Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:12][S:13]([CH2:16][C:17]#[N:18])(=[O:15])=[O:14].C([O-])(=O)C.[NH4+]>C(O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:16]([C:17]#[N:18])[S:13]([CH3:12])(=[O:15])=[O:14])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)CC#N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN(C)c1ccc(C=C(C#N)S(C)(=O)=O)cc1
Temperature: 0 °C
Yield: 93.2 %

Procedure:
To a solution of p-dimethylaminobenzaldehyde (2.20 g, 15 mmol) dissolved in 30 mL of absolute ethanol was added 1.8 g (15 mmol) of methylsulfonylacetonitrile and 1.2 g (15 mmol) of ammonium acetate. The mixture was heated at reflux under nitrogen for 1 hr and then poured into 150 g of ice water. The precipitated solid was filtered and air dried. The crude material was crystallized from absolute ethanol to give 3.5 g (93%) of (1) as a yellow solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH3:32])[N:27]=[C:26]2[Sn](CCCC)(CCCC)CCCC>CN(C=O)C.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.[Cu]I>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH3:32])[N:27]=[C:26]2[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(OC)cc12
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C=O)cn3COCC[Si](C)(C)C)nn2C
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 82.1 %

Procedure:
In a 25 mL round-bottomed flask, 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (439 mg, 1.23 mmol) and 5-methoxy-1-methyl-3-(tributylstannyl)-1H-indazole (556 mg, 1.23 mmol) were dissolved in DMF (3.00 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (71.2 mg, 61.6 μmol) and CuI (46.9 mg, 246 μmol, Eq: 0.20) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 2.5 h. The reaction mixture was concentrated under high vacuum and the residue was purified by chromatography (80 g column, 50 μm from Analogix, 0-50% EtOAc in hexanes over 30 min) to give 2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (443 mg, 1.01 mmol, 82.2%) as a yellow solid. MS (M+H)+=438 (>90% purity); 1H NMR (CDCl3) δ: 10.50 (s, 1H), 9.34 (s, 1H), 8.37 (d, J=2.3 Hz, 1H), 8.30 (s, 1H), 7.39 (d, J=9.1 Hz, 1H), 7.19 (dd, J=9.1, 2.3 Hz, 1H), 5.80 (s, 2H), 4.21 (s, 3H), 4.07 (s, 3H), 3.59-3.73 (m, 2H), 0.91-1.06 (m, 2H), 0.00 (s, 8H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:15])[CH2:13][CH3:14])[C:9]2[C:4](=[C:5]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:25][N:26]=[C:27]=[O:28]>ClC(Cl)C>[CH3:25][NH:26][C:27]([NH:15][CH:12]([C:10]1[C:9]2[C:4](=[C:5]([C:16]3[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=3[CH3:22])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1)[CH2:13][CH3:14])=[O:28]
Reactant: CCC(N)c1cc(C)nc2c(-c3c(C)cc(C)cc3C)cccc12
Reactant: CN=C=O
Solvent: CC(Cl)Cl
Product: CCC(NC(=O)NC)c1cc(C)nc2c(-c3c(C)cc(C)cc3C)cccc12

Procedure:
A mixture of 1-[2-methyl-8-(2,4,6-trimethyl-phenyl)-quinolin-4-yl]-propylamine (55 mg), methyl isocyanate (0.3 ml), in dichloroethane (1 ml) was heated at 60° C. for 1 hrs. The mixture was quenched with water and extracted with chloroform. The organic layer was separated, dried and concentrated to give the crude material as a colorless oil. The oil was purified by preparative thin layer chromatography using 3% methanol in chloroform as solvent to give 42 mg of the title compound as a white glass foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:7]=1>[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1cnccn1
Agent: [Pd]
Product: Nc1ccc(F)cc1Nc1cnccn1
Reaction time: 8 h
Yield: 44.1 %

