Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9]([C:11]([OH:13])=O)[S:8][C:6]=2[N:7]=1.[CH3:20][C:21]1([CH3:31])[NH:26][CH2:25][CH2:24][N:23]([CH:27]2[CH2:30][O:29][CH2:28]2)[CH2:22]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][N:23]([CH:27]4[CH2:30][O:29][CH2:28]4)[CH2:22][C:21]3([CH3:31])[CH3:20])=[O:13])[S:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CC1(C)CN(C2COC2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CN(C2COC2)CCN1C(=O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carboxylic acid (100 mg, 0.33 mmol), 3,3-dimethyl-1-oxetan-3-ylpiperazine (62 mg, 0.36 mmol), HATU (278 mg, 0.37 mmol) and DIPEA (65 μL, 0.37 mmol) in DCM (3 mL) was allowed to stir at r.t. for 18 h. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, MeOH:DCM, 0-2%) affording the title compound as a yellow solid. LCMS (method H): RT 2.67 min, [M+H]+ 453.3
Reaction SMILES: [C:1]1([CH:7]=[N+:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[O-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)C1C=CC=CC=1.C(N)(C)(C)C>O>[CH:7](=[N:8][C:10]([CH3:13])([CH3:12])[CH3:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[N+]([O-])=Cc1ccccc1
Solvent: O
Solvent: O=Cc1ccccc1
Solvent: CC(C)(C)N
Product: CC(C)(C)N=Cc1ccccc1

Procedure:
The imine starting material may be commercially purchased or synthetically prepared. If desired, the imine may be prepared by a condensation reaction between an aldehyde and a primary amine. In one embodiment of the present invention, the imine precursor for α-phenyl-N-tert-butyl nitrone (PBN) is prepared by combining benzaldehyde and t-butyl amine at room temperature, in the absence of a solvent, to form the corresponding benzylidene-t-butyl amine (imine) and water. It was found that the resulting imine was sufficiently pure for use in the next step without the need for purification or removal of water by-product contained therein. Thus, the present method reduces time and cost, and improves efficiency, in comparison with traditional transformations.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.CS(O[CH2:31][C:32]1([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][O:36][C:35]([CH3:39])([CH3:38])[O:34][CH2:33]1)(=O)=O>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12](=[O:13])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[CH:8][N:9]2[CH2:31][C:32]2([NH:40][C:41](=[O:42])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][O:36][C:35]([CH3:38])([CH3:39])[O:34][CH2:33]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c[nH]c2c1
Reactant: CC(C)(C)OC(=O)NC1(COS(C)(=O)=O)COC(C)(C)OC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
To a solution of the product of Example 13, Step B (0.11 g; 0.32 mmol) in anhydrous DMF (0.6 ml) 60% NaH in mineral oil (0.02 g; 0.5 mmol) was added and the mixture was stirred for 1 h at room temperature under N2. To it, a product of Step A (0.13 g; 0.383 mmol) was added and the resulting mixture was stirred for 3 days at ˜55° C. under N2, cooled to room temperature and diluted to 15 ml with Et2O, washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was purified by FCC (SiO2, CH2Cl2/EtOAc 8:2) to give the title compound (0.07 g; 37%) as a colourless solid. 1H-NMR (CDCl3) 1.23 (s, 9H); 1.46 (s, 3H); 1.53 (s, 3H); 3.71 (d, 2H, J=11.8 Hz); 3.84-3.94 (m, 15H); 4.12 (s, 1H); 4.76 (s, 2H); 6.96 (dd, 1H, J=2.2, 8.8 Hz); 7.06 (s, 2H); 7.16 (d, 1H, J=2.2 Hz); 7.44 (s, 1H); 8.24 (d, 1H, J=8.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:16][C:14]=1[NH2:15].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:12][C:13]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)=[CH:16][C:14]=2[NH2:15])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCN(c2ccc(NS(=O)(=O)c3cccc(F)c3)c(N)c2)CC1
Yield: 56.5 %

