Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH3:19])[C:17]2[CH:16]=[CH:15][N:14]=[N:13][C:12]=2[C:11]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28])=[O:9])=C>CO.Cl>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH3:19])[C:17]2[CH:16]=[CH:15][N:14]=[N:13][C:12]=2[C:11]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28])=[O:9]
Reactant: C=COCCONC(=O)c1c(Nc2ccc(I)cc2F)c2nnccc2n1C
Agent: Cl
Solvent: CO
Product: Cn1c(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c2nnccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
To a solution of 7-(2-fluoro-4-iodo-phenylamino)-5-methyl-5H-pyrrolo[3,2-c]pyridazine-6-carboxylic acid (2-vinyloxy-ethoxy)-amide (148 mg, 0.3 mmol) in methanol (5 mL) was added concentrated hydrochloric acid (3 drops) and the reaction mixture stirred at room temperature for 10 minutes. The reaction mixture was concentrated in vacuo and the resultant residue dissolved in acetonitrile/water, neutralised with triethylamine and subjected to reverse-phase HPLC (Phenomenex Luna 5 phenyl/hexyl, 0.1% HCO2H in water on a gradient of acetonitrile 90:10 to 15:85) to give the title compound as an orange solid (82 mg, 52%). LCMS (method A): RT=5.89 min, M+H+=471. 1H NMR (d6-DMSO, 400 MHz) 3.58 (2H, s), 3.91 (2H, s), 3.95 (3H, s), 6.44 (1H, t, J=8.85 Hz), 7.18 (1H, d, J=8.56 Hz), 7.53 (1H, dd, J=11.02, 1.92 Hz), 7.94 (1H, s), 8.43 (1H, d, J=6.27 Hz), 9.31 (1H, d, J=6.52 Hz), 12.09 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH:13]([C:22]([OH:24])=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2.Cl[C:29]1[C:38]([C:39]([OH:41])=[O:40])=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH:13]([C:22]([OH:24])=[O:23])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:29]3[C:38]([C:39]([OH:41])=[O:40])=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)=[CH:19][CH:20]=1)[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Br)ccc2nc1NC(Cc1ccc(O)cc1)C(=O)O
Reactant: O=C(O)c1cc2ccccc2nc1Cl
Product: O=C(O)c1cc2cc(Br)ccc2nc1NC(Cc1ccc(Oc2nc3ccccc3cc2C(=O)O)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 96, 6-bromo-2-[1-carboxy-2-(4-hydroxy-phenyl)-ethylamino]-quinoline-3-carboxylic acid is reacted with 2-chloro-quinoline-3-carboxylic acid to provide the title compound in good yield.
Reaction SMILES: C(O)(=O)C.[CH2:5]([NH:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)=[C:13]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:25][C:24]=2[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:12][N:11]=1)=[O:9])[CH3:6].[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>CO>[CH2:5]([NH:7][C:8]([C:10]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:19][CH:20]=2)=[C:13]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:25][C:24]=2[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:12][N:11]=1)=[O:9])[CH3:6]
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(C=O)cc1
Reactant: C1COCCN1
Solvent: CC(=O)O
Solvent: CO
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Reaction time: 8 h
Yield: 98.4 %

Procedure:
Acetic acid (0.37 ml, 6.44 mmol) was added dropwise to a mixture of 5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-(4-formyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (730 mg, 1.29 mmol), morpholine (0.225 ml, 2.58 mmol), 3A powdered molecular sieves (730 mg) and MeOH (21 ml). This was left to stir overnight under N2. The mixture was then evaporated in vacuo and the resultant crude partitioned between CH2Cl2 (3×40 ml) and sat. NaHCO3 solution (40 ml). The combined, dried (Na2SO4) organics were evaporated in vacuo to give crude 5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (810 mg) as a yellow solid, LC/MS: RT=2.365 min. 638.4 (MH+).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1([CH2:22][N:23]([CH3:34])[C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1>CO>[OH:3][C:4]1([CH2:22][N:23]([CH3:34])[C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:16][CH:17]=2)[CH2:6][CH2:5]1
Reactant: COC(=O)c1ccc(N(C)CC2(O)CCN(CCc3ccc(S(C)(=O)=O)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CC1(O)CCN(CCc2ccc(S(C)(=O)=O)cc2)CC1)c1ccc(C(=O)O)cc1
Temperature: 50 °C
Yield: 88.6 %

