Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:16]2[CH2:19][CH:18]([NH2:20])[CH2:17]2)=[CH:11][CH:10]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:29]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:16]2[CH2:17][CH:18]([NH:20][S:34]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)(=[O:36])=[O:35])[CH2:19]2)=[CH:11][CH:10]=1
Reactant: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccnc1
Temperature: 0 °C
Yield: 68.5 %

Procedure:
0.79 cm3 of triethylamine is added, at room temperature under an argon atmosphere, to a solution of 0.7 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylamine in 25 cm3 of dichloromethane. The mixture is cooled to around 0° C. before adding thereto a solution of 1.2 g of pyrid-3-ylsulfonyl chloride in 25 cm3 of dichloromethane, and then it is stirred at room temperature for 16 hours. The reaction mixture is diluted with 50 cm3 of dichloromethane and is then washed with twice 25 cm3 of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluant: dichloromethane/methanol (97.5/2.5 by volume)]. 0.7 g of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}pyrid-3-ylsulfonamide is obtained in the form of a cream-colored foam which solidifies in the presence of isopropanol into a cream-colored powder melting at 164° C.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][NH2:26]>>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][NH:26][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: NCCc1ccccc1F
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: COc1cc(CNCCc2ccccc2F)ccc1Oc1ccc(C(N)=O)cn1
Yield: 84.5 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-fluorophenethylamine (0.0256 g, 0.184 mmol) gives the title compound (0.0615 g, 84.7%): TOF MS ES+ 396.2 (M+H)+, HRMS calcd for C22H23N3O3F 396.1723 (M+H)+, found 396.1722, min 0.39; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.8 min, 98.9% purity.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32]
Reactant: COC(=O)[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Yield: 97 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)-cyclohexanecarboxylate (2.42 g, 5.43 mmol) in methanol was treated with 600 mg of 10% Pd/C and hydrogenated at 55 psi of H2 in a Parr shaker overnight. The catalyst was filtered and the filtrate concentrated in vacuo to give 1.64 g of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)-cyclohexanecarboxylate as a white solid. This was used without further purification.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11](C)[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]([O:20][C:21](=[O:39])[C@@H:22]([NH2:38])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:39])[CH:22]([NH:38][C:12](=[O:14])[CH2:11][NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Product: CC(C)(C)OC(=O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)CNC(=O)N1CCCCCC1
Yield: 46.3 %

Procedure:
A solution of the product from Example AE ((S)-2-[(azepane-1-carbonyl)-amino]-propanoic acid) (0.50 g, 2.38 mmol) and the product from Example A ((S)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (0.76 g, 2.33 mmol) were coupled according to the procedure described in Example AH. The reaction mixture was purified by chromatography (silica gel, 1:1 EtOAc/heptane) to give the title compound as a white foam (0.55 g, 43%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C:10]23[C:16]([CH3:18])([CH3:17])[C:13]([CH3:19])([CH2:14][CH2:15]2)[C:12](=[O:20])[CH2:11]3)[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[CH:31]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:29]=[CH:28][C:25]=1[CH:26]=O.C([O-])(=O)C.[NH4+]>CCO>[Cl:21][C:5]1[C:6]([NH:9][C:10]23[C:16]([CH3:17])([CH3:18])[C:13]([CH3:19])([CH2:14][CH2:15]2)[C:12](=[O:20])[CH2:11]3)=[C:7]2[N:8]=[C:26]([C:25]3[CH:28]=[CH:29][C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:31][C:24]=3[O:23][CH3:22])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: COc1cc(N2CCOCC2)ccc1C=O
Reactant: CC12CCC(Nc3c(Cl)cnc(N)c3N)(CC1=O)C2(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cc(N2CCOCC2)ccc1-c1nc2c(NC34CCC(C)(C(=O)C3)C4(C)C)c(Cl)cnc2[nH]1
Temperature: 70 °C

