Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.Cl[CH2:26][C:27]1[N:31]2[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:30]2=[N:29][C:28]=1[C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1.[NH:44]1[C:48]([C:49]([O:51][CH3:52])=[O:50])=[N:47][CH:46]=[N:45]1>>[CH3:52][O:51][C:49]([C:48]1[N:47]=[CH:46][N:45]([CH2:26][C:27]2[N:31]3[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:30]3=[N:29][C:28]=2[C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:44]=1)=[O:50]
Reactant: COC(=O)c1ncn[nH]1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: COC(=O)c1ncn(Cc2c(-c3ccc(C)cc3)nc3ccc(C)cn23)n1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and methyl 1H-1,2,4-triazole-5-carboxylate. The two isomers were separated by silica gel chromatography eluted with 20% acetone to flash out the less polar spot and 50% acetone to flash out the second spot (more polar spot). Compound 10: m/e+ 362 for C20H20N5O2 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 7.95 (s, 2H), 7.65 (d, J=8.0 Hz, 2H), 7.56 (d, J=9.1 Hz, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.10 (dd, J=1.4, 9.1 Hz, 1H), 6.15 (s, 2H), 3.98 (s, 3H), 2.38 (s, 3H), 2.31 (s, 3H) ppm; Compound 11: m/e+ 362 for C20H20N5O2 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.74 (s, 1H), 7.58 (d, J=9.5 Hz, 1H), 7.54 (d, J=7.7 Hz, 2H), 7.24 (d, J=7.7 Hz, 2H), 7.14 (d, J=9.5 Hz, 1H), 5.81 (s, 2H), 3.98 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H) ppm.
Reaction SMILES: ON[C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[S:11]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]#[N:30])[CH:27]=3)[N:22]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:21]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12])=[O:4].C(C1C=C2C(=CC=1)N(S(C)(=O)=[O:47])C=C2C1CCN(S(Cl)(=O)=O)CC1)#N.S(Cl)(Cl)(=O)=O.C([C@@H]([C@H](C(O)=O)O)O)(O)=O.N1CCCC[C@@H]1C(O)=O>>[C:29]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:21]=[C:20]2[CH:17]1[CH2:16][CH2:15][N:14]([S:11]([N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C@@H:5]2[C:3]([OH:47])=[O:4])(=[O:12])=[O:13])[CH2:19][CH2:18]1)#[N:30]
Reactant: CS(=O)(=O)n1cc(C2CCN(S(=O)(=O)Cl)CC2)c2cc(C#N)ccc21
Reactant: CS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCCC[C@@H]3C(=O)NO)CC2)c2cc(C#N)ccc21
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C(O)[C@H]1CCCCN1
Solvent: O=S(=O)(Cl)Cl
Product: CS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCCC[C@@H]3C(=O)O)CC2)c2cc(C#N)ccc21
Yield: 86 %

Procedure:
10% Palladium on carbon (0.49 g) was added to a solution of 1-benzyloxycarbonyl-4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (0.98 g, 2.24 mmol) [prepared as described in Step 2 above] in 80% ethanol/tetrahydrofuran (10 ml) under an argon atmosphere. The reaction mixture was stirred under an atmosphere of hydrogen gas (1 atm) for 2 h. The reaction mixture was degassed, filtered through Celite and concentrated in vacuo to give 4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (97%) as a white solid. This material was converted to N-hydroxy-1-[4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide by converting it to 4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl chloride by following Example 16, Step 1, coupling the sulfonyl chloride with (R)-pipecolinic acid (L)-tartrate salt to give 1-[4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (86%) by following Example 14, Step 6 and then converting the acid to the final compound by following Example 16, Steps 3 and 5; mp: 143.3-143.9° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:10][CH2:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)cnc1Cl
Yield: 49.4 %

