Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](Br)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](B(O)O)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[CH2:1]([O:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:25]3[CH:24]=[C:23]4[C:28](=[CH:27][CH:26]=3)[N:20]([CH3:19])[CH:21]=[CH:22]4)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: Brc1cnc2ccn(OCc3ccccc3)c2c1
Product: Cn1ccc2cc(-c3cnc4ccn(OCc5ccccc5)c4c3)ccc21

Procedure:
The entitled compound was prepared from 1-(benzyloxy)-6-bromo-1H-pyrrolo[3,2-b]pyridine and (1-methyl-1H-indol-5-yl)boronic acid according to the procedure described in Example 1.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3]1.S(=O)(=O)(O)O.[C:23]1([NH:29]N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C.C(O)C>[CH2:6]1[C:7]2[NH:29][C:23]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:2]=2[CH2:3][CH:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1CCC(=O)CC1C(=O)OCC
Reactant: NNc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1Cc2[nH]c3ccccc3c2CC1C(=O)OCC
Temperature: 25 °C
Yield: 59.4 %

Procedure:
To 20 ml of ethanol were added 2.66 g of diethyl 4-oxocyclohexane-1,2-dicarboxylate, 2.45 g of concentrated sulfuric acid and 1.08 g of phenylhydrazine. The mixture was refluxed for 2 hours and then cooled to room temperature. Thereto were added 50 ml of ethyl acetate and 50 ml of water. The mixture was adjusted to pH 7.5 with an aqueous saturated sodium hydrogencarbonate solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethanol to obtain 1.87 g (yield: 59%) of diethyl 1,2,3,4-tetrahydrocarbazole-2,3-dicarboxylate as colorless needles.
Reaction SMILES: [C:1]1([CH3:32])[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:27]([O:29]CC)=[O:28])=[C:9]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[S:10][CH:11]=2)=[CH:3][CH:2]=1.[Li+].[OH-].OO.[OH-].[Na+]>O>[C:1]1([CH3:32])[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:27]([OH:29])=[O:28])=[C:9]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[S:10][CH:11]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(-c2ccc(C)cc2)csc1NC(=O)c1cc(OC)c(OC)c(OC)c1
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: O
Product: COc1cc(C(=O)Nc2scc(-c3ccc(C)cc3)c2C(=O)O)cc(OC)c1OC

