Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=O)=[N:9][N:10]=2)[CH:7]=1.Cl.Cl.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:20]=1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:32]3[CH2:33][CH2:34][CH:29]([C:20]4[C:21]([C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=[CH:24][C:19]=4[F:18])[CH2:30][CH2:31]3)=[O:13])=[N:9][N:10]=2)[CH:7]=1
Reactant: Fc1cccc(C(F)(F)F)c1C1CCNCC1
Reactant: CCOC(=O)c1nnc2ccc(Br)cn12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2c(F)cccc2C(F)(F)F)CC1
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (72 mg, 0.27 mmol) in THF (2.2 mL) was added a solution of LiOH monohydrate (12 mg, 0.29 mmol) in H2O (1.5 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The mixture was concentrated under reduced pressure. The obtained residue was diluted in DMF (2.8 mL) under an atmosphere of N2. To this mixture was added 4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine hydrochloride (23, 75 mg, 0.27 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (236 mg, 0.53 mmol), and diisopropylethylamine (0.14 mL, 0.80 mmol). The mixture was stirred at ambient temperature for 18 h. The resulting mixture was diluted with H2O (20 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were washed with a saturated brine solution (30 mL) and concentrated under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0 to 50% EtOAc in hexanes) to provide (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a light orange film (80 mg, 64%): 1H NMR (300 MHz, DMSO-d6) δ 9.12-9.10 (m, 1H), 8.00-7.95 (m, 1H), 7.74-7.68 (m, 1H), 7.65-7.50 (m, 3H), 5.29-5.15 (m, 1H), 4.82-4.68 (m, 1H), 3.41-3.19 (m, 2H, overlaps with H2O), 3.07-2.97 (m, 1H), 2.34-2.19 (m, 1H), 2.15-2.02 (m, 1H), 1.93-1.75 (m, 2H); ESI MS m/z 472 [M+H]+.]
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:14]1[C:15]([CH3:23])=[CH:16][C:17]2[N:18]([CH:20]=[CH:21][N:22]=2)[N:19]=1>CN(C)C=O>[CH3:11][C:5]([CH3:12])([CH2:6][S:7](=[O:9])(=[O:8])[NH2:10])[CH2:4][O:3][C:14]1[C:15]([CH3:23])=[CH:16][C:17]2[N:18]([CH:20]=[CH:21][N:22]=2)[N:19]=1
Reactant: Cc1cc2nccn2nc1Cl
Reactant: CC(C)(CO)CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2nccn2nc1OCC(C)(C)CS(N)(=O)=O
Temperature: 25 °C

Procedure:
1.12 g of 60% oily sodium hydride was suspended in 25 ml of dimethylformamide. To this suspension, 1.51 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide was added, followed by stirring at room temperature (15° to 20° C.) under reduced pressure for i hour. To this mixture was added 1.51 g of 6-chloro-7-methylimidazo[1,2-b]pyridazine, followed by stirring at 60° C. for 2 hours. After dimethylformamide was distilled off underreduced pressure, ice water was added to the residue, which was subsequently adjusted to pH 6 by the addition of 5 N hydrochloric acid andthen extracted with tetrahydrofuran. The extract was washed with 20 ml of saturated saline and then dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate-methanol (5:5:1). The fraction containing the desired product was concentrated and recrystallized by the addition of ethyl ether-ethyl acetate (5:1). The resulting crystal was collected by filtration, to yield0.522 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][OH:21])[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][O:21][S:23]([CH3:22])(=[O:25])=[O:24])[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1Cc2ccc(CO)cc2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (5° C.) of 5-hydroxymethyl-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester (11 Kg, 38.8 mol, step 7) and Et-3N (7.04 L, 50.6 mol) in DCM (55 L) was added methanesulphonyl chloride (2.97 L, 38.4 mol) so that the internal temp <10° C. After stirring for 0.5 h at 5° C. the solution was used below in step 9.
