Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]([CH2:26][C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:12]([C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[N:13]3[C:18]=2[CH:17]=[CH:16][C:15]([OH:19])=[CH:14]3)=[O:9])=[CH:4][CH:3]=1.Cl.Cl[CH2:37][C:38]1[S:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[S:39]1[C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=[C:38]1[CH2:37][O:19][C:15]1[CH:16]=[CH:17][C:18]2[N:13]([C:12]([C:20](=[O:25])[C:21]([CH3:23])([CH3:24])[CH3:22])=[C:11]([CH2:26][C:27]([CH3:33])([CH3:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]=2[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:9])[CH:14]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)c2ccc(Cl)cc2)c2ccc(O)cn2c1C(=O)C(C)(C)C
Reactant: ClCc1nc2ccccc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cc1c(C(=O)c2ccc(Cl)cc2)c2ccc(OCc3nc4ccccc4s3)cn2c1C(=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
A suspension of ethyl 3-{1-[(4-chlorophenyl)carbonyl]-3-(2,2-dimethylpropanoyl)-6-hydroxyindolizin-2-yl}-2,2-dimethylpropanoate (85.0 mg, 0.176 mmol), 2-(chloromethyl)-1,3-benzothiazole-HCl (60.1 mg, 0.263 mmol), and potassium carbonate (97.1, 0.703 mmol) in DMF (3.0 mL) is stirred at 50° C. for 1 h. The mixture is cooled to 23° C. then filtered, concentrated in vacuo, and purified by flash chromatography (SiO2, hexanes to 1:1 hexanes:EtOAc) to yield ethyl 3-[6-(1,3-benzothiazol-2-ylmethoxy)-1-[(4-chlorophenyl)carbonyl]-3-(2,2-dimethylpropanoyl)indolizin-2-yl]-2,2-dimethylpropanoate (74 mg, 67%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][N:8]=1)=[O:6].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+].[Cl-]>C1COCC1>[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]=1)=[O:6]
Reactant: COC(=O)c1n[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1nn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
Sodium hydride (0.37 g, 60%, 9.3 mmol) was added to a solution of indazole-3-carboxylic acid methyl ester (1.5 g, 8.5 mmol) in dry THF (50 mL) at 0° C. Benzyl bromide (1.59 g, 9.3 mmol) was then added and the reaction mixture was warmed to 25° C. and stirred for 8 h. The reaction mixture was poured onto saturated NaCl solution (100 mL) and extracted with 3×200 mL of diethyl ether. The combined extracts were dried (MgSO4) and concentrated under reduced pressure. The crude compound was purified by flash chromatography using cyclohexane/ethyl acetate (70:30) and recrystallised from cyclohexane/ethyl acetate to afford the title compound as a yellow solid (1.89 g,84%). Mp 72–73° C. 1H NMR (300 MHz, CDCl3) ppm 4.07 (s, 3H), 5.72 (s, 2H), 7.22–7.40 (m, 8H), 8.24–8.27 (m, 1H). MS(EI) m/z 266 [M+]. Anal. Calcd. for C16H14N2O2: C, 72.17; H, 5.30; N, 10.52. Found: C, 72.12; H, 5.15; N, 10.85.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34](=[O:35])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:20])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=1)([CH3:22])[CH3:23]
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 44.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.80 g) and 2,6-diisopropylphenyl isocyanate (0.72 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)urea (0.62 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:16][N:17]=[C:18]([O:19][C@@H:20]4[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]4[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:11]=23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:62](Cl)(=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64].Cl>ClCCl>[C:23]([O:22][C@@H:21]1[C@@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[O:46][C@H:20]1[O:19][C:18]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])=[CH:7][CH:6]=2)[NH:16][N:17]=1)(=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(O)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OC(=O)C(C)(C)C)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[2-(4-hydroxyphenyl)ethyl]-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazolo[3,4-b]pyridine (1.6 g) in dichloromethane (20 mL) were added triethylamine (0.44 mL) and pivaloyl chloride (0.31 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound (1.76 g).
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([CH2:7][NH:8][C:9](=[O:30])[CH:10]([C:13]2[CH:18]=[C:17]([O:19][CH2:20][CH3:21])[CH:16]=[C:15]([O:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:14]=2[F:29])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.CCOC(C)=O>C1COCC1>[C:33]1([S:39]([N:26]2[CH2:25][CH2:24][CH:23]([O:22][C:15]3[C:14]([F:29])=[C:13]([CH:10]([O:11][CH3:12])[C:9]([NH:8][CH2:7][C:6]4[CH:31]=[CH:32][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)=[O:30])[CH:18]=[C:17]([O:19][CH2:20][CH3:21])[CH:16]=3)[CH2:28][CH2:27]2)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOc1cc(OC2CCNCC2)c(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc(OC2CCN(S(=O)(=O)c3ccccc3)CC2)c(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2)c1
Temperature: 0 °C
Yield: 100.2 %

