Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[C:4]([OH:16])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C1(C)C=CC=CC=1>CN(C)C=O.O>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[C:4]([O:16][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:3]=1
Reactant: O=C1c2ccccc2-c2c(Cl)cc(O)cc21
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cc(Cl)c2c(c1)C(=O)c1ccccc1-2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4-Chloro-2-hydroxy-9H-fluoren-9-one (48.6 g) was dissolved in N,N-dimethylformamide (150 ml), potassium carbonate (58.3 g) and ethyl 4-bromobutyrate (33.5 ml) were added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was cooled to 40° C., and toluene (300 ml) and water (300 ml) were added to allow for layer separation. The obtained aqueous layer was extracted again with toluene (100 ml). The obtained organic layers were combined, washed twice with water (100 ml), anhydrous sodium sulfate and activated carbon (2.5 g) were added, and the mixture was stirred at room temperature for 5 min. The insoluble material was filtered off through celite, and the solvent in the filtrate was evaporated. To the obtained residue was added hexane (220 ml), and the mixture was stirred at 50° C. for 10 min and at room temperature for 1 hr. The precipitated solid was collected by filtration, and washed with hexane. The obtained solid was dried under reduced pressure to give the title compound (66.9 g). In addition, the solvent in the obtained filtrate was evaporated, to the residue were added ethyl acetate (5 ml) and hexane (20 ml), and the mixture was stirred at room temperature for 1 hr. The precipitated solid was collected by filtration, and washed with hexane. The obtained solid was dried under reduced pressure to further give the title compound (2.5 g).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[N:30]1([CH:36]2[CH2:41][CH2:40][CH2:39][N:38]([C:42]3[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=3)[CH2:37]2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:48][C:45]3[CH:46]=[CH:47][C:42]([N:38]4[CH2:39][CH2:40][CH2:41][CH:36]([N:30]5[CH2:31][CH2:32][O:33][CH2:34][CH2:35]5)[CH2:37]4)=[CH:43][CH:44]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(N2CCCC(N3CCOCC3)C2)cc1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCCC(N5CCOCC5)C4)cc3)nn12
Yield: 36.3 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (100.0 mg, 0.0003480 mol), N,N-Diisopropylethylamine (0.0909 mL, 0.000522 mol) and 4-(3-Morpholin-4-yl-piperidin-1-yl)-phenylamine (0.182 g, 0.000696 mol) were dissolved in 1-Methoxy-2-propanol (0.99 mL, 0.010 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 61.16 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(3-morpholin-4-yl-piperidin-1-yl)-phenyl]-amine as a lyophilized powder. (M+H)=486.3. 1H NMR (400 MHz, DMSO, d6) δ 9.20 (m, 1H), 8.92 (s, 1H), 7.84 (dd, 1H, J=1.67, 5.97 Hz), 7.61 (d, 2H, J=9.00 Hz), 7.45 (m, 1H), 7.21 (d, 1H, J=8.00 Hz), 7.15 (m, 1H), 6.91 (m, 4H), 4.33 (m, 2H), 3.77 (s, 3H), 3.74 (m, 2H), 3.42 (m, 3H), 2.90 (m, 2H), 2.67 (m, 2H), 2.13 (m, 2H), 1.75 (m, 2H), 1.61 (m, 2H).