Procedure:
A mixture of 2-nitro-3-chloroaniline (4.47 g, 25.9 mmol), methylpiperazine (3.1 g, 31 mmol) and K2CO3 (5.41 g, 39 mmol) in acetonitrile was stirred at 70° C. for 48 h. The mixture was filtered and purified by column chromatography (SiO2, CH2Cl2/MeOH/Heptane/NH3 4:1:5×0.2%) to give 1.6 g of product (unreacted starting material was isolated): 1H-NMR δ 7.66-7.45 (m, 5H), 6.78 (d, 1H), 6.62 (d, 1H), 6.50 (dd, 1H), 3.39-3.35 (m, 4H), 3.02-2.99 (m, 4H); MS (posES-FIA) m/z 333.0 (M++H). The product (1.06 g, 4.49 mmol) was dissolved in EtOH:THF (4:1). Raney-Ni and hydrazine (1.12 mL, 22 mmol) were added. The reaction was stirred at room temperature for 3 h until the yellow color disappeared. Filtration through wet Celite pad, followed by removal of the solvent afforded 0.802 g of 2-amino-5-(4-methyl-1-piperazinyl)aniline which was used without further purification in the next step. 3-Fluorobenzenesulfonyl chloride (0.133 g, 0.68 mmol) was added to a solution of 2-amino-5-(4-methyl-1-piperazinyl)aniline (0.141 g, 0.68 mmol) and pyridine (514 mL, 6.39 mmol) in CH2Cl2. After 1 h the mixture was washed with aq NaHCO3 (10%), dried (MgSO4) and the solvent was removed. Purification by chromatography (SiO2, CH2Cl2/methanol/heptane, 4:1:5) gave 3-fluoro-N-[2-amino-4-(4-methyl-1-piperazinyl)-phenyl]benzenesulfonamide (0.140 g, 57%). MS (posES-FIA) m/z=found: 365.2, calcd: 364.14; Anal. (C17H22ClFN4O2S.3H2O) C, H, N, S. The reaction produced a small amount of bis-sulfonylated compound 3-fluoro-N-[2-{[(3-fluorophenyl)sulfonyl]amino}-4-(4-methyl-1-piperazinyl)-phenyl]benzenesulfonamide (0.010 g, 3%). The products were transformed into their HCl-salt before analysis; MS (posES-FIA) m/z=found. 523.5, calcd: 522.12. Anal. (C23H25ClF2N4O4S2) C, H, N, S.
Reaction SMILES: [CH2:1]=[O:2].[F:3][CH:4]([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6]>C(=O)(O)[O-].[K+]>[OH:2][CH2:1][C:4]([F:3])([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=O
Reactant: COC(=O)C(F)C(=O)OC
Agent: O=C([O-])O
Agent: [K+]
Product: COC(=O)C(F)(CO)C(=O)OC
Reaction time: 2 h
Yield: 89.8 %