Procedure:
An aqueous 2N sodium hydroxide solution (3.4 mL) was added to methanol (20 mL) solution of the compound (0.78 g) obtained in Step 2 and heated under reflux for three hours. The solvent was removed under reduced pressure and to the residue was added with ether and water to be separated. The aqueous layer was washed with ether and the remaining aqueous layer adjusted to pH 5 to 7 with 3N hydrochloric acid and stirred at 50° C. for thirty minutes. The precipitate was collected by filtration and washed with water and then dried under reduced pressure to obtain the titled compound (0.67 g) as crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=1.[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([C:26]1[CH:36]=[CH:35][CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[C:27]=1[CH2:28][O:29]C(=O)C)[N:19]=[CH:18]2)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([C:26]1[C:27]([CH2:28][OH:29])=[C:33]([C:2]3[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=3)[CH:34]=[CH:35][CH:36]=1)[N:19]=[CH:18]2)([CH3:14])([CH3:12])[CH3:13]
Reactant: Cn1cc(Br)cc1C(N)=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)ccc2c1=O
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2CO)cc1C(N)=O
Yield: 20 %

Procedure:
This compound was prepared with the same method as described in Example 1 by using 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid amide (intermediate-3) and acetic acid 2-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (intermediate 4). The desired compound was prepared in two steps (20% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.04 (d, J=1.5 Hz, 1H), 8.01 (dd, J=1.8, 8.4 Hz, 1H), 7.48-7.45 (m, 2H), 7.28-7.23 (m, 2H), 7.08 (d, J=1.8 Hz, 1H), 4.35 (s, 2H), 3.89 (s, 3H), 1.41 (s, 9H). LC-MS calcd for C25H26N4O3 (m/e) 430.20, obsd 431 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[Br:14]Br>C(Cl)(Cl)(Cl)Cl.[W]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH2:13][Br:14])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrBr
Reactant: COC(=O)c1ccc(C)cc1OC
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1OC
Yield: 96.1 %

Procedure:
To a refluxing mixture of methyl 2-methoxy-4-methyl-benzoate (21.625 g, 120 mmol) in CCl4 (240 mL) was added dropwise a solution of bromine (6.19 mL, 120 mmol) in CCl4 (75 mL) over 1.5 h. During the bromine addition the reaction was irradiated with a 250 W tungsten lamp. After the addition, the reaction was refluxed for 15 min and concentrated, and vacuum pumped to give methyl 2-methoxy-4-(bromomethyl)benzoate as an oil (29.864 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[C:30](O)=[O:31])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:33][OH:34]>>[OH:34][NH:33][C:30]([C@@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]1[NH:23][S:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)=[CH:19][CH:18]=1)(=[O:22])=[O:21])=[O:31]
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CCCC[C@H]3C(=O)O)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CCCC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 46 %