Reaction SMILES: [OH:1][C@@:2]1(/[CH:12]=[CH:13]/[C:14](/[CH3:20])=[CH:15]\[C:16]([O:18][CH3:19])=[O:17])[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH:4]=[C:3]1[CH3:11].[CH3:21][Si](C)(C)N[Si](C)(C)C.[Li].CI>O1CCCC1>[OH:1][C@@:2]1(/[CH:12]=[CH:13]/[C:14](/[CH3:20])=[CH:15]\[C:16]([O:18][CH3:19])=[O:17])[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[C:4]([CH3:21])=[C:3]1[CH3:11]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: COC(=O)/C=C(C)\C=C\[C@@]1(O)C(C)=CC(=O)CC1(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)/C=C(C)\C=C\[C@@]1(O)C(C)=C(C)C(=O)CC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 1a (27.8 g, 0.1 mole) in anhydrous tetrahydrofuran (THF, 600 ml) was cooled to 0° C. with an ice bath under an atmosphere of nitrogen. Lithium hexamethyl disilazane (1.0 M solution in THF, 150 ml) was added dropwise via a syringe over about 30 minutes. The resulting solution was stirred at 0° C. for 30 minutes and the ice bath was removed. A solution of methyl iodide (8.09 ml, 18.4 g, 0.13 mole) in anhydrous THF (20 ml) was added via a syringe over 20 minutes. The resulting solution was stirred at ambient temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution (200 ml) and water (200 ml) and extracted with ethyl acetate (3×150 ml). The combined organic solution was dried (MgSO4), filtered and concentrated. The residue was purified on a silica gel column eluted with ethyl acetate and hexane. The title compound was obtained as a white solid (17.1 g). 1HNMR (CDCl3): δ7.84 (d, 1H), 6.16 (d, 1H), 5.75 (s, 1H), 3.70 (s, 3H), 2.44 (d, 1H), 2.34 (d, 1H), 2.00 (s, 3H), 1.88 (s, 3H), 1.83 (s, 3H), 1.07 (s, 3H), 1.00 (s, 3H). MS (ESI—): m/e=291.
Reaction SMILES: [CH3:1][C:2]1([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O-:10])=O.F[P-](F)(F)(F)(F)F.[N:41]1([O:50][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.NO>CN(C=O)C>[OH:50][NH:41][C:8]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1([CH3:1])[NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[C:25]([CH3:33])[CH:24]=2)=[CH:19][CH:20]=1)(=[O:13])=[O:14])=[O:10]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3(C)CCCCC3C(=O)[O-])cc2)c2ccccc2n1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3(C)CCCCC3C(=O)NO)cc2)c2ccccc2n1
Reaction time: 8 h
Yield: 38.7 %

Procedure:
To a solution of racemic (1S,2R)-2-methyl-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxylate (0.075 g) in DMF (0.8 mL) was added BOP (0.1 g, 1.3 eq), diisopropylethylamine (0.122 mL, 4 eq) and hydroxylamine hydrochloride (0.024 g, 2 eq). The reaction was stirred for 8 h and purified by direct injection onto an HPLC to afford racemic (1S,2R)-N-hydroxy-2-methyl -2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxamide (0.03 g, 40%) as a white powder. MS: 484.1 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[I:13]I.S(=O)(=O)(O)O>CC(O)=O>[Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([I:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C)cc1Br
Reactant: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1cc(I)c(C)cc1Br
Temperature: 100 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a round-bottom flask was added a mixture of methyl 2-bromo-4-methylbenzoate (2.00 g, 7.86 mmol, 1.00 equiv) in AcOH (20 mL). I2 (2.45 g, 9.65 mmol, 1.10 equiv), NaIO4 (950 mg, 4.42 mmol, 0.50 equiv), and sulfuric acid (0.1 mL, 0.15 equiv) were added and the resulting mixture was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction was carefully quenched with Na2S2O3 (aq., sat.). The resulting mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to yield 2.50 g (81%) of the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([CH:15]([C:21](O)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[K+]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH:13]([C:15](=[CH2:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)O)C1CN(C(=O)OCc2ccccc2)C1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C(=O)OCC)C1CN(C(=O)OCc2ccccc2)C1
