Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[CH:62]=[CH:61][C:13]([CH2:14][N:15]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C:23]3[CH:24]=[C:25]([CH2:38][N:39]4[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41][CH2:40]4)[CH:26]=[N:27][C:28]=3[NH:29][C:30]3[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=3)[N:17]=2)=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH3:70][S:71](Cl)(=[O:73])=[O:72]>ClCCl>[CH3:8][O:9][C:10]1[CH:62]=[CH:61][C:13]([CH2:14][N:15]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[C:16]2[N:17]=[C:18]([C:23]3[C:28]([NH:29][C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=4)=[N:27][CH:26]=[C:25]([CH2:38][N:39]4[CH2:44][CH2:43][N:42]([S:71]([CH3:70])(=[O:73])=[O:72])[CH2:41][CH2:40]4)[CH:24]=3)[N:19]=[C:20]([CH3:22])[N:21]=2)=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3Nc3cnc(OC)nc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
TFA (4.00 mL, 51.9 mmol) was added slowly to an ice-bath cooled stirred solution of tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(2-methoxypyrimidin-5-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate (413 mg, 0.551 mmol) in dichloromethane (5.00 mL, 78 mmol) and the resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum to remove as much TFA as possible. The sticky residue was taken up in dichloromethane (5.00 mL) to which triethylamine (0.384 mL, 2.76 mmol) and methanesulfonyl chloride (0.129 mL, 1.654 mmol) were slowly added at 0° C. The mixture was stirred at 0° C. for 1 h and concentrated. The crude product was partitioned between 1 N NaOH(aq) and dichloromethane (20 mL each), and the separated aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product which was purified by flash column chromatography (ISCO Combiflash system, pure DCM to 3% MeOH in DCM w/NH3) to give N,N-bis(4-methoxybenzyl)-4-(2-(2-methoxypyrimidin-5-ylamino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (277 mg, 0.381 mmol, 69.1% yield) as a brown foam. m/z (ESI, +ve ion) 727.2 (M+H)+.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:30])[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[CH3:14].CI>C1COCC1.C(OCC)(=O)C>[CH2:13]([O:15][C:16](=[O:30])[C:17]1([CH3:1])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]1)[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 105 %

Procedure:
To a stirring solution of diisopropylamine (20.0 mmol, 2.02 g) in THF (50 mL) cooled to -78° C. was added n-butyllithium (21.7 mmol, 8.68 mL of a 2.5M solution in hexanes). N-tert-butoxycarbonyl isonipecotic acid ethyl ester (16.7 mmol, 4.5 g) was then added dropwise followed by methyl iodide (16.7 mmol, 2.37 g)and the reaction allowed to warm to room temperature. The mixture was then diluted with ethyl acetate (500 mL) and washed with water (1×200 mL), 10% KHSO4 (200 mL) and brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 4.76 g of the title compound as a pale yellow oil.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:14]1[S:15][CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=1)CC(C)C)=[O:7])(C)(C)C.[C:24]([NH:34][C@H:35](C(O)=O)[CH2:36][CH:37]([CH3:39])[CH3:38])([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C(N[C@H](C(N[C@H](C(O)=O)CC(C)C)=O)CC(C)C)(OCC1C=CC=CC=1)=O>>[CH2:27]([O:26][C:24]([NH:34][C@@H:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:6]([NH:8][CH2:9][C:14]1[S:15][CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=1)=[O:7])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1csc([C@H](CC(C)C)NC(=O)OC(C)(C)C)n1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Product: CCOC(=O)c1csc(CNC(=O)[C@H](CC(C)C)NC(=O)OCc2ccccc2)n1

Procedure:
Following the procedure of Example 13, except substituting 1-(tert-butoxycarbonyl)amino-1-(4-carboethoxythiazol-2-yl)methane for (1S)-1-(tert-butoxycarbonyl)amino-1-(4-carboethoxythiazol-2-yl)-3-methylbutane, and N-Cbz-L-leucine for N-Cbz-L-leucinyl-L-leucine, the title compound was prepared (0.120 g, 32%). MS (MH+): 434.2.
Reaction SMILES: CO[C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].COC(C1ON=C(OC[C:36]2[C:37]([C:42]3C=CC=CN=3)=[N:38]OC=2C)C=1)=O.C(N)(C)C>>[CH:37]([NH:38][C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4])([CH3:42])[CH3:36]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)ns1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Solvent: CC(C)N
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NC(C)C)sn1
Yield: 77 %