Procedure:
(5-Fluoro-2-nitrophenyl)pyrazin-2-yl-amine (415 mg, 1.77 mmol) in IMS (15.0 ml) was added to palladium on charcoal (10 wt %, 45.0 mg) and stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo. The product was purified by chromatography (SiO2, 0-10% 2M ammonia methanol/DCM) to yield the title compound (160 mg, 0.78 mmol, 44%). 1H NMR (MeOD, 400 MHz): δ 8.04 (2H, m), 7.83 (1H, m), 7.21 (1H, dd, J 9.9, 2.8 Hz), 6.84 (1H, dd, J 8.7, 5.6 Hz), 6.74 (1H, ddd, J 8.9, 8.2, 2.9 Hz).
Reaction SMILES: C1(=O)OC(=[O:5])C2=CC=CC=C12.[NH2:12][C:13]1[N:18]=[C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[C:15]([Cl:26])[N:14]=1.S([O-])(O)=O.[Na+].[OH-].[Na+]>C(O)(C)C.C(OC(C)C)(C)C.O>[NH2:12][C:13]1[N+:18]([O-:5])=[C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[C:15]([Cl:26])[N:14]=1
Reactant: CCCCCCNc1cc(Cl)nc(N)n1
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Solvent: O
Product: CCCCCCNc1cc(Cl)nc(N)[n+]1[O-]
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
5.95 g of urea/H2O2 complex and 9.07 g of phthalic anhydride were suspended in 90 ml of isopropanol, in a three-necked flask. The mixture was stirred for 30 min at room temperature (20-25° C.). 10 g of 2-amino-4-hexylamino-6-chloropyrimidine were then added while controlling the exotherm at +30° C. After reaction for 3 hours, 100 ml of sodium hydrogen sulfite were poured thereinin to destroy the residual oxidizing agents. The mixture was permitted to separate out by settling and the upper phase was concentrated under vacuum. The residue obtained was taken up in a water (80 ml)/30% sodium hydroxide (20 ml) mixture. The solid obtained was reimpasted in 150 ml of isopropyl ether. The solid was filtered off and washed. It was dried in a heated desiccator. 4.52 g of the expected compound were thus obtained, for a yield of 42%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17](S(C3C=CC(C)=CC=3)(=O)=O)[CH:16]=2)[S:12][CH:11]=1)=[O:9].O[Li].O>C1COCC1.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[S:12][CH:11]=1)=[O:9]
Reactant: COc1cccc(CNC(=O)c2csc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncccc34)c2)c1
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(CNC(=O)c2csc(-c3c[nH]c4ncccc34)c2)c1
Temperature: 150 °C
Yield: 59.3 %

Procedure:
N-(3-Methoxybenzyl)-5-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)thiophene-3-carboxamide (70 mg, 0.14 mmol) was dissolved in THF (4 mL) and LiOH hydrate (42 mg, 1 mmol) was added in water (1 mL). The reaction mixture was heated to 150° C. in the microwave for 10 minutes. The reaction mixture was diluted with EtOAc and the organic layer was washed with 10% citric acid, saturated sodium bicarbonate, and then dried over sodium sulfate and concentrated to an oil, which was purified by column chromatography on silica (50 to 100% EtOAc/hexanes) to give the product as a white solid 30 mg, 0.083 mmol, 59%. 1H NMR 500 MHz (DMSO-d6) 12.00 (1H, s), 8.88 (1H, t), 8.32 (2H, m), 8.01 (1H, s), 7.87 (1H, s), 7.83 (1H, s), 7.26 (2H, m), 6.92 (2H, m), 6.93 (2H, m), 6.82 (1H, d), 4.43 (2H, d), 3.70 (3H, s). MH+ 364.10
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:19](Cl)(=[O:26])[O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23]>C(OCC)(=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:26])[O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a two-phase solution of 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine (5.0 g, 23 mmol) in ethyl acetate (45 mL)/3N aqueous sodium hydroxide (20 mL) was added 2,2,2-trichloroethyl chlorocarbonate (4.5 mL, 33 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The obtained organic layer was washed with 5% aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure to give the title compound (5.0 g, 55%) as a white powder.
Reaction SMILES: C([N:8]1[CH2:35][C:10]2([CH2:15][N:14]3[N:16]=[C:17]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:24][CH:23]=4)[C:18]([C:19]([NH2:21])=[O:20])=[C:13]3[NH:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1>C(Cl)Cl.CO.[Pd]>[O:28]([C:25]1[CH:24]=[CH:23][C:22]([C:17]2[C:18]([C:19]([NH2:21])=[O:20])=[C:13]3[NH:12][CH2:11][C:10]4([CH2:9][NH:8][CH2:35]4)[CH2:15][N:14]3[N:16]=2)=[CH:27][CH:26]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC1(CN(Cc3ccccc3)C1)C2
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC1(CNC1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.6 %

