Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][C@H:16]([CH2:19][NH:20][C:21]([O:23]C(C)(C)C)=O)[CH2:15]2)=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1>Cl.O1CCOCC1>[NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:21]([NH:20][CH2:19][C@H:16]2[CH2:17][CH2:18][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[C:29]([Cl:30])[C:2]([NH2:1])=[CH:3][C:4]=3[O:31][CH3:32])[CH2:15]2)=[O:23])=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCCCCCN1CC[C@H](CNC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(N)c(Cl)cc1C(=O)NCCCCCN1CC[C@H](CNC(=O)c2cc(Cl)c(N)cc2OC)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
4-Amino-N-(5-((3R)-3-tert-butoxycarbonylaminomethylpyrrolidin-1-yl)pentyl)-5-chloro-2-methoxybenzamide (1.45 g) was dissolved in 4N hydrochloric acid-dioxane solution (10 ml) and the mixture was stood at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure. Dimethylformamide (30 ml) was added to the residue and the mixture was neutralized with triethylamine (1.37 ml). 4-Amino-5-chloro-2-methoxybenzoic acid (0.66 g) and 1-hydroxybenzo-triazole (0.49 g) were added thereto, and the mixture was stirred at 0° C. for 15 min. Then, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.69 g) was added, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure. Aqueous potassium carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.30 g of 4-amino-N-((3R)-1-(5-(4-amino-5-chloro-2-methoxybenzoylamino)pentyl)pyrrolidin-3-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: Br.Cl[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)=[CH:7][CH:6]=1.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(OCC)(=O)C.O.C(O)C>[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[N:27]2[CH2:28][CH2:29][N:30]([CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][C:8]([C:11]4[N:12]=[C:13]([NH2:16])[S:14][CH:15]=4)=[CH:7][CH:6]=3)[CH2:31][CH2:32]2)[CH:20]=[CH:19][CH:18]=1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Reactant: Nc1nc(-c2ccc(CCCl)cc2)cs1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1nc(-c2ccc(CCN3CCN(c4cccc5cccnc45)CC3)cc2)cs1

Procedure:
To a 35 ml round-bottomed flask equipped with condenser and N2 inlet were added 0.746 g (2.34 mmol) of 4-(4-(2-chloroethyl)phenyl-2-aminothiazole hydrobromide, 0.50 g (2.34 mmol) of N-(8-quinolyl)piperazine (prepared from 8-aminoquinoline by reaction with diethanolamine in hydrobromide at 200° C.), 0.621 g (5.86 mmol) of sodium carbonate, 50 mg of sodium iodide, and 10 ml of ethanol. The reaction was heated at reflux for 25 hours, cooled, and the reaction mixture taken up in ethyl acetate/water. The layers were separated, the ethyl acetate layer dried and evaporated. The residue was chromatographed on silica gel using chloroform/methanol as eluent and the product fractions combined in methanol and precipitated with a solution of hydrochloride in ether. The precipitate was stirred with ether/methanol to afford a crystalline solid, m.p. >225° C., 277 mg (27%). NMR (free base in CDCl3): 2.8 (m, 8H), 3.5 (m, 4H), 7.0-8.2 (m, 11H).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:16])[CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29]CC)=[O:28].[OH-].[Na+].Cl>O.CN(C=O)C>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:16])[CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:26][C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)CBr
Reactant: O=c1c2ccc(Cl)cc2oc2c(Cl)c(O)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COc1ccc2c(=O)c3ccc(Cl)cc3oc2c1Cl
Reaction time: 4 h
Yield: 62.2 %

Procedure:
A mixture of 4,6-dichloro-3-hydroxy-9-oxo-9H-xanthene (2.0 g), potassium carbonate (3.4 g), ethyl bromoacetate (4.2 g) and DMF (60 ml) was stirred at 60°-65° C. for 4 hours. After cooling the mixture, sodium hydroxide (4 g) and water (100 ml) were added and the resulting mixture was stirred at 90°-100° C. for 30 minutes. After cooling, the mixture was rendered acidic with hydrochloric acid and the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from DMF gave 1.5 g of 4,6-dichloro-9-oxo9H-xanthene-3-yloxyacetic acid. m.p. 270° C. This compound gave a mass spectrum having a molecular ion peak at m/e 338.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]([C:19]([O:21]CC)=[O:20])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>O1CCCC1CO.O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]([C:19]([OH:21])=[O:20])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCC1CCCO1
Product: O=C(O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reaction time: 0.33 h