Procedure:
48 g (0.48 mol) of potassium bicarbonate were dissolved in 535 g (6.59 mol) of aqueous formaldehyde solution (37% strength by weight) in a 4-liter glass flask. 841 g (5.6 mol) of dimethyl α-fluoromalonate were added dropwise to this solution., with stirring, in the course of 31/2 hours; the temperature was kept meanwhile within the range from 20° to 25° C. Stirring was continued for 2 hours at the same temperature, and during this time dimethyl α-hydroxymethyl-α-fluoromalonate was precipitated in the form of a colorless solid. 2,500 g of an aqueous, saturated solution of ammonium sulfate were then added to the reaction mixture, which was then extracted with methylene dichloride. The extraction solution was dried by means of anhydrous sodium sulfate. 906 g (90% of theory) of dimethyl a-hydroxymethyl-α-fluoromalonate were obtained after removing the methylene dichloride by distillation (bath temperature 40° C., 25 mbar).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]1[CH2:19][C:18]([N+:26]([O-:28])=[O:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:16][C:15]1=[O:29].C1C[O:33]CC1>CCCCCC>[OH:33][CH:16]1[CH2:17][C:18]([N+:26]([O-:28])=[O:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:19][N:14]([CH3:13])[C:15]1=[O:29]
Reactant: C1CCOC1
Reactant: CN1CC(c2ccccc2)([N+](=O)[O-])CCC1=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CN1CC(c2ccccc2)([N+](=O)[O-])CC(O)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a solution of 118 ul (0.833 mmol) diisopropylamine in 3 ml THF were added 520 ul (0.833 mmol) of a 1.6M n-BuLi solution in hexane at −5° C. The solution was stirred for 15 minutes at 0° C. and then cooled to −70° C. A solution of 150 mg (0.641 mmol) rac-1-methyl-5-nitro-5-phenyl-piperidin-2-one (example A.9, step 1) in 1.5 ml THF was added dropwise. The brown solution was stirred at −70° C. for 45 minutes. 517 mg (1.282 mmol) (oxodiperoxy(pyridine) (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone)molybdenum(IV)) were added portionwise at −70° C. The mixture was stirred at −70° C. for 1 hour and then allowed to warm to 0° C. After 1 hour at 0° C., the mixture was quenched with 2.5 ml of a saturated solution of sodium sulfite. Water and ethyl acetate were added. The aqueous layer was extracted once with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 82 mg (51%) of the title compound as a light brown oil. MS (m/e): 251.1 (MH+).
Reaction SMILES: [OH-:1].[Na+].[CH2:3](Cl)[C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1.Cl.[CH3:15][NH:16][O:17][CH3:18]>O.C(#N)C>[CH3:18][O:17][N:16]([CH3:15])[C:3]([C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1)=[O:1]
Reactant: CNOC
Reactant: [OH-]
Reactant: ClCc1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CON(C)C(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
Sodium hydroxide (12.0 g, 300 mmol) in water (15 mL) was added slowly to a solution of piperonyl chloride (5.55 g, 30 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.53 g, 36 mmol) in acetonitrile (200 mL). The mixture was stirred at room temperature for 0.5 h. Acetonitrile was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Column chromatography on silica gel eluting with ethyl acetate:hexanes (30:70) gave 5.5 g (88%) of the title compound as a yellow oil. MS (ES+) m/z 210.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 7.34 (m, 1H), 7.26 (d, 1H, J=1.3 Hz), 6.86 (d, 1H, J=8.1 Hz), 6.05 (s, 2H), 3.61 (s, 3H), 3.38 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[S:10]([C:13]1[CH:32]=[CH:31][C:16]2[N:17]([CH3:30])[C:18]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)=[N:19][C:15]=2[CH:14]=1)(=[O:12])=[O:11])=[O:5])[CH3:2].[ClH:39].C(=O)([O-])[O-].[NH4+:44].[NH4+]>C(O)C>[ClH:39].[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[S:10]([C:13]1[CH:32]=[CH:31][C:16]2[N:17]([CH3:30])[C:18]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:44])[NH2:29])=[CH:24][CH:23]=3)=[N:19][C:15]=2[CH:14]=1)(=[O:12])=[O:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCCN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C
Yield: 57 %

Procedure:
Prepared analogously to Example 32 from 1-methyl-2-[(4-cyanophenyl)oxymethyl]benzimidazol-5-yl-sulfonic acid-N-(3-ethoxycarbonyl-n-propyl)-N-phenylamide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 57% of theory, C28H31N5O5S (549.7); EKA mass spectrum: (M+H)+=550.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])(C)(C)C>O1CCOCC1.C(OCC)(=O)C>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH2:10][CH2:9][NH2:8]
Reactant: COc1ccccc1OCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccccc1OCCN

Procedure:
Under an atmosphere of Nitrogen, 3N HCl (3 ml) was added to a solution of [2-(2-methoxy-phenoxy)-ethyl]-carbamic acid tert-butyl ester (320 mg, 1.20 mmol) in dioxane (3 ml). The mixture was heated to reflux (2 h). Upon cooling, the reaction mixture was taken up in ethyl acetate, and extracted several times with H2O. The combined H2O extracts were then made alkaline by addition of NaOH 2N, and extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4), and the solvent was evaporated. The obtained product (180 mg, 90%) was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[C:14]([CH3:15])[N:4]2[N:3]=1.[NH2:16][CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.O>COCCO>[CH3:15][C:14]1[N:4]2[N:3]=[C:2]([NH:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]2=[N:12][N:13]=1
Reactant: Cc1nnc2c3c(c(Cl)nn12)CCCC3
Reactant: NCCN1CCCC1
Solvent: COCCO
Solvent: O
Product: Cc1nnc2c3c(c(NCCN4CCCC4)nn12)CCCC3

Procedure:
A solution of 10.0 g of 6-chloro-3-methyl-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine and 12.8 g of 1-(2-aminoethyl)pyrrolidine in 50 ml of 2-methoxyethanol was heated at reflux for 15 hours. The reaction mixture was poured into 150 ml of cold water and the white precipitate which formed was separated by filtration and air dried to give 3-methyl-6-[2-(1-pyrrolidinyl)ethylamino]-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine melting at about 184°-186° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12].Cl.[NH2:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>C(Cl)Cl>[CH2:14]([O:13][C:11]([NH:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:12])[CH:15]=[CH2:16]
Reactant: C=CCOC(=O)Cl
Reactant: CCOC(=O)CC(N)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)NC(CC(=O)OCC)c1cccc([N+](=O)[O-])c1

Procedure:
Diisopropylethylamine (66 ml) and allyl chloroformate (22 ml) in 150 ml of methylene chloride were added at 0° C. to a solution of ethyl 3-amino-3-(3-nitrophenyl)-propionate hydrochloride from II.1b (47 g) in 350 ml of methylene chloride. After a reaction time of 30 min, HCl (1N, 100 ml) was added. The organic phase was separated off, washed with water, dried over MgSO4 and concentrated. A white solid was obtained (yield: 56.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([Cl:31])=[O:30])=[CH:27][CH:26]=1>>[ClH:31].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([F:24])=[CH:26][CH:27]=3)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(N3CCN(CCCCN)CC3)c2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: COc1ccc2cccc(N3CCN(CCCCNC(=O)c4ccc(F)cc4)CC3)c2c1
Product: Cl
Yield: 60 %

Procedure:
The expected compound was prepared from 1-(7-methoxy-1-naphthyl)-4-(4-amino-1-butyl)piperazine and 4-fluorobenzoyl chloride.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][OH:29])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[N:23]=[CH:24][N:25]=[C:26]([CH2:28][O:29][S:33]([CH3:32])(=[O:35])=[O:34])[CH:27]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N1CCc2cc(Oc3cc(CO)ncn3)ccc21
Solvent: C1CCOC1
Product: CS(=O)(=O)OCc1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1
Reaction time: 0.25 h

Procedure:
5-(6-Hydroxymethyl-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (0.1001, 0.232 mmol) is dissolved in THF (6 mL) and TEA (0.18 mL, 1.29 mmol) is added followed by methanesulphonyl chloride (0.028 mL, 0.361 mmol). The solution is stirred for 15 min before being partitioned between ethyl acetate and saturated aqueous sodium chloride. The layers are separated and the organic layer is washed further with water. The organic layer is then removed, dried, and concentrated to obtain the title compound. MS (ESI) m/z 510.0 (m+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11](COCC[Si](C)(C)C)C=1.Br[C:36]1[CH:37]=[C:38]([S:42]([N:45]([CH3:47])[CH3:46])(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1.C([O-])(O)=O.[Na+].C(#[N:55])C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:36]3[CH:37]=[C:38]([S:42]([N:45]([CH3:47])[CH3:46])(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=3)[CH:16]=2)[NH:11][N:55]=1
Reactant: CN(C)S(=O)(=O)c1cccc(Br)c1
Reactant: CC#N
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(S(=O)(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 5 mL Personal Chemistry microwave reaction vial were added 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (0.0496 g, 0.103 mmol), 3-Bromo-N,N-dimethyl-benzenesulfonamide (0.0417 g, 0.143 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (13.9 mg, 0.017 mmol), acetonitrile (1 mL) and saturated aqueous NaHCO3 (1 mL). The vial was sealed, purged with N2, and irradiated in a Personal Chemistry Optimizer at 90° C. for 15 min. The layers were separated, and the aqueous phase was extracted 3× with EtOAc. The combined organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in 5 mL of a solution consisting of 1 part HClO4 (70%, ACS) and 20 parts glacial acetic acid, and the solution was stirred at rt for 1 h. The reaction mixture was concentrated under vacuum, and neutralized to pH 7 with saturated NaHCO3 followed by solid NaHCO3. The quenched reaction mixture was partitioned between EtOAc and water, the layers were separated, and the aqueous phase was extracted 2× with EtOAc. The combined organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. Purification by mass-triggered LC (positive mode, ESI) through a C-18 reverse-phase column (Thomson Instrument Co. ODS-A 100 A, 5μ, 50×21.3 mm, eluting at 20 mL/min with acetonitrile (containing 0.1% formic acid) and water (containing 0.1% formic acid) in a 5-95% gradient afforded the title compound, which upon lysophilization appeared as a light yellow powder (10.4 mg, 25%). 1H-NMR (500 MHz, d6-DMSO) δ=13.91 (br. s, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.12 (m, 1H), 8.01 (br.s, 1H), 7.76 (m, 2H), 7.67 (dd, J=2.0, 7.5 Hz, 1H), 7.45 (m, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.09 (t, J=8.0 Hz, 1H), 3.85 (s, 3H), 2.66 (s, 6H); MS: m/z 409.1 [MH+].
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9].I[CH3:19].O>C1COCC1>[CH3:3][O:4][CH2:5][CH2:6][N:7]([CH3:19])[S:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: CI
Reactant: COCCNS(=O)(=O)c1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCN(C)S(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.5 %