Procedure:
To a solution of (RS)-N-(4-cyano-benzyl)-2-[5-ethoxy-2-fluoro-3-(piperidin-4-yloxy)-phenyl]-2-methoxy-acetamide (300 mg) in THF (3 ml) were added benzenesulfonyl chloride (127 mg) and triethylamine (138 mg). The mixture was stirred over the weekend. Ice-water and EtOAc were added and the pH of the aqueous phase was adjusted to 2. The mixture was extracted with EtOAc. The organic phase was washed with saturated NaHCO3 soln. and water, dried, filtered and evaporated to give (RS)-2-[3-(1-benzenesulfonyl-piperidin-4-yloxy)-5-ethoxy-2-fluoro-phenyl]-N-(4-cyano-benzyl)-2-methoxy-acetamide (396 mg) as an off-white solid. MS 582.2 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].BrC(C)(C)C([O-])=O>CN(C)C=O.O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:17]([CH3:26])([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:3][CH:4]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)(Br)C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(C=O)cc1
Yield: 42 %

Procedure:
24.42 g (200 mmol) of 4-hydroxybenzaldehyde are dissolved in 250 ml of N,N-dimethylformamide and treated with 27.64 g (200 mmol) of potassium carbonate. At 100° C., 53.55 g (240 mmol) of tert-butyl α-bromoisobutyrate are added dropwise. The mixture is stirred for another hour, a further 200 mmol of potassium carbonate and 240 mmol of tert-butyl (α-bromoisobutyrate are added and, after 4 hours at 100° C., 1 l of water is added. Following extraction with diethyl ether, washing with 1 N aqeuous sodium hydroxide solution and saturated sodium chloride solution and drying over magnesium sulphate, the solvent is distilled off and the residue is purified by flash chromatography on silica gel (cyclohexane→cyclohexane/ethyl acetate 20:1→10:1→5:1) and dried under reduced pressure. The target compound is obtained in the form of colourless crystals in a yield of 42%.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=[C:4]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[N:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([Br:27])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24].Cl>O1CCOCC1.CC(O)=O>[Br:27][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:2]2[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=[C:4]([C:11]3[S:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[N:3]=2)=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Cl
Reactant: Nc1ccc(Br)c(C(=O)O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Br)c(C(=O)O)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
A 18-mL vial was charged with 4-chloro-2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidine (87 mg, 0.318 mmol, 1.05 eq.), 5-amino-2-bromo-benzoic acid (65 mg, 0.3 mmol, 1 eq.). AcOH (1 ml) and 4 N HCl in dioxane (5 drops). The resulting mixture was stirred under Ar at 110° C. for 2 hr. After cooling to rt, The volatile material was removed under reduced pressure and the residue was treated with dichloromethane to give the title compound (105 mg, 77% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12](O)=[O:13])[CH:8]=[C:7]2[OH:15].[Cl-].[NH4+].C[N:21](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([NH2:21])=[O:13])[CH:8]=[C:7]2[OH:15]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc2c(O)cc(C(=O)O)nc2c1Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc2c(O)cc(C(N)=O)nc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Chloro-4-hydroxy-7-methoxy-quinoline-2-carboxylic acid (115 mg, 0.45 mmol) and ammoniumchloride (36 mg, 0.68 mmol) were dissolved in DMF (4 mL). HATU (342 mg, 0.9 mmol) and NMM (159 mg, 1.58 mmol) were added and the mixture was stirred at r.t. overnight. An additional amount of ammoniumchloride (72 mg, 13.5 mmol) was added and heated to 53° C. for 18 h. The reaction mixture was cooled to r.t. and concentrated to give 8-chloro-4-hydroxy-7-methoxy-quinoline-2-carboxylic acid amide as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:35])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](Br)=[C:29]([CH3:34])[CH:28]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13].[CH3:36][C:37]1[CH:38]=[C:39]([NH2:52])[CH:40]=[CH:41][C:42]=1B1OC(C)(C)C(C)(C)O1.C1(C)C=CC=CC=1.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][O:8][C:9](=[O:35])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:42]3[CH:41]=[CH:40][C:39]([NH2:52])=[CH:38][C:37]=3[CH3:36])=[C:29]([CH3:34])[CH:28]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(Br)c(C)c2)c[nH]1)C(C)C
Reactant: Cc1cc(N)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(N)cc3C)c(C)c2)c[nH]1)C(C)C
Temperature: 100 °C