Procedure:
As described for example 14e, 3-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-isothiazole-5-carboxylic acid methyl ester (120 mg, 0.34 mmol), instead of 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester, was converted, using isopropyl amine (24 mg, 0.41 mmol), to the title compound (99 mg, 77%) which was obtained as a white solid after purification by chromatography (silica, heptane:ethyl acetate=4:1 to 1:4). MS: m/e=377.2 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:37])=[C:23]([N:25]4[CH2:34][CH2:33][C:32]5[C:27](=[C:28]([F:36])[CH:29]=[CH:30][C:31]=5[F:35])[CH2:26]4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.CCOCC>[F:35][C:31]1[CH:30]=[CH:29][C:28]([F:36])=[C:27]2[C:32]=1[CH2:33][CH2:34][N:25]([C:23]1[C:22]([NH2:37])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:18]=3)[CH:24]=1)[CH2:26]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(N4CCc5c(F)ccc(F)c5C4)c3)cn2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1N1CCc2c(F)ccc(F)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{4-[6-Amino-5-(5,8-difluoro-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (26 mg, 0.051 mmol) was dissolved in MeOH (20 mL), 1.0 M of HCl in Et2O (20 mL) was added, and the mixture was stirred at rt overnight. The solvent was removed in vacuo to give the title compound as a brown solid. 1H NMR (400 MHz, CD3OD): δ=2.33-2.42 (m, 4H), 3.08 (t, J=5.2 Hz, 2H), 3.23-3.36 (m, 2H), 3.39 (t, J=5.6 Hz, 2H), 3.59 (d, J=12.8 Hz, 2H), 4.24 (s, 2H), 4.62-4.72 (m, 1H), 6.99-7.04 (m, 2H), 7.97 (s, 1H), 8.01 (s, 1H), 8.07 (s, 1H), 8.39 (s, 1H). MS(ES+): m/z=411.08 (42) [MH+]. HPLC: tR=2.10 min (ZQ2, polar—5 min).
Reaction SMILES: C([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH2:14][CH2:15][N:16]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])(=[O:29])=[O:28])[CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[CH:11][CH:12]=1)=[O:7])(C)(C)C>Cl.O1CCOCC1>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[S:27]([N:16]([CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[CH2:15][CH2:14][CH2:13][C:10]1[S:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][CH:11]=1)(=[O:28])=[O:29]
Reactant: CC(C)(C)OC(=O)c1ccc(CCCN(CCCc2cccc(Cl)c2)S(=O)(=O)c2ccccc2Cl)s1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CCCN(CCCc2cccc(Cl)c2)S(=O)(=O)c2ccccc2Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(3-((2-chloro-benzenesulfonyl)-(3-(3-chloro-phenyl)-propyl)-amino)-propyl)-thiophene-2-carboxylic acid tert-butyl ester prepared of Example 6, Step A (0.010 g, 0.010 mmol) in 4N HCl in 1,4 dioxane (3 mL) and the reaction was stirred overnight at room temperature. HCl (g) was bubbled in until reaction was determined to be complete by thin layer chromatography. The reaction mixture was concentrated in vacuo. The resulting organic residue was azeotroped with CCl4 to produce a powder (5 mg). 1H NMR (400 MHz, CDCl3) δ 8.00 (d, 1H, J=4), 7.00-7.72 (m, 8H), 6.75 (d, 1H, J=4), 3.20-3.40 (m, 4H), 2.81 (m, 2H), 2.52 (m, 2H), 1.90 (m, 2H), 1.80 (m, 2H), 1.20 (m, 2H); MS 509.9 (M−1).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Br[C:9]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]2[C:15](=[O:27])[N:14]3[C:28]([CH3:31])=[N:29][N:30]=[C:13]3[N:12]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:11]=2[N:10]=1>CN(C=O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:17]2[C:16]3[C:15](=[O:27])[N:14]4[C:28]([CH3:31])=[N:29][N:30]=[C:13]4[N:12]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:11]=3[N:10]=[C:9]2[N:4]2[CH2:5][NH:6][CH:7]=[N:3]2)=[CH:20][CH:21]=1.[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:17]2[C:16]3[C:15](=[O:27])[N:14]4[C:28]([CH3:31])=[N:29][N:30]=[C:13]4[N:12]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:11]=3[N:10]=[C:9]2[N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH:20][CH:21]=1
Reactant: CCCCCn1c2nc(Br)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCn1c2nc(-n3cncn3)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Product: CCCCCn1c2nc(N3CNC=N3)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.2 %
Yield: 27 %

Procedure:
Sodium hydride 60% in mineral oil (18 mg, 0.74 mmol) was added to a solution of 1H-1,2,4-Triazole (45 mg, 0.65 mmol) in DMF (10 mL) at room temperature. After stirring for 1 hour at room temperature, 7-bromo-6-(4-methoxybenzyl)-3-methyl-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (200 mg, 0.40 mmol) in DMF was added to above solution and the mixture was stirred overnight. The reaction was quenched with a drop of water and the reaction mixture was purified by pre LC-MS to give the desired product (53 mg, 27.2%) and its region-isomer 6-(4-methoxybenzyl)-3-methyl-9-pentyl-7-(1H-1,2,4-triazol-1-yl)-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (53 mg, 27%). LCMS calculated for C22H26N9O2(M+H): 448.2; found 448.2.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[F:15][C:16]([F:37])([S:33](F)(=[O:35])=[O:34])[C:17]([F:32])([F:31])[C:18]([F:30])([F:29])[C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22]>C1(C)C=CC=CC=1>[C:16]([S:33]([NH:7][CH2:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])(=[O:35])=[O:34])([C:17]([C:18]([C:19]([C:20]([C:21]([F:23])([F:24])[F:22])([F:25])[F:26])([F:28])[F:27])([F:30])[F:29])([F:32])[F:31])([F:37])[F:15]
Reactant: CN(C)CCCN
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)CCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
A mixture of dimethylaminopropylamine, H2NC3H6N(CH3)2 (12.2 g, 0.12 mole), triethylamine, (C2H5)3N (8.1 g, 0.08 mole) and toluene (60 g) was first prepared at ambient temperature and about atmospheric pressure in an inert atmosphere of nitrogen. To this mixture was added perfluorohexanesulfonyl fluoride, C6F13SO2F (41.0 g, 0.10 mole). The total mixture was then heated in a stainless steel reaction vessel at 90° C. for a period of about 3 hours forming a homogeneous reactant solution. During this period the aforementioned Reaction (a) takes place to produce intermediate N-[3-(N',N'-dimethylamino)propyl]perfluorohexane sulfonamide, C6F13SO2N(H)C3H6N(CH3)2.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([CH3:17])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)Cl>[Br:20][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH:4]([CH:3]([CH3:17])[C:2]([F:18])([F:19])[F:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(c1ccc(C)cc1)C(C)C(F)(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(c1ccc(CBr)cc1)C(C)C(F)(F)F

Procedure:
2.25 g (8.2 mmol) of ethyl 4,4,4-trifluoro-3-methyl-2-(4-methylphenyl)butanoate, 1.53 g (8.6 mmol) of N-bromosuccinimide and 67 mg (0.41 mmol) of 2,2′-azobis-(2-methylpropionitrile) in 36 ml of trichloromethane were stirred under reflux overnight. After the reaction had gone to completion, the succinimide was filtered off and the filter residue was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 40:1). This gave 2.667 g (7.5 mmol, 92% of theory) of a yellowish oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][NH:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:32][C:33]([F:37])([F:36])[CH2:34]I.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[CH:18][N:17]([CH2:34][C:33]([F:37])([F:36])[F:32])[N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)CI
Reactant: c1ccc(COc2ccc(-c3n[nH]cc3-c3ccncc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Temperature: 60 °C

Procedure:
To a solution of 4-[3-(4-Benzyloxy-phenyl)-1H-pyrazol-4-yl]-pyridine (0.42 g) in dimethyl formamide (7 ml) was added cesium carbonate (0.65 g) and 1,1,1-Trifluoro-2-iodo-ethane (0.29 ml). The reaction mixture was heated at 60° C. for 24 h, poured into water and extracted 3× with dichloromethane. Purification via biotage MPLC chromatography, eluting with 5% methanol/0.5% ammonium hydroxide/70% ethyl acetate/hexane provided the title compound. MS: (M+H m/z=410.0).
Reaction SMILES: BrC1C=C(C=CC=1)C(NC(C1N=NC(NC2C=C(S(CC)(=O)=O)C=CC=2OC)=NC=1)C)=O.[Br:33][C:34]1[CH:35]=[C:36]([CH:52]=[CH:53][CH:54]=1)[C:37]([NH:39][CH:40]([C:42]1[N:47]=[N:46][C:45](S(C)(=O)=O)=[N:44][CH:43]=1)[CH3:41])=[O:38].[Cl:55][C:56]1[CH:57]=[C:58]([CH:60]=[CH:61][C:62]=1[N:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1)[NH2:59].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:33][C:34]1[CH:35]=[C:36]([CH:52]=[CH:53][CH:54]=1)[C:37]([NH:39][CH:40]([C:42]1[N:47]=[N:46][C:45]([NH:59][C:58]2[CH:60]=[CH:61][C:62]([N:63]3[CH2:64][CH2:65][O:66][CH2:67][CH2:68]3)=[C:56]([Cl:55])[CH:57]=2)=[N:44][CH:43]=1)[CH3:41])=[O:38]
Reactant: CC(NC(=O)c1cccc(Br)c1)c1cnc(S(C)(=O)=O)nn1
Reactant: Nc1ccc(N2CCOCC2)c(Cl)c1
Agent: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(NC(=O)c1cccc(Br)c1)c1cnc(Nc2ccc(N3CCOCC3)c(Cl)c2)nn1
Yield: 16.7 %

