Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)[O-].[Li+].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH2:22][C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])=[CH:10][CH:9]=1.BrCC(OC(C)C)=O.[C:37](OCC)(=[O:43])[C:38](OCC)=[O:39]>>[OH:39][C:38]1[C:37]([OH:43])=[C:22]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[N:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=2)[C:15]=1[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]
Reactant: COc1ccc(N(CC(=O)OC(C)C)CC(=O)OC(C)C)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)OC(=O)CBr
Agent: CC(C)[O-]
Agent: [Li+]
Product: COc1ccc(-n2c(C(=O)OC(C)C)c(O)c(O)c2C(=O)OC(C)C)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 0.7 %

Procedure:
Lithium isopropoxide (2M in THF) (10.4 mL, 20.8 mmol) was added to a mixture of diisopropyl 2,2′-((4-methoxyphenyl)azanediyl)diacetate (21) (2.69 g, 8.32 mmol) [prepared using the same procedure as Example B step (i) using isopropyl 2-bromoacetate] and diethyl oxalate (1.13 mL, 8.32 mmol), the mixture was stirred at 65° C. for 16 h. A further portion of lithium isopropoxide (2M in THF) (5.2 ml, 10.4 mmol) was added and the reaction stirred at 65° C. for 3 h. The reaction was quenched with acetic acid (5 mL) and the volatiles removed in vacuo, the crude product was took up in EtOAc (100 mL) and partitioned with water (100 mL), the aqueous was washed with EtOAc (2×100 mL) combined organics were washed with brine (150 mL), dried (MgSO4), filtered and solvents removed in vacuo to afford a brown oil. The crude product was recrystallised from hot i-PrOH (50 mL), to provide a white solid. The solid was purified by silica gel chromatography (12 g, 0-50% EtOAc in isohexane) to afford diisopropyl 3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (UL2-020) (21 mg, 1%) as a white solid: m/z 378 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 8.62 (s, 2H), 7.12-7.01 (m, 2H), 6.93-6.84 (m, 2H), 4.80 (sept., J=6.3 Hz, 2H), 3.78 (s, 3H), 0.95 (d, J=6.2 Hz, 12H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([C:19]1[O:23][N:22]=[C:21]([OH:24])[CH:20]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:15]([C:19]1[O:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[C:21](=[O:24])[CH:20]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1cc(=O)n(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])o1
Yield: 45.5 %

Procedure:
After mixing 15.0 g of 4-chloro-3-nitrobenzotrifluoride, 11.3 g of 5-t-butyl-3-hydroxyisoxazole, 11.0 g of potassium carbonate, and 80 ml of dimethyl sulfoxide, the mixture was reacted for 4 hours at 80° C. After cooling, the reaction mixture obtained was poured into water to deposit crystals which were then recovered by filtration and recrystallized from a mixture of water and methanol to provide 10.0 g of the desired compound with a yield of 45.5%. The melting point thereof was 116° to 117° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15]1([CH2:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCCC1>[C:15]1([CH2:21][C:22]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 55.9 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.78 g, 4.1 mmol), phenylacetyl chloride (1.1 mL, 8.2 mmol), and triethylamine (1.8 mL, 13 mmol) in tetrahydrofuran (10 mL) provided 2-phenyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-acetamide (0.70 g). Mp 180-181° C.; Anal. Calcd. for C20H19NO2: C, 78.66; H, 6.27; N, 4.59; Found: C, 78.53; H, 6.13; N, 4.75.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:43])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:33])=[C:28]([CH2:39][CH:40]([CH3:42])[CH3:41])[CH:27]=3)=[CH:22][CH:21]=2)C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.C([O-])=O.[NH4+].[ClH:48]>[Pd].CO.O.C(OCC)(=O)C>[ClH:1].[ClH:48].[OH:43][C@H:8]([C:5]1[CH:6]=[N:7][CH:2]=[CH:3][CH:4]=1)[CH2:9][NH:10][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])=[O:33])=[C:28]([CH2:39][CH:40]([CH3:42])[CH3:41])[CH:27]=2)=[CH:24][CH:25]=1
Reactant: CC(C)Cc1cc(-c2ccc(CCN(C[C@H](O)c3ccc(Cl)nc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(C)(=O)=O
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)Cc1cc(-c2ccc(CCNC[C@H](O)c3cccnc3)cc2)ccc1C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The mixture of tert-butyl [(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl][2-[3′-isobutyl-4′-[[(methylsulfonyl)amino]-carbonyl]-4-biphenylyl]ethyl]carbamate (310 mg), ammonium formate (155 mg) and palladium on carbon powder (155 mg) in methanol (5 ml) and water (0.5 ml) was refluxed for 30 minutes. The catalyst was filtered off, and the filtrate was poured into water and extracted with chloroform-methanol (19:1). The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give pyridine product. To a solution of the product in ethyl acetate (1.8 ml) was added 4N hydrogen chloride in ethyl acetate (1.8 ml), and the mixture was stirred at room temperature for 16 hours. The resultant solid was collected by filtration and dried to give 4′-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]-ethyl]-3-isobutyl-N-(methylsulfonyl)-4-biphenylcarboxamide dihydrochloride (93 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([O:15][CH3:16])[C:4]=1/[CH:17]=[C:18](\[CH3:24])/[C:19]([O:21]CC)=[O:20].COC1C2C(=CC=CC=2)C(OC)=CC=1/C=C(\C)/C(O)=O>CCOC(C)=O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([O:15][CH3:16])[C:4]=1/[CH:17]=[C:18](\[CH3:24])/[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)/C(C)=C/c1c(OC)c(OC)c2ccccc2c1OC
Agent: COc1cc(/C=C(\C)C(=O)O)c(OC)c2ccccc12
Solvent: CCOC(C)=O
Product: COc1c(/C=C(\C)C(=O)O)c(OC)c2ccccc2c1OC

