-cyclohexylmethyl-1H-benzoimidazol-2-yl)-phenylethynyl]-benzonitrile (0.27 g, 0.6 mmol) in methanol was added 10% palladium on carbon and stirred for 16 h at 25° C. under hydrogen balloon pressure. The reaction mixture was filtered through a bed of celite and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (10-20% ethyl acetate/n-hexane) to yield the compound as an off-white powder (23%). MS (Turbo Spray): m/z=454.4 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][CH2:11]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.Cl.[CH3:25][NH:26][CH3:27]>ClCCl.O>[CH3:25][N:26]([CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:27]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(OCCCCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CN(C)CCCOc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
A mixture of 3-(4-nitrophenoxy)propyl chloride (2 g, 9.27 mmol), potassium carbonate (7.69 g, 46.4 mmol) and acetonitrile (15 mL) were stirred in a sealed tube and dimethylamine hydrochloride (3.78 g, 46.4 mmol) added quickly. The mixture was stirred and heated overnight at 80° C. The mixture was cooled well before opening the pressure tube, then water and dichloromethane were added and the aqueous layer was extracted with dichloromethane. The combined organics were dried and evaporated giving the title product. 1H NMR (400 MHz, CDCl3): 1.95 (2H, t, J 7 Hz); 2.2 (6H, s); 2.35-2.45 (2H, m); 4.05 (2H, t, J 7 Hz); 6.9 (2H, d, J 8 Hz); 8.1 (2H, d, J 8 Hz).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[C:11]1([C:17](=O)[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(O)(=O)C>[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][N:10]=[C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: Cc1ccccc1NN
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1NN=C(C(=O)c1ccccc1)c1ccccc1
Yield: 101.8 %

Procedure:
A mixture of 2-methylphenyl hydrazine hydrochloride (0.79 g, 5.0 mmol) and 1,2-diphenyl-ethane-1,2-dione (1.05 g, 5 mmol) in 20 mL of glacial acetic acid was refluxed for 30 min. The reaction was poured into water and extracted with ethyl acetate. The combined organics was dried over MgSO4 and concentrated to give 1.6 gram of 1,2-diphenylethane-1,2-dione (2-methylphenyl)-hydrazone as an orange solid. MS (ESI) m/z 315 ([M+H]+);
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21]([OH:23])=O)=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH2:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)(Cl)Cl>[CH:1]1[C:10]2[C:5](=[C:6]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])=[CH:16][CH:15]=[CH:14]4)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(O)c1cccc2cc(-c3cccc4cnccc34)ccc12
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)c1cccc2cc(-c3cccc4cnccc34)ccc12

Procedure:
6-(isoquinolin-5-yl)-1-naphthoic acid (55 mg, 0.18 mmol), 2-aminothiazole (24 mg, 0.23 mmol), DIPEA (0.048 mL, 0.27 mmol) and HATU (0.1 g, 0.27 mmol) were stirred in CHCl3 (1 mL) at room temperature overnight. The solid formed was filtered, rinsed with CHCl3, MeOH and dried under vacuum to give the titled compound as a solid. MS (ESI pos. ion) m/z: 382. (M+H). Calc'd Exact Mass for C23H15N3OS: 381.
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[O:15][C:16]1[C:17]([F:24])=[CH:18][C:19]([F:23])=[C:20]([CH:22]=1)[NH2:21].[C:25]([C:29]1[CH:33]=[C:32]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[N:31]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([C:29]1[CH:33]=[C:32]([NH:34][C:35]([NH:21][C:20]2[CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[C:17]([F:24])=[CH:18][C:19]=2[F:23])=[O:36])[N:31]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)[N:30]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Reactant: COc1cc2ncnc(Oc3cc(N)c(F)cc3F)c2cc1OC
Product: COc1cc2ncnc(Oc3cc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c(F)cc3F)c2cc1OC
Yield: 96.7 %

Procedure:
The title compound was prepared from 5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluoroaniline (100 mg, 0.3 mmol) and phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (140 mg, 0.4 mmol) using the procedure in Example 115C to give 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluorophenyl)urea (170 mg, 0.29 mmol, 96%). 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.86 (s, 1H), 8.58 (s, 1H), 8.22 (t, 1H), 7.61 (t, 1H), 7.58 (s, 1H), 7.42-7.34 (m, 5H), 6.35 (s, 1H), 4.01 (s, 3H), 4.00 (s, 3H), 2.39 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 589 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:35])/[CH:3]=[CH:4]/[S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[O:23])[CH:15]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6].C[Si](C)(C)[O:38][NH2:39]>C1COCC1>[OH:38][NH:39][CH:3]([CH:2]([CH3:35])[CH3:1])[CH2:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[O:23])[CH:15]=2)=[CH:12][CH:13]=1)(=[O:6])=[O:7]
Reactant: C[Si](C)(C)ON
Reactant: CC(C)/C=C/S(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1
Solvent: C1CCOC1
Product: CC(C)C(CS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)NO
Temperature: 25 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
To a solution of N-[(4′-{[(1E)-3-methylbut-1-en-1-yl]sulfonyl}biphenyl-3-yl)methyl]-4-oxo-3,4-dihydroquinazoline-2-carboxamide obtained in Reference Example 106 (0.180 g, 0.369 mmol) in THF (4 mL) was added O-(trimethylsilyl)hydroxylamine (0.271 mL, 2.22 mmol) at room temperature, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate-diethyl ether to give the title compound as a white powder (0.125 g, 65%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:7][C:2]([NH:20][C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CCCO)c1
Reactant: COc1cccc(CCNc2nc(Cl)ncc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(CCNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Temperature: 100 °C
Yield: 90.3 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.50 g, 1.7 mmol) (prepared according to Example 8, Step A) and 3-(3-aminophenyl)propan-1-ol (0.34 g, 2.3 mmol) in 1,4-dioxane (14.3 mL) was added p-toluenesulfonic acid monohydrate (0.12 g, 0.61 mmol). The mixture was heated at 100° C. for 16 hours and the reaction was complete. To the mixture was added NaHCO3 aqueous solution (saturated). The organic solvent was removed under vacuum. Water and EtOAc were added to the residue. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as a light brown gel (0.634 g, 92%). LCMS for C22H26ClN4O2 (M+H)+: m/z=413.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:21][C@@H:22]([CH2:26][CH:27]1[CH2:29][CH2:28]1)[C:23]([NH2:25])=[O:24]>>[C:23]([C@@H:22]([NH:21][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])[CH2:26][CH:27]1[CH2:29][CH2:28]1)(=[O:24])[NH2:25]
Reactant: NC(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1
Agent: Cl
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48 e) and (S)-2-amino-3-cyclopropyl-propanamide hydrochloride as starting materials, MS (EI): m/e=384.2 [M+H]+.