Procedure:
Ethyl cyanoacetate (5 mmol), and 1-(3,4,5-trimethoxyphenyl)ethanone (5 mmol) are dissolved in toluene (5 mL). Morpholine (5 mmol) is added followed by activated molecular sieves (4A). The reaction is stirred at 80° C. for 12 hours. The reaction is cooled to room temperature, filtered and concentrated. The residue is taken up in toluene (5 mL), ethanol (5 mL) and sulfur is added (0.16 g; 5 mmol). The reaction mixture is heated with mixing at 70° C. for 12 hours. The reaction is cooled to room temperature and the solvents are evaporated. The residue is purified by HPLC to provide ethyl 2-amino-4-(3,4,5-trimethoxyphenyl)thiophene-3-carboxylate. Ethyl 2-amino-4-(3,4,5-trimethoxyphenyl)thiophene-3-carboxylate (5 mmol) is treated with 4-methylbenzoyl chloride (5 mmol) in THF (10 mL). The reaction is stirred at room temperature for 10 hours. The reaction is diluted with 1N NaOH (10 mL) and ethyl acetate (15 mL). The layers are separated, the organic layer is dried with anhydrous sodium sulfate, filtered and concentrated. The residue is purified by flash chromatography to provide ethyl 4-p-tolyl-2-(3,4,5-trimethoxybenzamido)thiophene-3-carboxylate. Ethyl 4-p-tolyl-2-(3,4,5-trimethoxybenzamido)thiophene-3-carboxylate is hydrolyzed under a variety of conditions (e.g. LiOH, water; LiOH, H2O2, water; or NaOH, water) to provide the title compound
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH3:16])=[C:6]([C:17]([O-:19])=[O:18])[C:5]=1[C:20]([O:22]CC)=[O:21])[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:15]([O:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:20]([OH:22])=[O:21])[C:6]=1[C:17]([OH:19])=[O:18])[CH3:16]
Reactant: CCOC(=O)c1c(C(=O)[O-])c(OCC)c2ccccc2c1OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1c(C(=O)O)c(C(=O)O)c(OCC)c2ccccc12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
Ethyl 1,4-diethoxy-2,3-naphthalenedicarboxylate (32 g, 89 mmol) was added to a solution of sodium hydroxide (20 g) in ethanol (200 ml) and water (40 ml) and stirred for 1.5 h at 60° C. The reaction was cooled and the thick white suspension was filtered. The solid was dissolved in a mixture of ethyl acetate (200 ml) and water (800 ml). The layers were separated and the aqueous was acidified with hydrochloric acid (2M, 120 ml). The aqueous was extracted with ethyl acetate (2×) and the combined organics were dried (MgSO4). Evaporation of the solvent under vacuum gave the title compound as a white solid (25 g, 92%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].[C:57]([O:60][CH2:61][C:62](Cl)=[O:63])(=[O:59])[CH3:58]>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:62](=[O:63])[CH2:61][O:60][C:57](=[O:59])[CH3:58])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC(=O)COC(C)=O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-amino-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (40 mg) in dry methylene chloride (0.4 ml) was cooled to 0° C. To this solution was added a solution of acetoxyacetyl chloride (9 mg) in methylene chloride (0.5 ml). The reaction mixture was stirred at 0° C. for 30 minutes, and quenched with a drop of methanol. Purification by preparative tlc on silica gel (1000 microns, 5% i-PrOH/CH2Cl2) gave 36 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)O1>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:32]5[CH:33]=[N:34][NH:35][CH:36]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3cn[nH]c3)cc1OCC2
Yield: 78 %

Procedure:
Following the same procedure as for 182, 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole provided 217 in 78% yield. LS/MS (ESI+): m/z 362 (M+H). 1H NMR (400 MHz, DMSO) δ 13.02 (s, 1H), 8.37 (d, J=8.4, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 7.54-7.38 (m, 1H), 7.30 (t, J=12.5, 1H), 5.91 (dt, J=13.2, 6.6, 1H), 4.57-4.46 (m, 4H), 1.50 (d, J=6.6, 6H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=O)=[CH:7]2.N.O[N:27]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:19][CH:20]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:27])=[O:13])=[CH:7]2
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Temperature: 25 °C
Yield: 89.6 %

