Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=[N:9]1)=O)(C)(C)C.Br[C:23]1[CH:24]=[N:25][C:26]([C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])=[N:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[N:27][C:26]([C:29]3[CH:30]=[C:31]([NH2:32])[CH:33]=[CH:34][CH:35]=3)=[N:25][CH:24]=2)[CH:12]=[N:8]1
Reactant: Nc1cccc(-c2ncc(Br)cn2)c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: Nc1cccc(-c2ncc(-c3cn[nH]c3)cn2)c1
Temperature: 90 °C
Yield: 83.8 %

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (20.7 g; 70.4 mmol; 1.0 eq.), 3-(5-Bromo-pyrimidin-2-yl)-phenylamine (intermediate 4, 17.6 g; 70.4 mmol; 1.0 eq.), bis(triphenylphosphine)palladium(II) chloride (4.94 g; 7.04 mmol; 0.10 eq.) and potassium carbonate (14.6 g; 105 mmol; 1.5 eq.) were suspended in dioxane (540 mL) and water (273 mL). The reaction mixture was then heated at 90° C. for 16 h. It was filtered through Celite and the filtrate was extracted with EtOAc. Organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The gum obtained was then triturated Et2O (100 mL). The resulting solid was filtered off and dried under high vacuum to give the title compound as a beige solid (14 g, 87%). 1H NMR (300 MHz, DMSO-d6) δ 13.21 (brs, 1H), 9.12 (s, 2H), 8.44 (m, 1H), 8.14 (m, 1H), 7.67 (t, J=2.0 Hz, 1H), 7.57-7.54 (m, 1H), 7.14 (t, J=7.8 Hz, 1H), 5.25 (s, 2H), 6.68 (ddd, J=7.8 Hz, 2.0 Hz, 1.0 Hz, 1H). HPLC (Condition A): Rt 1.24 min (purity 72.1%). MS (ESI+): 238.2.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.C1CCN2C(=NCCC2)CC1.[C:22]([O:26][C:27](=[O:49])[CH2:28][C@H:29]([C:39]1[O:40][CH2:41][C@@H:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:43]=1)[CH2:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([O:26][C:27](=[O:49])[CH2:28][C@H:29]([C:39]1[O:40][CH:41]=[C:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:43]=1)[CH2:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)[C@@H]1COC([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)=N1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reaction time: 0.08 h