Yield: 86.3 %

Procedure:
To 732 mg (2.28 mmol) of ethyl hydrogen (1-benzyloxycarbonyl-3-azetidinyl)malonate dissolved in 70 ml of acetonitrile were added 1.05 g (5.67 mmol) of Eshenmoser's salt and a catalytically effective amount of potassium acetate, followed by 4.5 hours of heating under reflux. After evaporation of the solvent, the resulting residue was mixed with 100 ml of ethyl acetate, washed with 10% citric acid aqueous solution, 10% sodium sulfite aqueous solution and saturated brine in that order, and then dried over anhydrous sodium sulfate. By evaporating the solvent, 569 mg (86%) of the title compound was obtained.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]>>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:14]([C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([F:10])[CH:12]=2)[OH:15])=[CH:7][N:6]=1
Reactant: O=Cc1cccc(F)c1
Reactant: Clc1ncc(Br)c(Cl)n1
Product: OC(c1cccc(F)c1)c1cnc(Cl)nc1Cl
Yield: 79 %

Procedure:
The compound was prepared from 5-bromo-2,4-dichloropyrimidine (Aldrich) and 3-fluorobenzaldehyde (Aldrich) in 79% yield in an analogous manner as described in Example 1. 1H NMR (300 MHz, CDCl3) δ 8.85 (s, 1H), 7.35 (m, 1H), 7.14 (m, 3H), 7.14 (m, 3H), 6.077 (s, 1H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[CH:8]([NH2:10])[CH3:9].C(N(CC)CC)C.[CH:18]1([CH2:21]Br)[CH2:20][CH2:19]1>C(#N)C>[CH:18]1([CH2:21][NH:10][CH:8]([C:3]2[N:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH3:9])[CH2:20][CH2:19]1
Reactant: CC(N)c1ncccn1
Reactant: BrCC1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(NCC1CC1)c1ncccn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1-pyrimidin-2-yl-ethylamine hydrochloride (50 mg, 0.313 mmol), triethylamine (95 mg, 1 mmol) and cyclopropylmethyl bromide (0.034 ml, 0.344 mmol) in acetonitrile was stirred at 80° C. overnight. After evaporation of the solvents, addition of aqueous sodium hydrogencarbonate, extraction (3 times with dichloromethane), drying of the combined organic layers over sodium sulfate and evaporation of the solvents, crude cyclopropylmethyl-(1-pyrimidin-2-yl-ethyl)-amine was obtained which was used immediately in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:32]=[CH:31][CH:30]=[CH:29][C:7]=2[O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[CH:19]([NH2:26])[CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:13][C:12]=2[Cl:28])[N:3]=[CH:2]1.N1C=CC=CC=1.[C:39](Cl)(=[O:41])[CH3:40]>ClCCl>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:32]=[CH:31][CH:30]=[CH:29][C:7]=2[O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[CH:19]([NH:26][C:39](=[O:41])[CH3:40])[CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:13][C:12]=2[Cl:28])[N:3]=[CH:2]1
Reactant: NC(C(=O)Nc1ccc(CCOc2ccccc2-c2c[nH]cn2)c(Cl)c1)C1CCOCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC(C(=O)Nc1ccc(CCOc2ccccc2-c2c[nH]cn2)c(Cl)c1)C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
To a solution of N-(4-(2-(2-(1H-imidazol-4-yl)phenoxy)ethyl)-3-chlorophenyl)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetamide (40 mg, 0.088 mmol) in dichloromethane (3 mL) was added pyridine (29 μL, 0.352 mmol) and acetyl chloride (29 μL, 0.264 mmol). The reaction was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The crude product was dissolved in methanol (4 mL) and refluxed for 2 h. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 5%-10% MeOH/DCM as eluent) to afford the desired product as a white solid (27 mg, 0.054 mmol, 61%). 1H NMR: 1.42-1.58 (m, 3H), 1.68 (d, 1H, J=12.8 Hz), 2.03-2.07 (m, 1H), 2.08 (s, 3H), 3.24-3.31 (m, 4H), 3.94 (t, 2H, J=11.2 Hz), 4.39 (t, 2H, J=6 Hz), 4.61 (t, 1H, J=8.4 Hz), 6.81 (d, 1H, J=8.4 Hz), 6.99 (d, 2H, J=8 Hz), 7.18-7.24 (m, 3H), 7.37 (dd, 1H, J=8 Hz, 1.6 Hz), 7.60 (s, 1H), 7.77 (s, 1H),
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([C:23]#[C:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CN(C=O)C.CCN(CC)CC.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[N:22]=[C:21]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:20]([C:36]([F:38])([F:39])[F:37])=[CH:19][N:18]=2)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(CNC(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CNC(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 10% Pd/C (200 mg) and methyl 2-(2-((2-((4-(((tert-butoxycarbonyl)amino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethynyl)phenyl)acetate (A13) (412 mg, 0.762 mmol) in DMF (5 mL) and Et3N (1 mL) was stirred under a hydrogen atmosphere at room temperature for 16 h. The resulting mixture was filtered through Celite, washing with EtOAc (200 mL) then the combined filtrates were evaporated in vacuo to give the title compound A14 as a white solid (306 mg, 74%); 1H NMR (400 MHz, d6-DMSO) δ 10.19 (s, 1H), 8.68 (s, 1H), 7.68 (d, J=8.5 Hz, 2H), 7.34 (t, J=6.0 Hz, 1H), 7.27-7.16 (m, 6H), 4.09 (d, J=6.0 Hz, 2H), 3.76 (s, 2H), 3.59 (s, 3H), 3.11-2.95 (m, 4H), 1.40 (s, 9H). LCMS-A: rt 6.637 min; m/z 545 [M+H]+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[O:12][CH3:13].[CH2:15]([N:17]([CH2:28][CH3:29])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[N:26]=1)[C:21](O)=O)[CH3:16]>>[CH3:13][O:12][C:5]1[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]1[N:14]=[C:21]([C:20]2[CH:24]=[C:25]([CH3:27])[N:26]=[C:18]([N:17]([CH2:28][CH3:29])[CH2:15][CH3:16])[CH:19]=2)[O:1][N:2]=1
Reactant: COc1cccc(C(=N)NO)c1OC
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Product: CCN(CC)c1cc(-c2nc(-c3cccc(OC)c3OC)no2)cc(C)n1

Procedure:
The title compound is prepared in analogy to Example 5 starting from N-hydroxy-2,3-dimethoxy-benzamidine and 2-diethylamino-6-methyl-isonicotinic acid; LC-MS: tR=1.16*min; [M+1]+=369.03.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)=O)(C)(C)C.C(=O)([O-])O.[Na+].I[C:26]1(C(OC(C)(C)C)=O)[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([N:35]([S:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[O:52][C:53]([F:56])([F:55])[F:54])(=[O:45])=[O:44])C(OC(C)(C)C)=O)[CH:33]=2)[N:28]=[N:27]1>CN(C)C=O>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH:35][S:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[O:52][C:53]([F:54])([F:55])[F:56])(=[O:45])=[O:44])[CH:33]=2)[NH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)C(I)(C(=O)OC(C)(C)C)N=N2)S(=O)(=O)c1ccccc1OC(F)(F)F
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1ccccc1OC(F)(F)F
Temperature: 120 °C
Yield: 58.3 %

Procedure:
N-[3-(1H-Indol-2-yl)-1H-indazol-5-yl]-2-trifluoromethoxybenzenesulfonamide can be obtained in the following way: 213.3 mg N-tert-butoxycarbonylindole-2-boronic acid in dimer form and 243 μl of a saturated sodium hydrogencarbonate solution and then 63.4 mg of tetrakis(triphenylphosphine)palladium[0] are added to a solution of 150 mg of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-trifluoromethoxybenzenesulfonylamino)indazolecarboxylate in 4.5 ml of dimethylformamide. The suspension is heated in the region of 120° C. for 18 hours. After cooling to a temperature in the region of 20° C., the catalyst is filtered through sintered glass with Celite® 535, and the filtrate is concentrated to dryness under reduced pressure in a rotary evaporator. The reaction crude is purified by preparative HPLC chromatography coupled to a mass detector (LC/MS, conditions A). The fractions containing the expected product are pooled and concentrated, and then the base is released from the trifluoroacetate salt by being taken up in 10 ml of dichloromethane and washed with 10 ml of a saturated sodium hydrogencarbonate solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 60.5 mg of N-[3-(1H-indol-2-yl)-1H-indazol-5-yl]-2-trifluoromethoxy-benzenesulfonamide are thus obtained in the form of a white solid melting at 172-174° C. (analytical LC/MS analysis: Tr=3.73 minutes; [M+H]+=473.07).
