Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[CH:23]([O:26]C(=O)C)[CH2:24][F:25])(=[O:17])=[O:16])=[O:13])[N:4]=1.Cl>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[CH:23]([OH:26])[CH2:24][F:25])(=[O:16])=[O:17])=[O:13])[N:4]=1
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2sccc2C(CF)OC(C)=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2sccc2C(O)CF)n1
Reaction time: 1 h
Yield: 88.6 %

Procedure:
650 mg (0.0015 mole) of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-3-(1-acetoxy-2-fluoroethyl)-2-thiophenesulfonamide synthesized in Example 4 was dissolved in 5 ml of aqueous sodium hydroxide solution and then stirred at normal temperature for one hour. The reaction mixture was adjusted to pH4 by adding 5% aqueous HCl solution and then extracted with methylene chloride. The extract was concentrated to obtain 540 mg (Yield: 92%) of the pure title compound.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([F:10])=[C:8]([F:11])[CH:7]=[C:6]([Br:12])[C:5]=1[OH:13])[CH:2]=C.[O:14]=[O+][O-]>ClCCl.CO>[OH:13][C:5]1[C:6]([Br:12])=[CH:7][C:8]([F:11])=[C:9]([F:10])[C:4]=1[CH2:1][CH:2]=[O:14]
Reactant: C=CCc1c(O)c(Br)cc(F)c1F
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: O=CCc1c(O)c(Br)cc(F)c1F
Temperature: 25 °C

Procedure:
A solution of 7.8 gm (31.45 mMol) 2-allyl-3,4-difluoro-6-bromophenol in 100 mL dichloromethane and 20 mL methanol was cooled to −78° C. and was then saturated with ozone. After 20 minutes the reaction mixture was purged with nitrogen for 10 minutes and was then treated with 5 mL dimethylsulfide. The reaction mixture was allowed to warm gradually to room temperature. After 15 hours the reaction mixture was concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][C:14]=1[C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:11])[CH3:10]>C(Cl)(Cl)Cl>[C:9]([NH:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:2]([CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH3:1])=[CH:15][C:14]=1[C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(CBr)cc1C(C)(C)C
Reactant: CNC1CCCCC1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(CN(C)C2CCCCC2)cc1C(C)(C)C

Procedure:
48 gm of N-methyl-cyclohexylamine were added to 56 gm of 4-acetylamino-3-tert.butyl-benzyl bromide in 500 ml of chloroform, and the mixture was refluxed for 1.5 hours. Subsequently, the reaction mixture was extracted three times with water, and the organic phase was evaporated. The residue was purified column-chromatograhically on silicagel with chloroform/methanol (5:1), and 4-acetylamino-3-tert.butyl-N-cyclohexyl-N-methyl-benzylamine hydrochloride, m.p. 240-243° C (decomp.), was crystallized from a solution of the purified base in absolute ethanol/ether by addition of absolute ethanolic hydrochloric acid.
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].Cl.[NH2:11][CH2:12][CH2:13][SH:14]>Cl.C(O)(C)C>[ClH:1].[ClH:1].[CH3:9][C:8]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:3][S:14][CH2:13][CH2:12][NH2:11]
Reactant: Cc1[nH]cnc1CO
Reactant: NCCS
Agent: Cl
Solvent: CC(C)O
Product: Cc1nc[nH]c1CSCCN
Yield: 164.7 %

Procedure:
A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g.) and cysteamine hydrochloride (23.0 g.) in concentrated aqueous hydrochloride acid (450 ml.) was heated under reflux for 17 hours. Concentration followed by re-evaporation with water afforded a residue which was dissolved in isopropyl alcohol, concentrated to low bulk and cooled to afford 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (40.6 g.), m.p. 185°-191°.
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.[ClH:18]>CC(O)C.CCOCC>[Cl:18][CH2:3][CH2:2][CH:1]=[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cl
Reactant: OC(c1ccccc1)(c1ccccc1)C1CC1
Solvent: CC(C)O
Solvent: CCOCC
Product: ClCCC=C(c1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 93 %

