Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][NH:5][CH3:6].C([O-])([O-])=O.[K+].[K+].[C:21]([O:30]N1C(=O)CCC1=O)([O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=O>CC(C)=O.O>[C:10]([O:9][C:8]([NH:7][C@H:3]([CH2:4][N:5]([CH3:6])[C:21]([O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])=[O:30])[CH2:2][OH:1])=[O:14])([CH3:13])([CH3:12])[CH3:11]
Reactant: CNC[C@H](CO)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C[C@H](CO)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Yield: 20 %

Procedure:
To a solution of crude tert-butyl (R)-3-hydroxy-1-(methylamino)propan-2-ylcarbamate in acetone (30 mL) and water (10 mL), there was added K2CO3 (12.8 g, 92.4 mmol), followed by Teoc-OSu (8.0 g, 30.8 mmol). The resulting mixture was stirred at rt until no starting material remained (˜1 h). Acetone was removed under vacuum and the aqueous residue was extracted with CH2Cl2 (4×15 mL). The combined organic layers were concentrated and the crude residue was purified by flash column chromatography to give (2R)-2-(t-butoxycarbonylamino)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-1-ol (2.12 g, 20% steps). 1H NMR (400 MHz, CDCl3): 5.08 (br, 1H), 4.14 (m, 2H), 3.66-3.42 (m, 4H), 3.02 (m, 1H), 2.90 (s, 3H), 1.40 (S, 9H), 0.98 (m, 2H), 0.02 (s, 9H); MS m/z 349 (M+H+).
Reaction SMILES: Cl.OC(COC1C=CC([Cl:26])=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.[OH:28][CH:29]([CH2:44][O:45][C:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)C=[CH:48][CH:47]=1)[CH2:30][NH:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.Cl.OC(COC1C=CC(OC)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:26].[OH:28][CH:29]([CH2:44][O:45][C:46]1[CH:47]=[CH:48][C:51]([CH2:52][CH2:53][CH3:54])=[CH:50][CH:55]=1)[CH2:30][NH:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2cccc3ccccc23)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: Cl
Product: CCCc1ccc(OCC(O)CNC(C)(C)Cc2ccc(OC)cc2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M−15,0.8), 251(18), 250 (100), 163 (5), 121 (19), 114 (7), 110 (5), 107 (7), 91 (6).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([C:21](O)=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:38]([C@H:45]1[CH2:49][O:48][C:47](=[O:50])[NH:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[Cl-].[Li+]>C1COCC1.C(OCC)(=O)C>[CH2:38]([C@H:45]1[CH2:49][O:48][C:47](=[O:50])[N:46]1[C:21]([C@@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[O:22])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid (described herein above) (13.39 g, 0.038 mol) in THF (200 mL) at −20° C. were added triethylamine (13.32 mL, 0.096 mol) and pivaloyl chloride (11.76 mL, 0.096 mol) subsequently. Stirring was continued for two hours at the same temperature, and to this mixture were added (S)-4-benzyl-oxazolidin-2-one (8.13 g, 0.046 mol) and lithium chloride (1.94 g, 0.046 mol). The reaction mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water two times and saturated sodiumbicarbonate. The separated organic phase was dried on Na2SO4 and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO2, EtOAc/H, 1:2) to yield (S)-4-benzyl-3-[(3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carbonyl]-oxazolidin-2-one 9.47 g (49%) as a white solid ES-MS m/e: 509.3 (M+H+) and (S)-4-benzyl-3-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carbonyl]-oxazolidin-2-one 9.40 g (48%) as a white solid ES-MS m/e: 509.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)[NH2:17].Cl.C(=O)(O)[O-].[Na+]>O.C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)=[C:14]([F:13])[CH:15]=2)[N:3]=1
Reactant: COC(=O)c1cc(Cl)nc(N)n1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)nc(N)n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
0.209 g (1.12 mmol) of methyl 2-amino-6-chloropyrimidine-4-carboxylate (prepared according to G. Doyle Daves, Fred Baiocchi, Roland K. Robins, and C. C. Cheng, J. Org. Chem., 26 (1961), 2755-2763) and 0.4 g (1.12 mmol) of [3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amine (example XIX) are suspended in 5 ml of water and 5 ml of ethanol. 0.11 ml (1.34 mmol) of 37% strength hydrochloric acid is added. The mixture is stirred at 100° C. for 18 hours. After cooling, the mixture is neutralized using an aqueous saturated sodium bicarbonate solution. The resulting precipitate is filtered off with suction and dried. This gives 0.46 g of product (68% of theory).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH2:28]([O:30][C:31](=[O:39])[CH2:32][C:33]1[N:34]=[C:35]([NH2:38])[S:36][CH:37]=1)[CH3:29].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH2:28]([O:30][C:31](=[O:39])[CH2:32][C:33]1[N:34]=[C:35]([NH:38][C:8](=[O:10])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:12]=2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[S:36][CH:37]=1)[CH3:29]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(F)c(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 87, 250 mg, 0.82 mmol) in methylene chloride (8.22 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.45 mL, 0.90 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 10 min and at 25° C. for 20 min. The reaction mixture was then treated with a solution of (2-amino-thiazol-4-yl)-acetic acid ethyl ester (337 mg, 1.81 mmol) in tetrahydrofuran (4.11 mL) and N,N-diisopropylethylamine (0.34 mL, 1.97 mmol). This solution was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded {2-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (208.7 mg, 53.7%) as a pale-yellow gum: EI-HRMS m/e calcd for C21H22F4N2O3S (M+) 472.1444, found 472.1442.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH2:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]([N:28]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29](Cl)=[O:30])[CH3:27]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][NH:24][C:29]([N:28]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:26][CH3:27])=[O:30])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN)c1
Reactant: CCN(Cc1ccccc1)C(=O)Cl
Product: CCN(Cc1ccccc1)C(=O)NCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 131, Step 2, using the following starting materials: (2′-aminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester, N-ethyl-N-benzylcarbamoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH2:18][CH3:19])[C:7](=[O:17])[CH:8]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:22][CH3:23].Cl[C:25]1[N:30]=[C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[S:38]([N:41]([CH3:43])[CH3:42])(=[O:40])=[O:39])[C:28]([Cl:44])=[CH:27][N:26]=1>>[Cl:44][C:28]1[C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[S:38](=[O:40])(=[O:39])[N:41]([CH3:42])[CH3:43])=[N:30][C:25]([NH:1][C:2]2[CH:21]=[CH:20][C:5]3[N:6]([CH2:18][CH3:19])[C:7](=[O:17])[CH:8]([NH:11][C:12]([CH:14]4[CH2:15][CH2:16]4)=[O:13])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:22][CH3:23])=[N:26][CH:27]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)C(NC(=O)C2CC2)CCc2c1ccc(N)c2OC
Product: CCN1C(=O)C(NC(=O)C2CC2)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)c2OC