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[C:19]([NH2:25])[CH:18]=2)=[N:15][NH:14][C:13](=[O:26])[CH2:12]1.C1COCC1>C(O)(=O)C>[CH3:10][CH:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]3[N:23]([CH3:24])[C:1]([C:2]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)=[N:25][C:19]=3[CH:18]=2)=[N:15][NH:14][C:13](=[O:26])[CH2:12]1
Reactant: CNc1ccc(C2=NNC(=O)CC2C)cc1N
Reactant: O=C(O)c1ccncc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc2c(c1)nc(-c1ccncc1)n2C
Reaction time: 16 h

Procedure:
A mixture of 12.3 g of isonicotinic acid, 23.2 g of 5-methyl-6-(3-amino-4-methylaminophenyl)-4,5-dihydropyridazin-3-one, 16.2 g of N,N'-carbonyldiimidazole and 600 ml of THF is stirred at 25° for 16 hours. After the usual working up, an oily mixture of 5-methyl-6-(3-amino-4-N-methylisonicotinamidophenyl)- and 5-methyl-6-(3-isonicotinamido-4-methylaminophenyl)-4,5-dihydropyridazin-3-one is obtained and is dissolved in 400 ml of acetic acid. After the solution has been boiled for 3 hours, then cooled and submitted to the usual working up, 5-methyl-6-[1-methyl-2-(4-pyridyl)-5-benzimidazolyl]-4,5-dihydropyridazin-3-one is obtained; dihydrochloride, decomposition above 298°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]2([O:13][CH3:14])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:16](N(CC)CC)[CH3:17].ICC.O>O1CCCC1>[Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]2([O:13][CH3:14])[CH2:12][CH2:11][N:10]([CH2:16][CH3:17])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: COC1(c2cccc(Cl)c2F)CCNC1
Solvent: O
Solvent: CCI
Solvent: C1CCOC1
Product: CCN1CCC(OC)(c2cccc(Cl)c2F)C1
Temperature: 25 °C
Reaction time: 26 h
Yield: 38.1 %

Procedure:
To a solution of (+)-3-(3-chloro-2-fluorophenyl)-3-methoxypyrrolidine (0.25 g, 1.08 mmol) and triethylamine (0.305 ml, 2.17 mmol) in tetrahydrofuran (20 ml), was added iodoethane (0.13 ml, 1.63 mmol) and the solution was stirred at ambient temperature for 26 h. Water (20 ml) was added and the aqueous phase was extracted with EtOAc (2×50 ml), the combined organic phase was dried (Na2SO4) and the solvent was evaporated. Purification by HPLC on waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 65:35) gave the title compound 0.106 g (38%). [a]D=+16.5° (methanol). The amine was converted to the fumaric acid salt and recrystallized from 2-propanol/diisopropyl ether: M.p. 131-133° C. MS m/z (rel. intensity, 70 eV) 257 (M+, 9), 242 (bp), 227 (44), 157 (44), 71 (89).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14]([OH:16])=O)=[O:5])[CH3:2].[CH:17]1([C:21]2[N:22]=[C:23](/[CH:26]=[CH:27]/[C:28]3[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=3)[S:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][C:14]([NH:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28](/[CH:27]=[CH:26]/[C:23]2[S:24][CH:25]=[C:21]([CH:17]3[CH2:20][CH2:19][CH2:18]3)[N:22]=2)[CH:29]=1)=[O:16])[CH3:2]
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reactant: CCOC(=O)c1ccccc1CCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1CCC(=O)Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Reaction time: 16 h
Yield: 95.4 %

Procedure:
A solution composed of 0.44 g of 2-(ethoxycarbonyl)benzenepropanoic acid and 25 ml of methylene chloride was added to a solution composed of 0.51 g of (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, 0.4 g of N-ethyl-N-(dimethylaminopropyl)carbodiimide, 1.0 g of 4-dimethylaminopyridine and 25 ml of methylene chloride at 0° C. After 16 hr., the reaction mixture was washed with 30 ml of water, dried (MgSO4) and the solvents removed by rotary evaporation. The residual materials were recrystallized from ethyl ether to yield 0.87 g of (E)-2-[3-[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenylamino]-3-oxopropyl]benzoic acid ethyl ester; m.p.110°14 111° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[NH:6][CH:7]=[C:8]([O:12]CC2C=CC=CC=2)[C:9](=[O:11])[CH:10]=1)=[N+]=[N-].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H][H].C(N(C(C)C)CC)(C)C>CN(C)C=O.[Pd]>[NH2:1][CH2:4][C:5]1[NH:6][CH:7]=[C:8]([OH:12])[C:9](=[O:11])[CH:10]=1
Reactant: [N-]=[N+]=NCc1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NCc1cc(=O)c(O)c[nH]1

Procedure:
A suspension of 2-(azidomethyl)-5-[(phenylmethyloxy)]-4-oxo-1,4-dihydropyridine (641 mg, 2.5 mmole) in 7 ml of dimethylformamide was treated with p-toluenesulfonic acid monohydrate (951 mg, 5 mmole), and the resulting solution was treated with 10% palladium on charcoal (641 mg). The mixture was stirred under 1 atmosphere of hydrogen for 75 minutes. The hydrogen was purged with argon, and diisopropylethylamine (871 μl, 5 mmole) was added. The resulting mixture was used immediately in the following reaction.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:15]([O-])(=[O:18])[C:16]#[CH:17].[Na+].S(Cl)(Cl)=O.[C:25]([Cl:29])(=[O:28])[C:26]#[CH:27]>C1C=CC=CC=1>[C:25]([Cl:29])(=[O:28])[C:26]#[CH:27].[C:15]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:18])[C:16]#[CH:17]
Reactant: C#CC(=O)[O-]
Reactant: OCCCCCc1ccccc1
Agent: C#CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: C#CC(=O)OCCCCCc1ccccc1

Procedure:
With stirring, 1 gram of 5-phenylpentanol was added dropwise to a mixture of 0.25 g of sodium hydride (60% oil suspension) and 25 ml of dried benzene. The mixed solution is further stirred at ambient temperatures for one hour. A benzene solution of propiolic acid chloride is prepared by stirring a mixture of 0.62 g of sodium propiolate, 0.80 g of thionyl chloride, and 20 ml of dried benzene at ambient temperatures for five hours. The benzene solution of propiolic acid chloride thus prepared is added to the mixed solution, stirred at ambient temperatures for five hours, and refluxed for one hour. After the reaction is completed, the reaction solution is washed successively with water and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue is subjected to silicagel column chromatography to yield 5-phenylpentyl propiolate (compound 1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:27]=[CH:26][C:22]2[N:23]=[CH:24][NH:25][C:21]=2[CH:20]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[NH:23]1[C:22]2[CH:26]=[CH:27][C:19]([NH:18][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:16]#[N:17])=[CH:20][C:21]=2[N:25]=[CH:24]1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc2nc[nH]c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc4[nH]cnc4c3)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 159.8 mg (1.2 mmol) of 5-aminobenzimdazole and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed for 1 hr. The work up gave 233.6 mg (67.7%) of the product as a brown solid, m.p. 230°0 C. (dce.), mass (electrospray, m/e): M+H 345.9. HRCIMS: calcd 346.1304 for C19H15N5O2 (M+), obsd 346.1325.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[N:5]=[C:4]([OH:12])[N:3]=1.[H][H]>CO.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([OH:12])=[N:5][C:6]=1[CH3:11]
Reactant: [H][H]
Reactant: Cc1nc(O)nc(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1nc(O)nc(C)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