Procedure:
Potassium carbonate (224 mg, 1.619 mmol) was added to a mixture of ((S)-1-{(S)-2-[4-(4-bromo-3-methyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (150 mg, 0.324 mmol) and 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (90.6 mg, 0.389 mmol) in toluene (0.6 mL, 6 mmol) and water (0.3 mL, 20 mmol). The reaction mixture was degassed and flushed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (44.9 mg, 0.039 mmol) was added under nitrogen and then the reaction mixture was capped and heated at 100° C. overnight, cooled to RT and partitioned between ethyl acetate (10 mL) and water (2 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give a brownish oil, which was purified by silica gel chromatography (12 g silica gel, 0-100% EtOAc/hexanes). Desired fractions were combined and concentrated to give the title compound as a light yellowish foam (135 mg, 85% yield). (m/z): [M+H]+ calcd for C28H35N5O3 490.27 found 490.6.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3]C1.[CH3:6][C:7]([OH:12])([CH:9]([CH3:11])[CH3:10])[CH3:8].[CH2:13](N(CC)CC)C>>[C:5]([O:12][C:7]([CH3:8])([CH:9]([CH3:11])[CH3:10])[CH3:6])(=[O:1])[C:4]([CH3:13])=[CH2:3]
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Reactant: CC(C)C(C)(C)O
Product: C=C(C)C(=O)OC(C)(C)C(C)C
Reaction time: 24 h

Procedure:
Into a 500 mL flask containing a stir bar, and fitted with a condenser, was placed 180 g of anhydrous tetrahydrofuran, 40 g of 2,3-dimethyl-2-butanol and 40.93 g of triethylamine under a N2 atmosphere. To this was dropwise added 40.927 g of purified methacroyl chloride from an addition funnel. Reaction was allowed to warm moderately. After 24 hrs of stirring, the tetrahydrofuran was roto-evaporated from the solution and 100 mL of ethyl acetate was added. The salts were then filtered off though a Buchner funnel. The ethyl acetate was then stripped by use of a rotory-evaporator. A vacuum distillation column was set up with an 8 inch Vigreaux column, stir bar and a few small boiling chips. A fractional distillation was performed and 19.8 g of the product was recovered in the fraction which had a boiling point of approximately 80-87° C. at 6-7 Torr of pressure. 1H NMR was used to confirm structure and purity.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7](=[N:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH3:8])[CH2:3]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:23][S:24]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7](=[N:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[CH3:8])[CH2:3]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCC(O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCC(OS(C)(=O)=O)C1
Reaction time: 0.5 h

Procedure:
To a solution of 32.2 g of 3-hydroxy-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidine in 500 ml of methylene chloride, were added, with ice-cooling, 9.3 ml of methanesulphonyl chloride, followed by 16.7 ml of triethylamine. The mixture was stirred for 30 minutes, with ice-cooling, and then water was added, after which the mixture was extracted with methylene chloride and the extract was washed with water and dried, to give 36 g of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18].Cl[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1.O>CS(C)=O>[N+:26]([C:23]1[CH:22]=[N:21][C:20]([O:18][C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][C:8]=2[Cl:7])=[CH:25][CH:24]=1)([O-:28])=[O:27]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)nc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
7.6 g of anhydrous sodium carbonate and 9.8 g of 2-chloro-4-trifluoromethylphenol were added to 20 ml of dimethyl sulfoxide, and a solution having 7.9 g of 2-chloro-5-nitropyridine dissolved in 10 ml of dimethyl sulfoxide was added dropwise thereto at room temperature (i.e., about 20° to 30° C.) while stirring. After completion of the dropwise addition, the mixture was allowed to react at 50° C. for 30 minutes. After completion of the reaction, the reaction product was poured into water, followed by extracting with methylene chloride. The extracted phase was washed with water and dried, and the solvent was then distilled off to obtain 13 g of a crystal. The thus obtained crystal was recrystallized from n-hexane to obtain 9.8 g of a titled compound having a melting point of 69° to 72° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:37]5[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Reactant: OC1CCNC1
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCC(O)C1
Yield: 24 %