Procedure:
To a solution (35 mL) of 7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (3.3 g) in N,N-dimethylformamide were added under ice-cooling 1-hydroxybenzotriazole ammonia salt (2.0 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.5 g), and the mixture was stirred from under ice-cooling to room temperature for 15 hr. The reaction solution was concentrated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained pale-yellow oil was crystallized from ethyl acetate to give the title compound (2.95 g, yield 90%) as pale-yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[F:12][C:13]1([F:20])[CH2:18][CH2:17][CH:16](O)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[F:12][C:13]1([F:20])[CH2:18][CH2:17][CH:16]([O:8][C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N+:9]([O-:11])=[O:10])[CH2:15][CH2:14]1
Reactant: OC1CCC(F)(F)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)cc1OC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.213 g DTAD was added into a solution of 5-fluoro-2-nitro-phenol, 0.105 g 4,4-difluorocyclohexanol, 0.25 g triphenylphospine in 2 ml of anhydrous methylene chloride at rt. The reaction mixture was stirred at rt overnight when TLC analysis indicated the consumption of the 5-Fluoro-2-nitro-phenol. The reaction mixture was diluted with methylene chloride (50 ml) and washed with 10% potassium carbonate solution. The aqueous layer was extracted with methylene chloride (2×25 ml) and the combined organics washed with sodium hydrogecarbonate solution (25 ml). The organic layer was passed through a phase separator and concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 100%→1:1 iso-hexane/EtOAc).
Reaction SMILES: [I:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:15]=[O:16]>>[I:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:15]=[O:16]
Reactant: Cn1nccc1I
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1ncc(C=O)c1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
To a cooled (0° C.) solution of 5-iodo-1-methyl-1H-pyrazole (1.3 g, 6.3 mmol) in dimethyl formamide (2 mL), under an atmosphere of nitrogen, was added phosphorus oxychloride (1.72 mL, 18.8 mmol, 3.0 eq.). The resulting mixture was stirred at room temperature for 4 hr before partitioning between ethyl acetate (80 mL) and 2M aqueous potassium carbonate (80 mL). The aqueous layer was extracted again with ethyl acetate (80 mL). The organic extracts were combined and washed with water (3×50 mL) and then dried over magnesium sulphate. The resulting mixture was filtered and the filtrate evaporated under reduced pressure to give the title compound as an orange solid (0.58 g, 39%).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[Br:9][C:10](=[CH2:13])[CH2:11]Br>>[Br:9][C:10](=[CH2:11])[CH2:13][O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: Oc1ccccc1O
Reactant: C=C(Br)CBr
Product: C=C(Br)COc1ccccc1O
Yield: 52 %

Procedure:
This compound was prepared in 52% yield from catechol and 2-bromoallyl bromide according to the procedure for 2p in Example IX. Yellow oil; 1H NMR (CDCl3): δ 4.70 (s, 2H), 5.68 (s, 1H), 5.70-5.71 (m, 1H), 5.95-5.96 (m, 1H), 6.81-6.97 (m, 4H); 13C NMR (CDCl3): δ 73.10, 113.09, 115.33, 119.17, 120.28, 122.82, 127.06, 144.83, 146.12; HRMS (FAB): 243.95575 calcd for C9H9BrOS [M]+. found 243.9557 (−0.2 ppm, 0.0 mmu).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:32][CH3:33])[C:30]=1[CH3:31])[C:6]([NH:8][CH2:9][C:10]1[CH:24]=[CH:23][C:13]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][C:11]=1[N+:25]([O-])=O)=[O:7]>C(O)C.[Pd]>[NH2:25][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][C:10]=1[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:28]=[C:29]([O:32][CH3:33])[C:30]([CH3:31])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: COc1cc(C(=O)NCc2ccc(CNC(=O)OC(C)(C)C)cc2[N+](=O)[O-])cc(OC)c1C
Agent: [Pd]
Solvent: CCO
Product: COc1cc(C(=O)NCc2ccc(CNC(=O)OC(C)(C)C)cc2N)cc(OC)c1C
Yield: 100.1 %

Procedure:
To a solution of compound 65d (0.170 g, 0.37 mmol) in ethanol (3 mL) was added 10% palladium/carbon (30 mg). The reaction mixture was hydrogenated (1 atm) overnight. The solution was filtered and the filtrate was concentrated to give compound 65e (0.159 g, 100%) as a brown oily solid. ESI-MS m/e 430.5 (M+1).
Reaction SMILES: [I:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>C1COCC1>[NH2:15][C:9]1[C:8]([O:7][C:6]2[CH:16]=[C:2]([I:1])[C:3]([O:20][CH3:21])=[CH:4][C:5]=2[CH:17]([CH3:19])[CH3:18])=[CH:13][N:12]=[C:11]([NH:14][C:31](=[O:32])[CH2:30][Cl:29])[N:10]=1
Reactant: O=C(Cl)CCl
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C(C)C)c(Oc2cnc(NC(=O)CCl)nc2N)cc1I
Temperature: 25 °C
Yield: 61.8 %

