Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C@H:5]([NH2:17])[CH2:6][CH:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][OH:9])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:18])[C@H:5]([NH2:17])[CH2:6][CH:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:8][O:9][S:27]([CH3:26])(=[O:29])=[O:28])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H](N)CC(CO)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](N)CC(COS(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
(R)-4-BOC-amino-5-hydroxy-pentanoic acid ethyl ester (36 g, 137.8 mmol) prepared in Step A and triethylamine (38.4 mL, 275.5 mmol) were dissolved in dichloromethane (200 mL). Methanesulfonylchloride (11.7 mL, 151.5 mmol) was added in drops thereto, and the mixture was stirred for 1 h at 0° C. to room temperature. After completion of the reaction, 1N hydrochloric acid solution was added, which was then extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate to give the title compound.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6](F)=[C:5]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[C:4]=1[CH3:23])#[N:2].C(N(CC)CC)C.[CH3:31][NH:32][C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>CS(C)=O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6]([N:35]2[CH2:36][CH2:37][C@H:33]([NH:32][CH3:31])[CH2:34]2)=[C:5]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[C:4]=1[CH3:23])#[N:2]
Reactant: Cc1c(-c2cccs2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: CN[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN[C@H]1CCN(c2c(-c3cccs3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 59.3 %

Procedure:
4-Cyano-7-fluoro-N,N,5-trimethyl-6-(thiophen-2-yl)-1,3-benzoxazole-2-carboxamide (I-308) (160 mg, 0.49 mmol) was dissolved in dimethyl sulfoxide (8.7 ml), and at room temperature, triethylamine (81 μl, 0.58 mmol) was added. The solution was gradually heated from room temperature up to 150° C., and a solution of (3S)-3-(methylamino)pyrrolidine (62 μl, 0.58 mmol) dissolved in dimethyl sulfoxide (1 ml) was added all at a time. After stirred at the same temperature for 50 minutes, this was cooled to room temperature. The solvent was evaporated away under reduced pressure, and the resulting residue was fractionated with chloroform and saturated brine. The aqueous layer was further fractionated twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was roughly purified by preparative TLC (eluent, chloroform:7 N ammonia/methanol solution=95:5, v/v), and the roughly-purified product was again purified by preparative TLC (eluent, chloroform:methanol=9:1, v/v) to obtain the entitled compound (119 mg, 60%) as a yellow amorphous substance.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.Cl[CH:26]([C:31]([CH3:33])=[O:32])[C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH:26]([C:27]([O:29][CH3:30])=[O:28])[C:31](=[O:32])[CH3:33])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: COC(=O)C(Cl)C(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(C(C)=O)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 43.8 %

Procedure:
6.6 g (0.02 mole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid are heated at 80° C. with 4.5 g of methyl 2-chloroacetoacetate and 4.2 g of triethylamine in 100 ml of dimethylformamide for 3 hours. The solution is then concentrated in vacuo, the residue is stirred with 50 ml of water and the resulting solid product is washed with methanol and water and recrystallized from glycol monomethyl ether. 3.9 g (44% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-{4-[2-oxo-1-(methoxycarbonyl)-1-propyl]-1-piperazinyl}-3-quinolinecarboxylic acid of decomposition point 224° to 228° C. are isolated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)=[N:14][O:15][C:16]=2[CH:17]=[O:18])=[N:6][CH:5]=1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>CO>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2C=O)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Yield: 85.3 %