Procedure:
The intermediate 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 79A and pyrrolidin-3-ol were reacted as described in Example 80 to yield 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-(3-hydroxypyrrolidin-1-yl)ethoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea (59 mg, 24%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.85 (s, 1H), 8.30 (s, 1H), 7.65-7.50 (m, 2H), 7.35-7.05 (m, 4H), 6.50 (s, 1H), 5.05 (s, 1H), 4.45-4.25 (m, 3H), 4.15-3.85 (m, 6H), 3.75-3.65 (d, 1H), 3.45 (M, 2H), 2.00 (m, 2H), 1.25 (s, 9H); LC-MS (ESI) m/z 579 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[O-].[Na+].Cl>C(O)C.O>[C:19]1(/[CH:18]=[CH:2]/[C:1]([C:4]2[CH:17]=[CH:16][C:7]([CH2:8][CH:9]3[S:13][C:12](=[O:14])[NH:11][C:10]3=[O:15])=[CH:6][CH:5]=2)=[O:3])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Reactant: O=Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(C(=O)/C=C/c3ccccc3)cc2)S1
Yield: 24.5 %

Procedure:
To a slurry of 5-(4-acetylbenzyl)thiazolidine-2,4-dione (4.0 mmol, 1.0 g), and benzaldehyde (4.0 mmol, 0.41 ml) in ethanol (10 ml) was added sodium methoxide (4.8 mmol, 260 mg). The solution was heated to reflux for 1.5 hours, then more benzaldehyde was added and the mixture was heated another 1.5 hours, then cooled, diluted with water (60 ml), acidified with 2N HCl and extracted with ethyl acetate (2×50 ml). The combined extracts were washed with water (50 ml), dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from isopropanol to give title product as a pale yellow solid (0.33 g, 24%); m.p. 147°-149° C.
Reaction SMILES: [C:1]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].O1CCOCC1.[OH-].[CH2:24]([N+:31](C)(C)C)[C:25]1C=CC=C[CH:26]=1.C(#N)C=C>CO>[C:1]([C:4]1([CH2:26][CH2:25][C:24]#[N:31])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2]
Reactant: NC(=O)C1c2ccccc2-c2ccccc21
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: C=CC#N
Solvent: C1COCCO1
Product: N#CCCC1(C(N)=O)c2ccccc2-c2ccccc21
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A 4.2 g. portion of 9-carbamoylfluorene was dissolved in 300 ml. of dioxane at 45° C. To the solution was added 0.4 ml. of Triton B (40% benzyltrimethylammonium hydroxide in methanol) and 1.1 g. of acrylonitrile. The reaction mixture was stirred at 70° C. for one hour and was then allowed to cool to ambient temperature and stand overnight. The dioxane was removed under vacuum, and the remaining oil was taken up in ethyl acetate/water. The layers were separated, and the organic layer was washed three times with water and once with saturated sodium chloride solution. The organic layer was then dried over magnesium sulfate, filtered and evaporated under vacuum to a foam, which was taken up in dichloromethane. The solution was boiled, and hexane was added until crystallization occurred. The mixture was chilled overnight, and the crystals were collected by filtration. The crystals were washed with hexane and dried under vacuum at 40° to obtain 3.2 g. of the desired product, m.p. 148°-152°, with sintering at 143°.
Reaction SMILES: [CH3:1][Mg]I.[C:4]([C:7]1[N:8]=[C:9]([CH2:33][CH2:34][CH2:35][CH3:36])[N:10]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[C:12]#[N:13])(=[O:6])[CH3:5].[Cl-].[NH4+]>O1CCCC1>[CH2:33]([C:9]1[N:10]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:11]([C:12]#[N:13])=[C:7]([C:4]([OH:6])([CH3:1])[CH3:5])[N:8]=1)[CH2:34][CH2:35][CH3:36]
Reactant: C[Mg]I
Reactant: CCCCc1nc(C(C)=O)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCc1nc(C(C)(C)O)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1 ml of a 2M solution of methylmagnesium iodide in tetrahydrofuran was added dropwise at room temperature, whilst stirring, to a solution of 840 mg of 4-acetyl-2-butyl-5-cyano-1-tritylimidazole [prepared as described in Preparation 5(ii)] in 15 ml of tetrahydrofuran, and the resulting mixture was stirred at 40° C. for 1 hour. The mixture was cooled, and then a saturated aqueous solution of ammonium chloride was added to it dropwise. The tetrahydrofuran layer was separated and concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 539 mg of the title compound as a colorless solid, melting at 151°-152° C.