Procedure:
Following a procedure analogous to Example 113 Cyclopropanecarboxylic acid (7-amino-1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-amide (45 mgs) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide was converted to the title compound (48 mgs). 1H NMR (400 MHz, (CD3)2SO) δ 9.41 (s, 1H), 8.70 (s, 1H), 8.55 (d, J=8.1 Hz, 1H), 8.39 (d, J=8.8 Hz, 1H), 8.28 (s, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.67 (d, J=9.1 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.27 (t, J=7.7 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H), 4.19-4.30 (m, 2H), 3.69 (s, 3H), 3.48 (m, 1H), 3.04 (dd, J=13.7 Hz, J=5.4 Hz, 1H), 2.65 (s, 6H), 2.33-2.41 (m, 1H), 2.04-2.12 (m, 2H), 1.67 (m, 1H), 1.02 (t, J=6.8 Hz, 3H), 0.56-0.67 (m, 4H). LCMS: found 629.11 (m+1).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:10]1[C:14]2[CH:15]=[CH:16][C:17](/[CH:19]=[CH:20]/[Sn](CCCC)(CCCC)CCCC)=[CH:18][C:13]=2[O:12][CH2:11]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O>CN(C=O)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:10]1[C:14]2[CH:15]=[CH:16][C:17](/[CH:19]=[CH:20]/[C:2]3[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=3)=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: CCCC[Sn](/C=C/c1ccc2c(c1)OCO2)(CCCC)CCCC
Reactant: Nc1ncc(Cl)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncc(Cl)cc1/C=C/c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 3-bromo-5-chloro-2-pyridinamine (318 mg, 1.5 mmol), [(E)-2-(1,3-benzodioxol-5-yl)ethenyl](tributyl)stannane (250 mg, 1.7 mmol) (A. J. Bridges, A. Lee, C. E. Schwatrz, M. J. Towle, B. A. Littlefield, Bioorg. Med. Chem., 1993, 1, 403), palladium acetate (19 mg, 0.08 mmol) and tri-o-tolylphosphine (50 mg, 0.16 mmol) in DMF (0.5 ml) and triethylamine (0.5 ml) in a teflon pressure vessel was heated in a microwave (full power) for 20 sec, allowed to cool to RT heated in a microwave for a further 20 sec and then 1 min 20 sec. After allowing to cool, the reaction mixture was poured into water (20 ml) and extracted with EtOAc (3×20 ml). The combined extracts were washed with water (2×20 ml), dried over MgSO4 and concentrated. Recrystallisation from EtOAc—hexane gave the title compound as a brown solid (170 mg, 0.6 mmol):
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=1)=[O:10].[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=1)=[O:10]
Reactant: COC(=O)CCc1ccc(C(=O)NCc2ccccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1ccc(C(=O)NCc2ccccn2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 80.2 %