Procedure:
Compound 99g was prepared from 98g (0.073 g, 0.22 mmol) as described above for 29a to give 0.068 g (0.22 mmol, 100%) of the product as a tan solid following flash chromatography (1:3 EtOAc:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[C:20](OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>>[Cl:1][C:2]1[C:3]2[C:10](=[O:19])[C:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:20][O:9][C:4]=2[CH:5]=[C:6]([OH:8])[CH:7]=1
Reactant: O=C(Cc1ccc(O)cc1)c1c(O)cc(O)cc1Cl
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=c1c(-c2ccc(O)cc2)coc2cc(O)cc(Cl)c12
Temperature: 140 °C
Reaction time: 70 h

Procedure:
A solution consisting of 1-(2-chloro-4,6-dihydroxyphenyl)-2-(4-hydroxyphenyl)-ethanone (50 mg), acetic anhydride (1.2 mL) and sodium acetate (44 mg) was prepared. The solution was heated at 140° C. for 50 min, cooled to room temperature and stirred for 70 h. The soution was quenched with saturated sodium bicarbonate (10 mL), water (1 mL) and methanol (10 mL). After stirring for 3 h the solution was acidified to pH 5 with saturated potassium diphosphate and extracted with ethyl acetate (3×15 mL). The organics were dried over Na2SO4, filtered and concentrated in vacuo. The resulting yellow oil was diluted with toluene and dehydrated for 1.5 h using a Dean-Starke trap. Chromatography using reverse phase preperative HPLC provided the title compound (18 mg). 1H NMR (DMSO-d6): 11.07 (s br, 1H), 9.46 (s br, 1H), 7.03 (d, 1H, J=8.4 Hz), 6.88 (d, 1H, J=2.4 Hz), 6.79 (s, 1H), 6.78 (d, 2H, J=8.7 Hz), 2.18 (s, 3H); MS: 303 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=O>C(O)C.N1CCCCC1>[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:13][C:12]1=[O:18]
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.7 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (60 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][C:23](O)=[O:24])[CH:9]=2)=[CH:4][CH:3]=1.OS(O)(=O)=O.CC[O-].[Na+].Cl.[CH3:36][NH:37][OH:38].[OH-].[Na+]>CCCCCC.C(Cl)Cl.C(O)(=O)C.O.CO.CCOC(C)=O.C(O)C>[CH3:36][N:37]([OH:38])[C:23]([CH2:22][CH2:21][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[N:11]=1)=[O:24]
Reactant: CNO
Reactant: COc1ccc(-n2nc(CCC(=O)O)cc2-c2ccc(Cl)cc2)cc1
Agent: CC[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-n2nc(CCC(=O)N(C)O)cc2-c2ccc(Cl)cc2)cc1
Temperature: 10 °C
Yield: 87.9 %