Procedure:
A suspension of CuBr2 (20.88 g, 93.5 mmol) and HMTA (13.1 g, 93.5 mmol) in degassed DCM (250 ml) was treated with DBU (14.0 ml, 93.5 mmol) and the dark solution formed was stirred in a water bath for 5 minutes. A solution of ethyl(4S)-2-[(1R)-1-(2-tert-butoxy-2-oxoethyl)-4-cyclohexylbutyl]-4,5-dihydro-1,3-oxazole-4-carboxylate (preparation 152) (9.24 g, 23.4 mmol) in degassed DCM (30 ml) was added dropwise to the reaction mixture and stirred at room temperature for a further 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc and washed with a 1:1 solution of NH3(aq): NH4Cl. The aqueous extract was washed with EtOAc (2×380 ml). The combined organic extracts were washed with 2M HCl (500 ml), sat. NaHCO3 (500 ml) and brine (500 ml). The organic extracts were dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The crude material was purified on a silica column eluting with a solvent gradient of EtOAc:pentane (0:100) gradually changing to (25:75) to afford the title compound as colourless oil which formed needles on standing (7.39 g, 80%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=[C:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]([CH3:25])[CH3:24])=[CH:4][CH:3]=1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28].C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.O>[CH:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH:35]=3)=[CH:3][CH:4]=2)[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[N:10]=1)([CH3:25])[CH3:24]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(C)c1ccccc1-c1nc(C(C)(C)O)cn1-c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(C)c1ccccc1-c1nc(C(C)(C)O)cn1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a 50 mL round bottom flask attached with Vigreux column and magnetic stir bar was added 2-[1-(4-Bromo-phenyl)-2-(2-isopropyl-phenyl)-1H-imidazol-4-yl]-propan-2-ol (297 mg, 743 μmol), 3-methylsulfonylphenyl boronic acid (193 mg, 968 μmol), PdCl2dppf (60 mg, 10 mol %), K2CO3 (310 mg, 2.23 mmol), 1,2-dimethoxyethane (14 mL) and H2O (4 mL). The reaction solution was allowed to stir at 80° C. for 2 hrs. The reaction solution was diluted with EtOAc (150 mL) and filtered through a Celite padded Buchner funnel to remove spent Pd. The filtrate was transferred to a separatory funnel and washed with aq NH4Cl (100 mL) and aq NaCl (100 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 100% Hx to 90% EtOAc to afford 303 mg (86% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.14 (s, 1H), 8.02 (d, 1H), 7.89 (d, 1H), 7.89 (d, 1H), 7.78 (d, 2H), 7.72 (t, 1H), 7.37-7.34 (m, 3H), 7.26 (d, 2H), 7.18-7.16 (m, 2H), 4.84 (s, 1H), 3.26 (s, 3H), 2.85 (sept, 1H), 1.50 (6H), 0.96 (d, 6H); MS (ES): 475.4 [M+H]+, 497.5 [M+Na]+.
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[C:11]1[N:15]2[N:16]=[CH:17][CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[Cl-].[CH:58]1[C:70]2[CH:69]([CH2:71][O:72][C:73]([NH:75][C@@H:76]3[C@@H:81]([NH3+:82])[C:80]([F:84])([F:83])[CH2:79][CH2:78][CH2:77]3)=[O:74])[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:62]=2[CH:61]=[CH:60][CH:59]=1>CN(C=O)C.O>[CH:58]1[C:70]2[CH:69]([CH2:71][O:72][C:73](=[O:74])[NH:75][C@H:76]3[CH2:77][CH2:78][CH2:79][C:80]([F:84])([F:83])[C@@H:81]3[NH:82][C:8]([C:6]3[S:7][C:3]([CH:2]([F:1])[F:20])=[C:4]([C:11]4[N:15]5[N:16]=[CH:17][CH:18]=[CH:19][C:14]5=[N:13][CH:12]=4)[CH:5]=3)=[O:10])[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:62]=2[CH:61]=[CH:60][CH:59]=1
Reactant: [NH3+][C@@H]1[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1(F)F
Reactant: O=C(O)c1cc(-c2cnc3cccnn23)c(C(F)F)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCCC(F)(F)[C@@H]1NC(=O)c1cc(-c2cnc3cccnn23)c(C(F)F)s1)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.08 h

Procedure:
To 5-(difluoromethyl)-4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxylic acid (26 mg, 0.088 mmol) in DMF (0.4 mL) were added BOP (58 mg, 0.13 mmol) and DIEA (0.062 mL, 0.35 mmol). The mixture was left to stir for 5 min, treated with (1R,6S)-6-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2,2-difluorocyclohexanaminium chloride (36 mg, 0.088 mmol), and left to stir for 2 h. The mixture was diluted with water and extracted with EtOAc (×3). The combined organics were dried (sodium sulfate), concentrated, and purified by flash chromatography to afford 9H-fluoren-9-ylmethyl[(1S,2R)-2-({[5-(difluoromethyl)-4-(imidazo[1,2-b]pyridazin-3-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate. LRMS (APCI) calc'd for (C33H28F4N5O3S) [M+H]+, 650.2. found 650.2.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]([N-]C(C)C)(C)C.[Li+].IC>O1CCCC1>[CH3:15][CH:7]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]1
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 638.7 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (10.0 g, 50.2 mmol) in tetrahydrofuran (50 mL) was added lithium diisopropylamide (2.0 M in THF, 1.5 mL, 3.01 mmol) at −78° C. After 1 h, iodomethane (0.19 mL, 3.01 mmol) was added and the reaction mixture was allowed to warm to ambient temperature over 48 h before being quenched with 1M ammonium chloride and extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue purified by flash column chromatography (SiO2, 9:1 hexanes/ethyl acetate) to give tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (4.1 g, 38%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 4.24-4.12 (m, 2H), 3.32-3.20 (m, 1H), 2.94-2.75 (m, 1H), 2.61-2.38 (m, 3H), 1.50 (s, 9H), 1.05 (d, J=6.9 Hz, 3H).
Reaction SMILES: Cl.[C:2]1([CH:8]2[O:12][N:11]=[C:10]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]1[N:29]([CH2:30][C:31](O)=[O:32])[N:28]=[C:27]([C:34]([F:37])([F:36])[F:35])[CH:26]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1>ClCCl>[C:2]1([CH:8]2[O:12][N:11]=[C:10]([C:13]3[N:14]=[C:15]([N:18]4[CH2:23][CH2:22][N:21]([C:31](=[O:32])[CH2:30][N:29]5[C:25]([CH3:24])=[CH:26][C:27]([C:34]([F:37])([F:36])[F:35])=[N:28]5)[CH2:20][CH2:19]4)[S:16][CH:17]=3)[CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C2CC(c3csc(N4CCNCC4)n3)=NO2)cc1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]piperazine hydrochloride (i.e. the product of Example 7, Step E) (200 mg, 0.57 mmol) and 5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid (0.120 g, 0.57 mmol) in dichloromethane (10 mL) at room temperature was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.110 g, 0.57 mmol), triethylamine (0.086 g, 0.85 mmol) and 1-hydroxy-benzotriazole hydrate (0.020 g, 0.14 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with dichloromethane (30 mL), and washed with water (20 mL) and brine (20 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by column chromatography using 3% methanol in chloroform as eluant to give 180 mg of the title product, a compound of the present invention as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:15]=[CH:14]1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>ClC1C=CC=CC=1Cl>[CH2:22]([O:21][C:19]([C:16]1[N:15]=[C:14]2[C:24](=[O:25])[NH:1][C:2]3[C:3](=[CH:4][C:5]([N:8]4[CH:12]=[CH:11][N:10]=[CH:9]4)=[CH:6][CH:7]=3)[N:13]2[C:17]=1[CH3:18])=[O:20])[CH3:23]
Reactant: CCOC(=O)c1ncn(-c2cc(-n3ccnc3)ccc2N)c1C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1nc2c(=O)[nH]c3ccc(-n4ccnc4)cc3n2c1C
Temperature: 180 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
A mixture of 1-(2-amino-5-(1-imidazolyl)phenyl)-4-ethoxycarbonyl-5-methyl-1H-imidazole (1.0 g, 3.2 mmol), 1,1'-carbonyldiimidazole (2.6 g, 16.0 mmol) in 1,2-dichlorobenzene (50 ml) was stirred at 180° C. for 16 h under N2. The precipitate was filtered off and submitted to flash chromatography on silica gel 60 eluting with dichloromethane/methanol (4:1) to give 400 mg (37%) of the title compound. M.p. >250° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].CCN(CC)CC.[Cl:18][CH2:19][C:20](Cl)=[O:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:18][CH2:19][C:20]([NH:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: N[C@H](CO)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N[C@H](CO)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
To a solution of (S)-2-amino-2-phenylethanol (0.852 g, 6.21 mmol), Et3N (0.952 mL, 6.83 mmol), DMAP (76 mg, 0.621 mmol) in CH2Cl2 (10 mL) at 0° C. was added 2-chloroacetyl chloride (0519 mL, 6.52 mmol), and the resulting mixture was stirred at 0° C. for 15 min. The reaction mixture was washed with aqueous HCl (1 M, 20 mL), then sat. NaHCO3 (20 mL), dried (Na2SO4), concentrated, further dried under high vacuum and (S)-2-chloro-N-(2-hydroxy-1-phenylethyl)acetamide (0.60 g, 45.2% yield) was obtained as white solid. LCMS (m/z): 214 (MH+), 0.44 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[CH:31][CH:32]=2)=[CH:24][CH:25]=1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: c1cscn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(I)cc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(-c3nccs3)cc2)cc1
Yield: 99.9 %

Procedure:
The title compound (90 mg, 99%) was prepared from thiazole (0.07 g, 0.8 mmol) and (R)-2-[4-(4-iodo-benzyl)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.2 mmol) using the procedure of Example 146, step 1; 1HNMR (400 Hz, CDCl3) δ 7.88 (d, J=8.4 Hz, 2H), 7.84 (d, J=3.2 Hz, 1H), 7.30 (d, J=3.2 Hz, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.10 (d, J=8 Hz, 2H), 6.86 (br d, J=7.2 Hz, 2H), 4.10 (br, 2H), 3.96 (s, 2H), 3.9-3.75 (br, 2H), 3.40 (br, 2H), 2.03-1.84 (br, 4H), 1.46 (s, 9H); MS?
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:18][CH:17]=1)[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH2:29]([O:31][C:32](=[O:38])/[CH:33]=[CH:34]/[C:35](O)=[O:36])[CH3:30].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C@H:3]([NH:2][C:35](=[O:36])/[CH:34]=[CH:33]/[C:32]([O:31][CH2:29][CH3:30])=[O:38])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:20][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: CCOC(=O)/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/C(=O)N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (R)-benzyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate (87.6 mg, 0.183 mmol) is added a solution of HCl in 1,4-dioxane (0.456 mL, 1.825 mmol) at room temperature. After stirring for 3 hours, the reaction mixture is concentrated under reduced pressure to give (R)-benzyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride. A mixture of (R)-benzyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride, fumaric acid monoethyl ester (33.4 mg, 0.220 mmol), EDCI (63.3 mg, 0.330 mmol), DIPEA (0.058 ml, 0.330 mmol) and HOAt (44.9 mg, 0.330 mmol) in DMF (1.8 ml) is allowed to stir at room temperature for 3 hour. The reaction mixture is diluted with water, and then the products are extracted with EtOAc. The organic layer is washed with NH4OH, 1M HCl aq and brine, dried over Na2SO4, filtered, and concentrated to give crude. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100) to give (R,E)-ethyl 4-(4-(benzyloxy)-1-(3′-chlorobiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobut-2-enoate (72.9 mg); HPLC retention time=1.40 minutes (condition B); MS (m+1)=506.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (t, J=7.1 Hz, 3 H) 2.58 (A of ABX, Jab=16.4 Hz, Jax=5.3 Hz, 1 H) 2.6 (B of ABX, Jab=16.4 Hz, Jbx=5.1 Hz, 1 H) 2.88 (A of ABX, Jab=13.6 Hz, Jax=8.1 Hz, 1 H) 3.03 (B of ABX, Jab=13.6 Hz, Jbx=6.3 Hz, 1 H) 4.24 (q, J=7.1 Hz, 2 H) 4.56-4.64 (m, 1 H) 5.12 (A of AB, J=12.1 Hz, 1 H) 5.18 (B of AB, J=12.1 Hz, 1 H) 6.57 (br d, J=9.1 Hz, 1 H) 6.77 (A of AB, J=15.4 Hz, 1 H) 6.81 (B of AB, J=15.4 Hz, 1 H) 7.19 (br d, J=8.1 Hz, 2 H) 7.29-7.47 (m, 10 H) 7.53-7.54 (m, 1 H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].CN(C)C=O.[C:21]1([CH2:27][O:28][CH2:29][CH2:30][CH2:31]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>COC(C)(C)C.O>[C:21]1([CH2:27][O:28][CH2:29][CH2:30][CH2:31][O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCCOCc1ccccc1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(OCCCOCc2ccccc2)c1

Procedure:
To a 3-L reaction vessel was charged and stirred cesium carbonate (209.6 g), 3-hydroxybenzaldehyde (67.6 g), dimethylformamide (DMF, 250 mL) and 3-bromopropyl phenylmethyl ether (113.4 g) at ambient temperature for ˜18 h. Water (567 mL) was added followed by tert-butyl methyl ether (907 mL). The bottom aqueous layer was separated and the organic layer washed with 1N sodium hydroxide (2×567 mL) and water (1×567 mL). The organic solution was concentrated to a minimum after which ethanol (200 proof, 907 mL) was added and the solution concentrated to a minimum and filtered though a 1-μm filter.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH2:10])[CH:3]=1.[C:18]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:23]=CC=C[CH:19]=1.C(O)(C)C.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:18]([CH3:23])[CH3:19])=[C:4]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[CH2:10])[CH:3]=1
Reactant: C=C(c1ccc(C)cc1)c1cc(Br)ccc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C=C(c1ccc(C)cc1)c1cc(Br)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 22.5 h

Procedure:
To a cold solution (0° C.) of 125 mg (0.4 mmol) of 4-bromo-2-[(1-p-tolyl)vinyl]phenol (Compound R) in 5 mL of tetrahydrofuran was added 125 mg (0.5 mmol) of triphenylphosphine and 0.04 mL (31 mg, 0.5 mmol) of isopropanol followed by 0.07 mL (82 mg, 0.5 mmol) of diethylazodicarboxylate. The dark yellow solution was removed from the ice bath, allowed to warm to ambient temperature on its own and stirred overnight (22.5 hours). The reaction mixture was concentrated in vacuo to a gummy yellow solid. Purification by flash chromatography (silica, 1% ethyl acetate in hexane) gave the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][N:28]5[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:23][CH:22]=4)=[O:19])=[CH:13][C:12]=3[CH:34]=2)=[CH:4][CH:3]=1.[CH3:35][I:36]>CN(C)C=O>[I-:36].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([CH2:27][N+:28]5([CH3:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:25][CH:26]=4)=[O:19])=[CH:13][C:12]=3[CH:34]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCCCC4)cc2)CCS3)cc1
Reactant: CI
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C[N+]4(C)CCCCC4)cc2)CCS3)cc1
Product: [I-]