Compound 1 (1.0 g), 5% Pd—C (131 mg) were suspended in methanol (60 mL). Evacuation and replacement with hydrogen were repeated three times. Subsequently, the suspension was vigorously stirred at room temperature (20 to 30° C.) for 8 hours under hydrogen atmosphere. After the reaction was completed, the mixture was filtered through Celite and the filtered product was washed with methanol. The filtrate was evaporated under reduced pressure to give 853 mg of a crude desired product of Compound 3 as a yellow solid.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[CH:20][N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[CH:20][N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH3:5]
Reactant: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1-c1cccc(F)c1
Agent: CP(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(N)c1nc2sccn2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a stirred solution of 7-(1-azidoethyl)-6-(3-fluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.32 g, 1.0 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (1.22 mL, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate, and the mixture was extracted with aqueous 1 N HCl solution (three times). The combined extract was neutralized with solid NaHCO3 and extracted with dichloromethane (two times). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated to give the desired product (0.17 g, 58%). LCMS calculated for C14H13FN3OS (M+H)+: m/z=290.1. Found: 290.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[C:14]([CH2:16][C:17](O)=[O:18])#[N:15].C(N=C=NC(C)C)(C)C>O1CCCC1>[C:14]([CH2:16][C:17]([NH:6][C:5]1[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:18])#[N:15]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: N#CCC(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: COc1cc(NC(=O)CC#N)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
3,4,5-Trimethoxyaniline (10.00 g, 54.6 mmol) and cyanoacetic acid (4.78 g, 56.19 mmol) were mixed in 100 mL of tetrahydrofuran and heated to reflux. To the resultant solution 1,3-diisopropylcarbodiimide (8.8 mL, 56.29 mmol) was added dropwise. The mixture was cooled in an ice-bath and the solid was collected by filtration washing with tetrahydrofuran. The filtrate was slowly poured into water and stirred for 30 minutes. The white solid was collected by filtration, washed with water and dried to give 2.58 g of 2-cyano-N-(3,4,5-trimethoxyphenyl)acetamide as a white solid, mp 146-147° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.61 (s, 3H), 3.74 (s, 6H), 3.86 (s, 2H), 6.90 (s, 2H), 10.23 (s, 1H); MS (ES) m/z251.1 (M+H)+
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([NH:21][C:22]([NH2:24])=[NH:23])[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1.[F:25][CH2:26][CH:27]([O:30][CH2:31][C:32]([CH:34]1[C:39](=O)[CH2:38][CH2:37][O:36][CH2:35]1)=O)[CH2:28][F:29]>CN(C=O)C>[F:25][CH2:26][CH:27]([O:30][CH2:31][C:32]1[C:34]2[CH2:35][O:36][CH2:37][CH2:38][C:39]=2[N:23]=[C:22]([NH:21][C:11]2[CH:12]=[CH:13][C:14]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)=[C:9]([O:8][CH3:7])[CH:10]=2)[N:24]=1)[CH2:28][F:29]
Reactant: O=C1CCOCC1C(=O)COC(CF)CF
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3c(c(COC(CF)CF)n2)COCC3)ccc1-n1cnc(C)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
Potassium carbonate (222 mg, 1.61 mmol) was added to 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (149 mg, 0.40 mmol) in DMF (1 mL) and set under N2 atmosphere. The DMF (1 mL) solution of 3-(2-(1,3-difluoropropan-2-yloxy)acetyl)dihydro-2H-pyran-4(3H)-one (95 mg, 0.40 mmol) was added dropwise to the reaction mixture and stirred for 16 hours at 50° C. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and the crude product was purified by silica flash chromatography using a gradient of methanol in dichloromethane (0 to 4%) affording the title compound (120 mg, 67% yield).