Procedure:
6-[3-(3,4-Difluoro-phenyl)-5-formyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (3.50 g, 9.35 mmol) in methanol (125 mL) was treated with sodium borohydride (737 mg, 18.7 mmol) for 30 min at room temperature. Addition of aqueous citric acid solution (10%, 300 mL) and extraction with ethyl acetate afforded the title compound (3.0 g, 85%) as a white solid. MS: m/e=377.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=2[C:9]=1[C:10]([C:12]1[CH:13]=[C:14]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:15]([O:24]COCCOC)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)=[O:11])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl.CCOCC>[CH2:1]([C:5]1[O:6][C:7]2[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=2[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([OH:24])=[C:14]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:13]=1)=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1cc(-c2ccccc2)c(OCOCCOC)c(-c2ccccc2)c1
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1oc2ccccc2c1C(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
At ambient temperature, to a stirred solution of (2-n-butyl-benzofuran-3-yl)-(2′-[(2-methoxyethoxy)methoxy]-[1,1′;3′,1″]terphenyl-5′-yl)-methanone (0.371 g, 0.695 mmol) in CH2Cl2 (3.71 mL) was added trifluoroacetic acid (3.71 nmL). After 0.5 h, the reaction was diluted with ether (50 mL), washed with H2O (3×), dried (MgSO4) and concentrated. The crude product was purified on Biotage KP-Sil eluting with 10% acetone/hexane to give 0.281 g (90%) of the title compound. 1H NMR (DMSO-d6) δ0.77 (t, 3H), 1.22 (sextet, 2H), 1.64 (quintet, 2H), 2.87 (t, 2H), 7.29-7.65 (m, 14H), 7.66 (s, 2H), 9.39 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([CH3:41])=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1.[OH-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([CH3:41])=[CH:36][CH:37]=[N:38]2)=[CH:33][CH:32]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Cc1ccnc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4c(C)ccnc4c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 56.7 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (225 mg, 0.67 mmol), (prepared as described for the starting material in Example 1), potassium carbonate (106 mg, 0.77 mmol) and 7-hydroxy-4-methylquinoline (122 mg, 0.77 mmol), (Chem. Berich. 1967, 100, 2077), in DMF (7.5 ml) was stirred at 100° C. for 5 hours then allowed to cool to ambient temperature. The reaction mixture was treated with 1M aqueous sodium hydroxide solution (40 ml) and stirred at ambient temperature for a few minutes. The crude solid was collected by filtration washing with water. The resultant solid was dissolved in dichloromethane (2 ml) and was filtered through phase separating paper. The filtrate was evaporated under vacuum to give a solid residue which was triturated with ether, filtered and dried to give 6-methoxy-4-(4-methylquinolin-7-yloxy)-7-(3-morpholinopropoxy)quinazoline (175 mg, 57%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]1([C:14]2[C:22]3[C:17](=[CH:18][C:19]([CH:23]=O)=[CH:20][CH:21]=3)[N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:15]=2)[CH2:13][CH2:12]1>>[CH:11]1([C:14]2[C:22]3[C:17](=[CH:18][C:19](/[CH:23]=[C:3]4/[C:2](=[O:10])[NH:1][C:9]5[C:4]/4=[CH:5][CH:6]=[CH:7][CH:8]=5)=[CH:20][CH:21]=3)[N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[N:15]=2)[CH2:12][CH2:13]1
Reactant: O=C1Cc2ccccc2N1
Reactant: C[Si](C)(C)CCOCn1nc(C2CC2)c2ccc(C=O)cc21
Product: C[Si](C)(C)CCOCn1nc(C2CC2)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21
Yield: 85.5 %

Procedure:
According to the method of Example A19, indolin-2-one (17 mg, 0.13 mmol) and 3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (40 mg, 0.13 mmol) were reacted to obtain crude product. The crude mixture was purified by prepTLC (SiO2 2% MeOH in DCM) to provide the title compound as a yellow solid (48 mg, 88%). MS ESI 432.2 [M+H]+, calcd for [C25H29N3O2Si+H]+ 432.6.
Reaction SMILES: [F:1][C:2]1([F:39])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:16]=[C:17]([CH:32]=[CH:33][C:34]=3[CH3:35])[CH2:18][N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:12][CH:13]=2)[N:8]([CH3:36])[S:7]1(=[O:38])=[O:37].C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:39][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH:16]=[C:17]([CH2:18][N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:32]=[CH:33][C:34]=3[CH3:35])=[CH:12][CH:13]=2)[N:8]([CH3:36])[S:7]1(=[O:38])=[O:37]
Reactant: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1ccc(CN2CCNCC2)cc1-c1ccc2c(n1)N(C)S(=O)(=O)N2CC1CC1(F)F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Tert-butyl 4-(3-{1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-2,2-dioxido-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridin-5-yl}-4-methylbenzyl)piperazine-1-carboxylate (43-1) (3.3 g, 5.7 mmol, 1.0 eq) was dissolved in DCM (40 mL) and TFA (4.4 mL, 56.7 mmol, 10 eq) was added and the reaction mixture stirred at ambient temperature for 45 minutes. Toluene (10 mL) was added and the reaction mixture was concentrated. The residue was dissolved in EtOAc (100 mL) and then washed with sodium bicarbonate (3×20 mL), water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated to afford 1-[(2,2-difluorocyclopropyl)methyl]-3-methyl-5-[2-methyl-5-(piperazin-1-ylmethyl)phenyl]-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (43-2) as a tan solid. No further purification was necessary. HRMS m/z (M+H) 463.1925 found, 463.1926 required.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[C:21]([C@:26]([NH:42]C(=O)OC(C)(C)C)([CH3:41])[CH2:27][O:28][P:29]([O:36]C(C)(C)C)([O:31]C(C)(C)C)=[O:30])[CH:20]=[CH:19]3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.Cl.CCOCC>O>[P:29]([OH:31])([OH:36])([O:28][CH2:27][C@:26]([NH2:42])([C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([S:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH:17]=2)[CH:22]=1)[CH3:41])=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1ccc2cc(Sc3cccc(OCc4ccccc4)c3)ccc2c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: C[C@](N)(COP(=O)(O)O)c1ccc2cc(Sc3cccc(OCc4ccccc4)c3)ccc2c1
Yield: 4 %

