Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](S(C(F)(F)F)(=O)=O)[C:5]([S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])=[CH:4][C:3]=1[Cl:22].[CH3:23][S:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(Cl)Cl.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:22][C:3]1[CH:4]=[C:5]([S:15]([C:18]([F:19])([F:20])[F:21])(=[O:16])=[O:17])[C:6]([C:28]2[CH:29]=[CH:30][C:25]([S:24][CH3:23])=[CH:26][CH:27]=2)=[CH:7][C:2]=1[Cl:1]
Reactant: O=S(=O)(c1cc(Cl)c(Cl)cc1S(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CSc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CSc1ccc(-c2cc(Cl)c(Cl)cc2S(=O)(=O)C(F)(F)F)cc1
Yield: 67.2 %

Procedure:
Under nitrogen, 5 g (4.3 mmol) of Pd(PPh3)4 was added to a stirred solution of 7.9 g (17.8 mmol) of 1,2-dichloro-4,5-bis(trifluoromethanesulfonyl)benzene (Step 4), 3.0 g (18 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 2) and 7.4 g (54 mmol) of anhydrous K2CO3 powder in 90 mL of toluene. The reaction was stirred at reflux for 48 hours, and diluted with CH2Cl2. The resulting solution was washed with water and brine, and dried over MgSO4. Purification by silica gel plug with ethyl acetate/hexane (5:95 to 30:70) gave 4.8 g (56%) of 1,2-dichloro-4-[4-(methylthio)phenyl]-5-(trifluoromethanesulfonyl)benzene as a colorless solid: NMR (CDCl3) δ 2.54 (s, 3H), 7.33 (s, 4H), 7.50 (S, 1H), 7.56 (S, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([CH:13]([OH:34])[CH2:14][N:15]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:16]([CH3:26])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:10]=1[N+:37]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CN(C=O)C.[Pd]>[NH2:37][C:10]1[CH:11]=[C:12]([CH:35]=[CH:36][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:13]([OH:34])[CH2:14][N:15]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:16]([CH3:26])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(CC(C)N(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(CC(C)N(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c(N)c2)cc1
Temperature: 40 °C

Procedure:
To a solution of 4-benzyloxy-3-nitro-α-[N-benzyl-N-(1-methyl-2-p-methoxyphenylethyl)aminomethyl]benzyl alcohol (100 gms, 0.19 M) in DMF (500 ml) was added 10% Pd/C. The resulting mass was heated to 40° C. and ammonium formate (36 gms, 0.57 M) was added in lots in 1 hour. The reaction mass was heated slowly to 70-75° C. for 1 hour, then cooled to 50° C. The catalyst was removed by filtration and the clear filtrate evaporated. The residue was stirred in water (500 ml) and basified with liq. Ammonia. The reaction mass was extracted in 1.0-lit toluene, washed organic extract with water, dried on sodium sulfate and evaporated to obtain title compound. (80 gms, 84.21%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:30]=[CH:29][C:13]3[NH:14][C:15]([C@@H:17]4[CH2:21][CH2:20][CH2:19][N:18]4[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][C:10]2[CH:30]=[CH:29][C:13]3[NH:14][C:15]([C@@H:17]4[CH2:21][CH2:20][CH2:19][N:18]4[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[N:16][C:12]=3[CH:11]=2)[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CNc3ccc(F)cc3)ccc2[nH]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CN(Cc3ccc([N+](=O)[O-])cc3)c3ccc(F)cc3)ccc2[nH]1
Temperature: 40 °C
Yield: 93.4 %

Procedure:
The product from Example 99B (0.65 g, 1.58 mmol), 1-(bromomethyl)-4-nitrobenzene (0.479 g, 2.22 mmol), and potassium carbonate (0.547 g, 3.96 mmol) were combined in dimethyl formamide (15 mL) and heated at 40° C. for 3 hours then diluted with water and filtered. The product was purified by combi-flash 24 g silica column, eluting with 0-5% methanol in dichloromethane to give 0.805 g (93%) of the title compound.
Reaction SMILES: Cl[CH:2]([C:7]1[O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]=1[CH2:12][CH3:13])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=1>>[CH2:12]([C:11]1[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][C:7]=1[CH:2]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=1)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH3:13]
Reactant: CCc1c(C(Cl)CC(C)C)oc2ccccc12
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: CCc1c(C(CC(C)C)Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)oc2ccccc12