Reaction SMILES: Cl.NC(C[C:18]1[CH:26]=[C:25]([Cl:27])[C:24]([O:28][CH3:29])=[C:23]2[C:19]=1[CH:20]=[N:21][N:22]2[S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])C(NCCCCC1C=CC=CC=1)=O.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[N:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>ClCCl.CCOC(C)=O>[C:39]1([S:45]([NH:22][CH:23]([CH2:19][C:20]2[C:19]3[C:23](=[C:24]([O:28][CH3:29])[C:25]([Cl:27])=[CH:26][CH:18]=3)[N:22]([S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:31])=[O:32])[N:21]=2)[C:24]([NH:49][CH2:54][CH2:53][CH2:52][CH2:51][C:50]2[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=2)=[O:28])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1ccncc1
Reactant: COc1c(Cl)cc(CC(N)C(=O)NCCCCc2ccccc2)c2cnn(S(=O)(=O)c3ccccc3)c12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1c(Cl)ccc2c(CC(NS(=O)(=O)c3ccccc3)C(=O)NCCCCc3ccccc3)nn(S(=O)(=O)c3ccccc3)c12
Reaction time: 18 h

Procedure:
2-Amino-3-(1-benzenesulfonyl-6-chloro-7-methoxy-1H-indazol-4-yl)-N-(4-phenyl-butyl)-propionamide hydrochloride (0.31 g, 0.54 mmol) is dissolved in a mixture of dichloromethane (4 mL) and pyridine (1.5 mL). Benzenesulfonyl chloride (0.12 mL, 0.9 mmol) is added portionwise and the reaction is allowed to stir for a total of 18 h. The reaction is diluted with EtOAc and washed with water, 1N HCl three times, water, brine and dried over MgSO4. The solution is concentrated and purified by column chromatography (silica, 5% EtOAc/CH2Cl2 to provide 2-benzenesulfonylamino-3-(1-benzenesulfonyl-6-chloro-7-methoxy-1H-indazolyl)-N-(4-phenyl-butyl)-propionamide.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:6]1[S:7][C:8]([CH:11]2[O:16]CC(C)(C)CO2)=[CH:9][CH:10]=1)[CH2:4][OH:5].C(N(CC)CC)C.C[Si](Cl)(C)C.[S:31]1[C:35]2[CH:36]=[C:37]([S:40](Cl)(=[O:42])=[O:41])[CH:38]=[CH:39][C:34]=2[N:33]=[CH:32]1.Cl>C(Cl)Cl.CO>[CH:11]([C:8]1[S:7][C:6]([C@H:3]([NH:2][S:40]([C:37]2[CH:38]=[CH:39][C:34]3[N:33]=[CH:32][S:31][C:35]=3[CH:36]=2)(=[O:41])=[O:42])[CH2:4][OH:5])=[CH:10][CH:9]=1)=[O:16]
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Reactant: CC1(C)COC(c2ccc([C@H](N)CO)s2)OC1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: O=Cc1ccc([C@@H](CO)NS(=O)(=O)c2ccc3ncsc3c2)s1
Reaction time: 0.25 h

Procedure:
To a solution of (2R)-2-amino-2-[5-(5,5-dimethyl-1,3-dioxan-2-yl)thiophen-2-yl]ethanol hydrochloride (11.54 g, 39.3 mmol) in DCM (262 mL) at 0° C. was added slowly triethylamine (25 mL, 179 mmol). The mixture was stirred 15 minutes, after which TMSCl (5.52 mL, 43.2 mmol) was added. The mixture was stirred for 30 minutes at 0° C. and then 1,3-benzothiazole-6-sulfonyl chloride (9.64 g, 41.2 mmol) was added. The reaction mixture was allowed to reach room temperature overnight, and then 1N HCl (100 mL) and MeOH (50 mL) were added and the reaction mixture was stirred for 2 hours. The organic layer was separated and the aqueous layer was extracted 5 times with ethyl acetate (5×300 mL). The organic layers were combined and washed twice with a saturated solution of sodium bicarbonate (2×250 mL), then washed with brine (250 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was swished with ether to obtain the pure desired product.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([CH2:15][N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].Br[CH2:23][CH2:24][O:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][C:30]([CH3:36])=[N:31]2.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([CH2:15][N:16]3[CH2:17][CH2:18][N:19]([CH2:23][CH2:24][O:25][C:26]4[CH:35]=[CH:34][CH:33]=[C:32]5[C:27]=4[CH:28]=[CH:29][C:30]([CH3:36])=[N:31]5)[CH2:20][CH2:21]3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCOc2ccc(CN3CCNCC3)cc21