Procedure:
(R)-tert-butyl 2-(6-(3-(benzyloxy)phenylthio)naphthalen-2-yl)-1-(di-tert-butoxyphosphoryloxy)propan-2-ylcarbamate was dissolved in acetic acid (2.0 mL, 0.035 mol) and 10 M hydrogen chloride in water (0.5 mL) and stirred for 1 d. Removal solvent and concentration gave an oil, which was added to water and ether. The aqueous layer was concentrated and purified by preparative HPLC 0.1% TFA water/ACN to give (R)-2-amino-2-(6-(3-(benzyloxy)phenylthio)naphthalen-2-yl)propyl dihydrogen phosphate as a solid (1.1 mg, 4%). LCMS 1.56 496.25 (M+1, 40%), 991.66. HNMR shows quite pure. 1H NMR (400 MHz, MeOD) δ=7.98 (s, 1H), 7.89 (d, J=8.5 Hz, 2H), 7.82 (s, 1H), 7.65 (d, J=6.7 Hz, 1H), 7.43 (d, J=10.4 Hz, 1H), 7.39-7.25 (m, 6H), 7.05-6.95 (m, 3H), 5.06 (s, 2H), 4.29 (dd, J=5.0, 11.0 Hz, 1H), 4.16 (dd, J=5.4, 11.0 Hz, 1H), 1.86 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:11][OH:12]>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([CH:8]=[N:11][OH:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1C=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Nc1ncccc1C=NO
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 84.7 %

Procedure:
To a solution of 2-amino-3-formylpyridine (1.00 g, 8.19 mmol) in pyridine (20 mL) was added hydroxylamine hydrochloride (854 mg, 12.3 mmol) at room temperature, which was stirred for 1 hour and 40 minutes at room temperature. The reaction solution was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (951 mg, 85%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][SH:3].C(N(CC)CC)C.Cl[C:16]1[C:21]([C:22]#[N:23])=[C:20]([NH:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)[N:29]=[CH:28]3)[N:19]=[CH:18][N:17]=1>C1COCC1>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][S:3][C:16]1[C:21]([C:22]#[N:23])=[C:20]([NH:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)[N:29]=[CH:28]3)[N:19]=[CH:18][N:17]=1)[CH3:7]
Reactant: CCOC(=O)CS
Reactant: N#Cc1c(Cl)ncnc1Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CSc1ncnc(Nc2ccc3c(cnn3Cc3cccc(F)c3)c2)c1C#N

