Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=[O:5].[NH2:17][C:18]1[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=1.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:17][C:18]1[C:19]([NH:1][C:2]2[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=2)=[O:5])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Nc1cccnc1Nc1ccccc1C(=O)c1cccc(Cl)c1
Temperature: 180 °C

Procedure:
A stirred mixture of 35 g (0.152 mole) of 2-amino-3'-chlorobenzophenone and 23.4 g (0.182 mole) of 3-amino-2-chloropyridine was heated at 180° C. for 2 hr. The hot melt was allowed to cool to 110° C., after which 100 ml of hot toluene was added dropwise with vigorous stirring. The mixture was allowed to cool while stirring to 30° C. and 50 ml of methylene chloride was added. After stirring for an additional 1/2 hour, the mixture was filtered and the filter cake suspended in methylene chloride with stirring for 1/2 hr and methylene chloride was separated by filtration. The filter cake containing the product (25.4 g) was partially dissolved in hot methanol (total volume 150 ml) and 50% aqueous sodium hydroxide was added until the mixture was basic. Ice water was added and the solution was extracted with methylene chloride. This methylene chloride extract was washed with water and dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in isopropyl alcohol and boiled with charcoal. The mixture was filtered, reduced in volume to give a first crop of crystals weighing 16 g (33%). A portion of the crystals was recrystallized from isopropyl alcohol to give a brick red solid melting 119°-120° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH3:15])[CH2:4][S:5][C:6]1[O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.C([O:19][C@@H:20]1[C@H:24]([O:25]C(=O)C)[C@@H:23]([CH2:29][O:30]C(=O)C)[O:22][C@H:21]1[N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][C:37]([Cl:44])=[N:38][C:39]=2Cl)(=O)C.C[O-].[Na+]>CO>[O:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=[C:6]1[S:5][CH2:4][C@H:3]([NH:2][C:39]1[C:40]2[N:41]=[CH:42][N:34]([C:35]=2[N:36]=[C:37]([Cl:44])[N:38]=1)[C@@H:21]1[O:22][C@H:23]([CH2:29][OH:30])[C@@H:24]([OH:25])[C@H:20]1[OH:19])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[C@@H](N)CSc1nc2ccccc2o1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@H](CSc1nc2ccccc2o1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 12.5 %

Procedure:
The title compound was prepared essentially according to method A as described above in Example 1 by reacting 2-[(R)-2-amino-1-propylthio]benzoxazole hydrochloride [prepared by alkylation of 2-mercaptobenzoxazole (3.5 g, 23 mmol) using methanesulphonic acid, 2-[(R)-N-tert-butyloxycarbonylamino]-1-propyl ester (7.2 g, 30 mmol) followed by acidic hydrolysis] (1.7 g, 6 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.7 g, 6.0 mmol), followed by deacylation of the purified product using sodium methoxide in methanol. This provided the title N-[(R)-1-(2-benzoxazolyl)thio2-propyl]-2-chloroadenosine (0.37 g, 28%) as a foam after column chromatography. 1H NMR (DMSO-d6) δ1.38 (3H, d, --CHCH3), 3.40-3.75 (4H, m, H-5'a and H-5'b and --CH2 --), 3.94 (1H, q, H-4), 4.12 (1H, q, H-3'), 4.52 (1H, m, H-2'), 5.06 (1H, t, 5'-OH), 5.22, 5.49 (2H, 2d, 2'- and 3'-OH), 5.82 (1H, d, H-1'), 7.26-7.35 (2H, m, Ar--H), 7.53-7.64 (2H, m, Ar--H), 8.39 (1H, s, H-8), 8.48 (1H, d, --NH).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([Cl:20])[CH:3]=1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>>[Cl:20][C:4]1[CH:3]=[C:2]([NH:24][CH:21]2[CH2:23][CH2:22]2)[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=1
Reactant: O=C(Nc1nc2cc(Cl)cc(Cl)n2n1)c1cccnc1
Reactant: NC1CC1
Product: O=C(Nc1nc2cc(Cl)cc(NC3CC3)n2n1)c1cccnc1
Yield: 47.5 %

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B10), 100 mg; 0.32 mmol; 1.0 eq) and cyclopropylamine (113 μL; 1.62 mmol; 5.00 eq) to give the title compound as a white solid (50 mg, 43%). HPLC, Rt: 2.59 min. (purity 92.6%). LC/MS, M+(ESI): 328.8, M−(ESI): 326.9.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[C:4](Cl)[CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[OH-].[K+]>CS(C)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[C:4]([N:20]2[CH:21]=[CH:22][C:17](=[O:16])[CH:18]=[CH:19]2)[CH:3]=1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: Oc1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(-n2ccc(=O)cc2)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 90.1 %