Procedure:
5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (3.6 g, 9 mmol) and 5.1 mL triethylamine was added to 120 mL dry THF, and the reaction mixture was cooled in an ice bath and stirred under nitrogen atmosphere. Chloroacetyl chloride (1.8 mL, 22.5 mmol) dissolved in 5 mL THF was added dropwise, and the reaction mixture was stirred for four hours, during which time the reaction mixture was allowed to slowly warm to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water and methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting oil was purified by flash chromatography 0%-20% “Magic Base”/methylene chloride) to give 2.65 g of N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-2-chloro-acetamide as the major fraction.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[C:5](/[CH:12]=[CH:13]/[C:14]([O:16]CC)=[O:15])[CH:4]=[N:3]1.[OH-].[Na+].Cl>CO>[CH3:1][N:2]1[C:6]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[C:5](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])[CH:4]=[N:3]1
Reactant: CCOC(=O)/C=C/c1cnn(C)c1-c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1ncc(/C=C/C(=O)O)c1-c1cccs1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a mixture of ethyl (2E)-3-[1-methyl-5-(2-thienyl)-1H-pyrazol-4-yl]acrylate (2.0 g) and methanol (20 ml) was added 2N aqueous sodium hydroxide solution (7.6 ml) and the mixture was stirred at 60° C. for 30 min. 1N Hydrochloric acid was poured into the reaction mixture, and the precipitated solids were collected by filtration, washed with water and dried with airflow to give (2E)-3-[1-methyl-5-(2-thienyl)-1H-pyrazol-4-yl]acrylic acid (1.69 g, 95%) as crystals. Recrystallization thereof from methanol-isopropyl ether gave colorless prism crystals. melting point: 210-212° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([NH:14][C:15](=[O:29])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[Cl:28])[CH:9]=[CH:10][C:11]=1[CH2:12]O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([NH:14][C:15](=[O:29])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][C:19]=2[Cl:28])[CH:9]=[CH:10][C:11]=1[CH2:12][Cl:3]
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CO)c(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CCl)c(Cl)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
1.12 mL (16.440 mmol) thionyl chloride was added to a solution of 1.620 g (4.110 mmol) N-(3-chloro-4-hydroxymethyl-phenyl)-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z32a) in 30 mL toluene and the mixture was stirred for 2 h at 80° C. The reaction mixture was evaporated down i. vac. and the residue recrystallised from ether/petroleum ether. The precipitate was filtered off, washed with petroleum ether and dried in a HV.
Reaction SMILES: OC(C1N=CC([C:11]2[S:15][C:14]([N+:16]([O-:18])=[O:17])=[C:13]([C:19]([NH2:21])=[O:20])[CH:12]=2)=CC=1)(C)C.CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[N:37]=[N:38][N:39]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:40]=3)=[CH:32][CH:31]=2)O1.C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>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>[N+:16]([C:14]1[S:15][C:11]([C:30]2[CH:31]=[CH:32][C:33]([C:36]3[N:37]=[N:38][N:39]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:46])([CH3:47])[CH3:48])[CH:40]=3)=[CH:34][CH:35]=2)=[CH:12][C:13]=1[C:19]([NH2:21])=[O:20])([O-:18])=[O:17]
Reactant: CC1(C)OB(c2ccc(-c3cn(COCC[Si](C)(C)C)nn3)cc2)OC1(C)C
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cn1
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: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2ccc(-c3cc(C(N)=O)c([N+](=O)[O-])s3)cc2)nn1
Temperature: 90 °C