Procedure:
Ethyl thioglycolate (also referred to as mercapto-acetic acid ethyl ester) Compound 4f (0.57 g, 4.75 mmol) and triethylamine (0.78 mL, 5.54 mmol) were added to a solution of 4-chloro-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidine-5-carbonitrile Compound 4e (1.5 g, 3.96 mmol) in THF (20 mL) at RT under nitrogen. The reaction mixture was refluxed for 6 hours, then partitioned between ethyl acetate and water. The organic layer washed with aqueous 10% NH4Cl, water and brine, then dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (1% methanol/dichloromethane) to yield {5-cyano-6-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrimidin-4-ylsulfanyl}-acetic acid ethyl ester Compound 4g (0.83 g, 45%) as a solid. 1H NMR (400 MHz, DMSO) δ 9.99 (1H, br s), 8.42 (1H, s), 8.13 (1H, d), 7.82 (1H, d), 7.82 (1H, d, J=8.9 Hz), 7.43 (1H, dd, J=1.9 Hz & 8.9 Hz), 7.36-7.34 (1H, m), 7.11-7.02 (3H, m), 5.69 (2H, s), 4.15-4.10 (4H, m), 1.18 (3H, t); MS (ES+) m/z 463.0 (MH+).
Reaction SMILES: [C:1]1([C:7](=[O:22])[C:8]([S:20][CH3:21])=[CH:9][CH:10]=[C:11]([N:17]([CH3:19])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.CN(C)C([C:36](OCC)=[O:37])=CC=[N+](C)C.CC[O-].[Na+]>C(O)C>[CH3:19][N:17]([CH3:18])[C:11](=[CH:10][CH:9]=[C:8]([S:20][CH3:21])[C:7]([C:1]1[CH:2]=[CH:3][C:4]([O:37][CH3:36])=[CH:5][CH:6]=1)=[O:22])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccccc1)N(C)C
Agent: CC[O-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc(OC)cc1)N(C)C

Procedure:
The procedure is as in Example 4 for the preparation of ethyl 6-phenyl-6-oxo-5-methylthio-2-dimethylamino-2,4-hexadienoate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (13.9 g), a 2M ethanolic solution of sodium ethylate (24.2 cc) and α-methylthio-4-methoxyacetophenone (9.5 g) in ethanol (97 cc). After purification on a silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluent, ethyl 2-dimethylamino-6-(4-methoxyphenyl)-5-methylthio-6-oxo-2,4-hexadienoate (6.1 g) is obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[N:31]=[CH:30][N:29]=[C:28]([NH2:32])[C:27]=3Br)[CH2:22][CH2:21]2)[CH2:4][CH2:3][CH2:2]1.[C:34]([O:38][C:39]([N:41]1[C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][CH:43]=[N:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[Cs+].[Cs+]>>[C:34]([O:38][C:39]([N:41]1[C:45]([C:27]2[C:28]([NH2:32])=[N:29][CH:30]=[N:31][C:26]=2[N:23]2[CH2:24][CH2:25][CH:20]([C:8]3[N:7]([CH2:6][CH2:5][N:1]4[CH2:4][CH2:3][CH2:2]4)[CH:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=4)[N:9]=3)[CH2:21][CH2:22]2)=[CH:44][CH:43]=[N:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)n1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4Br)CC3)n2)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4-c4ccnn4C(=O)OC(C)(C)C)CC3)n2)ccc1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The mixture of 6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-bromo-pyrimidin-4-ylamine (90.00 mg; 0.17 mmol; 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (61.75 mg; 0.21 mmol; and Cs2CO3 (114.00 mg; 0.35 mmol; in dioxane (5 ml) and water (0.5 ml) was purged with argon, and then added Pd (0) (t-Bu3)2 (6.26 mg; 0.01 mmol; 0.07 eq.). The resulting mixture was stirred at 50° C. overnight. The curde was purified by prep HPLC to afford the title compound.
Reaction SMILES: C[O-].[Na+].CO.[N+](C1C=CC=CC=1S([NH:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)=O)([O-])=O>O1CCOCC1>[CH:19]([NH2:18])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 102.7 %