Procedure:
A suspension of ethyl 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate from Step 2 (1 eq) in a mixture of tetrahydrofuran-methanol (0.15M) and 1N aqueous sodium hydroxide (2 eq) was heated at ca 50° C. with stirring for 20 minutes. After cooling, the mixture was diluted with water and acidified with 1N aqueous HCl. After stirring for 45 minutes, the precipitate was filtered, washed well with water and dried to afford the title acid as a cream-colored solid.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].O[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C)C=O>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([B:21]([OH:23])[OH:22])=[CH:17][CH:16]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: OCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1nc2ccc(OCc3ccc(B(O)O)cc3)cc2s1
Temperature: 60 °C
Reaction time: 0.79 h
Yield: 94.2 %

Procedure:
2-Cyano-6-hydroxybenzothiazole (2) (150 mg, 0.85 mmol, 1.1 equiv.) and 4-(hydroxymethyl)benzeneboronic acid (5) (166 mg, 0.77 mmol, 1 equiv.) were dissolved in 15 mL dry dimethylformamide (DMF) prior to the addition of cesium carbonate (277 mg, 0.85 mmol, 1 equiv.). The mixture was stirred at 60° C. for 45-50 minutes before it was allowed to cool to room temperature. 100 mL EtOAc was added to the reaction mixture, and the organic phase was washed three times with DI H2O. The aqueous layers were combined and washed three times with EtOAc. All of the organic layers were combined, washed twice with brine, dried over sodium sulfate, and concentrated. The crude material was purified on a silica column (90:10 EtOAc:methanol, dry loaded) to give 225 mg (94%) of the pure product. 1H NMR (400 MHz, d6-Acetone): δ 5.33 (2H, s), 7.23 (2H, s), 7.45 (1H, dd, J=9.0, 2.6 Hz), 7.52 (2H, d, J=8.0 Hz), 7.93 (3H, m), 8.16 (1H, d, J=8.8 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:33])([CH2:30][CH2:31][CH3:32])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:29])=[N:15][N:16]2[C:21]([O:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:20][C:19]([CH3:28])=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:33])([CH2:30][CH2:31][CH3:32])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:29])=[N:15][N:16]2[C:21]([O:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:20][C:19]([CH3:28])=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCCC(C)C)cc(C)cc12)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCCC(C)C)cc(C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 80 mg (0.091 mmol, 54% pure) of rac-[1-({[2,5-dimethyl-7-(3-methylbutoxy)pyrazolo[1,5-a]pyridin-3-yl]carbonyl}amino)-2-methylpentan-2-yl]carbamic acid tert-butyl ester (Example 124A) in 4 ml of dichloromethane was admixed with 0.140 ml (1.82 mmol) of trifluoroacetic acid. The resulting solution was stirred at room temperature overnight. After the reaction had ended, the solvent was drawn off under reduced pressure and the residue was purified by preparative HPLC chromatography (Method 21), which gave 17 mg (50% of theory) of the target compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])=[N:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:28][CH:16]1[CH:15]([C:12]2[N:13]=[CH:14][C:9]([OH:8])=[CH:10][N:11]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(OCc3ccccc3)cn2)C(O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(O)cn2)C(O)C1
Yield: 93.4 %

