Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[C:23]3[C:18](=[C:19]([Cl:25])[CH:20]=[C:21]([Cl:24])[CH:22]=3)[CH2:17][N:16]([CH3:26])[CH2:15]2)[CH:9]=1)(=[O:7])=[O:6].[OH:27][CH:28]([CH:39]([OH:50])[C:40]([O:42]N1C(=O)CCC1=O)=O)[C:29]([O:31]N1C(=O)CCC1=O)=O.[CH2:51]([N:53]([CH2:56][CH3:57])[CH2:54][CH3:55])C>CN(C=O)C>[Cl:24][C:21]1[CH:22]=[C:23]2[C:18](=[C:19]([Cl:25])[CH:20]=1)[CH2:17][N:16]([CH3:26])[CH2:15][CH:14]2[C:10]1[CH:9]=[C:8]([S:5]([NH:4][CH2:3][CH2:2][NH:1][C:29](=[O:31])[CH:28]([OH:27])[CH:39]([OH:50])[C:40]([NH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:55]3[C:23]4[C:57](=[C:19]([Cl:25])[CH:20]=[C:21]([Cl:24])[CH:22]=4)[CH2:56][N:53]([CH3:51])[CH2:54]3)[CH:9]=2)(=[O:6])=[O:7])=[O:42])(=[O:7])=[O:6])[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(ON1C(=O)CCC1=O)C(O)C(O)C(=O)ON1C(=O)CCC1=O
Reactant: CCN(CC)CC
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCN)c2)C1
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCNC(=O)C(O)C(O)C(=O)NCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N-(2-aminoethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (250 mg, 0.60 mmol, 1.00 equiv) in DMF (5 mL), bis(2,5-dioxopyrrolidin-1-yl) 2,3-dihydroxysuccinate (Intermediate 168.1) (92 mg, 0.27 mmol, 0.44 equiv) and triethylamine (280 mg, 2.77 mmol, 4.55 equiv) and the resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum, the residue diluted with 100 mL of ethyl acetate and then washed with 2×10 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, Water with 0.05% TFA and CH3CN (25% CH3CN up to 35% in 5 min, up to 100% in 2.5 min); Detector, uv 220&254 nm. This resulted in 88.4 mg (15%) of a TFA salt of N1,N4-bis(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethyl)-2,3-dihydroxysuccinamide as a white solid. 1H-NMR (400 MHz, CD3OD, ppm) δ 7.67 (d, J=7.6 Hz, 2H), 7.61 (s, 2H), 7.44 (t, J=7.6 Hz, 2H), 7.37 (d, J=7.6 Hz, 2H), 7.25 (d, J=2 Hz, 2H), 6.72 (s, 2H), 4.33 (t, J=6.4 Hz, 2H), 4.30 (s, 2H), 3.64 (m, 4H), 3.21 (s, 4H), 2.98 (m, 2H), 2.90 (m, 4H), 2.65 (m, 2H), 2.42 (s, 6H). MS (m/z): 943 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[CH:7][CH:6]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.50 g in 5 mL of dimethylformamide was treated with 60% sodium hydride (0.112 g) and after 15 minutes, 2-bromomethylnaphthalene (0.61 g) was added. The reaction mixture was stirred 45 minutes at room temperature, was quenched with 0.1 mL of acetic acid and was diluted with diethyl ether-ethyl acetate (10: 1, 50 mL). The mixture was washed with water (2×10 mL) and brine (1×10 mL), dried (1MgSO4) and chromatographed over 100 g of silica gel eluting with dichloromethane-hexane (1:1) to give 0.61 g of 4-[(2-naphthalenyl)methoxy]alpha-oxobenzeneacetic acid methyl ester, mp 101°-102° C.
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[NH2:12][N:13]1[CH2:17][CH2:16][N:15]=[C:14]1SC.N[CH2:21][CH2:22][OH:23]>C(O)(C)C>[S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[NH2:12][N:13]1[CH2:17][CH2:16][N:15]=[C:14]1[CH2:21][CH2:22][OH:23]
Reactant: NCCO
Reactant: CSC1=NCCN1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: NN1CCN=C1CCO
Temperature: 40 °C
Reaction time: 8 h

Procedure:
1-Amino-2-methylthio-2-imidazoline tosylate (3.03 g) and isopropanol (7.5 ml) are placed in a 25 ml round bottom flask, then 2-aminoethanol (1.22 g) is added. The mixture is heated to about 40° C. to give a solution. After stirring overnight at 25° C., the mixture is concentrated to a thick colorless oil. Crystals were form upon storage at -20° C. Trituration with 10 ml isopropanol and filtration gives 2.68 g (84.8%) of 1-amino-2-(2-hydroxyethyl)-2-imidazoline tosylate as colorless crystals with mp 91.8°-92.7° C.