Procedure:
5-Bromo-2-nitrothiophene-3-carboxamide (Intermediate 10 Step 4) (470 mg, 1.87 mmol), 4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,3-triazole (751 mg, 1.87 mmol), and Pd(PPh3)4 (108 mg, 0.094 mmol) were combined in a vial and evacuated/backfilled with nitrogen. THF (4.4 mL) and 2 N Na2CO3 (1.9 mL) were added. The reaction mixture was heated to 90° C. overnight. The black reaction was diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, combined with silica, and evaporated. Flash chromatography (dry load, 50-100% EtOAc/hexanes) afforded a brown solid that was triturated with CH2Cl2 and filtered to isolate the title compound as a yellow solid. The mother liquor was concentrated, triturated again, and filtered to isolate an additional batch of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH2:14])[CH3:2].[N:15]([C:18]1[CH:23]=[CH:22][C:21]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)=[CH:20][CH:19]=1)=[C:16]=[O:17].COC1C=C(C(F)(F)F)C=CC=1NC(NC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:13])[F:12])=[CH:6][C:5]=1[NH:14][C:16]([NH:15][C:18]1[CH:19]=[CH:20][C:21]([B:24]2[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]2)=[CH:22][CH:23]=1)=[O:17])[CH3:2]
Reactant: CCOc1ccc(C(F)(F)F)cc1N
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Agent: COc1cc(C(F)(F)F)ccc1NC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1

Procedure:
2-Ethoxy-5-trifluoromethylphenylamine is reacted with 2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane according to the preparation of 1-(2-methoxy-4-trifluoromethylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea described in Example 5. After purification, a beige-coloured powder of 1-(2-ethoxy-5-trifluoromethylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea is obtained, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:18]([O:17][CH2:16][CH2:15][CH2:14][O:10][C:9]1[C:2]([Br:1])=[C:3]([CH:6]=[CH:7][C:8]=1[O:11][CH3:12])[CH:4]=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(C=O)c(Br)c1O
Reactant: BrCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c(Br)c1OCCCOCc1ccccc1

Procedure:
Synthesized according to the methods of general procedure 4 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 2-bromo-3-hydroxy-4-methoxy-benzaldehyde (1.0 g, 4.32 mmol), (3-bromo-propoxymethyl)-benzene (0.76 mL, 4.32 mmol), cesium carbonate (2.11 g, 6.5 mmol), DMF (30 mL). Purification: flash chromatography (10% EtOAc/hexanes): yield 1.54 g (95%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.26 (s, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.46-7.18 (m, 5H), 6.95 (d, J=8.6 Hz, 1H), 4.56 (s, 2H), 4.14 (t, J=6.1 Hz, 2H), 3.92 (s, 3H), 3.77 (t, J=6.2 Hz, 2H), 2.15 (quin, J=6.5 Hz, 2H); MS (ESI): m/z=381 (M+1, positive).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH3:20])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:31])[F:32])=[CH:30][CH:29]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:20])[CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCc1cnc(NCCc2ccc(OC)c(C)c2)nc1
Product: CCc1cnc(N(CCc2ccc(O)c(C)c2)Cc2ccc(C(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from 5-ethyl-N-[2-(4-methoxy-3-methylphenyl)ethyl]pyrimidin-2-amine and 4-trifluoromethylbenzyl bromide.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl[C:8]1[N:17]=[C:16]([NH:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[OH-].[Na+]>O1CCCC1>[N:1]1([C:8]2[N:17]=[C:16]([NH:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CCN(CC)CCNc1nc(Cl)nc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(CC)CCNc1nc(N2CCCC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
A solution of 6.4 g of pyrrolidine in 50 ml of tetrahydrofuran was added to 10 g of 2-chloro-4-(2-diethylaminoethylamino)quinazoline hydrochloride in 100 ml of tetrahydrofuran. The reaction mixture was stirred at ambient temperature for about one hour and then was heated at reflux for 5 hours. The reaction mixture was poured into ice-water, made alkaline by the addition of dilute aqueous sodium hydroxide solution, and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue, a gummy solid, was triturated with about 5 ml of hexane, and the resulting mixture was chilled overnight in a refrigerator. The mixture then was filtered and the solid obtained was recrystallized from aqueous ethanol to give 2 g of 2-pyrrolidinyl-4-(2-diethylaminoethylamino)quinazoline; m.p. 87°-90°. The following analytical data were obtained: