Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:5]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[CH:7]=1.[Li+].CC([N-]C(C)C)C.[O:32]=[C:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.[Cl-]>C1COCC1>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][C:33]([OH:32])([C:11]2[S:12][C:8]([C:6]3[CH:5]=[C:4]([NH:13][C:14]4[N:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][N:15]=4)[CH:3]=[C:2]([CH3:1])[CH:7]=3)=[CH:9][N:10]=2)[CH2:34][CH2:35]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)s2)c1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
At −78° C., INTERMEDIATE 4 (200 mg, 0.595 mmol) in THF (3.0 mL) was added to LDA (892 μL, 1.784 mmol) and the reaction aged for 10 min followed by addition of tert-butyl 4-oxo-piperidine-1-carboxylate (474 mg, 2.379 mmol). The reaction was allowed to slowly warm to −20° C. over 4 hrs. To the mixture was added saturated aqueousammonium chloride solution and the product was extracted with ethyl acetate. The organic layer was washed with water and brine. The combined organic layer was dried, filtered and solvent reduced by rotovap. The residue was purified by column chromatography on silica gel (0-50% ethyl acetate in DCM) to give 260 mg (0.485 mmol, 82%) tert-butyl-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate as off-white solid. MS ESI: [M+H]+ m/z 536.2. 1H NMR (600 MHz, CDCl3): δ 8.60 (d, J=4.8 Hz, 1H); 7.81 (appr s, 2H); 7.74 (br s, 1H); 7.28 (s, 1H); 7.02 (s, 1H); 7.00 (d, J=4.8 Hz, 1H); 4.0 (br s, 2H); 3.28 (br s, 2H); 2.34 (s, 3H); 2.09 (m, 2H); 1.88 (m, 2H); 1.41 (s, 9H). rhSYK=+++
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[CH3:10]B(O)O.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:7]1[C:2]([CH3:10])=[N:3][CH:4]=[C:5]([F:9])[CH:6]=1
Reactant: CB(O)O
Reactant: Fc1cnc(Br)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ncc(F)cc1Br
Temperature: 110 °C
Yield: 32.2 %

Procedure:
2,3-Dibromo-5-fluoropyridine (5.0 g, 19.6 mmol), Pd(PPh3)4 (1.13 g, 0.98 mmol) and methyl boronic acid (3.52 g, 58.9 mmol) were combined in dioxane (50 mL) then treated with K2CO3 (8.13, 58.9 mmol) and water (10 mL). The mixture was purged with N2 then heated to 110° C. in a sealed vessel for 16 hours. The cooled mixture was partitioned between water (100 mL) and EtOAc (50 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 1-3% EtOAc/hexanes to afford the product as a white solid (1.20 g, 32% yield). MS (apci) m/z=190.2 (M+).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:16])=[C:13](I)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])(C)(C)C.CCCCC.[P:27](Cl)([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1.[NH4+].[Cl-].CCOC(C)=O>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:16])=[C:13]([P:27](=[O:28])([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1I
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1cc(O[Si](C)(C)C(C)(C)C)ccc1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-tert-butyldimethylsilyloxy-2-methylphenyliodide 1-2 (250 mg, 0.72 mmol) in 5 mL of THF, chilled to −78 was added 0.85 mL of a 1.7 M solution of t-butyllithium in pentane (1.44 mmol). The resulting pale yellow solution was stirred at −78° C. for 30 min. Then diethyl chlorophosphate (0.13 mL, 0.86 mmol) in 2 mL THF was added via a cannula needle. The resulting mixture was stirred at −78° C. for 30 min, then diluted with aqueous NH4Cl and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The resulting residue was subjected to MPLC on a 12 g column of SiO2 eluting with 15% EtOAc in hexanes (10 min) to provide diethyl 5-tert-butyldimethylsilyloxy-2-methylphenylphosphonate 1-3 as an oil. 1H NMR (300 MHz, DMSO-d6): δ 0.18 (s, 6H), 0.95 (s, 9H), 1.22 (t, 6H, J=6 Hz), 2.40 (d, 3H, J=1.5 Hz), 3.9-4.0 (m, 4H), 6.99 (dd, 1H, J=8, 2 Hz), 7.19 (m, 1H), 7.24 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[N:11]=[N:12][NH:13][N:14]=1.[C:15]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cc(Cl)cc(Br)c1-c1nn[nH]n1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nnnc1-c1c(F)cc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
A mixture of 5-(2-bromo-4-chloro-6-fluoro-phenyl)-2H-tetrazole (4.15 g, 14.95 mmol), K2CO3 (3.1 g, 22.43 mmol) and iodomethane (1.3 ml, 20.94 mmol) in DMF (30 ml) was stirred at 25° C. for 3 h. The mixture was partitioned between EtOAc (80 ml) and water (60 ml), the organic layer was separated, washed with water and brine, dried with Na2SO4 and concentrated. The remaining residue was purified by chromatography (silica gel; hexane/EtOAc 100:0-90:10) to obtain 5-(2-bromo-4-chloro-6-fluoro-phenyl)-1-methyl-1H-tetrazole as pale yellow solid (1.5 g, 35%) and the title compound (1.7 g, 39%) as reddish liquid. MS: 291.0 (MH+, 1Br).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH:16]([OH:18])[CH3:17])=[C:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:50][O:51][C:52](=[O:63])[CH2:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58](O)=[CH:57][C:56]=1[CH3:62]>C1(C)C=CC=CC=1>[CH3:50][O:51][C:52](=[O:63])[CH2:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:18][CH:16]([C:10]2[O:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[N:12][C:11]=2[CH:13]([CH3:15])[CH3:14])[CH3:17])=[CH:57][C:56]=1[CH3:62]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: CC(C)c1nc(-c2ccc(Br)cc2)oc1C(C)O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OC(C)c2oc(-c3ccc(Br)cc3)nc2C(C)C)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.3 %

Procedure:
To a solution of 1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethanol (9.05 g, 29.2 mmol) in toluene (300 ml) at 0° C. is added tri-n-butylphosphine (7.70 g, 38.1 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (8.84 g, 35.0 mmol), followed by addition of 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (6.30 g, 32.1 mmol). The resulting mixture is stirred for 18 hours while warmed up to room temperature. The reaction is quenched with water (100 ml) and the aqueous layer is extracted with EtOAc (2×100 ml). The combined organics are dried over Na2SO4 and concentrated, purified by silica gel chromatography (Hexanes/EtOAc, 9/1 to 8.5/1.5) to afford the 3-(4-{1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic acid methyl ester as a colorless oil (11.4 g, 80%). MS (MH+): 488.1.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.FC(F)(F)C(O)=O.[O:35]1[C:39]2([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36]1.C(N(CC)C(C)C)(C)C>ClC(Cl)C.O1CCCC1>[CH3:20][O:19][C:16]1[C:17]2[N:18]=[C:10]([NH:9][C:8]([N:42]3[CH2:43][CH2:44][C:39]4([O:35][CH2:36][CH2:37][CH2:38]4)[CH2:40][CH2:41]3)=[O:27])[S:11][C:12]=2[C:13]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:14][CH:15]=1
Reactant: C1COC2(C1)CCNCC2
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N3CCC4(CCCO4)CC3)nc12

Procedure:
From (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester with 1-oxa-8-aza-spiro[4.5]decane trifluoroacetate and N,N-diisopropylethylamine in dichloroethane and tetrahydrofuran. ES-MS m/e (%): 434 (M+H+, 100).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[N:26]1([CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3([C:48]([OH:50])=O)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[CH:38][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1.CCN(C(C)C)C(C)C>CN(C)C=O>[N:51]1([C:48]([C:42]2([C:39]3[CH:40]=[CH:41][C:36]([O:35][CH2:34][CH2:33][CH2:32][N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[CH:37][CH:38]=3)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[O:50])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1
Reactant: C1COCCN1
Reactant: O=C(O)C1(c2ccc(OCCCN3CCOCC3)cc2)CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCOCC1)C1(c2ccc(OCCCN3CCOCC3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.7 %

Procedure:
O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (200 mg, 0.5 mmol) was added to a solution of 4-[4-(3-Morpholin-4-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid hydrochloride (160 mg, 0.4 mmol), morpholine (54 μL, 0.6 mmol) and Hunig's base (180 μL, 1 mmol) in N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. The residue was partitioned between 2M NaOH solution (20 mL) and DCM (2×20 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1, by volume) to provide the title compound (182 mg, 100%) as a pale brown solid. 1H NMR (400 MHz, CDCl3) δ 1.93-2.04 (m, 4H), 2.20 (m, 2H), 2.42-2.55 (m, 6H), 3.22-3.43 (br m, 8H), 3.72 (t, 4H), 3.79 (m, 2H), 3.90 (m, 2H), 4.00 (t, 2H), 6.88 (d, 2H), 7.17 (d, 2H). LRMS APCI+ m/z 419 [MH]+.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Br[CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42]>>[ClH:1].[CH3:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:6][C@H:7]([NH:27][C:28](=[O:30])[CH3:29])[C@H:8]([OH:26])[CH2:9][NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COCCOCCBr
Reactant: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Agent: Cl
Product: COCCOCCOc1cc(F)cc(C[C@H](NC(C)=O)[C@H](O)CNC2(c3cccc(C(C)C)c3)CCCCC2)c1
Yield: 52 %

Procedure:
Using methods analogus to those previously described, compound 11 (0.4 mmol) is reacted with 1-bromo-2-(2-methoxyethoxy)ethane to afford the title compound 60 ( 0.21 mmol, 52%) as a hygroscopic white solid: 1H NMR (CDCl3) δ 9.4 (br, 1H), 8.5 (br, 1H), 8.32 (br, 1H), 7.54 (s, 1H), 7.38 (m, 2H), 7.26 (m, 1H), 6.56 (s, 1H), 6.47 (m, 2H), 4.34 (v br, water H), 4.1 (m, 4H), 3.83 (m, 2H), 3.70 (m, 2H), 3.58 (m, 2H), 3.38 (s, 3H), 2.96 (hept, J=7 Hz, 1H), 2.8-2.6 (m, 5H), 2.4-2.2 (m, 3H), 2.15 (s, 3H), 1.80 (m, 2H), 1.6 (m, 1H), 1.5-1.3 (m, 3H), 1.27 (d, J=7 Hz, 6H); MS (CI) m/z 559.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13](OCC)(=O)C>CO.S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:12])[C:9]([O:11][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: O=C(O)[C@H](O)c1cccc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)[C@H](O)c1cccc(Cl)c1
Yield: 93 %

Procedure:
A solution of (R)-2-(3-chlorophenyl)-2-hydroxyacetic acid (25 g, 133.69 mmol, 1.00 equiv.) in methanol (300 mL) and sulfuric acid (3 mL) was heated at reflux for about 16 hours, and then concentrated in vacuo. After the solution was poured into a water/ice mixture (200 mL), the pH value of the solution was adjusted to 9 with sodium carbonate. Standard extractive workup with ethyl acetate (2×100 mL), gave the title product as an off-white solid (24.8 g; yield=93%). 1H NMR (300 MHz, CDCl3) δ: 7.45 (s, 1H), 7.32 (m, 3H), 5.17 (d, J=4.5 Hz, 1H), 3.80 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1)=[O:6].N1C=CC=CC=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].CCN(CC)CC>C(Cl)Cl>[NH2:14][C:11]1[N:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([NH:1][C:30]([C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=3)=[O:31])[C:3]=2[CH3:18])=[CH:13][N:12]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1c(N)cccc1C(=O)Nc1cnc(N)nc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(NC(=O)c2cccc(C(F)(F)F)c2)cccc1C(=O)Nc1cnc(N)nc1

Procedure:
3-amino-N-(2-aminopyrimidin-5-yl)-2-methylbenzamide 42 (113 mg, 0.464 mmol) [prepared according to the procedure described for methylbenzamide5-amino-N-(2-aminopyrimidin-5-yl)-2-methylbenzamide in Example 1] was taken up in CH2Cl2 (4 mL) and pyridine (3 mL) and 3-(trifluoromethyl)benzoyl chloride (0.31 mL, 2.09 mmol) was added followed by NEt3 (0.13 mL, 0.928 mmol). Complete consumption of the amine starting material was indicated by LCMS. The crude reaction mixture was concentrated and the product purified using automated medium pressure chromatography (Isco—40 g column; eluting with a linear gradient from 97% CH2Cl2 (A line) to 100% 90/10/1 CH2Cl2/MeOH/NH3 (B line) on silica gel) to afford N-(2-amino-5-pyrimidinyl)-2-methyl-3-(((3-(trifluoromethyl)phenyl)carbonyl)amino)benzamide 43 as an off-white solid. MS m/z found 416 [MH+]; calc. for C20H16F3N5O2=415.13; and 2-methyl-3-(((3-(trifluoromethyl)phenyl)carbonyl)amino)-N-(2-(((3-(trifluoromethyl)phenyl)carbonyl)amino)-5-pyrimidinyl)benzamide 44 as an off-white solid. MS m/z found 588 [MH+]; calc. for C28H19F6N5O3=587.14.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][NH:32]C(=O)OC(C)(C)C)[CH2:27][CH2:26]1.Cl.O1CCOCC1>CS(C)=O>[NH2:32][CH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:24][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:26][CH2:27]1
Reactant: Fc1cccc(COc2cccc(-c3cc(F)ncc3Cl)n2)c1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: NC[C@H]1CC[C@H](Nc2cc(-c3cccc(OCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 102.5 °C
Reaction time: 40 h

Procedure:
To 5′-chloro-2′-fluoro-6-(3-fluorobenzyloxy)-2,4′-bipyridine (30 mg, 0.090 mmol) was added DMSO (0.8 ml), TEA (0.025 ml, 0.180 mmol), and tert-butyl (trans-4-aminocyclohexyl)methylcarbamate (41.2 mg, 0.180 mmol). The reaction mixture was flushed with argon and stirred at 100-105° C. for 40 hr. Formation of the intermediate product tert-butyl(trans-4-(5′-chloro-6-(3-fluorobenzyloxy)-2,4′-bipyridin-2′-yl-amino)cyclohexyl)methylcarbamate was indicated by LCMS. (LCMS (m/z): 541.4 (MH+), retention time=1.05 min.). The solvent DMSO was removed under reduce pressure. The Boc group was removed from the intermediate by adding 4M HCl in Dioxane (1.5 ml, 6.00 mmol), followed with stirring at ambient temperature for 90 minutes. The solvent was removed under reduced pressure. The crude product was dissolved in 1.0 ml of DMSO with 0.075 ml of water, filtered and purified by prep LC. After lyophilization, 28.3 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 441.3 (MH+), retention time=0.76 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.12-1.29 (m, 2 H) 1.29-1.47 (m, 2 H) 1.60-1.76 (m, J=14.76, 7.51, 3.66, 3.66 Hz, 1 H) 1.92 (d, J=12.60 Hz, 2 H) 2.16 (d, J=10.55 Hz, 2 H) 2.84 (d, J=6.74 Hz, 2 H) 3.58-3.71 (m, 1 H) 5.43 (s, 2 H) 6.92-6.99 (m, 2 H) 6.99-7.08 (m, 1 H) 7.18 (d, J=9.67 Hz, 1 H) 7.25 (d, J=7.62 Hz, 1 H) 7.30-7.42 (m, 2 H) 7.83 (t, J=7.77 Hz, 1 H) 8.01 (s, 1 H)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C1C=CC=CC=1>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NCCN1CCOCC1
Solvent: O
Solvent: c1ccccc1
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1

Procedure:
26 G. of p-chlorobenzaldehyde and 24 g. of N-(2-aminoethyl)-morpholine are boiled in 150 ml. of benzene for 3 hours under reflux with water being separated. Then, the mixture is evaporated to dryness and the residue is distilled at 165° C./0.01 mmHg. 5 G. of the resulting 4-{2-[(p-chlorobenzylidene)-amino]-ethyl}-morpholine, 2.3 g. of sodium acetate and 3 ml. of 30% hydrogen peroxide are stirred in 60 ml. of methanol overnight at room temperature. Thereafter, the mixture is evaporated to dryness and the residue is taken up in 50 ml. of methylene chloride and 50 ml. of water. The phases are separated and the aqueous phase extracted with 50 ml. of methylene chloride. The methylene chloride extract is dried over sodium sulfate and evaporated. The residue is chromatographed over a silica gel column with a mixture of chloroform and ethanol. The pure fractions are combined and evaporated. The residue is recrystallized from isopropanol, and 0.7 g. of p-chloro-N-(2-morpholinoethyl)-benzamide is obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[N:30]1([C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:33]3[CH2:34][CH2:35][N:30]([C:36]4[CH:45]=[CH:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:37]=4)[CH2:31][CH2:32]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCc1ccc(F)cc1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][CH:3]=1.[Br:11]N1C(=O)CCC1=O>ClCCCl>[Br:11][C:3]1[CH:4]=[C:5]([C:9]#[N:10])[C:6](=[O:8])[NH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(C#N)c(=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Product: Cc1[nH]c(=O)c(C#N)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 181.1 %

Procedure:
A mixture of 6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (26.23 g, 95.5 mmol) and N-bromosuccinimide (36.54 g, 205 mmol) in 1,2-dichloroethane (500 mL) heated to reflux for 18 hours, cooled to room temperature, and filtered. The solid was treated with water (1 L), stirred for 2 hours, filtered, washed with water, and dried under vacuum to provide 36.85 g (88%) of the desired product of sufficient purity for subsequent use. MS (DCI/NH3) m/z 230 (M+NH4)+; 1H NMR (DMSO-d6) δ 12.96 (br s, 1H), 8.34 (s, 1H), 2.36 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][CH:12](OCC)OCC.O.[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[C:3]2[O:10][CH:11]=[CH:12][C:4]=2[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: CCOC(COc1ccc(OC)cc1Br)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(Br)c2occc2c1
Temperature: 70 °C
Yield: 14 %

Procedure:
To a mixture of the product from step B (2.7 g, 8.5 mmol) in toluene (10 mL) was added PPA (1.0 mL). The reaction was heated at 70° C. for 1 hr. The reaction was cooled to room temperature. The mixture was diluted with EtOAc (200 mL) and the water phase was adjusted to pH 7-8 by NaOH (2 mol/L). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography (eluted with PE) to afford the title compound (0.27 g, 16%) as an oil. 1H-NMR (600 MHz, CDCl3) δ 7.68 (d, J=2.1 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 6.79 (d, J=2.1 Hz, 1H), 3.86 (s, 3H) ppm.
Reaction SMILES: [ClH:1].F[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][C:6]1[N:11]=[CH:10][C:9]2[C:12]([CH3:16])([CH3:15])[CH2:13][NH:14][C:8]=2[CH:7]=1.[Br-].[C:22](C1C=C(C=CC=1)C[Zn+])#[N:23]>>[ClH:1].[C:22]([C:20]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[N:11]=[CH:10][C:9]2[C:12]([CH3:16])([CH3:15])[CH2:13][NH:14][C:8]=2[CH:7]=1)#[N:23]
Reactant: N#Cc1cccc(C[Zn+])c1
Reactant: CC1(C)CNc2cc(Cc3ccccc3F)ncc21
Agent: Cl
Agent: [Br-]
Product: CC1(C)CNc2cc(Cc3cccc(C#N)c3)ncc21

Procedure:
Prepared in an analogous manner to 6-(2-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine hydrochloride (Preparation 119) using 3-cyanobenzylzinc bromide instead of 2-fluorobenzylzinc chloride. MS: [M+H]+=264.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C.[CH2:26]([O:28][C:29]([CH2:31][C:32](Cl)=[O:33])=[O:30])[CH3:27]>C(Cl)Cl>[CH2:26]([O:28][C:29](=[O:30])[CH2:31][C:32](=[O:33])[N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)[CH2:6][CH2:5][C:4]([O:3][CH3:2])=[O:18])[CH3:27]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COC(=O)CCNCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)N(CCC(=O)OC)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 96.4 %

Procedure:
N-(p-Nitrobenzyl)-β-alanine methyl ester hydrochloride (32.66 g) and triethylamine (38 ml) are dissolved in methylene chloride (200 ml), and a solution of ethoxycarbonylacetyl chloride (20.0 g) in methylene chloride (100 ml) is added dropwise to the mixture under ice-cooling. The mixture is stirred at the same temperature for one hour, and the mixture is filtered to remove precipitates (triethylamine hydrochloride). The filtrate is washed with 2% HCl, water, 2% NaOH and water, dried and then distilled to remove the solvent to give ethyl[N-(p-nitrobenzyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (40.4 g, 96.4%) as yellow oil.