Reaction SMILES: [CH:1]([N:4]([C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[C:21]([O:23]CC)=[O:22])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].[OH-].[K+].Cl>C(O)C>[CH:1]([N:4]([C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[C:21]([OH:23])=[O:22])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(N(C(C)C)S(=O)(=O)c2cccc(C(F)(F)F)c2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N(c1cccc(C(=O)O)c1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To ethyl 3-(N-isopropyl-3-(tri fluoromethyl)phenylsulfonamido)benzoate (330 mg, 0.794 mmol) in ethanol (5 mL) was added 2 N KOH solution (2.4 mL). The mixture was stirred at room temperature for 3 days, and then 4 N HCl solution (1.3 mL) was added. The mixture was concentrated until the water was gone. Then dichloromethane/methanol (50:1, 50 mL) was added, the solution was filtered, and the filtrate was concentrated to give 3-(N-isopropyl-3-(trifluoromethyl)phenylsulfonamido)benzoic acid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 (d, 6H, J=8 Hz), 4.62 (m, 1H), 7.30 (m, 1H), 7.45 (s, 1H), 7.60 (m, 1H), 7.80-8.10 (m, 5H), 13.18 (br s, 1H); MS (ESI) m/z 416 (M−H)−.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][C:16]([C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22](S(C)=O)[N:21]=3)=[C:17]([CH3:19])[N:18]=2)=[O:12])=[N:5][CH:4]=1)[CH3:2].[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[CH2:42][NH2:43])=[O:36])([CH3:33])([CH3:32])[CH3:31]>O1CCOCC1>[C:30]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[CH2:42][NH:43][C:22]1[N:21]=[C:20]([C:16]2[S:15][C:14]([NH:13][C:11]([NH:10][CH2:9][CH2:8][C:6]3[O:7][C:3]([CH2:1][CH3:2])=[CH:4][N:5]=3)=[O:12])=[N:18][C:17]=2[CH3:19])[CH:25]=[C:24]([CH3:26])[N:23]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCCC1CN
Reactant: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)=O)n3)s2)o1
Solvent: C1COCCO1
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(NCC4CCCN4C(=O)OC(C)(C)C)n3)s2)o1

Procedure:
This material is prepared from 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(2-methanesulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea (Example 40) and 2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester by an analogous procedure to Example 42 but replacing DMF by dioxane.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[C:17]([C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[CH:23][CH:24]=1)#[CH:18].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:11]1([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[C:18]#[C:17][C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:22]=[CH:23][CH:24]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(Br)c1
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cc([N+](=O)[O-])ccc2N2CCOCC2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A solution of 4-(2-bromo-4-nitrophenyl)morpholine (0.27 g, 0.95 mmol), tert-butyl (3-ethynylphenyl)carbamate, and bis(triphenylphosphine)palladium(II) chloride (67 mg, 95 μmol) in N,N-dimethylformamide (4.4 mL) was treated with N,N-diisopropylethylamine (0.21 mL, 1.2 mmol) and stirred at 80° C. for 16 h. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude residue. This material was purified by flash column chromatography to give the desired product (0.28 g, 70%) as a solid. LCMS for C23H26N3O5 (M+H)+: m/z=424.0.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:13]=[C:14]([CH:22]([OH:25])[CH2:23][OH:24])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34].O>ClCCl>[F:10][C:11]([F:26])([F:27])[C:12]1[CH:13]=[C:14]([CH:22]([CH2:23][O:24][CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[OH:25])[CH:15]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:17]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: OCC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CCOCOCC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.9 %

Procedure:
N-Ethyl-N,N-diisopropylamine (465 μl, 2.67 mmol) was added over 2 minutes, to a solution of (RS)-1-[3,5-bis(trifluoromethyl)phenyl]-1,2-ethanediol (Description 3, 488 mg, 1.78 mmol) and [2-(chloromethoxy)ethyl]trimethylsilane (315 μl, 1.78 mmol) in dichloromethane (3 mL) and the mixture was stirred at room temperature for 4 hours, then at 50° C. for 1 hour. The mixture was cooled and dichloromethane (20 mL) and water (20 mL) were added. The layers were separated and the aqueous layer was extracted with dichloromethane (10 mL). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (90:10) to give the title compound (352 mg, 49%). 1H NMR (400 MHz, CDCl3) δ 7.86 (2H, s), 7.79 (1H, s), 4.96 (1H, m), 4.73 (2H, s), 3.87 (1H, dd, J 11.1, 3.0 Hz), 3.73 (1H, br s), 3.61 (3H, m), 0.93 (2H, t, J 8.5 Hz), and 0.02 (9H, s).