Procedure:
Cyclopropyldiphenylmethanol (500 mg, 2.23 mmol) was dissolved in 1M HCl in i-PrOH (4.0 mL). The reaction mixture was then heated at 60° C. for 1 h. The reaction was cooled 20° C. and diluted with Et2O (100 mL). The organic solution was successively washed with H2O, NaHCO3 saturated aqueous solution and brine. It was then dried over MgSO4, filtered, concentrated in vacuo and chromatographed on a silica gel column by elution with Hexanes to give 4-Chloro-1,1-diphenyl-1-butene (506 mg, 93%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ2.59 (q, 2H, J=6.9 Hz), 3.58 (t, 2H, J=6.9 Hz), 6.12 (t, 1H, J=7.3 Hz), 7.16-7.42 (m, 10H) ppm.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[S:5][C:4]=1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:49][C:50]1[CH:51]=[C:52]([NH:57][C:58](=[O:70])[C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([C:68]#[N:69])([CH3:67])[CH3:66])[CH:60]=2)[CH:53]=[CH:54][C:55]=1[CH3:56]>CN(C=O)C>[C:68]([C:65]([C:61]1[CH:60]=[C:59]([CH:64]=[CH:63][CH:62]=1)[C:58]([NH:57][C:52]1[CH:53]=[CH:54][C:55]([CH3:56])=[C:50]([NH:49][C:12]([C:4]2[S:5][C:6]3=[N:7][CH:8]=[CH:9][N:10]=[C:11]3[C:3]=2[NH:2][CH3:1])=[O:14])[CH:51]=1)=[O:70])([CH3:67])[CH3:66])#[N:69]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: CNc1c(C(=O)O)sc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNc1c(C(=O)Nc2cc(NC(=O)c3cccc(C(C)(C)C#N)c3)ccc2C)sc2nccnc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A solution of 7-(methylamino)thieno[2,3-b]pyrazine-6-carboxylic acid 12 (1.6 g, 7.65 mmol), HATU (3.20 g, 8.41 mmol) and DIPEA (3.79 mL, 22.94 mmol) in DMF (20 mL) was stirred at rt for 30 min. N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (2.52 g, 7.65 mmol) was added and stirred overnight at 75° C. Quenched in ice/water and the resulting precipitate was collected. Purification by chromatography (10-20% EtOAc in CH2Cl2), co-evaporate with acetonitrile (2×), stirred in water at 70° C. for 1 h and filtrated to give the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-7-(methylamino)thieno[2,3-b]pyrazine-6-carboxamide 13 (2.06 g, 55.6%). 1H-NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.22 (s, 3H), 3.41 (d, J=5.5 Hz, 3H), 7.26 (d, J=8.6 Hz, 1H), 7.60 (t, J=7.8 Hz, 2H), 7.75 (d, J=7.8 Hz, 1H), 7.82 (d, J=1.9 Hz), 1H), 7.94 (d, J=7.8 Hz, 2H), 8.05 (m, 1H), 8.73 (d, J=2.3 Hz, 1H), 8.77 (d, J=2.3 Hz, 1H), 9.55 (br s, 1H), 10.31 (br s, 1H). (m/z)=485 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([OH:20])[CH:17]=[C:16]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Cl:22][C:23](Cl)([Cl:27])[CH2:24][CH2:25]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:22][C:23]([Cl:27])=[CH:24][CH2:25][O:20][C:18]1[CH:19]=[C:2]([Cl:1])[C:3]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])=[C:16]([Cl:21])[CH:17]=1
Reactant: ClCCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCCCOc1c(Cl)cc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 56.2 %

Procedure:
This compound was prepared in a manner analogous to that of Step D of Example 1, using 3.5 grams (0.0104 mole) of N-[3-(2,6-dichloro-4-hydroxyphenoxy)propyl](tert-butoxy)carboxamide, 2.3 grams (0.0125 mole) of 1,1,1,3-tetrachloropropane and 3.4 grams (0.0250 mole) of potassium carbonate in DMF. The crude product was purified with column chromatography on silica gel using a mixture of 1:3 hexane and methylene chloride as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]2[CH:12]([CH:13]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][CH2:16]2)[NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](Cl)=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30].[OH-].[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[CH:17]2[CH:12]([CH:13]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][CH2:16]2)[N:11]([C:32](=[O:33])[CH2:31][C:26]2[CH:27]=[CH:28][C:29]([Cl:30])=[C:24]([Cl:23])[CH:25]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: c1ccc(CN2CCNC3C(N4CCCC4)CCCC32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2ccccc2)C2CCCC(N3CCCC3)C21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(4aRS,5SR,8aRS)-1-Benzyl-5-(pyrrolidin-1-yl)perhydroquinoxaline (325 mg, 1.09 mmol) was dissolved in abs. CH2Cl2 (35 ml). 2-(3,4-Dichlorophenyl)acetyl chloride (291 mg, 1.3 mmol) was added dropwise and the mixture was stirred at room temperature. After 30 minutes, 2 N NaOH (35 ml) was added and the mixture was stirred vigorously for 2 hours. The aqueous phase was separated off. The organic phase was extracted by shaking three times with HCl (1 N). The aqueous phase was then brought to pH 8 with NaOH (2 N) and extracted by shaking three times with CH2Cl2. The organic phases were dried over Na2SO4 and evaporated in vacuo. A pale yellow solid was obtained.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[C:6]([CH3:12])=[C:5]([N+:13]([O-])=O)[CH:4]=1)#[N:2].[H][H]>CO.[Pd]>[NH2:13][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[C:6]=1[CH3:12]
Reactant: [H][H]
Reactant: Cc1c([N+](=O)[O-])cc(C#N)c2nc[nH]c12
Agent: [Pd]
Solvent: CO
Product: Cc1c(N)cc(C#N)c2nc[nH]c12