Procedure:
A 28% sodium methoxide/methanol solution (0.34 ml; 1.52 molar equivalents) was added to a solution of N-(2-nitrobenzenesulfonyl)benzhydrylamine (401.6 mg) in dry dioxane (3 ml) at room temperature in an argon atmosphere, followed by stirring for 23 hours at room temperature. The reaction solvents were removed by evaporation under reduced pressure, and water (10 ml), 2 N sulfuric acid (1.5 ml) and ether (15 ml) were added to the resulting concentrate, followed by extraction and solution separation. The organic layer was extracted again with water (5 ml). To the resulting aqueous layer, 5 N sodium hydroxide (1 ml) was added, and extraction was conducted twice with ether (13 ml), followed by drying over sodium sulfate, filtration, concentration and drying under vacuum to obtain benzhydrylamine (205.2 mg; yield: quantitative).
Reaction SMILES: O1CCCC1.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][C:11]=1[NH:18][C:19](=[O:35])[CH2:20][CH:21]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:28][C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)([CH3:9])([CH3:8])[CH3:7].[CH:36]1([CH2:42][Mg]Br)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(OCC)C>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:17])[CH2:42][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:12][C:11]=1[NH:18][C:19](=[O:35])[CH2:20][CH:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[O:28][C:29]2[C:34]1=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:9])([CH3:7])[CH3:8]
Reactant: Br[Mg]CC1CCCCC1
Reactant: CC(C)(C)c1ccc(C=O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)c1ccc(C(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 0.33 h
Yield: 76 %

Procedure:
8 ml of a tetrahydrofuran solution containing 100 mg (0.25 mmol) of N-(2-t-butyl-5-formylphenyl)-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 15) were cooled in an ice bath. 0.38 ml (0.38 mmol) of a 1M solution of cyclohexylmethylmagnesium bromide in diethyl ether was then added dropwise to the solution. The resulting mixture was stirred for 20 minutes at this temperature. It was then diluted with diethyl ether, and washed with dilute aqueous hydrochloric acid and then with water. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 20 g of silica gel. Elution with mixtures of methylene chloride and ethyl acetate ranging from 7:1 to 2:1 by volume afforded 95 mg (yield 76%) of the title compound as a foam-like substance.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([Cl:16])[C:9]=1[NH2:10].[C:17]([NH:20][C:21]1[NH:25][N:24]=[C:23]([S:26](Cl)(=[O:28])=[O:27])[N:22]=1)(=[O:19])[CH3:18].[OH-].[Na+]>C(Cl)Cl>[Cl:7][C:8]1[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([Cl:16])[C:9]=1[NH:10][S:26]([C:23]1[N:22]=[C:21]([NH:20][C:17](=[O:19])[CH3:18])[NH:25][N:24]=1)(=[O:27])=[O:28]
Reactant: Cc1ccc(Cl)c(N)c1Cl
Reactant: CC(=O)Nc1nc(S(=O)(=O)Cl)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(S(=O)(=O)Nc2c(Cl)ccc(C)c2Cl)n[nH]1
Reaction time: 3.5 h
Yield: 60 %

Procedure:
A 250 ml, 1-necked flask equipped with a magnetic stirrer and filled with nitrogen gas was charged with 15 ml of dry pyridine and 8.8 g (0.05 mole) of 2,6-dichloro-3-methylaniline. To the stirred solution was added 11.3 g (0.05 mole) of crude 5-acetylamino-3-chlorosulfonyl-1,2,4-triazole over 10-30 minutes. The resulting dark green mixture, which had a mild exotherm during the addition, was heated to 100°-105° C. with stirring for 3-4 hours. It was then dispersed between a mixture of methylene chloride and dilute aqueous sodium hydroxide and the organic layer was removed. Acidification of the aqueous phase and filtraton and drying of the precipitate that formed gave the title sulfonamide as a tan solid melting at 284° (dec.). The yield was 60 percent of theory. A sample of this compound which was recrystallized from a mixture of methanol and water was a pale ivory powder melting at 285°-285.5° C. (dec.) and had the following elemental analysis: Calc. for C11H11Cl2N5O3S %C, 36.3; %H, 3.04; %N, 19.23 Found 36.3; %H, 3.08; %N, 19.65
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[NH2:37][C:38]1[C:43]([Cl:44])=[CH:42][C:41]([C:45](=O)[CH3:46])=[CH:40][C:39]=1[Cl:48].[OH-].[K+]>C(O)C>[NH2:37][C:38]1[C:43]([Cl:44])=[CH:42][C:41]([C:45]2[CH:46]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)=[CH:40][C:39]=1[Cl:48]
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1cc(Cl)c(N)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(Cl)cc(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)cc1Cl
Yield: 25 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(4-amino-3,5-dichloro-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (31 mg, 25% yield).