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1>C(OCC)C>[NH2:1][C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1
Reactant: Fc1cc(OC(F)(F)F)nc(F)n1
Reactant: N
Solvent: CCOCC
Product: Nc1nc(F)cc(OC(F)(F)F)n1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
At -75° to -70° C. and over a period of 1 hour, 8.7 g (0.51 mol) of gaseous ammonia was gassed, while stirring, into a mixture of 51 g (0.255 mol) of 2,4-difluoro-6-trifluoromethoxypyrimidine in 200 ml of diethyl ether. The mixture was stirred for 1 1/2 hours at -70° C. and for 1 hour at room temperature. The reaction mixture was evaporated down under reduced pressure, taken up in methylene chloride and extracted with water. The organic phase was dried, evaporated down and chromatographed over silica gel (8:1 ligroin/ether mixture) to give 38.1 g (75.6% of theory) of the title compound as colorless crystals of melting point 86°-89° C.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:11]([CH3:13])[CH3:12])=[CH:8][CH:9]=2)[S:4][C:3]=1[C:14]([O:16]C)=O.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:23]([CH:26]=1)[C:24]#[N:25].Cl>>[C:24]([C:23]1[CH:26]=[C:19]([NH:18][C:14]([C:3]2[S:4][C:5]3=[N:6][C:7]([CH:11]([CH3:12])[CH3:13])=[CH:8][CH:9]=[C:10]3[C:2]=2[OH:1])=[O:16])[CH:20]=[CH:21][C:22]=1[O:27][CH2:28][C:29]([CH3:31])([CH3:30])[CH3:32])#[N:25]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: COC(=O)c1sc2nc(C(C)C)ccc2c1O
Agent: Cl
Product: CC(C)c1ccc2c(O)c(C(=O)Nc3ccc(OCC(C)(C)C)c(C#N)c3)sc2n1
Yield: 22.3 %

Procedure:
Methyl 3-hydroxy-6-isopropylthieno[2,3-b]pyridine-2-carboxylate (1.6 g) and 5-amino-2-neopentyloxybenzonitrile (2.6 g) were stirred at 170° C. for 2 hr. Then the reaction mixture was treated with diluted hydrochloric acid and the organic layer was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from water-containing dimethylformamide to give the title compound (0.6 g). melting point: 211-212° C.
Reaction SMILES: O[CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)(=O)C.CCCCCC>[NH:23]([CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:18])([CH3:17])[CH3:19])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2O
Reactant: Nc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2Nc1ccccc1
Yield: 79 %

Procedure:
Using N-(3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 235 and aniline, the title compound was synthesized in the same manner as in Example 297. Yield: 79%. Melting point: 151-152° C. (ethyl acetate-hexane).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:18][CH:19]=1
Reactant: Brc1ccc(OC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCC(Oc2ccc(Br)cc2)CC1
Temperature: 50 °C
Yield: 86.9 %

Procedure:
1 N HCl(aq) (45 mL) was added to a solution of 8-(4-bromophenoxy)-1,4-dioxaspiro[4.5]decane (2.8 g, 8.94 mmol) in THF (100 mL). The reaction was heated to 50° C. After 1 hour the reaction was cooled to room temperature and neutralized by addition of solid sodium bicarbonate. The reaction was extracted with ether (1×), the resulting organic layer was washed with water, dried (Na2SO4), filtered and concentrated. Purification on a Biotage SNAP cartridge KP Sil 100g (hexanes/ethyl acetate=9:1) afforded the title compound as a white solid (2.09 g, 87%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.02-2.13 (m, 2 H) 2.21-2.41 (m, 4 H) 2.61-2.74 (m, 2 H) 4.62-4.71 (m, 1 H) 6.81-6.89 (m, 2 H) 7.37-7.44 (m, 2 H)
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].C1CC=CC=1.[CH2:15]1[CH:19]2[CH:20]3C=CC([CH:18]2C=[CH:16]1)C3>>[CH2:6]([O:5][C:1]([CH:2]1[CH2:18][CH:19]2[CH2:20][CH:3]1[CH:16]=[CH:15]2)=[O:4])[CH2:7][CH2:8][CH3:9]
Reactant: C=CC(=O)OCCCC
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: C1=CCC=C1