Procedure:
First, a mixture containing 2.40 g of 4-amino-2-chloro-5-nitrobenzotrifluoride, 2.0 g of 4-hydroxypyridine, 684 mg of 86% potassium hydroxide, 15 ml of dimethylsulfoxide was heated in an oil bath at 70° C. for 2 hours. The mixture was cooled and ice water was added to the mixture. Precipitated crude crystals were filtered and recrystallized with methanol/ethyl acetate to give 2.69 g of crystals of 4-amino-5-nitro-2-(4-oxo-4H-pyridin-1-yl)-benzotrifluoride.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)([OH:4])=[O:3].[CH3:13]O>>[CH3:13][O:3][C:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
Methanol (50 ml) was cooled (0°) and saturated with hydrogen chloride gas. p-Carboxybenzaldehyde (5.0 g) was added and the resulting solution stirred at room temperature for 3 days. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 5M hydrochloric acid. The organic layer was washed twice with water and dried. The solvent was removed to afford the product as a white solid (5.40 g, 100%). δH (CDCl3) 3.96 (3H, s), 7.96 (2H, dd, J 6.8 and 1.7 Hz), 8.20 (2H, dd, J 6.8 and 1.7 Hz), 10.11 (1H, s) ppm.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH2:14][CH2:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC[C@H]1CC[C@H](CCC=Cc2ccc(OCCCC)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCC[C@H]1CC[C@H](CCCCc2ccc(OCCCC)cc2)CC1
Yield: 83.7 %

Procedure:
A mixture of 19 g of 1-butyloxy-4-[4-(trans-4-pentyl-cyclohexyl)-1-butenyl]benzene (cis/trans mixture), 200 ml of absolute toluene and 100 ml of absolute ethyl acetate: was treated with 2 g of palladium/carbon (10%) and hydrogenated at normal pressure and room temperature until the hydrogen uptake came to a standstill. The inorganic material was removed by filtration and the filtrate was concentrated. The residue was purified by chromatography on silica gel with toluene/ethyl acetate. Recrystallization from ethanol gave 16 g of pure 1-butyloxy-4-[4-(trans-4-pentylcyclohexyl)-l-butyl]benzene with m.p. (C-SB) 29° C. and cl.p. (SB --I) 43° C.
Reaction SMILES: CN(C)C=O.[C:6](Cl)(=O)[C:7]([Cl:9])=[O:8].[Cl:12][C:13]1[C:18]([Cl:19])=[C:17]([O:20][CH3:21])[CH:16]=[CH:15][C:14]=1CC(O)=O>ClCCl>[Cl:12][C:13]1[C:18]([Cl:19])=[C:17]([O:20][CH3:21])[CH:16]=[CH:15][C:14]=1[CH2:6][C:7]([Cl:9])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(CC(=O)O)c(Cl)c1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)Cl)c(Cl)c1Cl

Procedure:
0.5 ml of dimethylformamide and 60.9 g (0.48 mol) of oxalyl chloride were added to a solution of 37.3 g (0.16 mol) of 2,3-dichloro-4-methoxyphenylacetic acid in 0.5 l of dichloromethane. After evolution of gas had ceased (about 2 hours), the mixture was concentrated. The crude product was reacted further in the next step without any purification. Yield: quantitative.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:29]1[C:37]2[C:32](=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1>>[NH:29]1[C:37]2[C:32](=[C:33]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[N:11]=[C:10]([CH2:12][N:13]5[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]5)[CH:9]=[CH:8][C:6]=4[N:7]=3)[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4cccc5[nH]ccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (88 mg) was reacted with 1H-indol-4-ylboronic acid via General Procedure A to produce 22.8 mg of 109 following reverse phase HPLC purification. MS (Q1) 487.3 (M)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]3C(OC(C)(C)C)=O)=[O:15])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CCCCCC>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([CH:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17]3)=[O:15])=[CH:11][CH:12]=2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1C(=O)Nc1ccc(-c2ccncc2)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(-c2ccncc2)cc1)C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 105.4 %

Procedure:
To a suspension of N-[4-(4-pyridinyl)phenyl]-1-tert-butoxycarbonylindoline-2-carboxamide (100 mg) in ethyl acetate (0.60 mL) was added 4N hydrogen chloride-ethyl acetate (2.41 mL) and the mixture was stirred at ambient temperature for 1.5 hours. The resulting mixture was diluted with n-hexane (6.0 mL) and the solid was collected by filtration, and then washed with ethyl acetate/n-hexane (1:2, 1.0 mL) to give N-[4-(4-pyridinyl)phenyl]indoline-2-carboxamide (80 mg) as off-white crystals.
Reaction SMILES: CO.[H-].[Na+].[C:5]([N:9]=[N:10][C:11]1([N:17]=[C:18]=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:7])[CH3:6].[N-]=[C:21]=[O:22]>O>[C:5]([N:9]=[N:10][C:11]1([NH:17][C:18]([O:22][CH3:21])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Reactant: [N-]=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 30 ml of methanol in a 100 ml 3 neck round bottom flask equipped with a thermometer and magnetic stirrer was slowly added 2.1 grams (0.05 moles) of 57% sodium hydride. After the temperature came back to 25° C., 10.5 grams (0.05 moles) of 1-t-butylazo-1-isocyanatocyclohexane was added dropwise over 5 minutes. There was a 2° C. rise in temperature during the addition. After the addition was complete, the reaction was stirred an additional 30 minutes at room temperature. Gas chromatography indicated that the 1-t-butylazo-1-isocyanatocyclohexane had reacted almost immediately. The reaction mixture was poured into 300 ml water and the product extracted with 100 ml methylene chloride. The methylene chloride extract was separated, washed with water, 100 ml 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered and the methylene chloride evaporated under reduced pressure to leave 11.0 grams (91% crude yield) of a yellow liquid. The product had a strong carbonyl band at 1730 cm-1 and a sharp NH band at 3400 cm-1 in its infrared spectrum and the isocyanate band at 2225 cm-1 was absent.
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:6]=1)=[O:4].[CH2:19]([N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH2:27][NH2:28])[CH:20]=[CH2:21].C([O-])(=O)C>O>[CH2:19]([N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH2:27][NH:28][C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7]([S:15](=[O:17])(=[O:18])[NH2:16])[CH:6]=1)=[O:4])[CH:20]=[CH2:21]
Reactant: C=CCN1CCCC1CN
Reactant: COC(=O)c1cc(S(N)(=O)=O)cc2c1OCCO2
Agent: CC(=O)[O-]
Solvent: O
Product: C=CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)cc2c1OCCO2
Yield: 64.7 %

Procedure:
145 g of methyl-7-sulfamoyl-1,4-benzodioxane-5-carboxylate, 48 g of water and 89 g of 1-allyl-2-aminomethyl-pyrrolidine were introduced into a balloon flask provided with a condenser. The mixture was heated on a water bath until a test sample was soluble in dilute acids and then 1 liter of water was added. The precipitated carboxamide was redissolved by acetate formation. The solution formed was filtered on carbon black and then the base was precipitated by the addition of 20% ammonia. The resulting crystals were dried off, washed with water, dried and purified by passing over hydrochloride (M.P.: 228°-230° C.) followed by transformation into a base by treatment with 20% ammonia. 131 g of N-(1-allyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 143°-144° C.; yield: 64.8%). The structure was confirmed by nuclear magnetic resonance.
Reaction SMILES: [NH2:1][C:2]1[N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](Cl)=[O:20])[CH:8]=2)[N:3]=1.[CH3:25][C:26]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[C:27]=1[CH2:28][NH2:29]>C(Cl)Cl.O>[NH2:1][C:2]1[N:11]([CH2:12][CH2:13][CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([NH:29][CH2:28][C:27]3[C:26]([CH3:25])=[CH:33][C:32]([CH3:34])=[CH:31][C:30]=3[CH3:35])=[O:20])[CH:8]=2)[N:3]=1
Reactant: CCCN1Cc2cc(Oc3cccc(C(=O)Cl)c3)ccc2N=C1N
Reactant: Cc1cc(C)c(CN)c(C)c1
Solvent: ClCCl
Solvent: O
Product: CCCN1Cc2cc(Oc3cccc(C(=O)NCc4c(C)cc(C)cc4C)c3)ccc2N=C1N
Temperature: 0 °C