Procedure:
A mixture of 7-cyano-4-methyl-5-nitrobenzimidazole (0.91 g, 4.5 mmol) and 10% palladium-on-carbon (100 mg) in methanol (200 mL) is treated with an atmosphere of hydrogen (1 atm, balloon) for 14 hours. The resulting mixture is filtered through Celite and rotary evaporated. The residue is purified by flash chromatography (silica gel, 95:5 ethyl acetate:methanol) to afford 5-amino-7-cyano-4-methylbenzimidazole.
Reaction SMILES: [OH-].[K+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10]([N:13]=[N:14][C:15]1(Cl)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])[CH3:11].O>CO>[CH:10]([N:13]=[N:14][C:15]1([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:12])[CH3:11]
Reactant: CC(C)N=NC1(Cl)CCCCC1
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N=NC1(Oc2ccccc2)CCCCC1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5.95 grams (.09 moles) of 85% potassium hydroxide in 50 mls of methanol in a 125 ml erlenmeyer flask was added 8.46 grams (.09 moles) of phenol and the solution stirred for 15 minutes. The solution was cooled to 20° C and 15.0 grams (.08 moles) of 1-isopropylazo-1-chlorocyclohexane (from Example 3-2) was added dropwise over 5 minutes and the reaction mixture stirred an additional hour at 20°-25° C. The reaction mixture was poured into 300 mls water and the product extracted with 200 mls of pentane. The pentane solution was separated and washed successively with 100 ml portions of 10% sodium hydroxide, water, 10% HCl (twice), 15% HCl, water, 15% sodium bisulfite solution and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and it weighed 15.7 grams (76.5% crude yield). The infrared spectrum of the product was in agreement with the structure of 1-isopropylazo-1-phenoxycyclohexane. Gas chromatography indicated there was also a small amount of 1-isopropylazo-1-methoxycyclohexane from a competing reaction of the methanol with the 1-isopropylazo-1-chlorocyclohexane.
Reaction SMILES: [C:1](OC)(=O)[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CC1C=CC(C)=CC=1>CO>[C:2]1([CH3:1])[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Solvent: Cc1ccc(C)cc1
Solvent: CO
Product: COC(=O)c1ccc(C)cc1

Procedure:
U.S. Pat. No. 4,126,755 and the corresponding German Offenlegungsschrift P2244662.4 disclose a method of producing dimethyl terephthalate from high-boiling tarry residues resulting from the combined oxidation of p-xylene and methyl p-toluate with air, esterification of the resulting acids with methanol and after-treatment of the esterification reaction product, which comprises treating the high-boiling residues with methanol at a temperature above 250° C., and thereafter separating the resulting dimethyl terephthalate in accordance with conventional separation techniques.
Reaction SMILES: NC1C=CC=CC=1[C:4](O)=[O:5].[NH2:11][C:12]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Cl:21][C:18]1[CH:17]=[C:13]2[C:14]([O:16][C:4](=[O:5])[NH:11][C:12]2=[CH:20][CH:19]=1)=[O:15]
Reactant: Nc1ccccc1C(=O)O
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Yield: 89 %

Procedure:
Isatoic anhydrides were prepared from 2-aminobenzoic acid derivatives using the following procedure. A solution of 2-amino-5-chlorobenzoic acid (1.56 g, 9.7 mmol) in 25 mL of dry THF and triphosgene (1.00 g, 3.3 mmol) was stirred at room temperature for 18 h. The resultant solid was filtered, washed with cold acetone, and dried under vacuum to give 1.56 g (89%) of 5-chloroisatoic anhydride.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:15]([Sn](CCCC)(CCCC)C#CC)[CH2:16][CH2:17]C>C1(C)C=CC=CC=1.CCOC(C)=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>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:2]([C:15]#[C:16][CH3:17])=[CH:7][N:6]=1
Reactant: CCC(CC)Nc1nc(Cl)ncc1Br
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC#Cc1cnc(Cl)nc1NC(CC)CC
Temperature: 120 °C
Yield: 74.8 %