Procedure:
In 80 ml of carbon tetrachloride, 4.00 g (27.6 mmol) of 2-chloro-3-fluoro-5-methylpyridine was dissolved. To this solution, 7.37 g (41.4 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added, and the mixture was heated under reflux overnight. After completion of the reaction, the reaction liquid was returned to room temperature, and concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1). Thus, 3.06 g of 5-(bromomethyl)-2-chloro-3-fluoropyridine was obtained (Percentage Yield: 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:12](O)=[O:13])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[CH3:44][NH:45][NH2:46]>ClCCl>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:12]([N:45]([CH3:44])[NH2:46])=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2ccc(C(=O)O)cc2OCc2ccc(OC)cc2)cc1
Reactant: CNN
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(COc2ccc(C(=O)N(C)N)cc2OCc2ccc(OC)cc2)cc1
Temperature: -40 °C
Yield: 97.4 %

Procedure:
3,4-bis-(4-Methoxybenzyloxy)benzoic acid (0.792 g, 2.0 mmol) was dissolved in dichloromethane (20 ml) and treated with N,N-diisopropylethylamine (0.35 ml, 2.0 mmol). The solution was cooled to -40° C. and treated with methanesulphonyl chloride (0.15 ml, 2.0 mmol). The mixture was allowed to warm to room temperature for 10 minutes and then re-cooled to -40° C. and added to a solution of methylhydrazine (0.215 ml, 4 mmol) in dichloromethane (10 ml) at -40° C. The mixture was allowed to warm to room temperature for 1.5 h and then evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate which was washed with water and brine. Evaporation of the solvent gave the title compound (0.823 g, 94%); δH (CDCl3) 3.08 (3H, s), 3.74 (6H, s), 4.25 (2H, brs), 5.03 (4H, s), and 6.70- 7.40 (11H, m).
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCOC(C)=O.CCCCCC>C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3ccc(Br)cc3c2CC1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(c1ccccc1)N1CCc2[nH]c3ccc(-c4ccccc4)cc3c2CC1
Yield: 55.7 %

Procedure:
A mixture of 3-benzoyl-9-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.477 g, 4.00 mmol) and tetrakis(triphenylphosphine)palladium (0.462 g, 0.40 mmol) in dimethoxyethane (15.0 mL) and a solution of phenylboronic acid (0.585 g, 4.80 mmol) in dimethoxyethane (5.0 mL) and sodium carbonate (2 M, 12.0 mL) were reacted in a manner similar to Preparation 1. Column chromatography (silica gel, 60% EtOAc/hexane) afforded 0.817 g (56%) of the title compound as a solid: mp 78-79° C.; 1H NMR (300 MHz, CDCl3) δ 8.10-7.85, 7.71-7.57, 7.43-7.29, 7.18-7.05, 4.16-4.04, 3.70-3.65, 3.20-3.05, 2.95-2.80; MS (ESI+) m/z 367 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=3[CH3:26])[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][C:17]=3[CH3:26])[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: Cc1cc(C(F)(F)F)ccc1NC1CN(c2ncc(Cl)cc2C(=O)O)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4ccc(C(F)(F)F)cc4C)C3)CC2)cc1
Yield: 74.7 %

Procedure:
The title compound (D170) (43 mg) was prepared according to the experimental procedure described in Description 169 starting from 5-chloro-2-(3-((2-methyl-4-(trifluoromethyl)phenyl)amino)azetidin-1-yl)nicotinic acid (D119) (40 mg, 0.103 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (23.6 mg, 0.103 mmol).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]2[NH:7]C(=O)[O:9][C:10](=O)[C:5]=2[CH:4]=1.[CH:17]1([C:22](=O)[CH2:23][C:24]#[N:25])[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C.Cl>CN(C=O)C>[CH:17]1([C:22]2[C:23]([C:24]#[N:25])=[C:10]([OH:9])[C:5]3[C:6](=[CH:13][CH:14]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=3)[N:7]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N#CCC(=O)C1CCCC1
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2c(=O)o1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1c(C2CCCC2)nc2ccc(C(F)(F)F)cc2c1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.6 %