Procedure:
A mixture of 3-(2-amino-3-propyl-3,4-dihydro-quinazolin-6-yloxy)-benzoyl chloride (0.0008 mol) in DCM (20 mL) was stirred at 0° C. and 2,4,6-trimethylbenzylamine (0.0013 mol) was added. Then TEA (q.s.) was added, and the reaction mixture was stirred at room temperature. The mixture was stirred in H2O and the organic layer was separated. The remaining layer was washed again with H2O, then the organic layer was separated, dried, and filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (gradient eluent: CH2Cl2:(CH3OH:NH3)). The purest product fractions were collected, and the solvent was evaporated. The residue was triturated under diisopropyl ether:CH3CN, and then the resulting solids were filtered off and dried to yield the title compound as a solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][NH:28][CH3:29]>C(O)C>[CH3:27][N:28]([CH3:29])[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1
Reactant: CNC
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(N(C)C)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 21 from 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (23 mg, 0.062 mmol), ethanol (0.7 mL), and dimethylamine (0.461 mL, 0.923 mmol). The product was dried in vacuum oven at 50° C. for 5 hr and collected as 0.016 g (67%). LCMS E-S (M+H)=383.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (d, J=6.57 Hz, 6 H), 2.05-2.25 (m, 6 H), 3.14 (s, 6 H), 4.34 (d, J=4.80 Hz, 2 H), 4.99 (dt, J=13.39, 6.69 Hz, 1 H), 5.89 (s, 1 H), 6.94 (s, 1 H), 7.96 (s, 1 H), 8.64 (t, J=4.93 Hz, 1 H), 11.56 (br. s., 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH:11]([OH:13])[CH3:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([CH3:30])=[CH:28][C:27](O)=[CH:26][C:25]=2[CH3:32])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CO>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH:11]([O:13][C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([C:21]3[CH:22]=[CH:23][C:18]([C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:19][CH:20]=3)=[C:25]([CH3:32])[CH:26]=2)[CH3:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(C)(C)C)cc1
Reactant: CCOC(=O)c1ccc(C(C)O)s1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)c1ccc(C(C)Oc2cc(C)c(-c3ccc(C(C)(C)C)cc3)c(C)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A mixture of (±)-5-(1-hydroxy-ethyl)-thiophene-2-carboxylic acid ethyl ester (0.416 g, 2.08 mmol), 4′-tert-butyl-2,6-dimethyl-biphenyl-4-ol (0.561 g, 2.20 mmol), and PPh3 (0.787 g, 3.00 mmol) is dissolved in toluene (19 mL) and treated with 1,1′-(azodicarbonyl)dipiperidine (ADDP, 0.760 g, 3.01 mmol) and stirred overnight at rt. The mixture is diluted with MeOH until homogeneous and conc. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 40% giving (±)-5-[1-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carboxylic acid ethyl ester (0.604 g, 671%) as a clear syrup.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1.[Cl-].[C:14]([O:18][C:19](=[O:22])[CH2:20][Zn+])([CH3:17])([CH3:16])[CH3:15].CCOCC>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([O:18][C:19](=[O:22])[CH2:20][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH:10]([CH3:12])[CH3:11])[CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)Oc1cc(Br)ccc1Cl
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)Oc1cc(CC(=O)OC(C)(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-bromo-1-chloro-2-isopropoxy-benzene (2.48 g, 9.8 mmol, 1.0 eq.) and bis(tri-tert-butylphosphine)palladium(0) (501 mg, 0.98 mmol, 0.1 eq.) in dioxane (84 mL), a 0.5M solution of 2-tert-butoxy-2-oxoethylzinc chloride in Et2O (35.3 mL, 17.6 mmol, 1.8 eq.) was added. The resulting mixture was stirred at r.t. for 2 days. The mixture was filtered over celite and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane 100% to Heptane+8% AcOEt) to yield the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccnc2ccc(Br)cc12
Product: CCOC(=O)C1CCN(c2ccnc3ccc(Br)cc23)CC1
Yield: 64.1 %

Procedure:
500 mg 6-bromo-4-chloroquinoline and 340 mg ethyl 4-piperidine carboxylate were reacted by the same method as in Production Example 74, to give 480 mg of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N:12]=[C:13]=[O:14])[CH:8]=[CH:7][CH:6]=2.[C:15]([C:19]1[CH:28]=[C:27]2[C:22]([CH:23]([NH2:29])[CH2:24][CH2:25][O:26]2)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:19]1[CH:28]=[C:27]2[C:22]([CH:23]([NH:29][C:13]([NH:12][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[CH:11]=[C:2]([CH3:1])[N:3]=[CH:4]4)=[O:14])[CH2:24][CH2:25][O:26]2)=[CH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Reactant: CC(C)(C)c1ccc2c(c1)OCCC2N
Product: Cc1cc2c(NC(=O)NC3CCOc4cc(C(C)(C)C)ccc43)cccc2cn1
Reaction time: 8 h
Yield: 64 %