Procedure:
To a microwave vial is added a solution of (5-bromo-2-chloro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (0.5 g, 1.80 mmol) in anhydrous toluene (10 mL), tributyl(1-propynyl)-tin (1.1 mL, 3.6 mmol) and Pd(PPh3)4 (41.5 mg, 0.036 mmol). The reaction mixture is heated at 120° C. for 1 h by employing microwave. The reaction mixture is diluted with EtOAc, washed with NaHCO3 aqueous solution and water, dried over Na2SO4, and concentrated in vacuo. Purification with column chromatography (SiO2, EtOAC/hexane 1:5) gave 0.32 g of (2-chloro-5-prop-1-ynyl-pyrimidin-4-yl)-(1-ethyl-propyl)-amine
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1=[S:3].[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:23]=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[C:13]1([CH2:12][O:19][C:20]2[CH:21]=[C:22]([CH:23]=[C:7]3[S:1][C:2](=[S:3])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:5]3=[O:6])[CH:25]=[CH:26][C:27]=2[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CN1C(=O)C(=Cc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)SC1=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A solution of rhodanine-3-acetic acid (1 g, 5.20 mmol, 1 eq), 3,4-dibenzyloxybenzaldehyde (2.04 g, 6.25 mmol, 1.2 eq), and sodium acetate (1.3 g, 15.6 mmol, 3 eq) in acetic acid (30 ml) was heated to reflux, and stirred overnight. As the reaction mixture cooled to room temperature the product precipitated and it was filtered and washed with acetic acid, then petroleum ether. The gummy solid was dissolved in ethyl acetate (20 mL) and extracted into saturated aqueous sodium bicarbonate (2×30 mL). The basic extracts were combined, washed with ethyl acetate, and acidified to pH 1 with concentrated HCl. The aqueous solution was extracted with ethyl acetate (2×10 mL), and the organic extracts combined, dried over sodium sulfate and evaporated in vacuo. Recrystallization from ethyl acetate and petroleum ether gave the product which was suspended in water and freeze-dried overnight in vacuo to give the product as a fluffy yellow powder (2.1 g, 81%). mp 235–238° C.: 1H NMR (d6 DMSO) δ 7.79 (s, 1H, C═C—H), 5.25 (s, 2H, CH2Ph), 5.23 (s, 2H, CH2Ph), 4.73 (s, 2H, CH2CO2H). Anal. Found: C, 63.53; H, 4.31; N, 2.85; S, 13.05. Calcd for C26H21NO5S2: C, 63.39; H, 4.21; N, 2.84; S, 12.92.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH3:18])=[C:16]([NH:19][C:20]2[CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:23]=[CH:22][C:21]=2[N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.Br[C:42]1[CH:47]=[CH:46][N:45]=[C:44]([NH2:48])[CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:48][C:44]1[CH:43]=[C:42]([C:24]2[CH:23]=[CH:22][C:21]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[C:20]([NH:19][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[C:17]=3[CH3:18])[CH:25]=2)[CH:47]=[CH:46][N:45]=1
Reactant: Nc1cc(Br)ccn1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(-c2ccnc(N)c2)ccc1N1CCOCC1
Temperature: 120 °C