Product: CCCCOC(=O)C1CC2C=CC1C2
Reaction time: 1 h
Yield: 93 %

Procedure:
A mixture of butyl acrylate (41.62 g, 0.032 mol) and cyclopentadiene (31.76 g, 0.48 mol, freshly prepared from dicyclopentadiene) was stirred in a flask with cooling in a cold water bath. After 1 hour, the mixture was stirred at 55° C. for 30 minutes. The mixture was then distilled under reduced pressure (60-65° C. @0.4 mmHg) to give the product as a colorless oil (yield 70.29 g, 93%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([S:26][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCc2cc(OCCCCCCBr)ccc2N1
Reactant: Sc1ccccc1
Product: O=C1CCc2cc(OCCCCCCSc3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(6-bromohexoxy)-3,4-dihydro-carbostyril (m.p. 107.5°-108° C.) and thiophenol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[CH3:20])(=[O:12])=[O:11])[S:7][CH:8]=1.[CH3:21][N:22]1[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[N:24]=[CH:23]1>C(Cl)Cl>[Cl:19][C:15]1[C:14]([CH3:20])=[C:13]([S:10]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][S:27]([C:25]3[N:24]=[CH:23][N:22]([CH3:21])[CH:26]=3)(=[O:29])=[O:28])[N:5]=2)(=[O:11])=[O:12])[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCN)cs1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCNS(=O)(=O)c2cn(C)cn2)cs1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
A suspension of EXAMPLE 200A (200 mg, 0.60 mmol), 1-methylimidazole-4-sulphonyl chloride (109 mg, 0.60 mmol), TEA (61 mg, 0.60 mmol) in DCM (10 mL) was refluxed for 1 h. The reaction mixture was allowed to cool to room temperature and the solid was filtered off giving 161 mg (58%) of pure title compound: MS (Ionspray, [M+H]+) m/z 476; Anal. Calcd. (found) for C16H18ClN5O4S3: C, 40.4 (40.2) %; H, 3.8 (3.8)%; N, 14.7 (14.6)%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH:23]CC2C=CC(O)=C(OC)C=2)[CH:6]=[CH:5][C:4]=1[OH:34].C(N[CH:39]1[C:48]2[C:47]([C:49]([O:51][CH3:52])=[O:50])=[N:46][N:45]=[C:44]([C:53]([O:55][CH3:56])=[O:54])[C:43]=2[CH2:42][CH2:41][CH2:40]1)(=O)C>[Zn].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:34].[C:3]([NH:45][N:46]1[C:44]([C:53]([O:55][CH3:56])=[O:54])=[C:43]2[CH2:42][CH2:41][CH2:40][CH2:39][C:48]2=[C:47]1[C:49]([O:51][CH3:52])=[O:50])(=[O:2])[CH3:4]
Reactant: COC(=O)c1nnc(C(=O)OC)c2c1CCCC2NC(C)=O
Reactant: COc1cc(CNCCCNCCCCNCCCNCc2ccc(O)c(OC)c2)ccc1O
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)c1c2c(c(C(=O)OC)n1NC(C)=O)CCCC2
Product: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution was prepared by adding 2.59 g. of dl-6-acetamido-1,4-di(carbomethoxy)-5,6,7,8-tetrahydrobenzo[d]pyridazine to 100 ml. of glacial acetic acid. 5 g. of zinc dust were added and the resulting mixture stirred at ambient temperature for about 1 day. An additional 5 g. of zinc dust were added after 6 hours. The reaction mixture was then filtered to remove unreacted zinc dust and the resulting filtrate poured over ice. The filtrate was made basic with 14 N aqueous ammonium hydroxide and the alkaline mixture extracted several times with a chloroform-isopropanol solvent combination. The organic extracts were separated and combined, and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the solvent therefrom yielded dl-5-acetamido-1,3-di(carbomethoxy)-4,5,6,7-tetrahydro-2H-benzo[c]pyrrole formed in the above reaction; yield=1.83 g. Recrystallization from methanol yielded crystalline material melting at 231°-232° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[CH3:17][N:18]1[C:23]2[CH:24]=[CH:25][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1>>[ClH:1].[ClH:1].[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:4]=[N:3][C:2]([C:26]4[CH:25]=[CH:24][C:23]5[N:18]([CH3:17])[CH2:19][CH2:20][O:21][C:22]=5[CH:27]=4)=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:16][CH2:15]1