Procedure:
A mixture of 6-trifluoromethyl-1H-benzo[d][1,3]oxazine-2,4-dione (1.5 g, 4.22 mmol), 3-cyclopentyl-3-oxopropanenitrile (579 mg, 4.22 mmol), triethylamine (5.98 g, 8.23 ml, 59.1 mmol) and DMF (638 μl) was stirred for 72 h at room temperature. 1N HCl was added and the reaction mixture was extracted with EtOAc. The combined extracts were washed with brine, dried with Na2SO4 and evaporated. The remaining residue was triturated in EtOAc (8 ml) for 3 h. The solid was filtrated off and washed two times with EtOAc to afford the title compound (421 mg, 24%) as white solid. MS (ESI): 307.5 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6](=O)[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])[CH3:2].C([O-])(=O)C.[NH4+:23].CCCCCC>CO.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[C:6]([NH2:23])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)CC(=O)Cc1cc(F)c(F)cc1F
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C=C(N)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Yield: 79.6 %

Procedure:
3-Oxo-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1c (24.6 g, 94.5 mmol) was dissolved in 240 mL of methanol, and ammonium acetate (36.4 g, 473 mmol) was added to the solution. The reaction mixture was heated to reflux for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure, and then 100 mL of water was added to the residue. The mixture was extracted with ethyl acetate (200 mL×3), and the combined organic phase was washed with 200 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a light yellow solid. The resulting solid was dissolved in 50 mL of ethyl acetate at 80° C., and then 50 mL of n-hexane and seed-crystal were added to the solution. The mixture was cooled to room temperature, and, half an hour later, 100 mL of n-hexane was added. The mixture was stored in refrigerator overnight and then filtered under reduced pressure to obtain the title compound 3-amino-4-(2,4,5-trifluoro-phenyl)-but-2-enoic acid ethyl ester 1d (19.5 g, yield 80%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][C:18]([O:20]C)=O)[C:12](S(C)(=O)=O)=[N:11][C:10]=1[C:26]([O-:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][NH2:30].O1[CH2:35][CH2:34]CC1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][C:18](=[O:20])[N:30]([CH3:29])[C:12]2=[N:11][C:10]=1[C:26]([O:28][CH2:34][CH3:35])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: C1CCOC1
Reactant: COC(=O)CCn1c(S(C)(=O)=O)nc(C(=O)[O-])c(OCc2ccccc2)c1=O
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC(=O)N2C
Temperature: 22 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A solution of ethyl intermediate 9, 5-benzyloxy-1-(2-methoxycarbonylethyl)-2-methylsulfonyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylate, (0.594 g, 1.35 mmol) in tetrahydrofuran (10 ml) was treated with 10 ml (20 mmol) of a 2M solution of methylamine in tetrahydrofuran and the resulting mixture stirred at 22° C. for 1 h. The solvent was then evaporated in vacuo and the residue diluted with toluene and heated under reflux for 2.5 h. The reaction mixture was then diluted with ethyl acetate washed successively with saturated sodium bicarbonate and brine then dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by chromatography on silica gel (elution gradient of ethyl acetate 0–20% in toluene) gave 0.374 g (77% yield) of the title ester as white crystals; mp 121° C. (ethyl acetate/hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.31 (3H, t, J=7.1 Hz, CH3), 2.82 (2H, t, J=7.0 Hz, CH2), 3.42 (3H, s, NCH3), 4.27 (2H, t, J=7.0 Hz, CH2), 4.33 (2H, q, J=7.1 Hz, OCH2), 5.20 (2H, s, OCH2), 7.36 (3H, m, aromatics), 7.47 (2H, m, aromatics). Anal. Calcd for C18H19N3O5: C, 60.49; H, 5.35; N, 11.75. Found: C, 60.12; H, 5.04; N, 11.49.
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:25])[NH:17][C:18]3[C:23]/2=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)/[CH:9]=1.[CH:26]([C:28]1[S:32][CH:31]=[C:30](B(O)O)[CH:29]=1)=[O:27].C([O-])([O-])=O.[Na+].[Na+]>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.O>[F:24][C:20]1[CH:19]=[C:18]2[C:23](/[C:15](=[C:10]3/[CH:9]=[C:8]([C:30]4[CH:29]=[C:28]([CH:26]=[O:27])[S:32][CH:31]=4)[C:12]([CH3:14])([CH3:13])[O:11]/3)/[C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: O=Cc1cc(B(O)O)cs1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1csc(C=O)c1
Temperature: 80 °C