Procedure:
A solution of 7-(4-methylphenyl)-N-(4-piperidinomethyl-phenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide (0.08 g) and methyl iodide (0.013 ml) in dimethylformamide (20 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added ethyl acetate. Precipitated crude crystal was filtered, which were recrystallized from ethanol-hexane to give 1-(N-(7-(4-methylphenyl)-2,3-dihydro-1-benzo-thiepine-4-carbonyl)-4-aminobenzyl)-1-methylpiperidinium iodide (Compound 94) (0.077 g) as colorless crystals.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[N:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[N:26]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][CH:31]([NH2:35])[CH2:32]2)=[N:27]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CO>[CH3:14][O:15][C:16]1[N:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[N:26]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][CH:31]([NH:35][C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)=[O:13])[CH2:32]2)=[N:27]1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(N)C4)c2n1
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CO
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(NC(=O)c3ccc5c(c3)OCCO5)C4)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.1 %

Procedure:
To a solution of 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid (44 mg, 0.24 mmol) and 2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (48 mg, 0.16 mmol) in DMF (1 mL) was added HOBT (1-hydroxybenzotriazole; 33 mg, 0.24 mmol) and EDC; 47 mg, 0.24 mmol). The reaction mixture was stirred for 1.5 h at RT. The reaction mixture was diluted with CH3OH and purified directly by basic reverse phase HPLC to provide 22 mg (30%) of the title compound. MS (ESI): exact mass calculated for C25H23N5O4, 457.18; m/z found, 458.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.14 (s, 1H), 8.76 (d, J=5.1, 1H), 8.25 (d, J=9.1, 1H), 8.16 (d, J=5.1, 1H), 7.31-7.28 (m, 1H), 7.26-7.23 (m, 1H), 7.17 (d, J=9.1, 1H), 6.86 (d, J=8.4, 1H), 6.13 (d, J=7.7, 1H), 4.54-4.51 (m, 1H), 4.27-4.24 (m, 4H), 4.07 (s, 3H), 3.19 (dd, J=15.5, 5.1, 1H), 2.99-2.96 (m, 2H), 2.66 (dd, J=15.5, 7.7, 1H), 2.21-2.16 (m, 1H), 2.10-2.03 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]([S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:36]=[CH:35][C:18]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[N:30]([CH:31]([CH3:33])[CH3:32])[C:29]([CH3:34])=[N:28][CH:27]=4)[CH:23]=[CH:22][N:21]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7])=[CH2:5]>C1COCC1>[CH3:1][N:2]([CH3:3])[CH2:5][CH2:4][S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:36]=[CH:35][C:18]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[N:30]([CH:31]([CH3:32])[CH3:33])[C:29]([CH3:34])=[N:28][CH:27]=4)[CH:23]=[CH:22][N:21]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:7])=[O:8]
Reactant: C=CS(=O)(=O)N1CCN(c2ccc(Nc3nccc(-c4cnc(C)n4C(C)C)n3)cc2)CC1
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCN(S(=O)(=O)CCN(C)C)CC4)cc3)n2)n1C(C)C
Reaction time: 1 h

Procedure:
Dimethylamine (2.0 M) in THF (1.5 ml) was added to a stirred suspension of 2-{4-[4-(vinylsulphonyl)piperazin-1-yl]anilino}-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Example 29; 140 mg 0.3 mmol) in THF (3 ml) at room temperature. Additional dimethylamine solution (0.5 ml) was added after 2 hours. The reaction was stirred for 1 hour then stood overnight. The reaction was evaporated under reduced pressure, triturated with ether and filtered to give the title compound as a yellow solid. (134 mg 89%). NMR: 1.40 (d, 6H), 2.46 (s, 3H), 2.62 (t, 2H), 3.13 (t, 4H), 3.20-3.35 (2H and 4H)[under exchangeables], 5.68 (septuplet, 1H), 6.92 (d, 2H), 6.95 (d, 1H), 7.38 (s, 1H), 7.47 (d, 2H), 8.31 (d, 1H), 9.18 (s, 1H) [+duetero acetic acid: 3.01 (b d, 2H), 3.14 (t, 4H), 3.33 (t, 4H), 3.37 (m, 2H)]; m/z 478.