Procedure:
According to the procedure of Example 10, Step 2, the reaction of 113.6 mg (0.5 mmol) of cis-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxylic acid with hydroxylamine provided 53.7 mg of the title compound in 46% yield. MS: 470.1 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[I-].C([NH3+])(C)(C)C.Cl[CH2:29][C:30]([C:32]1[CH:48]=[CH:47][C:35]2[CH2:36][CH2:37][N:38]([C:41](=[O:46])[C:42]([F:45])([F:44])[F:43])[CH2:39][CH2:40][C:34]=2[CH:33]=1)=[O:31]>C1COCC1.C(OC)(C)(C)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:29][C:30](=[O:31])[C:32]2[CH:48]=[CH:47][C:35]3[CH2:36][CH2:37][N:38]([C:41](=[O:46])[C:42]([F:45])([F:43])[F:44])[CH2:39][CH2:40][C:34]=3[CH:33]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: O=C(CCl)c1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: CC(C)(C)[NH3+]
Agent: CC(C)(C)[O-]
Agent: [I-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 8.05 g (40.0 mmol) 4-benzyloxy-1H-pyridin-2-one in 50 mL THF is added at 0° C. subsequently 4.94 g (44.0 mmol) potassium tert-butylate, 739 mg (2.00 mmol) tert-butyl ammonium-iodide and 15.3 g (48.0 mmol) 1-[7-(2-chloro-acetyl)-1,2,4,5-tetrahydro-3-benzazepin-3-yl]-2,2,2-trifluoro-ethanone. The reaction mixture is stirred overnight at RT and poured onto 500 mL water. 100 ml tert-butylmethylether is added. The precipitate is collected and dried. The product, which contains 20% 1-[7-(2-chloro-acetyl)-1,2,4,5-tetrahydro-3-benzazepin-3-yl]-2,2,2-trifluoro-ethanone is used without further purification in the next step.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[C:12]3=[O:19])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:20](O)[CH2:21][CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[N:1]1([S:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[C:12]23[O:23][CH2:22][CH2:21][CH2:20][O:19]2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCO
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCCC3)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C1Nc2ccc(S(=O)(=O)N3CCCC3)cc2C12OCCCO2
Temperature: 25 °C
Yield: 168.9 %

Procedure:
A stirred mixture of 5-(pyrrolidin-1-ylsulfonyl)-1H-indole-2,3-dione (0.88 g, 3.14 mmol), 1,3-propanediol (0.92 mL, 1.26 mmol, 4 eq) and p-toluenesulfonic acid (1.19 g, 6.28 mmol, 0.2 mole % ) in benzene (100 mL) was refluxed with a Dean Stark Trap for 6 hours. The reaction was cooled to room temperature, washed with sat. aq. NaHCO3 (1×), water (2×), and brine (1×), dried over NaHCO3 (1×,), filtered and concentrated. The crude product was purified on Biotage KP silica gel eluting with 90/10 CH2Cl2/EtOAc to give the title compound as a white solid (0.72 g, 68% ). NMR (300 Mz, DMSO-d6): consistent. MS: (API-ES+) 338 [M+H] consistent.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH:14]=[C:13]3[C:29]2[CH:34]=[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:32]=[C:31]([NH:45][CH:46]([CH3:48])[CH3:47])[N:30]=2)=[N:8][N:9]=1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.C(Cl)(Cl)Cl.CC(O)C>[CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[C:29]2[CH:34]=[C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:32]=[C:31]([NH:45][CH:46]([CH3:48])[CH3:47])[N:30]=2)=[N:8][N:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(COc2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ccc(-c5nnc(NC(C)C)o5)cc34)nc(NC(C)C)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COc1ccc(COc2cc(-c3c[nH]c4ccc(-c5nnc(NC(C)C)o5)cc34)nc(NC(C)C)n2)cc1
Temperature: 100 °C
Yield: 90.7 %

Procedure:
A glass microwave reaction vessel was charged with N-isopropyl-5-(3-(2-(isopropylamino)-6-((4-methoxybenzyl)oxy)pyrimidin-4-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (100 mg, 0.150 mmol) and NaOH (0.3 mL, 3.00 mmol) in p-dioxane (1.0 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 1 h. The mixture was diluted with CHCl3/iPrOH (4:1) and washed with water. The organic layer was dried, filtered and concentrated to give the crude N-isopropyl-5-(3-(2-(isopropylamino)-6-((4-methoxybenzyl)oxy)pyrimidin-4-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (70 mg, 0.136 mmol, 91% yield), which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 514.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)(=O)C>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Reaction time: 16 h
Yield: 71.5 %