Procedure:
An oven dried 300 mL 3-necked round bottomed flask was equipped with a magnetic stirring bar, argon inlet, and drying tube. The flask was charged with 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanoic acid (10 gm, 28.03 mmol) followed by ethanol (100 mL). The resulting solution was cooled using an ice-water bath, the stirring solution was treated with concentrated H2SO4 (0.07 mL, 2.52 meq.). The flask was then removed from the ice-water bath, the argon inlet and drying tube were removed, and the flask was equipped with a condenser and thermocouple. The reaction mixture was heated to reflux and monitored by TLC (using a 1:2:6 MeOH:EtOAc:hexane solvent system). After stirring at reflux for 5 hours, the reaction flask was fitted with a short path distillation apparatus and ethanol was distilled off (70 mL). The resulting residue was cooled to 10° C. and treated dropwise with NaOEt (21 wt %, 37.7 mL, 101.04 mmol). The resulting mixture was then treated with N-methylhydroxylamine hydrochloride (3.51 gm; 42.05 mmol). The reaction flask was then re-equipped with a drying tube and argon inlet, and the reaction was stirred at ambient temperature. b) The reaction was allowed to stir for 18 hours at ambient temperature. TLC analysis (using 50% EtOAc in hexane and 10% methanol in CH2Cl2) showed completion of the reaction. The reaction flask was placed in an ice-water bath, and the reaction mixture was treated dropwise with a cooled (ice-water bath) mixture of glacial acetic acid (3.3 mL; 57.4 mmol) and 33 mL of distilled water. After completion of the addition of the aqueous acetic acid solution, the pH of the mixture was adjusted to between 6.4 to 6.8 with 1N NaOH (litmus). The mixture was then treated with additional distilled water (5 mL) where upon solid began to precipitate out. The reaction flask was then equipped with a short path distillation apparatus, and approximately 27 mL of solvent was removed (80 mm of Hg vacuum at 30-35° C.). The pH of the resulting mixture was re-adjusted to between 6.4 to 6.8, and the mixture was allowed to stir with cooling from an ice-water bath for 30 minutes. The solid was collected by filtration, and the solid product was washed with ice-cold distilled water. The air-dried product was then placed in a vacuum oven and dried for 18 hours at 60° C. under vacuum to give 9.51 gm of tepoxalin (87.9% yield, HPLC wt % purity of 98.6%).
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][NH:6][C:7]([C:9]1[C:14]([O:15]CC2C=CC=CC=2)=[C:13]([CH3:23])[N:12]=[C:11]([CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34](Br)=[CH:33][N:32]=3)[CH2:27][CH2:26]2)[N:10]=1)=[O:8])C.Br[C:40]1[CH:54]=[CH:53][C:43]([CH2:44][O:45][Si](C(C)(C)C)(C)C)=[C:42]([F:55])[CH:41]=1>>[F:55][C:42]1[CH:41]=[C:40]([C:34]2[CH:35]=[CH:36][C:31]([N:28]3[CH2:27][CH2:26][CH:25]([CH2:24][C:11]4[N:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:3])=[O:38])=[O:8])[C:14]([OH:15])=[C:13]([CH3:23])[N:12]=4)[CH2:30][CH2:29]3)=[N:32][CH:33]=2)[CH:54]=[CH:53][C:43]=1[CH2:44][OH:45]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1F
Reactant: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(Br)cn3)CC2)nc(C)c1OCc1ccccc1
Product: Cc1nc(CC2CCN(c3ccc(-c4ccc(CO)c(F)c4)cn3)CC2)nc(C(=O)NCC(=O)O)c1O
Yield: 21 %

Procedure:
In accordance with Examples 19-(2), 1-(10), 22-(4) and 1-(13), but using ethyl({[5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidin-4-yl]methyl}-6-methylpyrimidin-4-yl]carbonyl}amino)acetate instead of tert-butyl 5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylate, and [(4-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane instead of tert-butyl[(4-iodobenzyl)oxy]dimethylsilane, the title compound (yield 21%) was afforded as a white solid.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:41])[C@@H:6]([N:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:27])[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.C1(C)C=CC=CC=1.Cl>CO>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([N:28]2[C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:34]3[C:29]2=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:5]([OH:41])=[O:4])=[O:27])=[CH:18][CH:17]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)[C@H](CCCCNC(=O)c1ccc(C(=O)c2ccccc2)cc1)n1c2ccccc2c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(NCCCC[C@@H](C(=O)O)n1c2ccccc2c2ccccc21)c1ccc(C(=O)c2ccccc2)cc1
Yield: 94.6 %