Reactant: Cc1ccc2c(OCCBr)cccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc2c(OCCN3CCN(Cc4ccc5c(c4)N(S(C)(=O)=O)CCO5)CC3)cccc2n1
Reaction time: 48 h
Yield: 36.2 %

Procedure:
The title compound was prepared by reaction of 4-methanesulfonyl-6-(piperazin-1-ylmethyl)-3,4-dihydro-2H-benzo[1,4]oxazine (0.145 g, 1 mmol), 5-(2-bromoethoxy)-2-methylquinoline (0.266 g, 1 mmol) and N,N-diisopropylethylamine (1.29 g, 10 mmol) in isopropyl alcohol (8 mL). The mixture was heated at reflux with stirring in a reaction block for 48 h. The reaction mixture was cooled, and the isopropyl alcohol evaporated in vacuo. The residue was partitioned between dichloromethane (5 mL), and water (5 mL). The organic layer was added onto a 10 g pre-packed silica column and eluted with 0–10% methanol in ethyl acetate. Fractions containing desired material were combined and evaporated in vacuo to give the title compound (0.180 g, 36%) as a colourless solid. Mass Spectrum (APCl+): Found 497 (MH+). C28H32N4O4S requires 496.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([N:28](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:57])[CH2:34][CH2:35][NH:36][C:37](=[O:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]4[C:49]5=[N:50][O:51][N:52]=[C:48]5[C:47]([N+:53]([O-:55])=[O:54])=[CH:46][CH:45]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C)C=O.O1CCCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:57])[CH2:34][CH2:35][NH:36][C:37](=[O:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]4[C:49]5=[N:50][O:51][N:52]=[C:48]5[C:47]([N+:53]([O-:55])=[O:54])=[CH:46][CH:45]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N(CCCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)S(=O)(=O)c5ccccc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](NCCCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 18 h
Yield: 32.2 %

Procedure:
To a slurry of N-{3-[(3-{(3β)-cholest-5-en-3-yl [(2-nitrophenyl)sulfonyl]amino}propyl)amino]-3-oxopropyl}-6-(7-nitrobenzofurazan-4-ylamino)hexanamide (23, 58 mg, 0.059 mmol) and K2CO3 (139 mg, 1.008 mmol) in N,N-dimethylformamide (8 mL) and tetrahydrofuran (2 mL), was added thiophenol (61 μL, 0.590 mmol). After 18 h at 23° C., the suspension was filtered and solvent removed in vacuo. The crude product was purified by preparative reverse-phase HPLC (gradient: 59.9% MeCN, 40% H2O, and 0.1% TFA to 99.9% MeCN, 0% H2O, and 0.1% TFA over 10 min; retention time=7.6 min) to afford 7 (15 mg, 32%) mp 101-104° C.; 1H NMR (500.13 MHz, CDCl3) δ 9.54 (br s, 1H), 8.50 (d, J=8.9 Hz, 1H), 8.42 (br s, 1H), 8.01 (t, J=5.7, 1H), 7.82 (t, J=5.7 Hz, 1H), 6.39 (d, J=6.4 Hz, 1H), 5.36 (d, J=4.7 Hz, 1H), 3.43 (m, 1H), 3.22 (m, 1H), 3.11 (m, 2H), 2.93-2.84 (m, 3H), 2.39-2.28 (m, 2H), 2.22 (t, J=7.0 Hz, 2H), 2.04 (t, J=7.4 Hz, 2H), 1.97-0.94 (m, 36H), 0.92 (s, 3H), 0.86 (d, J=6.5 Hz, 3H), 0.84 (d, J=2.4 Hz, 3H), 0.82 (d, J=2.4 Hz, 3H), 0.61 (s, 3H); 13C NMR (125 MHz, DMSO d6) δ 171.9, 170.9, 145.1, 144.4, 144.1, 138.5, 137.9 122.4, 120.5, 99.0, 56.6, 56.0, 55.5, 49.3, 43.3, 41.8 (×2), 41.6, 40.5, 36.4, 36.1 (×2), 35.6, 35.5 (×2), 35.3, 35.2, 35.1, 34.3, 31.2, 27.7, 27.4, 27.3, 26.3, 26.0, 24.9, 24.4, 23.8, 23.2, 22.6, 22.4, 20.4, 18.7, 18.5, 11.6; IR (film) νmax 3257, 3093, 2940, 2858, 1636, 1548, 1377 cm−1; CI m/z 790.5605 (MH+, C45H72N7O5 requires 790.5595).