Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[CH:14][C:15]=1[Cl:16].[OH-].[K+].CCCCCCC>CS(C)=O>[Cl:8][C:5]1[N:4]=[N:3][C:2]([O:17][C:12]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=2)=[CH:7][CH:6]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: Clc1ccc(Cl)nn1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: CS(C)=O
Product: Clc1ccc(Oc2ccc(Cl)c(Cl)c2)nn1
Yield: 21.1 %

Procedure:
A solution of 3,6-dichloropyridazine (4.47 g, 30.0 mmol), 3,4-dichlorophenol (4.89 g, 30.0 mmol) and potassium hydroxide (1.68 g, 30.0 mmol) in dimethyl sulfoxide (20 mL) was heated at 60° C. overnight. The solvent was removed by evaporation in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50). Small amounts of starting material were removed by kugelrohr distillation. Crystallisation from ethyl acetate:heptane yielded the title compound (1.74 g, 21% yield) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:19][CH:20]1[CH2:22][O:21]1>CN(C=O)C>[O:21]1[CH2:22][CH:20]1[CH2:19][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(OCC2CO2)c1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (3-hydroxyphenyl)carbamate (1 g, 4.79 mmol) in DMF (15 mL) was added NaH (0.126 g, 5.26 mmol) at 0° C. After stirring for 30 min, 2-(bromomethyl)oxirane (0.716 g, 5.26 mmol) was added and the mixture stirred at 0° C. for 1 h before quenching with the addition of MeOH. After evaporation of this mixture, the resulting residue was dissolved in ethyl acetate and washed with water, dried and with sodium sulfate and concentrated with the resulting crude product used for next step without further purification.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.Cl[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=1>CN(C)C=O.O>[N+:30]([C:27]1[CH:28]=[CH:29][C:24]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[S:1][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[N:25][CH:26]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Clc1ccc(Cl)nc1
Reactant: Oc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2Sc2ccc(Cl)cn2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3.0 grams (0.023 mole) of 2-mercaptophenol and 7.0 grams of potassium carbonate stirring in 50 ml of dimethylformamide, 4.0 grams of 2,5-dichloropyridine is added and the mixture stirred overnight at room temperature. After stirring overnight, 4.0 grams of 2-chloro-5-nitropyridine is added and the mixture is again stirred at room temperature overnight. Excess H2O is then added to the reaction mixture and the aqueous mixture extracted with ethyl ether (200 ml), washed with saturated NaHCO3, H2O, brine, dried (MgSO4), filtered, and evaporated to yield the crude product.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[ClH:1].[N:20]1([CH2:26][CH2:27][CH:28]2[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][NH:36][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:32][CH2:33]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: NCCN1CCC(CCN2CCCCC2)CC1
Solvent: CC#N
Product: Cl
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCC(CCN3CCCCC3)CC2)c2ccccc21
Yield: 50 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[2-(piperidin-1-yl)ethyl]-piperidin-1-yl]ethanamine in a yield of 50% of theory. Colourless crystals, m.p. 223° C. (D.) (acetonitrile).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:28][CH2:29][C@H:30]([OH:45])[CH2:31][O:32][C:33]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]2[C:34]=1[CH2:35][CH2:36][C:37](=[O:44])[NH:38]2>>[OH:45][C@H:30]([CH2:31][O:32][C:33]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]2[C:34]=1[CH2:35][CH2:36][C:37](=[O:44])[NH:38]2)[CH2:29][NH:28][CH:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:17]=[CH:16][C:15]([NH:14][S:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)(=[O:12])=[O:13])=[CH:20][CH:19]=2)[CH2:22][CH2:23]1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1OC