Procedure:
To 30 mL of 1,4-dioxane were added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (600 mg, 1.85 mmol), 5-formylthiophene-3-boronic acid (348 mg, 2.23 mmol), PdCl2(PPh3)2 (60 mg, 0.085 mmol), 1M Na2CO3 aqueous solution (7.4 mL, 7.4 mmol). The mixture was heated at 80° C. under N2 for 3.5 hours, cooled to room temperature and poured into 200 mL of water. The mixture was extracted with EtOAc (3×80 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified through silica gel column with 1-5% MeOH/CHCl3 to give 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]thiophene-2-carbaldehyde as brown solid. Yield: 458 mg, 70%.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([C:20](=[O:27])[CH:21]=[C:22]([OH:26])[C:23](O)=[O:24])[C:8](=[O:19])[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:10]=1.[OH:33][C:34]1[C:42]2[N:41]=NN[C:38]=2[CH:37]=[CH:36]C=1.C([O-])(O)=O.[Na+].O>CN(C)C=O.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([C:20](=[O:27])[CH:21]=[C:22]([OH:26])[C:23]([NH:41][C@H:42]2[CH2:38][CH2:37][CH2:36][C@@H:34]2[OH:33])=[O:24])[C:8](=[O:19])[N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:10]=1
Reactant: O=C(O)C(O)=CC(=O)c1cc(Cc2ccc(F)cc2F)cn(Cc2ccccc2F)c1=O
Reactant: Oc1cccc2[nH]nnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(N[C@H]1CCC[C@@H]1O)C(O)=CC(=O)c1cc(Cc2ccc(F)cc2F)cn(Cc2ccccc2F)c1=O
Reaction time: 0.5 h

Procedure:
To a chilled solution of the 4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-hydroxy-4-oxobut-2-enoic acid 8 (150 mg, 0.338 mmol) in dimethylformamide (DMF) (2.0 mL), was added hydroxybenzotriazole (HOBT) (50 mg, 0.372 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDCI-HCl (71 mg, 0.372 mmol). The resulting mixture was stirred for 30 min. A solution of (1S,2S)-(+)-trans-2-aminocyclopentanol hydrochloride and NaHCO3 (31 mg, 0.372 mmol) was added. The resulting mixture was stirred for 2 h at 0-5° C. Thin layer chromatography (TLC) analysis indicated completion, hence cold water was added to the reaction mixture and then extracted with ethyl acetate (2×20 mL). The combined organic phase was separated and washed with water twice, then once with 1N HCl solution, then saturated aqueous NaHCO3 solution. Concentration in vacuo afforded the crude product which was passed through a short plug of silica gel eluting with chloroform, the eluent was concentrated and the residual triturated with hexanes affording the product as a yellow solid in 117 mg (66.0%). The residual solvent was removed in vacuo affording pure product as a yellow solid, mp 60.0-62.9° C., [α]20D +24.0 (c 0.01, MeOH), UV (MeOH) 396 nm (ε 14,455), 318 nm (ε 6327). 1H NMR (CDCl3, 500 MHz): δ 15.33 (bs, 1H), 8.16 (d, 1H, J=2.0 Hz), 8.08 (s, 1H), 7.61-6.85 (m, 9H), 5.22 (s, 2H), 4.11 (m, 1H), 3.94 (m, 1H), 3.78 (s, 1H), 2.23 (m, 1H), 2.10 (m, 1H), 1.88 (m, 1H), 1.78 (m, 2H), 1.59 (m, 1H). 13C NMR (CDCl3, 125 MHz): δ 181.3, 180.6, 163.4, 163.3, 162.4, 162.1, 162.0, 161.4, 161.3, 160.4, 160.1, 160.0, 159.2, 145.5, 143.9, 142.3, 141.6, 132.4, 132.4, 132.3, 131.5, 131.4, 131.3, 131.3, 131.2, 130.7, 130.6, 125.0, 124.9, 124.8, 122.8, 122.7, 122.5, 122.2, 122.2, 122.1, 122.1, 117.1, 115.9, 115.7, 115.6, 111.9, 111.9, 111.8, 111.7, 104.7, 104.5, 104.3, 98.3, 79.5, 79.3, 61.0, 60.6, 51.5, 47.7, 47.3, 32.9, 32.8, 32.7, 30.8, 30.7, 30.5, 21.7, 21.5. HRMS (M+H)+ calculated mass 527.1794 for C28H26F3N2O5. found 527.1799.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8](Cl)(Cl)Cl)[CH:5]=[CH:4][N:3]=1.NC1C=C(C)C=CN=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:1]2[C:23](=[O:24])[C:22]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]3[C:20]2=[O:25])[CH:7]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc(C(Cl)(Cl)Cl)ccn1
Agent: Cc1ccnc(N)c1
Product: Cc1ccnc(N2C(=O)c3ccccc3C2=O)c1