Procedure:
To a solution of 1-benzyl-2′-(4-phenoxyphenyl)-5′,7′-dihydro-4′H-spiro[azetidine-3,6′-pyrazolo[1,5-a]pyrimidine]-3′-carboxamide (200 mg, 0.43 mmol) in 10 mL of DCM and 10 mL of CH3OH was added 10% w/w Pd/C (100 mg). After stirring at RT under H2 for 16 hr, the mixture was filtered and concentrated. The residue was purified by pre-HPLC eluting from 25% to 90% CH3CN in 0.1% TFA in H2O. Fractions containing the desired product were combined and lyophilized overnight to afford 30 mg (19%) of desired product as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (br s, 1H), 8.84 (br s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.46-7.38 (m, 2H), 7.18 (t, J=8.0 Hz, 1H), 7.08 (d, J=8.0 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 6.81 (br s, 1 H), 4.23 (s, 2 H), 3.90-4.00 (m, 2 H), 3.78-3.87 (m, 2 H) and 3.47 (s, 2H). MS (ESI) m/e [M+1]+ 375.9.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C[Si]([C:14]#[CH:15])(C)C.C(N(CC)CC)C>CN(C)C=O>[C:14]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9])#[CH:15]
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccccc1I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1ccccc1OC
Yield: 50.9 %

Procedure:
2-Iodoanisole (10.5 g) and trimethylsilylacetylene (10.3 g) were reacted in dimethylformamide (50 ml), in the presence of dichloro-bis-triphenylphosphine palladium (1.0 g), cuprous iodide (0.5 g) and triethylamine (15 ml) in nitrogen atmosphere at 50° C. for 12 hr. The resulting reaction solution was evaporated, and to the resulting residue was added ethyl acetate and water. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was dissolved in methanol (100 ml), a 5N aqueous solution of sodium hydroxide (20 ml) was added thereto, and then reacted at 60° C. for 1 hr. The reaction solution was evaporated, and to the resulting residue was added ether and water. The resulting ether layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a pale yellow oil (3.02 g, yield; 51%). (232-2) 2-[2-Methoxyphenyl)ethynyl]-5-methoxybenzaldehyde
Reaction SMILES: [O:1]=[C:2]1[CH:10]([CH3:11])[C:9]2[C:4](=[C:5]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].[O:22]1CCOCC1>O>[NH2:3][C:4]1[C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[CH:6][CH:7]=[CH:8][C:9]=1[CH:10]([CH3:11])[C:2]([OH:22])=[O:1]
Reactant: C1COCCO1
Reactant: CC1C(=O)Nc2c(Oc3ccccc3Cl)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1cccc(Oc2ccccc2Cl)c1N