Procedure:
Using 2-(1-chloro-3-methylbutyl)-3-ethyl-1-benzofuran (300 mg) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (300 mg) synthesized in Example 2(2) and in the same manner as in Example A22(4), the title object compound (97.4 mg, 19%) was obtained as a yellow solid.
Reaction SMILES: Cl.C(O)C.[Br:5][C:6]1[C:7]([Cl:17])=[C:8]([N+:14]([O-])=O)[CH:9]=[C:10]([F:13])[C:11]=1[F:12]>O.[Fe]>[Br:5][C:6]1[C:7]([Cl:17])=[C:8]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[NH2:14]
Reactant: O=[N+]([O-])c1cc(F)c(F)c(Br)c1Cl
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(F)c(F)c(Br)c1Cl
Yield: 65.9 %

Procedure:
To a suspension of iron powder (38.6 g) in water (40 ml), with stirring vigorously at 50° to 60° C., was slowly added concentrated hydrochloric acid (5 ml). After mixed with ethanol (100 ml), 3-bromo-2-chloro-4,5-difluoronitrobenzene (58.8 g) was added portionwise to the suspension at 60° to 75° C. during 30 minutes. After stirring for 70 minutes, the hot reaction mixture was filtered and the insoluble materials were washed with hot ethanol (30 ml) and with benzene (100 ml) successively. The filtrate and washings were combined and mixed with ice water. The resulting organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated. The resulting residue was purified by silica gel chromatography eluting with dichloromethane-n-hexane (1:1) to give the title compound (34.5 g) as light brown prisms, mp 83°-86° C.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:12][C:13](Br)([CH2:16]Br)[CH:14]=O>C(O)(=O)C>[Br:12][C:13]1[CH:14]=[N:4][C:3]2[C:5]([CH:16]=1)=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=2[I:1]
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Reactant: O=CC(Br)(Br)CBr
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(I)c2ncc(Br)cc2c1
Temperature: 110 °C

Procedure:
2-Iodo-4-nitroaniline (5.3 g) in acetic acid (40 ml) was treated with 2,2,3 tribromopropanal (5.9 g) and the mixture was heated at 110° C. for 2 h after which it was cooled to room temperature and filtered. The filtered solid was washed with diethyl ether, suspended in water and treated with saturated sodium hydrogen carbonate. Extraction with ethyl acetate, drying over sodium sulphate, filtration and evaporation under reduced pressure gave the desired product, 3-bromo-8-iodo-6-nitro-quinoline, as a yellow solid after chromatography (silica; hexane/ethyl acetate) (M+379).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])[CH:5]=1)([O-])=O.O.C1CCCCC=1.[ClH:27]>C(O)C.[Pd]>[ClH:27].[ClH:27].[ClH:27].[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])[CH:5]=1
Reactant: N[C@@H](CCCCNc1cc([N+](=O)[O-])ccn1)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: C1=CCCCC1
Product: Nc1ccnc(NCCCC[C@H](N)C(=O)O)c1
Yield: 66 %

Procedure:
4 g (14.9 mmol) of Nε-(4-nitro-2-pyridyl)-L-lysine are suspended in 80 ml of ethanol and 8 ml of water in a 100 ml three-necked flask equipped with a thermometer and a reflux condenser. 6 g of palladium-on-charcoal (10% active and 50% moisture) are then introduced, followed by 40 ml of cyclohexene. The mixture is brought to reflux for 2 hours and is then cooled, before being filtered through celite. After having run 60 ml (4 eq) of 1N hydrochloric acid onto the filtrate, the latter is evaporated to dryness and the residue is taken up in ethanol and precipitated from acetone. After filtration, 3.4 g of product are obtained, i.e. a final yield of 66%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([N:27]1[CH2:31][CH2:30][C@H:29]([F:32])[CH2:28]1)=[O:26])[C@H:10]([C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Pt](=O)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([N:27]1[CH2:31][CH2:30][C@H:29]([F:32])[CH2:28]1)=[O:26])[C@H:10]([CH:12]1[CH2:24][CH2:23][CH:15]([C:16]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])[CH2:14][CH2:13]1)[CH3:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCOC(=O)c1ccc([C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N2CC[C@H](F)C2)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCCCOC(=O)C1CCC([C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N2CC[C@H](F)C2)CC1

