Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][CH2:24][NH2:25])(=[O:22])=[O:21])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]>>[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][CH2:24][NH:25][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])(=[O:21])=[O:22])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]
Reactant: CC(C)N1CCC(NS(=O)(=O)CCN)CC1
Reactant: O=C(O)c1ccc(Br)o1
Product: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Br)o2)CC1

Procedure:
5-Bromo-furan-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide was prepared by an analogous procedure as described in example 9 starting from 126 mg (1.1 equiv.) 5-bromo-furan-2-carboxylic acid and 150 mg (0.60 mmol) 2-amino-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-bromo-furan-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material. Yield: 121 mg MS (ES+): m/e=422, bromo pattern.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([N+:14]([O-])=O)=[C:10]([CH3:17])[N:9]1[CH3:18]>CO.[Pd]>[NH2:14][C:11]1[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]([CH3:18])[C:10]=1[CH3:17]
Reactant: Cc1c([N+](=O)[O-])c(=O)n(-c2ccccc2F)n1C
Agent: [Pd]
Solvent: CO
Product: Cc1c(N)c(=O)n(-c2ccccc2F)n1C
Temperature: 65 °C
Reaction time: 8 h

Procedure:
2-(2-Fluorophenyl)-1,5-dimethyl-4-nitro-1H-pyrazol-3(2H)-one (208 g, 828 mmol) and 10% Pd/C (25 g, 235 mmol) in MeOH (3000 ml) was subjected to hydrogenation over 98 hrs at 0.1 bar at RT. The resulting mixture was filtered over a pad of Celite® (filter material), washed with MeOH (1000 ml) and the filtrate was evaporated to dryness. To the solid was added DCM (300 ml) and this was heated at 65° C., followed by addition of toluene (900 ml). The DCM was removed under reduced pressure and the resulting mixture was allowed to cool to RT with stirring and left to stand at RT overnight. The mixture was filtered, washing with 1:1 toluene:heptane (200 ml) and heptane (800 ml) and dried under v to give the title compound as light yellow crystals.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:12][CH:13]=1.[C:21]([C:23]1[CH:36]=[CH:35][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1)#[CH:22]>C1COCC1.[Cu]I>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:22]#[C:21][C:23]3[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:35][CH:36]=3)=[CH:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(-c2ccc(Br)cn2)cc1
Reactant: C#Cc1ccc(OCCN2CCCC2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under an N2 atmosphere 773 mg (2.25 mmol) Cs2CO3, 14 mg (0.08 mmol) CuI and 87 mg (0.08 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 403 mg (1.5 mmol) 5-bromo-2-(4-chloro-phenyl)-pyridine and 322 mg (1.5 mmol) 1-[2-(4-ethynyl-phenoxy)-ethyl]-pyrrolidine in 10 mL THF and the reaction mixture is stirred for 4 h at RT. Then it is heated to 60° C. for 16 h. The mixture is evaporated down i. vac., the residue is combined with 30 mL water, 5 mL 3% NH3 solution and 60 mL EtOAc, the organic phase is separated off and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified first by chromatography (silica gel, EtOAc/MeOH/NH3 19:1:0.1) and then by HPLC.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:17]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:19]=1>>[F:13][C:14]1[CH:15]=[C:16]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:17]=[C:18]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[N:10][C:5]3=[N:4][CH:3]=2)[CH:19]=1
Reactant: OCc1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2cc(F)cc(-c3ccccc3C#N)c2)OC1(C)C
Product: N#Cc1ccccc1-c1cc(F)cc(-c2cnc3nc(CO)ccn23)c1

Procedure:
3-Bromoimidazo[1,2-α]pyrimidin-7-ylmethanol was coupled with 3′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-fluoro-5′-(7-hydroxymethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as a yellow solid: δH (360 MHz, DMSO) 4.71 (2H, d, J 6), 5.81 (1H, t, J 6), 7.31 (1H, d, J 7), 7.63 (1H, d, J 9), 7.74-7.95 (5H, m), 8.10 (1H, d, J 8), 8.14 (1H, s), 9.26 (1H, d, J 7); m/z (ES+) 345 (M++H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:15])=[O:7].[N+:16](C1OC(C(O)=O)=CC=1)([O-:18])=[O:17]>>[N+:16]([C:5]1[O:1][C:2]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])=[O:7])=[CH:3][CH:4]=1)([O-:18])=[O:17]
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Reactant: O=C1CCCCCN1C(=O)c1ccco1
Product: O=C1CCCCCN1C(=O)c1ccc([N+](=O)[O-])o1