Procedure:
Sodium hydride (144 mg, 3.6 mmol) was added in portions to a solution of N-(2-methoxyethyl)-4-iodobenzenesulphonamide (Method 40, 1 g, 3 mmol) in THF (10 ml) and the mixture stirred at ambient temperature for 15 minutes. Iodomethane (230 μl, 3.6 mmol) was added and the reaction stirred for 18 hours. Water (30 ml) was added cautiously and the mixture extracted with ether (40 ml). The combined organics were washed with brine (50 ml), dried and the volatiles evaporated. The residue was purified by flash chromatography on silica gel eluting with iso-hexane/EtOAc (100:0 increasing in polarity to 10:1) to give the title compound (730 mg, 69%) as a clear oil. NMR 2.78 (s, 3H), 3.16 (t, 2H), 3.22 (s, 3H), 3.45 (t, 3H), 7.42 (d, 2H), 7.80 (d, 2H); m/z 356.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)[Cl:17].S(Cl)(Cl)=O>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([Cl:17])=[O:15])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C

Procedure:
To an oven-dried round bottom flask containing 1-(benzo[d][1,3]dioxol-5-yl)-cyclopropanecarboxylic acid (A-8) (618 mg, 3.0 mmol) and CH2Cl2 (3 mL) was added thionyl chloride (1.07 g, 9.0 mmol) and N,N-dimethylformamide (0.1 mL). The reaction mixture was stirred at ambient temperature under an Ar atmosphere until the gas evolution ceased (2-3 h). The excess thionyl chloride was removed under vacuum and the resulting residue dissolved in CH2Cl2 (3 mL). The mixture was used without further manipulation.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[NH:27][CH:26]=[C:25]([C:28](O)=[O:29])[CH:24]=4)[CH:18]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:66][CH2:67][CH2:68][CH2:69][N:70]1[CH2:75][CH2:74][O:73][CH2:72][CH2:71]1>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[NH:27][CH:26]=[C:25]([C:28]([NH:66][CH2:67][CH2:68][CH2:69][N:70]5[CH2:75][CH2:74][O:73][CH2:72][CH2:71]5)=[O:29])[CH:24]=4)[CH:18]=3)=[CH:31][CH:32]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: NCCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN5CCOCC5)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (100 mg, 0.23 mmol) in 10 ml of anhydrous DMF were added HATU (106 mg, 0.28 mmol) and N,N-diisopropylethylamine (90 mg, 0.70 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of N-(3-aminopropyl)morpholine (68 mg, 0.47 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-morpholin-4-ylpropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 110 mg, 85%.