Procedure:
In a similar manner as described for Intermediate 23, 3-bromo-N{1-[3-(methylsulfonyl)-1,2,4-triazin-6-yl]ethyl}benzamide (Intermediate 6) (200 mg, 0.52 mmol), 3-chloro-4-morpholin-4-ylaniline (200 mg, 0.94 mmol) and 4-toluenesulfonic acid monohydrate (20 mg) in tetrahydrofuran (10 mL) gave 3-bromo-N-(1-{3-[(3-chloro-4-morpholin-4-ylphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (0.045 g) as a white solid. MS m/z 517, 519 (M+1, M+3).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=2[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:9][CH:8]=1.C(=O)=O.C(O)(C)C>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]2[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=2[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][CH:12]=1
Reactant: COc1ccc(Nc2ccccc2C(=O)N2CCCCC2)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(c1ccccc1Nc1ccc(O)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
Boron tribromide (10 ml in 25 ml of methylene dichloride) was added dropwise over a 30 minute period to a solution of 15.5 g of 1-[2-(4-methoxyphenylamino)benzoyl]piperidine in 80 ml of dry methylene dichloride cooled in a bath of Dry Ice and isopropyl alcohol. The reaction mixture was allowed to warm to room temperature and to stand overnight. The solvent was then removed in vacuo, and the residue was treated with 100 ml of distilled water and made basic with about 250 ml of saturated sodium bicarbonate solution. The solid which formed was collected by filtration and recrystallized from ethanol to give 10.2 g of 1-[2-(4-hydroxyphenylamino)benzoyl]piperidine, colorless powder, m.p. 199°-201° C.(decompn.).
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:23]=[CH:22][C:12]([CH2:13]P(=O)(OCC)OCC)=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[OH:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O.CCCCCC.CCOC(C)=O>C1COCC1>[CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12](/[CH:13]=[CH:35]/[C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[OH:32])=[CH:22][CH:23]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CCOP(=O)(Cc1ccc(-c2nc3ccc(C)cc3s2)cc1)OCC
Reactant: O=Cc1ccccc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc2nc(-c3ccc(/C=C/c4ccccc4O)cc3)sc2c1
Yield: 58.2 %

Procedure:
Prepared as described in the Alkene Formation section using diethyl 4-(6-methylbenzothiazol-2-yl)benzylphosphonate (0.30 g, 0.80 mmol) in dry THF (25 ml), potassium t-butoxide (0.19 g, 1.68 mmol) and 2-hydroxybenzaldehyde (0.097 g, 0.80 mmol) in dry THF (10 ml) to give the title compound (0.16 g, 60%) as a yellow solid after work-up and flash chromatography (1:1 Hexane/EtOAc).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:40])OC3C=CC=CC=3)[CH2:26]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1)(=[O:3])[NH2:2].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.CCN(CC)CC>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:40])[CH2:26]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1)(=[O:3])[NH2:2]
Reactant: C1COCCN1
Reactant: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)Oc3ccccc3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)N3CCOCC3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Yield: 45.7 %