Procedure:
6 mL of the 3-methyl-5-isocyanato-isoquinoline solution was added to the product of Example 1C (123 mg, 0.6 mmol). The reaction mixture was stirred overnight, and the percipitate formed was collected by filtration and washed with diethyl ether to give 0.15 g of the title compound (64% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 9.17 (s, 1 H), 8.46 (s, 1 H), 8.34 (d, J=6.8 Hz, 1 H), 7.66-7.73 (m, 2 H), 7.51 (t, J=8.0 Hz, 1 H), 7.25 (d, J=8.5 Hz, 1 H), 7.12 (d, J=7.1 Hz, 1 H), 6.98 (dd, J=8.0, 1.9 Hz, 1 H), 6.80 (d, J=2.0 Hz, 1 H), 4.82-4.89 (m, 1 H), 4.24-4.31 (m, 1 H), 4.10-4.18 (m, 1 H), 2.63 (s, 3 H), 1.99-2.14 (m, 2 H), 1.25 (s, 9 H). MS (ESL+) m/e 390 (M+H)+. Calc'd. For C24H27N3O2.0.5; H2O: C, 72.34; H, 7.08; N, 10.54. Found C, 72.52; H, 7.23; N, 10.53.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH:19]1([S:22](Cl)(=[O:24])=[O:23])[CH2:21][CH2:20]1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:22]([CH:19]2[CH2:21][CH2:20]2)(=[O:24])=[O:23])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)C1CC1

Procedure:
According to the general procedure A, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with cyclopropanesulfonyl chloride to obtain the desired product. (500 MHz, CDCl3): δ=7.38-7.37 (d, 1H), 7.35-7.34 (m, 1H), 7.27-7.26 (m, 1H), 7.20-7.0 (q, 1H), 6.68 (s, 1H, br), 6.15-6.12 (q, 1H), 5.65 (s, 1H, br), 3.25-3.20 (m, 1H), 2.4-2.3 (m, 2H), 2.0-1.8 (m, 2H); m/z=467 [M−1]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[C:10]1[CH:38]=[C:37]([CH3:39])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([N:28]([CH3:36])[CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)(=[O:27])=[O:26])=[CH:21][CH:20]=3)[N:16]=[N:17][C:12]=2[CH:11]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:10]1[CH:38]=[C:37]([CH3:39])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([S:25]([N:28]([CH3:36])[CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)(=[O:26])=[O:27])=[CH:23][CH:24]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(S(=O)(=O)N(C)CCN5CCCC5)cc4)nnc3c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2cc(O)ccc2Cl)cc2nnc(Nc3ccc(S(=O)(=O)N(C)CCN4CCCC4)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-N-methyl-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (0.297 mmol, 1.0 equiv) was dissolved in 10 mL anhydrous DCM and placed under an argon atmosphere. 4 mL of BBr3 (0.1 M) was added via syringe and the reaction was stirred at room temperature for 2 h. BBr3 was quenched with saturated NaHCO3 until pH=7. The mixture was filtered and washed with water and Et2O to give 4-[7-(2-chloro-5-hydroxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-N-methyl-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide, as a dark green solid (120.5 mg, 74% yield). Rf=0.61 1H NMR (DMSO-d6): δ 1.90 (m, 2H), 2.01 (m, 2H), 2.72 (s, 6H), 3.06 (m, 2H), 3.30 (t, J=5.6 Hz, 2H), 3.38 (t, J=6.0 Hz, 2H), 3.59 (m, 2H), 6.89 (dd, J=8.8 Hz, J=2.9 Hz, 1H), 6.96 (d, J=2.9 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.87 (d, J=8.9 Hz, 2H), 7.92 (d, J=0.9 Hz, 1H), 8.21 (d, J=1.7 Hz, 1H), 8.30 (d, J=9.0 Hz, H), 11.50 (s, 1H). MS (ES+) m/z=553 LC retention time 2.41 min. Elemental for C27H30Cl2N6O3S 5H2O Calculated: C, 47.72; H, 5.93; N, 11.37. Found: C, 46.59; H, 5.67; N, 11.42.