Procedure:
To a solution of methyl 3-[4-(2-pyridylmethylcarbamoyl)phenyl]propionate (212 mg) in methanol was added 1N sodium hydroxide solution (1 ml), and the mixture was stirred for 5 hours at 50° C. The mixture was concentrated in vacuo, and the residue was dissolved in water and was adjusted to pH 6 with 1N hydrochloric acid. The resulting precipitate was collected by filtration to give 3-[4-(2-pyridylmethylcarbamoyl)phenyl]propionic acid (162 mg).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(C)=O.C(N(CC)C(C)C)(C)C.N1C=CC=CC=1.S(=O)(=O)=O>C(Cl)Cl>[CH:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCC1CCCCC1
Agent: O=S(=O)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=CCCC1CCCCC1
Reaction time: 1 h
Yield: 97.5 %

Procedure:
3-Cyclohexyl-1-propanol (3.96 g, 27.8 mmol) was dissolved in DCM (90 mL) at 0° C. and treated sequentially with dimethyl sulfoxide (3.25 g, 41.7 mmol), N,N-diisopropylethylamine (8.98 g, 69.6 mmol) and sulfur trioxide pyridine-complex (11 g, 69.6 mmol). After one hour, the reaction mixture was diluted with DCM (100 mL) and washed with 1N aqueous HCl (3×50 mL), saturated sodium bicarbonate (3×50 mL), and brine. The organic layer was dried over MgSO4, filtered, and concentrated to yield the title intermediate as a light yellow oil (3.8 g). 1H NMR (d6-DMSO, 300 MHz) δ (ppm): 9.72 (s, 1H), 3.65-3.72 (m, 2H), 2.46 (t, 2H), 1.65-1.73 (m, 3H), 1.51-1.56 (m, 2H), 1.14-1.48 (m, 4H), 0.85-0.96 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9](/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][C:18]#[N:19])[N:8]=1.C(=O)([O-])[O-:24].[Na+].[Na+]>S(=O)(=O)(O)O>[F:22][C:2]([F:1])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9](/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][C:18]([NH2:19])=[O:24])[N:8]=1
Reactant: N#CCCC/C=C/c1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)CCC/C=C/c1nccc(NC(N)=NCC(F)(F)F)n1

Procedure:
A solution of trans-6-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]hex-5-enenitrile (400 mg.) in concentrated sulphuric acid (2 ml.) was kept at 20° for 18 hours then added dropwise to saturated aqueous sodium carbonate. The mixture was extracted with EtOAc (2×15 ml.) and the extract dried (MgSO4) and evaporated in vacuo to give trans-6-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yl]hex-5-enamide as an oil. The maleic acid salt was prepared in acetone (yield 205 mg; 36%), m.p. 177°-179°.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:18][CH:17]=[CH:16][C:15]=2[C:27]([F:30])([F:29])[F:28])=[O:10].Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:18][CH:17]=[CH:16][C:15]=2[C:27]([F:30])([F:28])[F:29])=[O:10]
Reactant: COc1ccccc1C(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccccc1O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Yield: 81.4 %

Procedure:
(2-Methoxyphenyl)[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone (0.853 g, 2.09 mmol) and pyridine hydrochloride are heated at 200° C. for 4 h. The reaction is worked up and purified as in Example above except eluting with 10:90 ethyl acetate:hexane to afford the title product as white solid (0.669 g, 81%). MS (ESI) m/z 392.0901; HRMS: calcd for C23H14F3NO2—H, 392.08984; found (ESI, [M−H]−), 392.0901.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])[CH2:6][CH2:7][C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[N:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)[CH:11]=1)=[O:9].Cl>O1CCCC1.CO.O>[Br:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:12]2[C:13]3[C:18](=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:10]([C:8](=[O:9])[CH2:7][CH2:6][C:5]([OH:28])=[O:4])=[CH:11]2)=[CH:26][CH:25]=1
Reactant: COC(=O)CCC(=O)c1cn(Cc2ccc(Br)cc2)c2ccc(Cl)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CCC(=O)c1cn(Cc2ccc(Br)cc2)c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 95.1 %