Procedure:
1-tert-Butoxycarbonyl-4-piperidone (4 g, 0.0201 mol, 1.3 eq) and 4-hydroxypiperidine (1.56 g, 0.054 mol, 1 eq) were stirred at room temperature in ethanol (20 ml) and acetic acid (2 ml) for 3 hours. To the solution was added 0.56 g of 5% palladium on carbon type 440 Johnson Matthey catalyst. The reaction was then hydrogenated under a pressure of 3 bar at room temperature for 16 hours. The catalyst was filtered off through CELITE™, washed with ethanol (40 ml) and evaporated in vacuo to an oil. The oil was dissolved in water (25 ml) and the aqueous washed twice with dichloromethane (2×20 ml). The aqueous was basified (5M aqueous sodium hydroxide, 12 ml) and the aqueous washed twice with dichloromethane (2×30 ml). The combined organics were dried (magnesium sulphate). The solution was filtered and evaporated in vacuo to give 4-(hydroxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester as a yellow oil (3.13 g, 71.5% yield, 95.4% purity HPLC area %).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:37][C:38]2[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=2[F:45])[C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[CH3:5].[Cl:46][C:47]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[C:48]=1[C:49](O)=[O:50]>>[Cl:46][C:47]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[C:48]=1[C:49]([NH:1][CH2:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:37][C:38]2[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:39]=2[F:45])[C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:20])(=[O:21])[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[CH3:5])=[O:50]
Reactant: CC(CCN)N1CCC(N(Cc2cc(Cl)ccc2F)c2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2)CC1
Reactant: Cc1cccc(Cl)c1C(=O)O
Product: Cc1cccc(Cl)c1C(=O)NCCC(C)N1CCC(N(Cc2cc(Cl)ccc2F)c2ccc(S(=O)(=O)N(Cc3ccccc3)Cc3ccccc3)cc2)CC1
Yield: 92.8 %