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)c5c4CCC(=O)N5)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from 3,4-dimethoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 242) and 5-(3-amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one (which was obtained in Example 12) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.80–1.95 (m, 2 H), 2.39 (t, J=7.2 Hz, 2 H), 2.50–2.75 (m, 5 H), 2.82 (t, J=7.2 Hz, 2 H), 3.45–3.55 (m, 2 H), 3.63 (s, 3 H), 3.72(s, 3 H), 3.70–3.85 (m, 3 H), 4.91 (brs, 1 H), 6.44 (d, J=8.8 Hz, 1 H), 6.60 (d, J=8.8 Hz, 1 H), 6.78 (d, J=9.1 Hz, 1 H), 6.88 (d, J=9.1 Hz, 1 H), 7.02 (d, J=8.5 Hz, 1 H), 7.18 (dd, J=8.5, 2.1 Hz, 1 H), 7.36 (d, J=2.1 Hz, 1 H), 8.72 (s, 1 H), 9.17 (brs, 1 H); MS (ES) m/z: 627.1 (MH+); HRMS Calcd. for C31H39N4O8S (MH+): 627.2489. Found: 627.2458.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:28])([F:27])[C@@:6]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=2)[CH:19]=1)([NH:8][S@@:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[CH3:7])C.[BH4-].[Li+].C(O)(=O)C.O>O1CCCC1>[Br:26][C:22]1[CH:21]=[C:20]([N:18]2[CH:19]=[C:15]([C@:6]([NH:8][S@@:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])([CH3:7])[C:5]([F:28])([F:27])[CH2:4][OH:3])[CH:16]=[N:17]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1cnn(-c2cccc(Br)c2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@](C)(c1cnn(-c2cccc(Br)c2)c1)C(F)(F)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
A solution of (R)-3-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-2,2-difluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester (700 mg, 2.42 mmol) in tetrahydrofuran (5 ml) was treated slowly with lithium borohydride (2M solution in tetrahydrofuran, 0.78 ml, 2.66 mmol) at 0° C., and the mixture was stirred at 25° C. for 2 hours. For the workup, acetic acid (0.26 ml, 4.5 mmol) was added slowly over a period of 15 minutes followed by water (2 ml), and the mixture was stirred for 30 minutes at 25° C. before it was quenched with a solution of sodium hydrogencarbonate (20 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (75 ml), dried over sodium sulphate, and evaporated at reduced pressure. The crude material thus obtained was purified by column chromatography on silica gel using a gradient of hexane/ethyl acetate=85:15 to 80:20 as the eluent to give the (R)-2-methyl-propane-2-sulfinic {(R)-1-[1-(3-bromo-phenyl)-1H-pyrazol-4-yl]-2,2-difluoro-3-hydroxy-1-methyl-propyl}-amide (460 mg, 67% yield) as a deep brown solid. MS (ISP): m/z=450.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[N:5][O:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:35]=[C:34]3[C:29]([CH:30]=[CH:31][CH:32]=[C:33]3[C:36]([O:38][CH3:39])=[O:37])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:4]1[C:3]([CH2:2][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:35]=[C:34]4[C:29]([CH:30]=[CH:31][CH:32]=[C:33]4[C:36]([O:38][CH3:39])=[O:37])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[C:7]([CH:8]([CH3:10])[CH3:9])[O:6][N:5]=1
Reactant: COC(=O)c1cccc2ccc(-c3ccc(O)cc3)cc12
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc12
Yield: 75 %

Procedure:
A solution of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (0.11 g, 0.36 mmol), methyl 7-(4-hydroxyphenyl)-1-naphthalenecarboxylate (0.083 g, 0.30 mmol), and cesium carbonate (137 mg, 0.42 mmol) in dimethylformamide (0.73 mL) was heated to 65° C. for 3 hours. The solution was partitioned between ethyl acetate and water. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The filtrate was purified by chromatography (silica gel, hexane to 1:4 ethyl acetate:hexanes) to provide the title compound (0.123 g, 75%). 1H NMR (DMSO-d6): δ 8.93 (s, 1H), 8.19-8.14 (m, 2H), 8.07 (d, J=9 Hz, 1H), 7.84 (dd, J=2, 9 Hz; 1H), 7.63 (d, J=8 Hz, 4H), 7.59-7.52 (m, 2H), 6.93 (d, J=9 Hz, 2H), 4.87 (s, 2H), 3.93 (s, 3H), 3.46 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6H). ESI LCMS m/z 546 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([NH2:15])=[C:6]2[C:10]=1[N:9]([CH2:11][CH3:12])[S:8](=[O:14])(=[O:13])[CH2:7]2.C(N(CC)CC)C.[C:24](Cl)(Cl)=[S:25]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH3:12])[S:8](=[O:14])(=[O:13])[CH2:7][C:6]=2[C:5]([N:15]=[C:24]=[S:25])=[C:4]([F:16])[CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: CCN1c2c(Cl)cc(F)c(N)c2CS1(=O)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN1c2c(Cl)cc(F)c(N=C=S)c2CS1(=O)=O

Procedure:
To a solution of 7-chloro-1-ethyl-5-fluoro-1,3-dihydro-2,1-benzisothiazol-4-amine 2,2-dioxide (0.5 g, 1.88 mmol) and triethylamine (0.6 mL) in anhydrous tetrahydrofuran (THF, 10 mL), thiophosgene (0.238 g, 1.1 eq) in THF (2 mL) was added dropwise at room temperature under a nitrogen atmosphere. The resulting reaction mixture was heated at reflux for 2 days. The solvents were removed in vacuo to give the title compound of Step A which was used in Step B.