Reactant: Clc1ccc(N2CCN(C3CC3)CC2)nn1
Reactant: CN1CCOc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CN1CCOc2cc(-c3ccc(N4CCN(C5CC5)CC4)nn3)ccc21
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 68, starting from 3-chloro-6-(4-cyclopropyl-piperazin-1-yl)-pyridazine and 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1,4-benzoxazine. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, 1H), 8.04 (d, 1H), 7.61 (m, 1H), 7.49 (m, 1H), 6.85 (d, 1H), 4.50 (broad m, 2H), 4.26 (m, 2H), 3.61 (broad m, 4H), 3.40 (m, 4H), 2.97 (s, 3H), 2.88 (broad m, 1H), 1.23 (m, 2H), 0.82 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[S:8][C:7]=2[CH:6]=[CH:5][C:4]=1[NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])#[N:2].C(O)(=[O:25])C.OO.[OH2:29]>>[C:1]([C:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[S:8](=[O:25])(=[O:29])[C:7]=2[CH:6]=[CH:5][C:4]=1[NH:16][C:17](=[O:22])[C:18]([CH3:19])([CH3:21])[CH3:20])#[N:2]
Reactant: O
Reactant: CC(=O)O
Reactant: CC(C)(C)C(=O)Nc1ccc2sc3ccccc3c2c1C#N
Agent: OO
Product: CC(C)(C)C(=O)Nc1ccc2c(c1C#N)-c1ccccc1S2(=O)=O
Temperature: 80 °C

Procedure:
A mixture of 1-cyano-2-pivaloylaminodibenzothiophene (Example 68; 0.034 g, 0.11 mmol) glacial acetic acid (2 ml) and 30% hydrogen peroxide (0.2 ml) was heated at 80° C. for 4 hours. The mixture was cooled and poured into water. The precipitate was filtered and washed extensively with water to give the title compound. NMR 9.95 (s, 1H), 8.57 (d, 1H), 8.32 (d, 1H), 8.11 (d, 1H), 7.95 (t, 1H), 7.82 (t, 1H), 7.75 (d, 1H), 1.28 (s, 9H); m/z 341.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:29]1[CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27][CH2:28]1)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC1CCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)CC1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 4-methylpiperidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.90 minutes; C22H22Cl2N4O2 (445.35); mass spectrum: (M+H)+=445.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH3:24][C:25]1[S:26][C:27]([CH2:31][NH2:32])=[C:28]([CH3:30])[N:29]=1>C(#N)C.O>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][CH2:31][C:27]4[S:26][C:25]([CH3:24])=[N:29][C:28]=4[CH3:30])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Reactant: Cc1nc(C)c(CN)s1
Solvent: CC#N
Solvent: O
Product: COc1cc2c(NCc3sc(C)nc3C)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-nitroquinoline (for a preparation see Intermediate 18, 1.5 g) in acetonitrile was added [(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amine (1.6 g) and the resulting mixture was stirred overnight at 80° C. Another portion of amine (0.64 g) was added and the mixture was stirred at 80° C. for 6 h. The reaction mixture was diluted with water, extracted with DCM and the organic phase were dried over Na2SO4, and concentrated to dryness to give a dark red oil. The residue was purified by flash chromatography on silica gel, eluting with DCM/methanol (99:1 then 95:5) to give 7-(3,5-dimethyl-4-isoxazolyl)-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-6-(methyloxy)-3-nitro-4-quinolinamine (1.13 g) as an orange oil.