Procedure:
Using general procedure E, 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-chloro-2-fluoro-benzyl)-amino]-N,N-dibenzyl-benzenesulfonamide (see EXAMPLE 209) (339 mg, 0.52 mmol) and 2-chloro-6-methylbenzoic acid (116 mg, 0.68 mmol) afforded 2-chloro-N-(3-{4-[(5-chloro-2-fluoro-benzyl)-(4-dibenzylsulfamoyl-phenyl)-amino]-piperidin-1-yl}-butyl)-6-methyl-benzamide as a yellow oil (387 mg, 100%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C:16](=O)[C:15]2([CH3:22])[CH3:21])=[CH:11][CH:10]=1>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]2([CH3:22])[CH3:21])=[CH:23][CH:24]=1
Reactant: COc1ccc(CN2CCNC(=O)C2(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN2CCNCC2(C)C)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
LiAlH4 (1 M in THF, 27.8 mL, 27.8 mmol, 1.5 equiv) was added to a solution of 4-(4-methoxy-benzyl)-3,3-dimethyl-piperazin-2-one (Step 108.3) (4.6 g, 18.5 mmol) in THF (100 mL) at 50° C., under an argon atmosphere. The resulting mixture was stirred for 2 h at 50° C., quenched by sequential addition of H2O (1 mL), 1 N NaOH (1 mL) and H2O (3 mL), filtered through a pad of celite and concentrated to afford 4.0 g of the title compound as a white solid: ESI-MS: 235.2 [M+H]+.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3[CH:23]=[C:22]([S:24]([NH:27][CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)(=[O:26])=[O:25])[C:21]([CH3:35])=[CH:20][C:19]=3[CH3:36])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.O.CCOC(C)=O>CC(N(C)C)=O>[NH2:17][C:18]1[C:19]([CH3:36])=[CH:20][C:21]([CH3:35])=[C:22]([S:24]([NH:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)(=[O:26])=[O:25])[CH:23]=1
Reactant: Cc1cc(C)c(S(=O)(=O)NCc2cccnc2)cc1NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: O
Solvent: C1CCNCC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)c(S(=O)(=O)NCc2cccnc2)cc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 9H-fluoren-9-ylmethyl(2,4-dimethyl-5-{[(pyridin-3-ylmethyl)amino]sulfonyl}phenyl)carbamate (1.2 g, 2.3 mmol) in DMA (4.5 mL) was added piperidine (0.8 mL, 7.9 mmol). The reaction stirred at room temperature for one hour and was then poured into a separatory funnel containing water and EtOAc. The reaction was extracted with EtOAc and the organic extracts were dried over Na2SO4 and concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH3:20][C:21]1[S:22][C:23]([C:27]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=2[CH:29]=O)=[C:24]([CH3:26])[N:25]=1.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:29]1[C:28]1[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:27]=1[C:23]1[S:22][C:21]([CH3:20])=[N:25][C:24]=1[CH3:26])([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: COc1ccc(-c2sc(C)nc2C)c(C=O)c1
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc(C)nc2C)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Reaction time: 4 h
Yield: 42.9 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (100 mg, 0.39 mmol) in DMF (5 mL) is added 2-(2,4-dimethyl-thiazol-5-yl)-5-methoxy-benzaldehyde (144 mg, 0.58 mmol) at room temperature. Oxone (239 mg, 0.39 mmol) in H2O (1 mL) is added and the solution is stirred for 4 hours. Saturated sodium thiosulfate solution (5 mL) is added and the mixture is extracted with EtOAc (3×10 mL) and H2O (10 mL). The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound (81 mg, 43%) as a pale brown foam. LCMS (ESMS): m/z 485.72 (M++1)
Reaction SMILES: OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH3:15][NH:16][C:17]1[N:22]=[C:21]([C:23]2[C:24]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH2:39])=[NH:38])=[CH:32][CH:31]=3)=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:47]([CH3:56])[C:48]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=O.CO.O>CS(C)=O>[CH3:15][NH:16][C:17]1[N:22]=[C:21]([C:23]2[C:24]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]4[NH:39][C:47]([CH3:56])=[C:48]([C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)[N:38]=4)=[CH:32][CH:31]=3)=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][N:18]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(NC(=N)N)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nc(-c4ccccc4)c(C)[nH]3)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)guanidine bis-TFA salt (0.200 g, 0.35 mmol) and potassium carbonate (0.20 g, 1.4 mmol) in 1 mL DMSO was added 2-bromo-1-phenylpropan-1-one (0.054 ml, 0.35 mmol). The reaction was allowed to stir at ambient temperature for 30 min, then 70° C. After 16 h, the reaction was quenched by addition of water and was extracted with EtOAc. The organic layer was dried over anhyd. Sodium sulfate, filtered, and concentrated in vacuo. The resulting green/brown oil was purified by silica gel chromatography (40 g, 0-100% 90/10 MC/MeOH in MC) to give an oil. This was lyophilized from MeOH/water to give N-methyl-4-(2-(4-(5-methyl-4-phenyl-1H-imidazol-2-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amine as an off-white solid. MS m/z=450 [M+H]+. Calc'd for C26H23N7O: 449.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.O.[NH2:14][NH2:15]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH2:11])[NH:14][N:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: N#CCC(=O)c1cccc(Cl)c1
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2cccc(Cl)c2)n[nH]1
Temperature: 80 °C
Reaction time: 15 h
Yield: 71.2 %

Procedure:
To a stirring solution of 3-(3-chlorophenyl)-3-oxo-propionitrile (2 g, 11.1 mmol) in absolute ethanol (20 mL) was added hydrazine hydrate (3.24 mL, 67 mmol). The reaction mixture was stirred at 80° C. for 15 h, cooled to room temperature, concentrated in vacuo, and absorbed on silica gel. Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 1.53 g (70%) of 5-(3-chloro-phenyl)-2H-pyrazol-3-ylamine as a green solid. 1H NMR (d6-DMSO) δ: 11.6 and 11.9 (2 broad s, 1H, NH+tautomer), 7.69 (s, 1H), 7.60 (d, 1H), 7.38 (t, 1H), 7.29 (d, 1H), 5.77 (broad s, 1H), 4.98 (broad s, 2H, NH2).