Procedure:
Methanolic KOH (0.050 g, 0.88 mmol) was added to a stirred solution of 6-(4-benzoyl-benzoylamino)-2-carbazol-9-yl-hexanoic acid methyl ester 6 (0.230 g, 0.44 mmol) in a mixture (1:2) of toluene (2 mL) and methanol (4 mL). The resulting reaction mixture was refluxed for 3 h. Subsequently, it was neutralized to pH 3-4 with dil. HCl and extracted with EtOAc (20 mL×2). The combined organic extract was washed with water (15 mL×2) and dried over anhydrous Na2SO4. Removal of solvent under reduced pressure provided 6-(4-benzoyl-benzoylamino)-2-carbazol-9-yl-hexanoic acid 7 (0.210 g, 98%) as a white solid.
Reaction SMILES: C(Br)C.[Mg].Cl[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([CH3:15])=[CH2:14])=[CH:8][CH:7]=1.Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Cl-].[NH4+]>[Ni](Cl)Cl.C1COCC1>[CH3:15][C:13](=[CH2:14])[CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][CH:8]=1
Reactant: C=C(C)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)Br
Agent: Cl[Ni]Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: C=C(C)Cc1ccc(C(C)C(=O)OCC)cc1
Temperature: 130 °C
Yield: 48.7 %

Procedure:
Under a nitrogen atmosphere, 5 ml of dry THF and 0.3 ml of ethyl bromide were added to 2.92 g of magnesium turnings for Grignard reaction, and the mixture was stirred. Heat was generated and the temperature of the mixture rose. Then, a solution composed of 16.65 g of p-chloro-(2-methyl-2-propenyl)benzene and 2 ml of THF was added dropwise, and the temperature of the mixture was raised to 130° C. Some amount of THF was added, and the mixture was heated under reflux at 100° C. for 4 hours. After cooling, 60 ml of THF was added, and the resulting reaction mixture was added dropwise to a solution composed of 18.1 g of ethyl α-bromopropionate, 0.065 g of nickel chloride and 40 ml of THF. After the addition, the mixture was stirred for 1 hour, and an aqueous solution of ammonium chloride was added. The mixture was extracted with diethyl ether. The ethereal extract was washed with an aqueous solution of sodium chloride, dried, concentrated and distilled to give 11.3 g (yield 48.7%) of ethyl α-[p-(2-methyl-2-propenyl)phenyl]propionate having the following properties.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][O:32][C@@H:33]1[C@@H:39]([CH2:40][O:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=2[Cl:50])[O:38][C@H:35]([O:36][CH3:37])[C@@H:34]1[OH:51]>CCOCC.C([O-])(O)=O.[Na+]>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][O:32][C@@H:33]1[C@@H:39]([CH2:40][O:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=2[Cl:50])[O:38][C@H:35]([O:36][CH3:37])[C:34]1=[O:51]
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To an ice-cold suspension of Dess-Martin periodinane (50.0 g, 118 mmol) in anhydrous CH2C12 (350 mL) under argon (Ar) was added a solution of the compound from Step A (36.2 g, 75 mmol) in anhydrous CH2C12 (200 mL) dropwise over 0.5 h. The reaction mixture was stirred at 0° C for 0.5 h and then at room temperature for 3 days. The mixture was diluted with anhydrous Et2O (600 mL) and poured into an ice-cold mixture of Na2S2O3.5H2O (180 g) in saturated aqueous NaHCO3 (1400 mL). The layers were separated, and the organic layer was washed with saturated aqueous NaHCO3 (600 mL), water (800 mL) and brine (600 mL), dried (MgSO4), filtered and evaporated to give the title compound (34.2 g) as a colorless oil, which was used without further purification in Step C below.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]=[C:26]=[O:27]>C1COCC1>[CH3:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:26]([NH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([F:17])([F:28])[F:29])=[O:27]
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.9 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methylphenylacetate (927 mg, 4.19 mmol) and Et3 N (645 μl, 4.63 mmol) in THF (10 ml) was added 2-trifluoromethylphenyl isocyanate (633 μl, 4.19 mmol) and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated to a small volume and diluted with n-hexane. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give tert-butyl 3-methyl-4-[N′-(2-trifluoromethylphenyl)ureido]phenylacetate (1.06 g, 62%) as a white crystalline powder. mp 178–180° C.; 1H-NMR (CDCl3) δ 1.44 (s, 9 H), 2.25 (s, 3 H), 3.51 (s, 2 H), 6.38 (br s, 1 H), 7.12–7.18 (m, 3 H), 7.36–7.37 (m, 1 H), 7.49–7.53 (m, 2 H), 8.13–8.16 (m, 1 H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)([OH:19])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:19])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NS(=O)(=O)O
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)O)cc1OC1CCCC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (66 g) and sulfamic acid (39.6 g) in glacial acetic acid (500 mL) is treated dropwise during 1 hour with a solution of sodium chlorite (35 g) in water (150 mL). The mixture is stirred at 20° C. during 1 hour and then it is treated with water (500 mL) dropwise during 30 minutes. The resulting solid is filtered, washed with water and dried, to give 3-cyclopentyloxy-4-methoxybenzoic acid (60.9 g) in the form of white crystals [Elemental analysis: C,65.8; H,6.7%; calculated: C,66.1; H,6.8%].
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[CH2:15][CH2:14][C:13]3[C:17]4[C:23]([NH:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]6[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=6)=[C:27]([Cl:40])[CH:26]=5)=[N:22][CH:21]=[N:20][C:18]=4[S:19][C:12]=3[C:11]=2[CH:10]=[N:9]1)(=O)=O.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(N(C(C)C)CC)(C)C>CC#N>[Cl:40][C:27]1[CH:26]=[C:25]([NH:24][C:23]2[N:22]=[CH:21][N:20]=[C:18]3[S:19][C:12]4[C:11]5[CH:10]=[N:9][N:8]([CH2:7][CH2:6][N:41]6[CH2:46][CH2:45][O:44][CH2:43][CH2:42]6)[C:16]=5[CH2:15][CH2:14][C:13]=4[C:17]=23)[CH:30]=[CH:29][C:28]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCc3c-5cnn3CCN3CCOCC3)cc2Cl)c1
Temperature: 70 °C
Yield: 58.6 %