Procedure:
4-(2,3-diamino-5-chloropyridin-4-ylamino)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (10) (300 mg, 0.97 mmol), 2-methoxy-4-morpholinobenzaldehyde (193 mg, 0.873 mmol) were taken in EtOH (15 ml) to which ammonium acetate (112 mg) was added and the reaction mixture was heated at 70° C. for 48 h. Crude LCMS showed the desired product along with trace of starting material. The reaction mixture was allowed to come to rt and the precipitated was filtered and washed well with ethanol to afford the desired product (495 mg, 24%) as an off white solid. NMR: δ (1H, 400M Hz, DMSO-d6): 0.91 (6H, s), 1.09 (3H, s), 1.40-1.50 (1H, m), 1.70-1.90 (2H, m), 2.40-2.60 (1H, m), 3.00-3.10 (1H, m), 3.20-3.40 (4H, m), 3.60-3.80 (5H, m), 3.94 (3H, s), 5.36 (1H, s), 6.64 (1H, s), 6.72 (1H, d, J=8.8 Hz), 7.94 (1H, d, J=8.8 Hz), 8.01 (1H, s), 12.29 (1H, s). LCMS (254 nm): [M+H]+ 510.25 (98.08%). HPLC: (220 nm) 97.36%
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH2:22](O)[CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH:28]=[CH:29][CH2:30][CH3:31].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Br:20][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH3:31]
Reactant: BrBr
Reactant: CCC=CCC=CCCCO
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC/C=C\C/C=C\CCCBr
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32 %

Procedure:
A solution of triphenylphosphine (20.9 g, 80 mmol) in CH2Cl2 (100 ml) was treated with Br2 (7.8 g, 49 mmol) in CH2Cl2 (15 mL, 0° C.) and the mixture was stirred at room temperature for 20 min. Into the slightly yellow suspension that formed, the crude mixture of 4 and 4Z,7Z)-4,7-decadien-1-ol (12.4 g) in CH2Cl2 (15 ml) was added dropwise. After stirring for 1 hour, a solution of saturated NaHCO3 (50 mL) and water (50 ml) were added. The mixture was extracted with pentane and combined extracts were stored overnight in a freezer. In this way, triphenylphosphine oxide could be crystallized and removed by filtration. Column chromatography followed by distillation at reduced pressure afforded 5 (3.48 g, 32% yield based on 1 of b.p. =80°-85° C./2.5 torr. 1H NMR (200 MHz) δ: 5.37 (m, 4H, CH=CH), 3.41 (t, J=6.6, 6.6 Hz, 2H, CH2 --Br), 2.80 (dd, J=6.4, 6.5 Hz, 2H, =CH--CH2 --CH=), 2.21 (dt, J=7.0, 6.9, 6.8, 6.9 Hz, 2H, CH2 -3), 2.07 (dq, J=7.4 Hz, CH2 -9), 1.91 (tt, J=6.7, 6.6, 7.0, 7.0, 2H, CH2 -2), 0.97 (t, J=7.5, 7.5 Hz, 3H, CH3). 13C NMR (100.6 MHz) δ: 132.1 (8), 129.8 (5), 127.6 (7), 127.0 (4), 33.4 (1), 32.5 (2), 25.6 (3), 25.5 (6), 20.6 (9), 14.3 (10). MS [EI, m/z (%)] 218 (M+, 15), 216 (17), 137 (6), 109 (13), 107 (18), 96 (14), 95 (78), 82 (18), 81 (74), 79 (22), 68 (27), 67 (100), 55 (17), 53 (15), 42 (11), 41 (38), 40 (40).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[O:14])=[CH:11][N:12]=2)[N:9]=1.O>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([CH:13]([C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)[OH:14])=[CH:11][N:12]=2)[N:9]=1