Procedure:
A solution of 110 mg (0.29 mmol) of tert-butyl (3RS,4RS)-4-(5-benzyloxy-pyrimidin-2-yl)-3-hydroxy-piperidine-1-carboxylate in 5 ml of methanol was treated with 20 mg of 5% palladium-charcoal and hydrogenated at room temperature for 12 hours. For the working-up, the catalyst was filtered off and washed with 20 ml of methanol. The methanol solution was evaporated under reduced pressure and the resulting oil was crystallized by the addition of ether. There were obtained 80 mg (93% of theory) of tert-butyl (3RS,4RS)-3-hydroxy-4-(5-hydroxy-pyrimidin-2-yl)-piperidine-1-carboxylate in the form of colourless, slightly delequesent crystals; MS: 296 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:7](=[O:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3]1.[CH3:18][Mg]Br>C(OCC)C>[OH:8][C:7]1([CH3:18])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3][C:2]1([CH3:17])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC(=O)C(C)(C)C1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H]1CCC(C)(O)C(C)(C)C1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of (R)-tert-butyl (3,3-dimethyl-4-oxocyclohexyl)carbamate (550 mg, 2.28 mmol) in diethyl ether (15 mL) was added methyl magnesium bromide (3 M, 3.00 mL) at −30° C. to −40° C. under nitrogen. The mixture was stirred at this temperature for 0.5 h and quenched with saturated aqueous ammonium chloride solution (150 mL). The aqueous layer was extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure. The residue was purified silica gel chromatography column (12% ethyl acetate in petroleum ether) to afford the title compound as a yellow oil (520 mg, 5.02 mmol, 88% yield). MS (ESI) m/z 258.2 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][C:25]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[N:32](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:31]=[C:30]4[C:55]3[CH:60]=[CH:59][N:58]=[C:57]([CH3:61])[CH:56]=3)=[O:26])[CH2:19]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1>C([SiH](CC)CC)C>[N:8]1([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][C:25]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[NH:32][N:31]=[C:30]4[C:55]3[CH:60]=[CH:59][N:58]=[C:57]([CH3:61])[CH:56]=3)=[O:26])[CH2:19]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(Cn5ncc6ccccc65)C4)cc23)ccn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2n[nH]c3ccc(C(=O)NC4CCCC(Cn5ncc6ccccc65)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (5 mL) was added to N-(3-((1H-indazol-1-yl)methyl)cyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide (0.1 mmol). The reaction was stirred at room temperature for 30 minutes. Triethylsilane (1 drop) was added to the reaction and stirred for an additional 5 minutes. The crude product purified using prep HPLC.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)(Cl)Cl.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH:27]=[O:28])=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(CO)cc2)c(C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(C=O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
{4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenyl}-methanol, prepared as described in Example 50, (0.5 g, 1.26 mmol) was dissolved in CHCl3 (10 mL) and Dess-Martin periodinane (0.59 g, 1.39 mmol) was added. The reaction was stirred at 25° C. for 16 h, dissolved in EtOAc (100 mL), and the EtOAc was washed with sat sodium thiosulfate solution (20 mL), water (20 mL) and brine, dried and stripped in vacuo. The residue was chromatographed on silica gel using 20% EtOAc/hexanes eluent to give 4-[6-methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-benzaldehyde (472 mg, 95% yield) as an amorphous solid. mass spec. (AP+): m/z 395 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:4]([CH:5]=[O:6])[CH:3]1[C:7]([O:9][CH3:10])=[O:8].[Cl:12][C:13](Cl)([Cl:18])[C:14]([F:17])([F:16])[F:15].[Cl-].[NH4+]>CN(C)C=O.[Zn]>[CH3:1][C:2]1([CH3:11])[CH:4]([CH:5]([OH:6])[C:13]([Cl:18])([Cl:12])[C:14]([F:17])([F:16])[F:15])[CH:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Reactant: COC(=O)C1C(C=O)C1(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CN(C)C=O
Product: COC(=O)C1C(C(O)C(Cl)(Cl)C(F)(F)F)C1(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
To a solution of 156 mg (1.00 mmol) of methyl 2,2-dimethyl-3-formylcyclopropane carboxylate and 0.226 ml (2.00 mmol) of 1,1,1-trichlorotrifluoroethane in 1 ml of dimethylformamide (DMF), 98 mg (1.50 mmol) of zinc powder was added at 0° C., and the mixture was stirred at 0° C. for 20 minutes, and at 50° C. for 7 hours. Then, 1 ml of a saturated ammonium chloride aqueous solution was added, and the mixture was extracted with diethyl ether (2 ml×5 times). The extract was dried over anhydrous magnesium sulfate, then filtered and concentrated under reduced pressure. The product was purified by thin layer chromatography (silica gel, dichloromethane/hexane=1/2) to obtain 232 mg of methyl 2,2-dimethyl-3-(1-hydroxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropanecarboxylate (a mixture of two stereoisomers in a ratio of 55:45) as a colorless oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH:14]=[C:15]([C:17](O)=[O:18])[N:16]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH:14]=[C:15]([C:17]([Cl:3])=[O:18])[N:16]=1
Reactant: O=C(O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1

Procedure:
Thionyl chloride (0.66 mL, 9 mmol) was added to a solution of 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylic acid (1 g, 3 mmol) in toluene (10 mL). The mixture was refluxed under argon for 1.5 h and concentrated to provide 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carbonyl chloride, which was used in the next step without purification. 1H NMR (300 MHz, CD2Cl2) δ 8.40 (s, 1H), 7.69-7.09 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O.N>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10]([NH2:22])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: ClCCl
Product: NC(=O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 36 %