Procedure:
2N Sodium hydroxide solution (0.21 mL, 0.42 mmol) was added dropwise to a stirred solution of methyl-4-[1-(4-bromobenzyl)-5-chloro-1H-indol-3-yl]-4-oxo-butyrate (59 mg, 0.14 mmol) in tetrahydrofuran (5 mL) and methanol (1 mL). The clear reaction mixture was stirred at room temperature until the reaction was complete (TLC control), and then diluted with water (10 mL), and acidified to pH 3 with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×20 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5% methanol in methylene chloride as eluent, afforded the title compound as a white solid (56 mg, 95%): Rf: 0.30 (5% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 12.1 (1H, br s, OH), 8.67 (1H, s, ArH), 8.13 (1H, d, J=2 Hz, ArH), 7.52 (3H, m, ArH), 7.24 (3H, m, ArH), 5.48 (2H, s, CH2N), 3.12 (2H, t, J=7 Hz, CH2CO), 2.57 (2H, t, J=7 Hz, CH2CO).
Reaction SMILES: [N:1]1([C:7]2C3C(=CC=CC=3)N(C3C=CC(C(F)(F)F)=CC=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+](NC(N)=O)([O-])=[O:27].CN(C)C=O>O>[N:1]1([C:7]([NH2:8])=[O:27])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: FC(F)(F)c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)N1CCNCC1

Procedure:
A mixture of 5.5 g of 3-(1-piperazinyl)-1-[4-(trifluoromethyl)phenyl]-1H-indazole, 4.8 g of nitrourea, and 80 ml of dimethylformamide was heated on a steam bath for 15 minutes. The reaction mixture was then poured into water and the resulting precipitate was collected, washed with water, and dried. The precipitate was purified on a Water's Model 500 Preparative High Pressure Liquid Chromatograph (2×) utilizing two silica gel columns and chloroform/methanol (5%) as the eluent. Concentration of the appropriate fractions yielded a solid which was recrystallized from acetonitrile to afford 2.3 g (37%) of 4-[1-(4-trifluoromethyl)phenyl)-1H-indazol-3-yl]-1-piperazine carboxamide, m.p. 138°-140°.
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:18][C:19]3[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Reactant: Cc1ccc(CCl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3cc(C)ccc3n2Cc2ccc(C)nc2)C1
Yield: 15.7 %

Procedure:
Preparation of the title compound was carried out according to General Method 4. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example 6) (214 mg, 1 mmol), 5-(chloromethyl)-2-methylpyridine (324 mg, 2.3 mmol) and NaH (120 mg, 3 mmol) were heated in DMF (4 ml) at 120° C. for 16 h to obtain 50 mg of 2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-((6-methylpyridin-3-yl)methyl)-1H-pyrido[4,3-b]indole after purification by silica gel chromatography (100-200 mesh or 230-400 mesh) using methanol-dichloromethane gradient
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][C:3]=1[CH3:24]>C(O)(=O)C.[Pd]>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][C:3]=1[CH3:24]
Reactant: Cc1ccc2nc(/C=C/c3nc(N4CCCC4)nn3C)nn2c1C
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc2nc(CCc3nc(N4CCCC4)nn3C)nn2c1C
Yield: 99.4 %

Procedure:
(E)-5,6-Dimethyl-2-(2-(1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)vinyl)-[1,2,4]triazolo[1,5-a]pyridine (45 mg) and Pd/C (5 mg) were stirred in acetic acid (0.7 ml) under hydrogen for 1 h. The mixture was filtered and concentrated to give the product (45 mg, 99.4%) as a light yellow solid. MS: m/z=326.2 (M+H+)
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:10]([N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[N:4]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]1=[O:8])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)n1cc(F)c(=O)n(C(=O)c2ccccc2)c1=O
Temperature: 70 °C
Yield: 50.3 %

Procedure:
2.6 g (0.02 mole) of 5-fluorouracil was suspended in 10 ml of absolute pyridine, and the suspension was stirred at 70° C to form a solution. 17 g (0.12 mole) of benzoyl chloride was added dropwise to the resulting solution followed by heating to 80° C for 1.5 hours while stirring. After completion of the reaction, the reaction mixture was concentrated under reduced pressure (25 mm Hg) to half its original volume, and 50 ml of ethyl acetate was added thereto. After the insoluble matter in the ethyl acetate was removed, the solution was washed twice with water, and dried over Glauber's salt, and the ethyl acetate removed therefrom under reduced pressure (25 mm Hg). Ethanol was then added to the residue, and the mixture heated to 80° C to form a solution followed by allowing the resulting solution to cool to precipitate crystals, which were then filtered to obtain 3.4 g of 1,3-di-N-benzoyl-5-fluorouracil in a yield of 51%.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=2)[N:4]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:50])C=1>C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][N+:30]([O-:50])([CH3:33])[CH2:31][CH2:32]4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=2)[N:4]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)CC5)ccn34)c12
Solvent: ClCCl
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CC[N+](C)([O-])CC5)ccn34)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide (25 mg, 0.045 mmol; prepared according to Example 45) in DCM (3 mL) at 0° C. was added metachloroperbenzoic acid (7.8 mg, 0.032 mmol). The reaction mixture was stirred at 0° C. for one hour. The reaction mixture was concentrated under reduced pressure and silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) provided the final product (10 mg). MS (ES+APCI) m/z=569 (M+H).