Procedure:
A mixture of 2-oxo-3-methyl-7-(2-chlorophenoxy)indoline (4 g.), sodium hydroxide (2.4 g.), dioxane (25 ml.) water (25 ml.) was refluxed under heating for 5 days with stirring. After cooling, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. To the residue was added water and the mixture was washed with diethyl ether. Ethyl acetate was added to the aqueous solution and adjusted to pH 4 to 5 with 5% sulfuric acid. The ethyl acetate layer was separated, washed with water and dried over magnesium sulfate and the solvent was distilled off under reduced pressure to give oily 2-[2-amino-3-(2-chlorophenoxy)phenyl]propionic acid (2.4 g.). This compound was dissolved in an aqueous solution of sodium bicarbonate and filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was dissolved in ethyl acetate and filtered. The filtrate was evaporated under reduced pressure, and the residue was dissolved in water and lyophilized to give light brown powder of the captioned compound (1.6 g.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)O)=[O:5])[CH3:2].[NH2:23][CH:24]1[CH2:29][N:28]([CH3:30])[C:27](=[O:31])[CH2:26][CH2:25]1.Cl.COC(C1C=C(Br)N(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O.ClC1C=C(C=CC=1F)N>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[NH:23][CH:24]1[CH2:25][CH2:26][C:27](=[O:31])[N:28]([CH3:30])[CH2:29]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: CN1CC(N)CCC1=O
Agent: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Cl
Agent: Nc1ccc(F)c(Cl)c1
Product: CCOC(=O)c1ccn(C(C)C)c1C(NC1CCC(=O)N(C)C1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for Step D2, but 2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step E4) and 5-amino-1-methylpiperidin-2-one [1228838-10-5] (free base was made from the purchased HCl salt) were used instead of 5-bromo-2-[(4-chloro-phenyl)hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester and 3-chloro-4-fluoroaniline respectively to afford the title compound (diastereomeric mixture) as an off-white solid. tR: 4.31 min (HPLC 1); ESI-MS: tR=1.13/1.15 min, [M+H]+ 432/434 (LC-MS 1); TLC: Rf=0.25 (EtOAc).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:11]=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:13][C:14]=1[C:15]([F:18])([F:17])[F:16].C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOC(C)=O.O>[Br:1][C:11]1[C:10]([CH3:9])=[C:14]([C:15]([F:18])([F:16])[F:17])[NH:13][C:12]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1cc(C)c(C(F)(F)F)[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1[nH]c(C(F)(F)F)c(C)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Bromosuccinimide (NBS) (17.7 g, 99.77 mmol) was portion wise added to an ice cooled solution of ethyl 4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (21 g, 95.02 mmol) and K2CO3 (13.7 g, 99.77 mmol) in acetonitrile. The reaction mixture was stirred for 2 h at RT. The reaction mixture was diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×300 mL). Combined organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to yield crude mass which was directly used to next step without further purification
Reaction SMILES: [C:1]([O-])(=[S:3])[CH3:2].[K+].Br[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:9]>C(O)C>[C:1]([CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:9])(=[S:3])[CH3:2]
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C(=O)CC(C)=S)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.6 %

Procedure:
Potassium thioacetate (2.28 g, 20 mmol) was added to a solution of 2-bromo-4′-methoxy acetophenone (4.58 g, 20 mmol) in absolute ethanol (150 ml). The reaction was stirred at ambient temperature under nitrogen for 16 hours at which time the white precipitate that had formed was filtered and the ethanol removed at reduced pressure. The residue was dissolved in dichloromethane (250 ml) and washed with water (200 ml), brine (200 ml), dried over Na2SO4 and the solvent removed at reduced pressure. The resulting residue was chromatographed on silica with a gradient from 10%-35% ethyl acetate in hexane to yield 3.4 g (76%) of 2-thioacetyl-4′-methoxy acetophenone. 1H NMR (CDCl3) δ2.36 p (s, 3h), 3.84 (s, 3h), 4.33 (s, 2h), 6.9 (d, 2h, J=9.2 Hz), 7.9 (d, 2h, J=9.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:31])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH:28]([F:30])[F:29])=[CH:13][CH:12]=1)=[O:10].[In]>C(O)C.[Cl-].[NH4+]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:31])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH:28]([F:29])[F:30])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(Nc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc2oc3c(OC(F)F)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1
Temperature: 80 °C