Procedure:
To a solution of the material prepared in Step A (2.8 g, 6.1 mmol) in acetic acid (100 mL) was added solid platinum(IV) oxide (0.75 g). The mixture was placed under 3 atm of hydrogen gas at ambient temperature for 36 h. The mixture was filtered through Celite, and the resulting solution was concentrated in vacuo affording the title compound as a 2:1 mixture of cis and trans cyclohexyl diastereomers, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](O)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.S(Cl)([Cl:22])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([Cl:22])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 10.65 g of 1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazole-5-carboxylic acid and 8 ml of thionyl chloride heated to reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure, and subjected to distillation under reduced pressure (110° C./5 mmHg) to obtain 8.39 g of 1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazole-5-carbonyl chloride of the formula:
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[OH:10][C:11]1[CH:20]=[CH:19][C:18]2[CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:16]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:15][CH2:14][C:13]=2[N:12]=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:6][O:10][C:11]1[CH:20]=[CH:19][C:18]2[CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:16]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:15][CH2:14][C:13]=2[N:12]=1
Reactant: CCOC(=O)C1c2ccc(O)nc2CCN1C(=O)OC(C)(C)C
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C1c2ccc(OC)nc2CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 27.7 %

Procedure:
Trimethyloxonium tetrafluoroborate (1.775 g, 12.00 mmol) was added to a mixture of 5-ethyl 6-tert-butyl 2-hydroxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (1.289 g, 4.00 mmol) and acetonitrile (18 mL) at 0° C. The mixture was stirred at 0° C. for 2 hr, and the reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogencarbonate solution (100 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 2→19% ethyl acetate/hexane) to give 5-ethyl 6-tert-butyl 2-methoxy-7,8-dihydro-1,6-naphthyridine-5,6(5H)-dicarboxylate (372 mg, 1.106 mmol, 28%) as a colorless oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH3:23])=[CH:20][C:19]([NH:24][C:25]1[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=1)=[CH:18][CH:17]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:57]1([CH2:62]/[CH:63]=[CH:64]/[CH2:65]O)[CH2:61][CH2:60][CH2:59][CH2:58]1>CN(C=O)C.ClCCl>[CH3:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH3:23])=[CH:20][C:19]([NH:24][C:25]1[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:65]/[CH:64]=[CH:63]/[CH2:62][N:57]4[CH2:61][CH2:60][CH2:59][CH2:58]4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=1)=[CH:18][CH:17]=2
Reactant: COc1cc2c(Nc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1O
Reactant: OC/C=C/CN1CCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OC/C=C/CN1CCCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
Diethyl azodicarboxylate (65 μl, 0.4 mmol) was added in portions to a suspension of 4-(2,3-dimethylindol-5-ylamino)-7-hydroxy-6-methoxyquinazoline (68 mg, 0.2 mmol), triphenylphosphine (107 mg, 0.4 mmol), (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (40 mg, 0.28 mmol) in DMF (0.4 ml) and dichloromethane (1.5 ml) cooled at 0° C. The reaction mixture was left to warm up to ambient temperature and was stirred overnight. The mixture was poured onto a column of silica and was eluted with methylene chloride followed by methylene chloride/methanol (98/2), followed by methylene chloride/3N ammonia in methanol (95/5 and 90/10) to give 4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-((E)-4-(pyrrolidin-1-yl)but-2-en-1-yloxy)quinazoline (51 mg, 55%).
Reaction SMILES: [CH2:1]([S:3]([CH:6]=[CH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH3:23])(=[O:5])=[O:4])[CH3:2]>Cl.CN(C)C=O.O.[Pd]>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH3:23])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Yield: 69.6 %