Procedure:
To 2 mL CH3CN were sequentially added 2-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl]ethyl methanesulfonate (80 mg, 0.13 mmol), morpholine (18 mg, 0.20 mmol), and diisopropylethylamine (35 mg, 0.27 mmol). The reaction mixture was then heated up to 70° C. for 14 h. Upon cooling down, the crude was purified by HPLC to afford the desired product as an off-white solid (45 mg, 54%). 1H-NMR (DMSO-d6) δ 8.38 (s, 1H), 7.80 (d, 1H), 7.53 (s, 1H), 7.44 (dd, 1H), 7.38 (m, 1H), 7.24 (m, 2H), 7.04 (td, 1H), 6.98 (d, 1H), 6.95 (s, 1H), 5.13 (s, 2H), 4.18 (t, 2H), 3.63 (t, 4H), 3.35 (t, 2H), 3.14 (t, 2H), 2.78 (t, 2H), 2.45 (t, 4H); LCMS RT=2.72 min; [M+H]+=591.2.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:9][CH:8]([NH:10][S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH2:7][CH2:6][CH:5]([C:17]2[N:18]([CH3:25])[N:19]=[CH:20][C:21]=2[N+:22]([O-:24])=[O:23])[O:4]1)C.CC1CC(=O)CCC(C2N(C)N=CC=2[N+]([O-])=O)O1>>[CH3:1][CH:3]1[CH2:9][CH:8]([NH:10][S:11]([C:13]([CH3:16])([CH3:14])[CH3:15])=[O:12])[CH2:7][CH2:6][CH:5]([C:17]2[N:18]([CH3:25])[N:19]=[CH:20][C:21]=2[N+:22]([O-:24])=[O:23])[O:4]1
Reactant: CCC1CC(NS(=O)C(C)(C)C)CCC(c2c([N+](=O)[O-])cnn2C)O1
Agent: CC1CC(=O)CCC(c2c([N+](=O)[O-])cnn2C)O1
Product: CC1CC(NS(=O)C(C)(C)C)CCC(c2c([N+](=O)[O-])cnn2C)O1

Procedure:
Following the procedure for Intermediate 13 starting from 2-methyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-one gave N-(2-methyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl)-2-methyl-propane-2-sulfinamide as an off-white solid (208 mg, 40% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 5.63-5.51 (m, 1H), 4.05 (s, 3H), 3.86-3.72 (m, 2H), 3.19-3.11 (m, 1H), 2.22-1.69 (m, 6H), 1.29-1.20 (m, 12H).