Procedure:
Synthesized as for N-(2-furoyl)caprolactam (Example XI) using 5-nitro-2-furoic acid in place of 2-furoic acid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1.CN([CH:24]=[O:25])C.[OH-].[Na+]>C1COCC1.O>[Br:13][C:14]1[CH:19]=[C:18]([CH:24]=[O:25])[C:17]([Cl:20])=[CH:16][N:15]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(Br)nc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cc(Br)ncc1Cl
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a stirred sol. of diisopropylamine (20.9 mL, 148 mmol) in dry THF (350 mL) at −5° C. was added dropwise BuLi (1.6M in hexane, 89.5 mL, 143 mmol), and the resulting sol. was stirred for 30 min at −5° C. The sol. was allowed to cool to −70° C., and a sol. of 2-bromo-5-chloropyridine (25.0 g, 130 mmol) in THF (100 mL) was added dropwise at −70° C. over 15 min such as the internal temperature did not exceed −65° C. The mixture was stirred at −70° C. for 30 min. DMF (10.5 mL, 136 mmol) was added dropwise over 20 min at such a rate that the internal temperature did not exceed −70° C. The orange mixture was stirred at −70° C. for 40 min. The mixture was allowed to warm up to rt, and was poured onto a mixture of water (200 mL) and aq. 1M NaOH (50 mL). The mixture was extracted with EtOAc (2×), and the combined org. extracts were washed back with aq. 1M NaOH (2×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:9→1:8→1:6→1:4→1:2→1:1) yielded the title compound (21.6 g, 72%). LC-MS: tR=0.74 min; ES+: 295.01.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([NH:6][C@@H:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8]([NH:10][CH2:11][C:12]#[N:13])=[O:9])=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:12]([CH2:11][NH:10][C:8]([C@@H:7]([NH:6][C:5]1[CH:18]=[CH:19][C:2]([C:36]2[CH:35]=[CH:34][C:33]([N:30]3[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:32][CH2:31]3)=[CH:38][CH:37]=2)=[CH:3][CH:4]=1)[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:9])#[N:13]
Reactant: CC(C)C[C@H](Nc1ccc(Br)cc1)C(=O)NCC#N
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](Nc1ccc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1)C(=O)NCC#N
Temperature: 105 °C

Procedure:
To (2S)-2-(4-bromoanilino)-N-(cyanomethyl)-4-methylpentanamide (555 mg, 1.71 mmol), and 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenylboronic acid (520 mg, 1.71 mmol) in DMF (20 mL) under dry nitrogen was added aqueous sodium carbonate (2 M, 2.55 mL, 5.13 mmol) followed by the catalyst PdCl2(dppf) (42 mg, 0.051 mmol). The reaction was heated to 105° C. for 0.75 hours and more PdCl2(dppf) (42 mg, 0.051 mmol) was added and the reaction mixture was heated for another 4–5 hours. Water was added and the product extracted with ether (2×), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (EtOAc/Hex, 4/6 then 1/1) to afford tert-butyl 4-{4′-[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)amino][1,1′-biphenyl]-4-yl}-1-piperazinecarboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[N:9]=[C:8]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)[C:7]=1[N+:28]([O-])=O)=[O:5])[CH3:2]>C(O)C.[Pd]>[NH2:28][C:7]1[C:8]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)=[N:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)=[N:11][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1nc(Nc2cccc(O)c2)nc(Nc2cccc(O)c2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1nc(Nc2cccc(O)c2)nc(Nc2cccc(O)c2)c1N

Procedure:
A suspension of 6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-5-nitro-2,4-pyrimidinediamine and 10% Pd/C (10% by weight) in ethanol was prepared and reacted in a Parr bottle under hydrogen gas (20 PSI) for 1 h. The reaction mixture was filtered through Celite. Purification by column chromatography gave 5-amino-6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.30 (bs, 1H), 7.18–7.10 (m, 3H), 7.00 (t, 2H, J=8.1 Hz), 6.59–6.54 (m, 1H), 6.33 (dd, 1H, J=2.1 and 11.1 Hz), 4.39 (q, 2H, J=6.9 Hz), 1.43 (t, 3H, J=6.9 Hz); LCMS: ret. time: 19.24 min.; purity: 100%; MS (m/e): 382 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:27].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][Br:27])=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)ncn1CCc1ccc(CO)cc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(OCc2ccccc2)ncn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 200 mg (0.60 mmol) 6-benzyloxy-3-[2-(4-hydroxymethyl-phenyl)-ethyl]-3H-pyrimidin-4-one (example 20.1a) in 2.0 mL of DCM is added at 0° C. 29 μL (0.30 mmol) phosphorus tribromide. The mixture is stirred 2 h at RT and is then added to 5% aqueous NaHCO3-solution. The layers are separated, the aqueous phase is extracted with DCM and the organic phase is washed with water. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH2:31])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl[C:33]1[O:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH:31][C:33]6[O:34][C:35]7[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=7[N:37]=6)([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(N)(CC4)CC5)n23)cc1
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(Nc6nc7ccccc7o6)(CC4)CC5)n23)cc1
Temperature: 65 °C
Yield: 102.1 %