Procedure:
(R)-5-(2-Ethylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (157 mg) was dissolved in a mixture of ethanolic hydrogen chloride [prepared by addition of acetyl chloride (0.043 mL) to ethanol (10 mL)], N,N-dimethylformamide (7.5 mL) and water (0.1 mL) and the solution was shaken under a hydrogen atmosphere (15 psi) at room temperature for 18 hours in the presence of 10% palladium on carbon (150 mg). The mixture was filtered through Arbacel (trade mark) filter aid and the residue was washed well with ethanol. The combined filtrate and washings were evaporated under reduced pressure and the residual oil was partitioned between ethyl acetate and 2M aqueous sodium carbonate solution. The organic layer was separated, washed three times with water followed by brine and then dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with dichloromethane/methanol/concentrated aqueous ammonia (90:10:1) gave the title compound as a gum (110 mg): TLC (CH2Cl2 /C2H5OH/NH3 ; 90:10:1): Rf =0.3; [α]25D =+62° (methanol, c=0.10). Anal. Calcd for C18H26N2O2S. 0.05 CH2Cl2:C,63.21; H,7.67; N,8.17. Found: C,63.55; H,7.61; N,8.41.
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:9]2[CH2:10][CH2:11][CH2:12][N:13]=[C:8]2[S:7][C:6]=1[C:14]([OH:16])=O)[CH2:3][CH3:4].C(OCC)C>S(Cl)(Cl)=O>[ClH:1].[CH2:2]([C:5]1[N:9]2[CH2:10][CH2:11][CH2:12][N:13]=[C:8]2[S:7][C:6]=1[C:14]([Cl:1])=[O:16])[CH2:3][CH3:4]
Reactant: CCCC1=C(C(=O)O)SC2=NCCCN21
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CCCC1=C(C(=O)Cl)SC2=NCCCN21
Yield: 203.8 %

Procedure:
In 35 ml of thionyl chloride was suspended 5.3 g of 3-propyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid hydrochloride obtained Example 12, followed by reflux under heating for 40 minutes. The reaction mixture was cooled with ice, and poured into dry diethyl ether. The precipitated crystals were collected by filtration to yield 5.78 g of 3-propyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonyl chloride hydrochloride as colorless powder. This powder was suspended in the mixture of 200 ml of pyridine and 20 ml of dimethylformamide. To the mixture were added 3.38 g of 3.5-dichloroaniline and 250 mg of 3,5-dimethyl-aminopyridine, followed by stirring at 60° C. for 18 hours. The reaction mixture was concentrated and to the mixture was added water. The precipitated crystals were collected by filtration, washed successively with water and cold methanol and suspended in ethanol. To the mixture was added saturated hydrogenchloride diethylether. The formed crystals were collected by filtration and recrystallized from ethanol to obtain 3.65 g of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:16]1[CH:15]=[CH:14][C:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:18][C:17]=1[N+:19]([O-:21])=[O:20]
Reactant: COc1cccc(B(O)O)c1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
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: O
Solvent: Cc1ccccc1
Product: COc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Yield: 76.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.8 g) was added to a mixture of 5 g 3-methoxyphenylboronic acid, 5 g 5-bromo-2-fluoronitrobenzene and 11 mL of 2 M sodium carbonate solution in 100 mL of toluene. The mixture was refluxed for 2 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate was washed with saturated sodium bicarbonate and brine and then dried and concentrated to give an oily solid. The solid was chromatographed on silica gel (ethyl acetate:hexane (1:6)) to give 4.3 g (77% yield) of 4-fluoro-3'-methoxy-3-nitrobiphenyl.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][Si:11]([CH2:14][CH2:15][O:16][CH2:17]Cl)([CH3:13])[CH3:12].[I:19][C:20]1[CH:21]=[N:22][NH:23][CH:24]=1>C(Cl)Cl>[I:19][C:20]1[CH:21]=[N:22][N:23]([CH2:17][O:16][CH2:15][CH2:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[CH:24]=1
Reactant: Ic1cn[nH]c1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(I)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, diisopropylethylamine (DIEA, 1.75 ml, 10 mmol) and trimethylsilylethoxymethyl chloride (SEMCl, 1.83 ml, 10 mmol) are added to a solution of 4-iodopyrazole (1.94 g, 10 mmol) in CH2Cl2 (100 ml). The mixture is stirred overnight at room temperature. The solvent is evaporated under vacuum. The residue is taken up in a diethyl ether/water mixture. The organic phase after drying and evaporation gives a colourless oil which is purified by eluting on silica gel with an AcOEt/CH2Cl2 (5/95) mixture.
Reaction SMILES: [Br:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10]CC)=[O:9])[CH:4]=1.[OH-].[Li+].Cl>C1COCC1.O>[Br:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=1
Reactant: CCOC(=O)c1cc(CBr)on1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(CBr)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
Ethyl 5-(bromomethyl)isoxazole-3-carboxylate (4.27 mmol, 1 g) and lithium hydroxide (10.68 mmol, 0.256 g) were dissolved in THF (6.5 ml) and water (6.5 ml). The resulting mixture was stirred for 30 min at RT. The pH was adjusted to 4 with 1 M HCl and diluted with water. The mixture was extracted three times with EtOAc. The combined organics were dried, filtered and evaporated. 0.543 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 4.88 (s, 2H), 6.92 (s, 1H), 14.09 (bs, 1H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1.CO>CC(N(C)C)=O>[C:4]1(=[O:6])[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[C:1](=[O:7])[CH:2]=[CH:3]1
Reactant: O=C1C=CC(=O)O1
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CC(=O)c1ccc(N2C(=O)C=CC2=O)cc1
Yield: 65 %