Reaction SMILES: [Br:1]Br.[N:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=1>C(O)(=O)C>[Br:1][C:11]1[C:12](=[O:15])[NH:13][CH:14]=[C:9]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][N:3]=2)[CH:10]=1
Reactant: O=c1ccc(-c2cnccn2)c[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]cc(-c2cnccn2)cc1Br
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3 ml of bromine are added to a stirred suspension of 5-(2-pyrazinyl)-2(1H)-pyridone (9.0 g) in 300 ml of glacial acetic acid warmed to a temperature of 50° C. The mixture is stirred at RT overnight, cooled in an ice bath to 16° C. and filtered. The filtered yellow solid is suspended in 100 ml of distilled H2O, to which sodium bisulfite is gradually added until the solid appears tan. A saturated potassium carbonate solution is slowly added until the pH is adjusted to 7.4, and the suspension is filtered. The filtered solid is washed with H2O and dried under high vacuum at 100° C. for 4 hours, giving the desired 3-bromo-5-(2-pyrazinyl)-2(1H)-pyridone which is recrystallized from methanol, M.P.>250° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1C(OCC)=O.[H-].[Na+].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ClCCl>CN(C=O)C.O>[C:17]1([S:23]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2ccccc21

Procedure:
To a stirred and cooled (to about 0° C.) solution of ethyl indole-2-carboxylate 10 (1 eq.) in DMF (2 ml/mmol) under N2, was added NaH (60% in oil, 1.2 eq.) portionwise. When gas evolution stopped, benzenesulfonyl chloride (1.2 eq.) was added. The reaction mixture was stirred for about 1 hour (TLC monitoring, eluent dichloromethane); a small amount of water then was added carefully and the DMF was evaporated. The crude residue was dissolved in ethyl acetate and washed with water and brine. After drying and evaporation of the solvents, the compound was purified by chromatography on silica gel (eluent: C6H12/EtOAc 9/1 to 7/3) to give the N-phenylsulfonylindole 62c.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[C:11]2[N:29](COCC[Si](C)(C)C)[C:28]([O:38][C@H:39]3[C@H:43]4[O:44][CH2:45][C@@H:46]([O:47][CH2:48][CH:49]([OH:52])[CH2:50][OH:51])[C@H:42]4[O:41][CH2:40]3)=[N:27][C:12]2=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.C[Si](C)(C)[O-].[K+]>C(Cl)Cl.C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]2[NH:29][C:28]([O:38][C@H:39]3[C@H:43]4[O:44][CH2:45][C@@H:46]([O:47][CH2:48][CH:49]([OH:52])[CH2:50][OH:51])[C@H:42]4[O:41][CH2:40]3)=[N:27][C:12]2=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3OCC(O)CO)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCC(O)CO[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
TFA (0.25 ml, 3.24 mmol) was added to a stirred solution of 3-[[(3R,3aR,6R,6aR)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]oxy]propane-1,2-diol (6.1 mg, 9.32 μmol) in DCM (0.25 ml). The reaction mixture was stirred at room temperature. After 2.5 hours, the reaction mixture was evaporated under reduced pressure. Potassium trimethylsilanolate (9.2 mg, 0.072 mmol) was added to a stirred solution of the residue in THF (0.5 ml). The reaction mixture was stirred at room temperature. After 1.5 hours, additional potassium trimethylsilanolate (18.2 mg, 0.142 mmol) was added to the reaction mixture. After an additional 1.5 hours, the reaction mixture was evaporated under reduced pressure to give a pale amber residue. This material was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile+0.05% TFA flush. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C27H26ClN3O6 523.15 observed m/e: 524.22 (M+H)+ (Rt 1.16/2 min); 1H NMR δ (ppm) (CD3OD): 7.98 (s, 1H), 7.74-7.78 (m, 4H), 7.71 (d, J=7.4 Hz, 2H), 7.48 (t, J=7.7 Hz, 2H), 7.39 (t, J=7.4 Hz, 1H), 5.59 (qt, J=5.1 Hz, 1H), 5.01 (t, J=5.3 Hz, 1H), 4.65 (t, J=5.0 Hz, 1H), 4.13-4.17 (m, 3H), 3.98-4.01 (m, 1H), 3.54-3.81 (m, 6H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH:17]([OH:21])[CH2:16][CH2:15]3)[C:7](=[O:22])[C:6]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:40][C:39](=[O:41])[O:38][N:37]=2)=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[CH2:16][CH2:15]3)[C:7](=[O:22])[C:6]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:40][C:39](=[O:41])[O:38][N:37]=2)=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2ccc3c(c2)CCC3O)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCCCc1nc(C)n(-c2ccc3c(c2)CCC3=O)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h
Yield: 49.3 %

Procedure:
To a solution of 6-butyl-3-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3 H)-one (0.055 g) in acetonitrile (2 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.085 g), and the mixture was stirred for 2 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.027 g, 49%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]=[CH:14][N:15]([CH3:17])[CH3:16])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C=NS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
0.325 g of 4-bromobenzenesulfonamide was admixed with 0.82 g of dimethylformamide dimethyl acetal in 1.6 ml of dry dimethylformamide and stirred at room temperature for 90 min. For workup, the reaction mixture was admixed with 10 ml of water, and the precipitate was filtered off with suction, filtered and dried under reduced pressure. 4-Bromo-N-[1-dimethylaminomethylidene]benzenesulfonamide was obtained in a yield of 85%. Molecular weight 289.97 (C9H11BrN2O2S); retention time Rt=1.3 min. [B]; MS (ESI): 290.96 (MH+).
Reaction SMILES: [F:1][C:2]([F:16])([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[Cl-].[Cl-].[NH3+:19][C@@H:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][NH+:23]=1)[CH3:21].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:16][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)([F:1])[C:3](=[O:5])[NH:19][C@@H:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:31])[F:32])=[CH:24][N:23]=1)[CH3:21]
Reactant: C[C@@H]([NH3+])c1ccc(OCC(F)(F)F)c[nH+]1
Reactant: COC(=O)c1ccc(C(F)(F)C(=O)O)cc1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)c1ccc(C(F)(F)C(=O)N[C@H](C)c2ccc(OCC(F)(F)F)cn2)cc1
Reaction time: 24 h
Yield: 65.2 %

Procedure:
To a solution of 0.400 g (1.72 mmol) difluoro[4-(methoxycarbonyl)phenyl]acetic acid in 3.50 ml CH2Cl2 was added 0.560 g (1.90 mmol) 2-[(1R)-1-ammonioethyl]-5-(2,2,2-trifluoroethoxy)pyridinium dichloride, 0.308 g (2.26 mmol) HOAT, 0.433 g (2.26 mmol) EDC, and 0.911 mL (5.21 mmol) DIEA, After 24.0 h at room temperature, the reaction mixture was diluted with CH2Cl2, washed three times with water, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 0-30% EtOAc:hexane) afforded 0.485 g (65%) Methyl 4-[1,1-difluoro-2-oxo-2-({(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}amino)ethyl]-benzoate. 