Procedure:
A solution of 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid* (0.25 g, 0.74 mmol) and 1,1′-carbonyldiimidazole (0.24 g, 1.47 mmol) in dichloromethane was stirred for 45 minutes before the addition of ammonia (2M solution in methanol, 3.68 ml, 7.36 mmol). The reaction mixture was stirred for 2 hours, solvent removed under reduced pressure and residue was purified over flash silica chromatography eluting with ethyl acetate/petroleum ether (1:4) to afford the title compound (0.091 g, 36% yield). LC/MS: (PS-A2) Rt 3.08 [M+H]+ 339.93.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:34])[C:19]([C:31]([OH:33])=[O:32])=[CH:20][N:21]3[C@@H:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:25][OH:26])=[CH:16][C:15]=2[C:35]2[CH:36]=[N:37][C:38]([NH:50][C:51]([NH:53][CH2:54][CH3:55])=[O:52])=[CH:39][C:40]=2[C:41]2[S:42][CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[N:45]=2)[CH2:10]1)=O)(C)(C)C.CS(O)(=O)=O>ClCCl>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:34])[C:19]([C:31]([OH:33])=[O:32])=[CH:20][N:21]3[C@@H:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:25][OH:26])=[CH:16][C:15]=2[C:35]2[CH:36]=[N:37][C:38]([NH:50][C:51]([NH:53][CH2:54][CH3:55])=[O:52])=[CH:39][C:40]=2[C:41]2[S:42][CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[N:45]=2)[CH2:10]1
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cc3c(=O)c(C(=O)O)cn([C@H](CO)C(C)(C)C)c3nc2N2CCC(NC(=O)OC(C)(C)C)C2)cn1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cc3c(=O)c(C(=O)O)cn([C@H](CO)C(C)(C)C)c3nc2N2CCC(N)C2)cn1
Temperature: 23 °C
Reaction time: 2 h
Yield: 11.3 %

Procedure:
To a solution of 7-(3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (Intermediate 105) (290 mg, 0.37 mmol, 1 equiv.) in dichloromethane (2 mL) was added methanesulfonic acid (0.048 mL, 0.73 mmol, 2 equiv.). The reaction was stirred at 23° C. for 2 h. The reaction was concentrated and re-suspended in water. The precipitate was discarded, and the filtrate was concentrated. The compound was purified via C18 silica gel chromatography and concentrated to afford 7-(3-aminopyrrolidin-1-yl)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-((5)-1-hydroxy-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (28.7 mg, 11%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH2:38].C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CN(C)CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(NCCCN(C)C)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide (100 mg, 0.20 mmol), N,N-dimethyl-1.3-propanediamine (260 μL, 2.0 mmol) and K2CO3 (283 mg, 2.0 mmol) in 1-butanol (5 mL) the title compound was obtained as a white powder (84 mg, 0.15 mmol, 75.8% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.01 (d, J=5.1 Hz, 1H), 7.45-7.63 (m, 4H), 7.28-7.32 (m, 2H), 7.15-7.20 (m, 3H), 6.04 (s, 1H), 3.24-3.31 (m, 3H), 2.31 (t, J=7.1 Hz, 2H), 2.17 (s, 6H), 1.66 (t, J=7.0 Hz, 2H), 1.35 (d, J=6.8 Hz, 6H). MS (ESI): 555.3 [M+H]+.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[F:14][C:15]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:17]([C:16]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:15]=1[F:14])=[O:18])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 2,5-difluorobenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.94 (t, 3 H) 1.33-1.41 (m, 2 H) 1.60-1.69 (m, 2 H) 2.19 (s, 3 H) 2.22 (s, 3 H) 3.93-4.00 (m, 2 H) 6.38 (s, 1 H) 7.24-7.35 (m, 2 H) 7.51-7.59 (m, 1 H); MS (ESI) m/z 324 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]C)=[O:18])=[CH:12][C:11]=3[Cl:21])[S:8][C:4]=2[CH:3]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][C:11]=3[Cl:21])[S:8][C:4]=2[CH:3]=1
Reactant: COC(=O)Cc1ccc(Nc2nc3ccc(Cl)cc3s2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(Nc2nc3ccc(Cl)cc3s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.9 %

Procedure:
Methyl (4-(6-chloro-2-benzothiazolyl)amino-3-chlorophenyl)acetate (271 mg, 0.74 mmol) was dissolved in THF (4.5 ml). To the resulting solution was added 0.5N NaOH (4.5 ml, 2.25 mmol), followed by stirring at room temperature for 15 hours. The reaction mixture was poured in ice-1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (4-(6-chloro-2-benzothiazolyl)amino-3-chlorophenyl)acetic acid (248 mg, 95%) as a pale yellow solid.