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[N:17]([CH2:33][CH2:34][N:35]=3)[C:18]([NH:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=3)=[N:19][C:20]=2[C:21]=1[O:22][CH3:23].C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH2:1]([S:3]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[N:17]([CH2:33][CH2:34][N:35]=3)[C:18]([NH:24][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=3)=[N:19][C:20]=2[C:21]=1[O:22][CH3:23])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: COc1c(OCCCN)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NCCCOc1ccc2c(c1OC)N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethanesulfonyl chloride (18 mg, 0.14 mmol) was diluted in dichloromethane (5 ml) and cooled to 0° C. A solution of N-[8-(3-amino-propyloxy)-7-methoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl]-nicotinamide hydrotrifluoroacetate (Step 2, 50 mg, 0.13 mmol) in dimethylformamide (5 mL) was added dropwise, and the mixture was stirred at −10° C. for 30 min. Triethylamine (0.07 mL) was added dropwise, and stirring was continued at −10° C. for another 30 min. The reaction mixture was stirred at rt overnight. Another equivalent of ethanesulfonyl chloride was added, and the mixture was stirred at rt for 12 h. The reaction mixture was quenched by the addition of water, and was extracted with dichloromethane. The combined organic extracts were concentrated to afford a white solid, which was triturated with ethyl acetate to remove residual dimethylformamide. After filtration the solid was carefully washed with water and dried in a vacuum oven. The title compound was obtained as a white solid (4.2 mg, 6.8%). HPLC MS RT=1.63 min, MH+=487.3. 1H NMR (DMSO-d6+2 drops TFA-d) δ: 1.18 (3H, t), 2.00 (2H, m), 2.99 (2H, quartet), 3.14 (2H, t), 4.01 (3H, s), 4.23-4.34 (4H, m), 4.57 (2H, m), 7.49 (1H, d), 7.91 (1H, m), 8.04 (1H, d), 8.95 (1H, m), 8.96 (1H, m), 9.49 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: NC1CC1
Solvent: ClCCl
Product: O=S(=O)(NC1CC1)c1ccc(Br)c(F)c1
Yield: 86.2 %

Procedure:
According to general procedure C, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and cyclopropylamine (0.25 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-cyclopropyl-3-fluorobenzenesulfonamide (0.37 g, 86%) was provided after purification. HRMS: calcd for C9H9BrFNO2S−H+, 291.94486; found (ESI, [M−H]−), 291.9462. HPLC purity 100.0% at 210-370 nm, 9.8 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[Si:13]([O:30][CH2:31][CH:32]([OH:35])[CH2:33][SH:34])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>C(#N)C>[Si:13]([O:30][CH2:31][CH:32]1[O:35][C:4]2[C:5]3[C:10]([C:1](=[O:12])[C:2](=[O:11])[C:3]=2[S:34][CH2:33]1)=[CH:9][CH:8]=[CH:7][CH:6]=3)([C:26]([CH3:29])([CH3:27])[CH3:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)[Si](OCC(O)CS)(c1ccccc1)c1ccccc1
Reactant: O=C1C=Cc2ccccc2C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)[Si](OCC1CSC2=C(O1)c1ccccc1C(=O)C2=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 187.4 %

Procedure:
To a solution of naphthalene-1,2-dione (0.103 g, 0.65 mmol) in acetonitrile (4.0 mL) was added 1-{[tert-butyl(diphenyl)silyl]oxy}-3-mercaptopropan-2-ol (0.226 g, 0.065 mmol) followed by diisopropylethylamine (0.114 mL, 0.065 mmol). The reaction mixture was stirred for 10 minutes at room temperature followed by addition of ethyl acetate (10 mL). The organic layer was washed with water (10 mL) and 1.0 N HCl (5 mL). The organic layer was dried with sodium sulfate and concentrated under reduced pressure. (ii) To the residue was added p-toluenesulfonic acid (0.48 g, mmol) followed by acetonitrile (5 mL). The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added ethyl acetate (10 mL) and the organic layer was extracted with water (10 mL). The organic layer was dried with sodium sulfate and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (SiO2, 100% dichloromethane) to give the product as a purple solid (0.061 g, 18%). M.p.=205-210° C.; 400 MHz 1H NMR (CDCl3) δ: 8.4-8.1 (m, 1H), 7.75-7.5 (m, 6H), 7.49-7.3 (m, 7H), 4.65-4.58 (m, 1H), 4.1-3.93 (m, 2H), 3.2-3.05 (m, 2H), 1.08 (s, 9H); LCMS: 501 [M+H].