Procedure:
A pear shaped flask was charged with 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine (0.20 g, 0.46 mmol, Example #7, Step B) and 2-chlorobenzo[d]oxazole (0.18 g, 1.1 mmol, TCI) in DMF (5.0 mL). To the suspension was added K2CO3 (0.16 g, 1.1 mmol) and the mixture was heated to about 65° C. for about 8.5 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved into EtOAc (25 mL) and washed with water and brine (25 mL each). The organic solution was dried over anhydrous MgSO4, filtered, and concentrated to dryness under reduced pressure to give N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)benzo[d]oxazol-2-amine (0.26 g, 95%, 95% purity by ELSD): LC/MS (Table 2, Method d) Rt=1.48 min; MS m/z: 554 (M+H)+.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]([N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)=[N:37][CH:38]=2)O1>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:18])[C:8]2=[CH:7][C:5]1[O:6][C:2]([C:33]2[CH:38]=[N:37][C:36]([N:39]3[CH2:40][CH2:41][NH:42][CH2:43][CH2:44]3)=[CH:35][CH:34]=2)=[CH:3][CH:4]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(Br)o1
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc(-c2ccc(N3CCNCC3)nc2)o1
Temperature: 120 °C

Procedure:
To 3-((5-bromofuran-2-yl)methylene)-5-chloroindolin-2-one (50 mg, 0.155 mmol) in dioxane/water (5% water) was added Cs2CO3 (152 mg, 0.466 mmol) and 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (54 mg, 0.186 mmol). The mixture was degassed with nitrogen for 5 minutes then heated in microwave for 20 minutes at 120° C. The solution was diluted with water and the solid formed was isolated by filtration. The solid purified by HPLC to yield 5-chloro-3-((5-(6-(piperazin-1-yl)pyridin-3-yl)furan-2-yl)methylene)indolin-2-one. LCMS (M+1=407).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][N:3]=1.Cl.[F:10][C:11]1[CH:21]=[CH:20][C:14]([O:15][CH:16]2[CH2:19][NH:18][CH2:17]2)=[CH:13][CH:12]=1.C(N(C(C)C)C(C)C)C>CC(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:18]2[CH2:19][CH:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:21][CH:20]=3)[CH2:17]2)[CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: Fc1ccc(OC2CNC2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(OC2CN(c3ccnc(Cl)c3)C2)cc1
Temperature: 84 °C
Yield: 90.3 %

Procedure:
To 2-chloro-4-fluoropyridine (160.0 mg, 1.216 mmol) and 3-(4-fluoro-phenoxy)-azetidine hydrochloride (248 mg, 1.216 mmol) in 2-propanol (3.0 mL) in a disposable sealed tube at RT was added N-ethyl-N-isopropylpropan-2-amine (0.530 mL, 3.04 mmol). The resulting reaction mixture was heated at 84° C. for 18 h, cooled to RT, concentrated, purified using MPLC (5 g cartridge, 12 g column, 0 to 60% EtOAc-hexanes) giving 2-chloro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyridine (306.1 mg).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N:17]([C:20]([C:22]2[C:27]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([C:39]([F:42])([F:41])[F:40])[CH:33]=3)(=[O:31])=[O:30])=[CH:26][C:25]([Cl:43])=[CH:24][N:23]=2)=[O:21])[CH2:18][CH3:19])=[N:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:18]([N:17]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][N:9]=1)[C:20]([C:22]1[C:27]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([C:39]([F:41])([F:42])[F:40])[CH:33]=2)(=[O:31])=[O:30])=[CH:26][C:25]([Cl:43])=[CH:24][N:23]=1)=[O:21])[CH3:19]
Reactant: CCN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1nn(C(=O)OC(C)(C)C)c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-{[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-ethyl-amino}-indazole-1-carboxylic acid tert-butyl ester was dissolved in a mixture of DCM and TFA (1:1) (5 mL). It was stirred at RT for 1 hour, concentrated, purified with HPLC to give 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid ethyl-(1H-indazol-3-yl)-amide. MS m/z: 557.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:33])C=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N+:4]([O-:33])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:11]=2[N:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3Br)nc2c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: [O-][n+]1ccc(-c2nc3cc(C(F)(F)F)ccc3o2)c(Br)c1
Temperature: 50 °C
Yield: 70.7 %