Procedure:
A solution of (R)-phenyl 1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyridin-2-yl)piperidin-3-ylcarbamate (30 mg, 0.055 mmol), morpholine (7.20 mg, 0.083 mmol), and Et3N (0.012 mL, 0.083 mmol) in CH2Cl2 (2 mL) was heated at 50° C. overnight. The reaction mixture was diluted with CH2Cl2, washed with satd. NaHCO3 and water, and concentrated. The residue was purified by prep-HPLC and the product containing fractions were collected, neutralized with saturated NaHCO3, extracted with CH2Cl2, separated, and concentrated to obtain 13.5 mg of (R)—N-(1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino) pyridin-2-yl)piperidin-3-yl)morpholine-4-carboxamide as a light yellow solid as free base.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]2([CH2:15][CH2:14]2)[CH2:12][N:11]2[N:16]=[C:17]([I:22])[C:18]([C:19]([OH:21])=O)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:26](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:19]([C:18]1[C:17]([I:22])=[N:16][N:11]2[CH2:12][C:13]3([CH2:15][CH2:14]3)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]=12)(=[O:21])[NH2:26]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(=O)O)c(I)nn2CC12CC2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(I)nn2CC12CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
To a stirred solution of Intermediate 350E (0.43 g, 1.026 mmol) in DMF (4 mL) was added NH4Cl (0.274 g, 5.13 mmol), HATU (0.780 g, 2.051 mmol) and DIPEA (0.537 mL, 3.08 mmol) and the resulting solution was stirred at RT for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3×25 mL) The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated. The residue was triturated with diethyl ether, filtered and dried to afford Intermediate 350F as an off-white solid (0.4 g, 89%). MS(ES): m/z=419 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 6.56 (br. s., 1H), 5.54 (br. s., 1H), 4.96 (br. s., 2H), 4.04 (br. s., 2H), 1.44 (s, 9H), 1.18 (m, 2H), 0.97-0.84 (m, 2H).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:15](Cl)([Cl:17])=[O:16]>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:17][C:15]([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16]
Reactant: OC1CCCCC1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cl)OC1CCCCC1

Procedure:
A mixture of cyclohexanol (500 mg, 5.0 mmol) and triethylamine (836 μl) in methylene chloride (4 ml) was added to a 0° C. solution of phosgene in toluene (5.3 ml, 20%). The resultant mixture was stirred at 0° C. for 2.5 hours. TLC showed completion of the reaction. The solvent was removed and anhydrous ether (50 m l) was added. The mixture was filtered and the filtrate was concentrated to give 726 mg of the desired product as a colorless oil which was used without further purification. IR (film) 1776 cm−1.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[O:6])[CH2:3][CH2:2]1.[C:19]([O:23][C:24](=[O:40])[NH:25]/[C:26](/N1C=CC=N1)=[N:27]/[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl>[C:30]([O:29][C:28]([NH:27]/[C:26](/[NH:18][C:15]1[CH:14]=[CH:13][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@@H:7]2[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[O:6])=[CH:17][CH:16]=1)=[N:25]/[C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:40])=[O:34])([CH3:33])([CH3:32])[CH3:31]
Reactant: Nc1ccc(N2CCC[C@@H]2C(=O)NC2CC2)cc1
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)n1cccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)Nc1ccc(N2CCC[C@@H]2C(=O)NC2CC2)cc1
Reaction time: 8 h

Procedure:
(R)-1-(4-Amino-phenyl)-pyrrolidine-2-carboxylic acid cyclopropylamide (Method 61; 1.2 g, 4.9 mmol) in DCM (60 ml) was added di-tert-butyl[(Z)-1H-pyrazol-1-ylmethylylidene]biscarbamate (1.9 g, 6.1 mmol) in one portion. The reaction was stirred overnight before removal of the solvent in vacuo. The residue was purified via column chromatography eluting with 20% ethylactetate/isohexane, 50% EtOAc/isohexane and finally 100% EtOAc. The title compound was obtained as a white foam (2.0 g, 81%). NMR (299.954 MHz, CDCl3) 11.63 (s, 1H), 10.09 (s, 1H), 7.60 (s, 1H), 7.40 (d, 2H), 6.45 (m, 3H), 3.92 (t, 1H), 3.59 (t, 1H), 3.19 (q, 1H), 2.69 (m, 1H), 2.29-2.22 (m, 2H), 2.03-1.84 (m, 2H), 1.53 (s, 9H), 1.49 (s, 9H), 0.80-0.68 (m, 2H), 0.44-0.32 (m, 2H); m/z 488.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:13]([NH2:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[ClH:1].[CH2:13]([NH:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Oc1ccc2nccc(Cl)c2c1
Reactant: CCCCCCCCCCN
Product: CCCCCCCCCCNc1ccnc2ccc(O)cc12
Product: Cl

Procedure:
In a manner similar to that described in Example 49, Part B, 4-chloroquinolin-6-ol and decylamine were transformed into the title compound as the hydrochloride salt: m.p. 197°-199° C.