Reactant: O=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium borohydride (103 mg, 2.62 mmol) was added to a solution of (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-quinolin-6-yl-methanone (Stage 1.2, 1.62 g, 5.25 mmol) in ethanol (17 mL) and the solution was stirred at rt for 4 h. Water was then added and the mixture extracted with 9:1 DCM/MeOH. The organic extracts were dried, filtered and concentrated to afford the title compound as a brown solid (tR 1.0 min (conditions 1), MH+=311).
Reaction SMILES: [CH:1]1([CH:4]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:5][CH:6]=[C:7]([C:21]#[N:22])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[CH2:3][CH2:2]1.[Mg]>CO.Cl>[CH:1]1([CH:4]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:5][CH2:6][CH:7]([C:21]#[N:22])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: N#CC(=CCC(c1ccc(Cl)cc1)C1CC1)c1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: [Mg]
Solvent: CO
Product: N#CC(CCC(c1ccc(Cl)cc1)C1CC1)c1cccc(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A solution of 0.9 gram (0.002 mole) of 1-cyclopropyl-1-(4-chlorophenyl) -4-cyano-4-(3-phenoxyphenyl)-3-butene in 15 ml of methanol was stirred, and 0.5 gram (0.002 mole) of magnesium was added. The reaction mixture was stirred for about one hour at which time an exothermic reaction occurred. The reaction mixture was cooled to 0° C. where it was stirred for one hour, and then it was allowed to warm to ambient temperature where it stirred for two hours. After this time the reaction mixture was diluted with 20 ml of aqueous 10% hydrochloric acid, and the mixture was extracted with diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.7 gram of 1-cyclopropyl-1-(4-chlorophenyl)-4-cyano-4-(3-phenoxyphenyl)butane. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]1[N:15]=[C:14]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[CH:12]=2)[N:7]=1.[CH2:28]([N:30]([CH2:45][CH3:46])[CH2:31][CH2:32][O:33][C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]([CH3:44])[CH3:43])[C:35]=1[CH:36]=O)[CH3:29]>>[CH2:45]([N:30]([CH2:28][CH3:29])[CH2:31][CH2:32][O:33][C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]([CH3:43])[CH3:44])[C:35]=1[CH2:36][N:20]1[CH2:21][CH2:22][CH:17]([NH:16][C:14]2[C:13]3[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[CH:12]=3)[N:7]=[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:27])[N:15]=2)[CH2:18][CH2:19]1)[CH3:46]
Reactant: COc1cc2nc(NCCN(C)C)nc(NC3CCNCC3)c2cc1OC
Reactant: CCN(CC)CCOc1cccc(N(C)C)c1C=O
Product: CCN(CC)CCOc1cccc(N(C)C)c1CN1CCC(Nc2nc(NCCN(C)C)nc3cc(OC)c(OC)cc23)CC1