Procedure:
To a mixture of 0.50 g of 2-(3-bromopyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 5 ml of chloroform, 0.58 g of 65% m-chloroperbenzoic acid was added. The reaction mixture was stirred while heating at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate, and washed with a saturated aqueous solution of sodium hydrogencarbonate (twice) and a saturated sodium chloride solution, sequentially. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.37 g of 3-bromo-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide (hereinafter, referred to as “active compound 28”).
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[CH:7]([NH:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[C:18]([N+:26]([O-:28])=[O:27])[CH:19]=[CH:20][CH:21]=3)[C:16](=[O:29])[C:15]=2[C:14]([NH2:30])=[CH:13][CH:12]=1)([CH3:9])[CH3:8].C(N(CC)CC)C.CO>CN1CCCC1=O>[CH:7]([NH:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[C:18]([N+:26]([O-:28])=[O:27])[CH:19]=[CH:20][CH:21]=3)[C:16](=[O:29])[C:15]=2[C:14]([NH:30][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:13][CH:12]=1)([CH3:9])[CH3:8]
Reactant: CC(C)Nc1ccc(N)c2c1C(=O)c1cccc([N+](=O)[O-])c1C2=O
Reactant: CCOC(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)Nc1ccc(NC(C)C)c2c1C(=O)c1c(cccc1[N+](=O)[O-])C2=O

Procedure:
5 ml of chloroformic acid ethyl ester are added dropwise to 10 g of 1-isopropylamino-4-amino-5-nitroanthraquinone in 50 ml of N-methylpyrrolidone at room temperature. 4 ml of triethylamine are then added dropwise and the mixture is stirred further, finally for a short time at 30°-40° C, until only small amounts of starting material remain detectable. After working up with methanol, 1-isopropylamino-4-ethoxycarbonylamino-5-nitroanthraquinone is obtained.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH2:23][CH2:22][C:21]([C:29](O)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:44]([N:47]1[C:51]([CH2:52][S:53]([C:55]2[CH:61]=[CH:60][C:58]([NH2:59])=[CH:57][CH:56]=2)=[O:54])=[CH:50][N:49]=[CH:48]1)[CH2:45][CH3:46]>O1CCCC1.O.N1C=CC=CC=1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH2:23][CH2:22][C:21]([C:29]([NH:59][C:58]4[CH:57]=[CH:56][C:55]([S:53]([CH2:52][C:51]5[N:47]([CH2:44][CH2:45][CH3:46])[CH:48]=[N:49][CH:50]=5)=[O:54])=[CH:61][CH:60]=4)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC2CC2)cc1
Reactant: CCCn1cncc1CS(=O)c1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCN3CC2CC2)cc1
Reaction time: 0.5 h

Procedure:
di-p-toluoyl-D-tartarate 1hydrate (894 mg) was dissolved in ethyl acetate (10 ml) and 1N hydrochloric acid (4.6 ml) to separate the layers. To the aqueous layer was added 25% aqueous solution of potassium carbonate (4.6 ml) and the mixture was extracted with 2-propanol-ethyl acetate (1:4) twice. The organic layer was collected, washed with saturated brine, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue was added tetrahydrofuran, and the solvent was distilled off again under reduced pressure to give (−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. Then, to a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (450 mg) in tetrahydrofuran (10 ml) were added one droplet of DMF and oxalyl chloride (0.12 ml) under nitrogen atmosphere and the mixture was stirred for 30 minutes. This solution was added dropwise to a solution of (−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl) aniline and pyridine (2.17 ml) in tetrahydrofuran (20 ml) at 0° C. under nitrogen atmosphere. The mixture was allowed to be at room temperature, stirred for 3 hours, and water was added to the mixture, and the mixture was extracted with ethyl-acetate. The organic layer was washed with 10% aqueous solution of acetic acid twice, an aqueous solution of saturated sodium bicarbonate twice and saturated brine once, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified by basic silica gel column chromatography (ethyl acetate→ethyl acetate:methanol=50:1), to give (−)-7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropylmethyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (411 mg) (Compound 454) as yellow amorphous.
Reaction SMILES: O=C[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6]C)[CH:4]=1.[CH3:12]COCC>>[OH:6][CH2:5][CH:8]([OH:9])[CH2:10][CH2:11][CH2:3][CH2:4][CH3:12]
Reactant: CCOCC
Reactant: COc1cc(C=O)ccc1O
Product: CCCCCC(O)CO

Procedure:
A solution of the title B ketal (1.87 g, 11.8 mmol) in methanol (30 ml) and concentrated HCl (2.5 ml) was stirred at room temperature 3 hours. The solution was basified by adding concentrated NH4OH solution (10 ml) and the solvent was removed in vacuo. Saturated NaCl solution (50 ml) was added to the residue and the product was extracted into ether (4×50 ml). The combined ether extracts were washed with saturated NaCl solution (50 ml), dried (MgSO4) and freed of solvent in vacuo leaving the title C diol as a yellow oil (1.13 g, 81%) 13-C NMR consistent. TLC:silica gel, Et2O, vanillin, Rf =0.25.