Procedure:
First, N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-carboxamide was prepared by reacting N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (prepared using the procedure of Example 4) with indium in ethanol and saturated ammonium chloride. To a 1 L 3-neck round bottom flask, fitted with a mechanical stirrer and reflux condenser was added N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (22.00 g, 46.99 mmol), ethanol (308.0 mL), sat. aq. NH4Cl (132.0 mL) and indium (32.37 g, 281.93 mmol). The reaction mixture was heated to 80° C. for 4-5 h (reaction monitored by HPLC). Additional indium (5.40 g, 47.03 mmol) was added to the reaction and heated to 80° C. until HPLC indicated completion. After cooling to room temperature the reaction was evaporated to dryness. DMF (200 mL) was added to the solids and heated to 70-75° C. The solution was filtered, washed with DMF (100 mL) and concentrated to a volume of 50 mL in vacuo. Water (3 L) was added to the reaction mixture, the solid was filtered, washed with water (66 mL) and dried in a vacuum oven (65° C.) overnight. The dried product appeared as a yellow solid (17.77 g, 77.4%). Purity 87.84% by HPLC; 1H NMR (500 MHz, DMSO-d6): 5.11 (bs, 2H), 6.86 (dd, J=2.3, 8.8 Hz, 1H), 7.46-7.51 (m, 3H), 7.53 (t, J=73.0 Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 8.80 (s, 2H), 10.93 (bs, 1H) ppm. m/z 437.1 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][C@H:20]([CH3:24])[CH2:21][NH:22][CH3:23])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:25].[C:26]([OH:30])(=O)[CH2:27][OH:28].OCC(N(CCOC1C=CC=C2C=1C(NC1C=CC(O)=C(C)C=1)=NC=N2)C)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[OH:25])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[O:19][C@H:20]([CH3:24])[CH2:21][N:22]([CH3:23])[C:26](=[O:30])[CH2:27][OH:28])[N:12]=[CH:11][N:10]=1
Reactant: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: O=C(O)CO
Agent: Cc1cc(Nc2ncnc3cccc(OCCN(C)C(=O)CO)c23)ccc1O
Product: C[C@H](CN(C)C(=O)CO)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12

Procedure:
The N-[(2R)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)propyl]-2-hydroxy-N-methylacetamide starting material was prepared by reacting 2-chloro-4-({5-[(1R)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-yl}amino)phenol with and glycolic acid using an analogous procedure to that described in Example 3 for the preparation of 2-hydroxy-N-[2-({4-[4-hydroxy-3-methylanilino]quinazolin-5-yl}oxy)ethyl]-N-methylacetamide, to give N-[(2R)-2-({4-[3-chloro-4-hydroxyanilino]quinazolin-5-yl}oxy)propyl]-2-hydroxy-N-methylacetamide in 57% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.91 (m, 1H), 2.97 (s, 3H), 3.39 (dd, 1H), 4.04 (d, 2H), 4.16 (m, 1H), 4.39 (m, 1H), 5.08 (m, 1H), 6.98 (d, 1H), 7.27 (m, 2H), 7.47 (dd, 1H), 7.70 (t, 1H), 7.97 (d, 1H), 8.43 (s, 1H), 9.85 (s, 1H), 9.99 (bs, 1H); Mass spectrum MH+ 417.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[C:12]([Cl:26])[CH:11]=1)(=O)C1C=CC=CC=1.[OH-].[K+].Cl>CO>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:13]1[C:14]([Cl:16])=[CH:15][C:10]([OH:9])=[CH:11][C:12]=1[Cl:26]
Reactant: O=C(Oc1cc(Cl)c(OCc2ccccc2Cl)c(Cl)c1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1cc(Cl)c(OCc2ccccc2Cl)c(Cl)c1
Temperature: 25 °C
Yield: 54.7 %

Procedure:
To a mixture of 2.87 g of 1-benzoyloxy-4-(2-chlorobenzyloxy)-3,5-dichlorobenzene and 100 ml of methanol was added dropwise 5.1 g of 10% (w/w) aqueous potassium hydroxide solution, while stirring at room temperature. After stirring at room temperature for 6 hours, the reaction mixture was made weakly acidic by the addition of 10% hydrochloric acid, and the methanol was removed by distillation under reduced pressure. The residue was extracted twice with 100 ml of ethyl acetate. The combined ether layer was washed with water, and dried with anhydrous magnesium sulfate, followed by removal of the solvent by distillation under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 1.17 g of 4-(2-chlorobenzyloxy)-3,5-dichlorophenol (55% yield), m.p. 108.3° C.