Procedure:
Following General Procedure H, Compound 185 (34.6 mg, 0.093 mmol) and Compound 188 (58.2 mg, 0.22 mmol) were converted into the final product AGN-221250 as a yellow solid.
Reaction SMILES: C(OC(N1C[CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[CH2:31]([S:37]CCN)[C:32]1[O:36][CH:35]=[CH:34][CH:33]=1.C(N1CCC(N)C1)(OC(C)(C)C)=O>>[O:36]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:31][S:37][CH2:11][CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15]
Reactant: NCCSCc1ccco1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Agent: CC(C)(C)OC(=O)N1CCC(N)C1
Product: O=C(NCCSCc1ccco1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(furfurylthio)ethylamine of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 399 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.92 (1H, br. s.) 10.46 (1H, s) 8.29 (1H, t, J=5.71 Hz) 8.06 (1H, d, J=6.05 Hz) 7.84 (1H, d, J=5.37 Hz) 7.56 (1H, td, J=1.10, 0.54 Hz) 7.44 (1H, d, J=5.37 Hz) 7.38 (1H, dd, J=3.51, 1.76 Hz) 6.80 (1H, d, J=6.15 Hz) 6.57 (1H, d, J=3.32 Hz) 6.36 (1H, dd, J=3.17, 1.90 Hz) 6.28 (1H, dd, J=3.22, 0.59 Hz) 3.78 (2H, s) 3.36-3.44 (2H, m) 2.59 (2H, dd, J=7.96, 6.20 Hz)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][C:14]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([S:50]([CH3:53])(=[O:52])=[O:51])=[CH:46][CH:45]=3)=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([S:50]([CH3:53])(=[O:51])=[O:52])=[CH:46][CH:45]=3)=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(S(C)(=O)=O)cc4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(Cc3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 75 °C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
4-(2-(5-Fluoro-6-methoxypyridin-3-ylamino)-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (384.7 mg, 0.5228 mmol) was dissolved in trifluoroacetic acid (Aldrich redistilled 99+%, 5.0 mL, 65 mmol) and the reaction flask was fitted with a reflux condenser and placed in a preheated oil bath (75° C.) and stirred overnight. Then, the reaction was cooled to room temperature, concentrated, and treated with saturated sodium bicarbonate and 5 N NaOH and then with 5 N HCl to adjust the pH to 6. Then, DCM was added and the layers were separated. The aqueous phase was filtered, and the collected solid was combined with the organic phase. The aqueous phase was extracted with DCM, and these organic extracts were combined with the organic phase, concentrated, and purified on a silica gel column (30:1 DCM/2 N ammonia in MeOH to 10:1 DCM/2 N ammonia in MeOH). The solvent polarity was increased after most of the product had eluted. The fractions with product were collected, concentrated, treated with MeOH, and filtered. The solid was washed with MeOH, collected, and dried under high vacuum. The material was <95% pure by HPLC, so the solid was washed with EtOAc, filtered, collected, and dried under high vacuum in a water bath (40° C.) and then at room temperature overnight to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (61.3 mg, 24% yield) as a yellow powder. 1H NMR (d6-DMSO, 400 MHz) δ 11.89 (s, 1H), 8.65 (d, J=2.15 Hz, 1H), 8.40 (d, J=2.15 Hz, 1H), 8.38-8.30 (m, 2H), 7.86 (d, J=8.22 Hz, 2H), 7.90-7.84 (m, 1H), 7.74 (br s, 1H), 7.53 (d, J=8.22 Hz, 2H), 4.09 (s, 2H), 3.93 (s, 3H), 3.17 (s, 3H), 2.41 (s, 3H). m/z (ESI, +ve ion) 496 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Cl:9])[C:3]=1I.CCCCCC.C([Li])CCC.FC(F)(F)S(O[Si:28]([CH3:31])([CH3:30])[CH3:29])(=O)=O>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[Si:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: Clc1cc(Br)cc(Cl)c1I
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Si](C)(C)c1c(Cl)cc(Br)cc1Cl
Reaction time: 1 h
Yield: 89.5 %