Procedure:
In dimethylacetamide, 98 g of maleic anhydride was reacted with 135 g of p-aminoacetophenone at 140° C. for 4 hours. After the reaction, methyl alcohol was added to the reaction solution to precipitate a solid. The precipitate was recovered by filtration and dried in vacuo to obtain 139 g (a yield of 65%) of p-maleimidoacetophenone.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:39][N:36]1[CH2:37][CH2:38][N:33]([C:31](=[O:32])[CH2:30][NH:29][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:34][CH2:35]1
Reactant: CN1CCN(C(=O)CN)CC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)CNC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(OC(F)(F)F)cc4s2)n3C)CC1

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]amide (41 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), 2-amino-1-(4-methyl-piperazin-1-yl)-ethanone (0.30 ml), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 549. 1H NMR (DMSO-d6, 400 MHz): δ 8.48 (t, 1H), 8.10 (s, 1H), 7.96 (s, 1H), 7.91 (d, 1H), 7.78 (d, 1H), 7.64 (br, 1H), 7.48 (d, 1H), 7.36 (d, 1H), 4.14 (d, 2H), 3.67 (s, 3H), 3.61 (m, 2H), 3.48 (m, 4H), 2.89 (s, 3H), and 2.32 (m, 2H).
Reaction SMILES: O[CH:2]([C:5]1[C:6]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:7][N:8](C)[C:9]=1C(C)(C)C)[CH2:3][CH3:4].F[C:20](F)(F)C(O)=O>>[CH2:2]([C:5]1[CH:9]=[N:8][N:7]([CH3:20])[C:6]=1[S:15]([NH2:18])(=[O:17])=[O:16])[CH:3]=[CH2:4]
Reactant: CCC(O)c1c(S(N)(=O)=O)nn(C)c1C(C)(C)C
Reactant: O=C(O)C(F)(F)F
Product: C=CCc1cnn(C)c1S(N)(=O)=O
Temperature: 25 °C

Procedure:
The alcohol (3.0 g) from Example 3 was stirred in 25 ml of trifluoroacetic acid at 68° C. for 30 minutes. The solution was allowed to cool to room temperature, and the volatile components were removed in vacuo to afford 510 mg of the desired sulfonamide, m.p. 157°-161° C.