Procedure:
A mixture of 2-(2-fluorophenyl)-3-methyl-N-(2-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinolin-4-amine (44.0 mg, 0.082 mmol), 4-bromopyridin-2-amine (14.1 mg, 0.082 mmol), dichlorobis(triphenylphosphine)palladium(II) (5.73 mg, 8.16 μmol) and sodium carbonate (14.68 mg, 0.245 mmol) in 1,4-dioxane (2.00 mL) and water (0.500 mL) in a microwave vessel was purged with nitrogen then heated in a microwave at 120° C. for 60 min, after which time LC-MS indicated no starting material remained and desired product was present. The reaction was partitioned between 30 mL EtOAc and 20 mL water. The organic separation was stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a yellow film. The product was isolated by preparative scale reversed-phase HPLC, affording a colorless solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.11 (1H, d, J=8.2 Hz), 7.92 (1H, d, J=5.5 Hz), 7.84 (1H, d, J=8.6 Hz), 7.60-7.69 (1H, m), 7.56 (1H, td, J=7.4, 2.0 Hz), 7.34-7.51 (2H, m), 7.26 (1H, t, J=7.4 Hz), 6.99-7.21 (5H, m), 6.63 (2H, dd, J=7.4, 2.3 Hz), 6.43 (1H, br. s.), 4.44 (2H, d, J=1.2 Hz), 3.88 (4H, t, J=4.7 Hz), 2.94-3.23 (4H, m), 2.15 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=506.2 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]([NH2:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>CC(O)C>[C:10]([NH:13][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1)([CH3:12])([CH3:11])[CH3:9]
Reactant: CC(C)(C)N
Reactant: Clc1cc(Cl)ncn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
251 mg of 4,6-dichloropyrimidine, 123 mg of 2-methylpropan-2-amine and 260 mg of DIPEA were dissolved in 2.5 mL of i-PrOH and charged into a screw cap vial and the vial obtained was kept overnight in a heating block at 90° C. The reaction was monitored by TLC and was completed after 12 hours. The mixture obtained was cooled to r.t., solvent was evaporated and pure N-tert-butyl-6-chloropyrimidin-4-amine was obtained by column chromatography using PE:EtOAc 10:1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]1[C:11]([O:38][CH3:39])=[CH:12][C:13]([O:36][CH3:37])=[C:14](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])[CH:15]=1>C(#N)C.[Pd](Cl)Cl>[NH:1]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:8]=[C:9]1[C:10]1[C:11]([O:38][CH3:39])=[CH:12][C:13]([O:36][CH3:37])=[C:14](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])[CH:15]=1
Reactant: COc1cc(OC)c(/C=C/C(=O)c2ccc(S(=O)(=O)Nc3ccccn3)cc2)cc1C#Cc1ccccc1N
Agent: Cl[Pd]Cl
Solvent: CC#N
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)Nc2ccccn2)cc1
Reaction time: 0.08 h
Yield: 43.6 %

Procedure:
A suspension of 4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}-N-pyridin-2-ylbenzenesulfonamide (Ex-57A, 735 mg, 1.36 mmol) in acetonitrile (100 mL) was purged with nitrogen for 10 minutes. Palladium(II) chloride (24 mg, 0.14 mmol) was added and the reaction mixture was refluxed for 3.5 hrs. The cooled reaction mixture was stirred with 3-mercaptopropyl functionalized silica gel (500 mg) for 5 minutes, filtered, and concentrated. The crude material was purified by column chromatography (2% MeOH in dichloromethane) to give 320 mg (44%) of the title compound as a red solid, mp 206–208° C. 1H-NMR (300 MHz, DMSO-d6) 11.13 (br s, 1H), 8.31 (s, 1H), 8.19 (d, 2H, J=7.80 Hz), 8.05 (m, 3H), 7.94 (br s, 1H), 7.82 (d, 1H, J=15.0 Hz), 7.74 (t, 2H, J=7.2 Hz), 7.49 (d, 1H, J=8.1 Hz), 7.41 (d, 1H, J=7.5 Hz), 7.21 (d, 1H, J=8.4 Hz), 7.05 (t, 1H, J=7.5 Hz), 6.95 (m, 2H), 6.82 (s, 2H), 4.03 (s, 3H), 3.98 (s, 3H). HRMS (ESI) Calcd. for C30H25N3O5S: (M+H)+; Found: 540.1576.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[I:24]N1C(=O)CCC1=O>O>[I:24][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12](=[O:16])[C:13](=[O:15])[C:14]=2[CH:1]=1
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(=O)c2cc(I)ccc2-c2ccccc21
Temperature: 35 °C
Reaction time: 36 h
Yield: 75.4 %

Procedure:
Into a 200 mL volume eggplant-shaped flask, 10.0 g of 9,10-phenanthrenequinone, 54.8 g of trifluoroacetic acid, and 21.6 g of N-iodosuccinimide were added at room temperature, heated to 35° C., and then stirred for 36 hours in an argon atmosphere. The reaction mixture was poured into icy water. The solid precipitate was collected by filtration and recrystallized with tetrahydrofuran, thereby to give 12.1 g of 2-iodo-phenantrene-9,10-dione (yield 75%) as an orange-colored solid.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[CH:19](Br)([CH3:21])[CH3:20]>>[CH:19]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)([CH3:21])[CH3:20]
Reactant: CC(C)Br
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Product: CC(C)n1c2ccccc2n2c(=O)c3ccccc3nc12

Procedure:
6-Isopropylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and isopropyl bromide.