Procedure:
The 2,6-Dichloro-4-bromoiodobenzene (4.48 g, 12.7 mmol) was dissolved in diethyl ether (50 ml). To the solution was then added dropwise a hexane solution of n-butyl lithium (1.56 M, 8.2 ml) at −78° C. At the same temperature, the mixture was then stirred for 1 hour. To the mixture was then added dropwise trimethylsilyl trifluoromethanesulfonate (3.2 ml, 16.5 mmol). The mixture was then stirred at −78° C. for 1 hour and at room temperature for 30 minutes. After the quenching of the reaction with water, the mixture was then extracted with ether. The resulting organic phase was then dried over magnesium sulfate. The solvent was then distilled off. The crude product thus obtained was then distilled under reduced pressure in a glass tube oven so that it was purified to obtain 3,5-dichloro-4-trimethylsilyl-bromobenzene (3.39 g; yield: 90%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]([NH2:16])=[O:15])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:6]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[C:33](F)[CH:32]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[C:35]([NH:1][C:2]3[S:3][C:4]([C:14](=[O:15])[NH2:16])=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=4)[N:6]=3)[CH:36]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: NC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(Nc3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2)CC1
Yield: 46.7 %

Procedure:
To a mixture of 0.35 g (1.38 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.2), 0.56 g (1.66 mmole) of 4-(3-fluoro-4-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (IV.21a) and 10 mL of dimethylformamide was added 2.24 g (6.90 mmole) of cesium carbonate. The mixture was heated at 70 degrees for 5 hours and then diluted with ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexanes (gradient 0:100-40:60) to give 0.37 g of 4-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazole-2-ylamino]-4-nitro-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester (VI.21).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([Cl:48])[C:34]=1[OH:49]>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1)=[CH:3][C:2]([C:37]1[CH:38]=[C:33]([Cl:32])[C:34]([OH:49])=[C:35]([Cl:48])[CH:36]=1)=[CH:11][CH:10]=2)(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CCCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl (trans-4-((6-bromo-3-butyrylquinolin-4-yl)amino)cyclohexyl)carbamate (49 mg, 0.10 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (47 mg, 0.16 mmol) to afford the desired product (35.2 mg, 61%) as a yellow-brown solid. ESI MS m/z 572 [C30H35Cl2N3O4+H]+
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:11][CH2:10][N:9](C(=O)C2C=CC(F)=CC=2)[CH2:8]1)=[O:6])[CH3:3]>>[CH2:2]([O:4][C:5]([C:7]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[CH2:11][CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)c2ccc(F)cc2)C1
Agent: Cl
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Temperature: 0 °C
Yield: 53.9 %

Procedure:
6M HCl aqueous solution (65 mL) was added to racemic 1-(4-fluoro-benzoyl)-3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (see Preparation 62) (6.3 g, 13.5 mmol) and the resulting mixture refluxed for 18 hours. The reaction mixture was evaporated to dryness. The resulting crystalline solid was dissolved in ethanol (25 mL), cooled to 0° C. and thionyl chloride added (1.46 mL, 19.81 mmol). The mixture was then heated at reflux for 16 hours. The mixture was partitioned between saturated sodium hydrogen carbonate solution (100 mL) and ethyl acetate (100 mL). The organic layer was separated, washed with water (100 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 2% methanol in dichloromethane to afford the title compound as a brown oil (2.5 g, 52%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]([CH3:13])=[CH2:12])=[C:4]([CH:14]([CH3:16])[CH3:15])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([CH:14]([CH3:16])[CH3:15])[CH:3]=1)[O:8][CH2:9][CH2:10][C:11]2([CH3:13])[CH3:12]
Reactant: C=C(C)CCOc1ccc(Br)cc1C(C)C
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)c1cc(Br)cc2c1OCCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-1-[(3-methylbut-3-en-1-yl)oxy]-2-(propan-2-yl)benzene (293 mg, 1.03 mmol) dissolved in dichloromethane (3.10 mL) was cooled to 0° C. and aluminum chloride (138 mg, 1.03 mmol) in dichloromethane (3.0 mL) was added via a syringe. The reaction mixture was stirred at 0° C. for 30 minutes. It was then poured into an Erlenmeyer flask containing a 10% aqueous NaOH solution and ice. The mixture was extracted with dichloromethane (2×), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel chromatography, eluting with 0-10% EtOAc/Hexanes to give the title compound as a colorless oil.
Reaction SMILES: [Cl:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.C(Cl)Cl.C[OH:16]>>[Cl:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N+:7]([O-:16])=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CO
Reactant: ClC1CCCc2ncccc21
Solvent: ClCCl
Product: [O-][n+]1cccc2c1CCCC2Cl

Procedure:
5-Chloro-5,6,7,8-tetrahydroquinoline from step 2 above was oxidized using the procedure as given in step 3 of Example 3. 5-Chloro 5,6,7,8-tetrahydroquinoline-N-oxide was obtained as a white solid (TLC Rf = 0.24 (97:3 CH2Cl2 : MeOH)).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[CH:23]=[O:24])=[CH:8][CH:7]=2)[CH:5]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-n2cnnc2)cc1
Product: O=C/C=C/c1ccc(-n2cnnc2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4H-1,2,4-triazol-4-yl)-benzaldehyde (prepared as described in WO 98/03476) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 200 (M+H)+.