1H NMR (CDCl3, 400 MHz) 8.32 (d, 1H, J=2.84 Hz); 8.10 (d, 2H, J=8.05 Hz); 7.93 (br d, 1H, J=5.95 Hz); 7.71 (d, 2H, J=8.25 Hz); 7.28 (d, 1H, J=2.75 Hz); 7.23 (d, 1H, J=17.12 Hz); 5.19 (m, 1H); 4.41 (q, 2H, J=7.87 Hz); 3.93 (d, 3H, J=0.55 Hz); 1.49 (d, 3H, J=6.68). ESMS+1 for C19H17F5N2O4: 433.1.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[Cl:17])(=[O:3])[CH3:2].[C:18]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])#[CH:19]>C(Cl)(Cl)Cl>[ClH:17].[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([C:18]#[CH:19])[CH:21]=1)(=[O:3])[CH3:2]
Reactant: C#Cc1cccc(N)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Solvent: ClC(Cl)Cl
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OC(C)=O)cc23)c1
Product: Cl
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A mixture of 4-chloro-7-methoxyquinazolin-6-yl acetate (7.75 g, 0.0307 mol), 3-ethynyl aniline (4 g, 0.0342 mol, 1.11 equiv) and chloroform (120 ml) was refluxed overnight. The reaction mixture was cooled to room temperature and the solution was filtered to give 10.2 g product. MS (ESI) m/z: 334 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH2:14][C:15](=O)[CH2:16][CH2:17][CH3:18])([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1.CO.O>[CH3:11][O:10][C:8]([C:7]1[CH:6]=[C:5]2[C:4](=[CH:13][CH:12]=1)[NH:1][C:15]([CH2:16][CH2:17][CH3:18])=[CH:14]2)=[O:9]
Reactant: CCCC(=O)Cc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCc1cc2cc(C(=O)OC)ccc2[nH]1
Yield: 71.2 %

Procedure:
Methyl 4-nitro-3-(2-oxopentyl)benzoate (5.42 g) is dissolved in a mixed solvent of tetrahydrofuran (20 ml) and methanol (20 ml), to which is added a suspension of sodium hydrosulfite (52.2 g) in water (60 ml). After having been refluxed for 2 hours, this is subjected to liquid-liquid separation by adding ethyl acetate (300 ml) and water (200 ml) thereto. The organic layer is washed with a saline solution, dried and concentrated. The resulting residue is purified through silica gel column chromatography to obtain 5-(methoxycarbonyl)-2-propylindole (3.16 g).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Br>CC(N(C)C)=O.CCOC(C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([N:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[C:27]([F:37])([F:36])[F:26])(=[O:18])=[O:17])=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CC(=O)N1CCN(c2ccc(S(=O)(=O)NCC(C)C)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)N1CCN(c2ccc(S(=O)(=O)N(Cc3ccccc3C(F)(F)F)CC(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A solution of 4-(4-acetyl-piperazin-1-yl)-N-isobutyl-benzenesulfonamide (100 mg, 0.295 mmol) in DMA (2 mL) was treated with NaH (60% dispersion in mineral oil, 18 mg, 0.443 mmol) and stirred at room temperature for 30 minutes. 2-(Trifluoromethyl)benzyl bromide (141 mg, 0.590 mmol) was added and the mixture heated at 90° C. for 1 hour. The cooled mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-100% EtOAc in DCM) gave the title compound (110 mg, 75%). 1H NMR (400 MHz, DMSO) δ 7.81 (d, J=7.9 Hz, 1H), 7.69-7.71 (m, 4H), 7.50 (t, J=7.6 Hz, 1H), 7.08 (d, J=8.8 Hz, 2H), 4.36 (s, 2H), 3.59 (d, J=5.26 Hz, 4H), 3.38 (dd, J=26.2, 5.0 Hz, 4H), 2.86 (d, J=7.2 Hz, 2H), 2.05 (s, 3H), 1.36 (t, J=6.7 Hz, 1H), 0.70 (d, J=6.6 Hz, 6H). LCMS (m/z Method B) ES+ 498.1 [M+1]+.