Procedure:
A process for the preparation of 2-amino-4-trichloromethylpyridine of the formula I, wherein 2-amino-4-picoline is reacted with phthalic anhydride to give 4-methyl-2-phthalimidopyridine, the latter is chlorinated and the product is hydrolyzed.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15](=O)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C[O-].[Na+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]CCBr>C1COCC1.CO>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:16][CH2:15][S:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCCCCCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(SCCCCCCBr)CC1
Yield: 61.4 %

Procedure:
To a solution of N-t-butyloxycarbonyl-4-acetylthiopiperidine (5.5 g) in a mixture of THF (50 ml) and methanol (50 ml) was added 28% sodium methoxide methanol solution (4.76 ml) with stirring under ice-cooling and stirred at the same temperature for 30 minutes. To the solution was added 1,6-dibromohexane (17.1 g) under ice-cooling, and the mixture was successively stirred at ambient temperature for 30 minutes and then stirred at 45° C. for 2 hours. The reaction mixture was concentrated in vacuo. The resulting residue was chromatographed on silica gel (500 ml) eluting with a mixture of n-hexane and ethyl acetate (6:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-(6-bromohexylthio)-N-t-butyloxycarbonylpiperidine (4.95 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][O:16][C:15]2=[O:25])=[O:13])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C=O)C>[Si:32]([O:26][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][C:12]([N:14]1[CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:17][O:16][C:15]1=[O:25])=[O:13])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: O=C(CCCC(O)c1ccc(F)cc1)N1C(=O)OCC1c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
30 g of 3-[5-(4-Fluorophenyl)-5-hydroxypentanoyl]4-phenyloxazolidin-2-one are dissolved in 50 ml of DMF. 14.3 g of imidazole and 19 g of tert-butyldimethylsilyl chloride in 25 ml of DMF are added, and the mixture is then stirred at room temperature until the reaction has gone to completion (2-4 h). The reaction solution is concentrated, water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated, giving 10:
Reaction SMILES: CS[CH:3]1[C:12]2[N:11]=[CH:10][N:9]=[CH:8][C:7]=2[CH:6]=[C:5]2[N:13]=[N:14][N:15]=[C:4]12.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].[ClH:24].BrC1C=C(C=CC=1)N>C(O)(C)C>[ClH:24].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][CH:3]1[C:12]2[N:11]=[CH:10][N:9]=[CH:8][C:7]=2[CH:6]=[C:5]2[N:13]=[N:14][N:15]=[C:4]12
Reactant: CSC1C2=NN=NC2=Cc2cncnc21
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CC(C)O
Product: Brc1cccc(NC2C3=NN=NC3=Cc3cncnc32)c1
Yield: 63.3 %

Procedure:
A mixture of 4-methylthiotriazolo[4,5-g]quinazoline (0.30 g, 1.38 mmol), 3-bromoaniline (2.1 mmol) and 3-bromoaniline hydrochloride (2.1 mmol) in isopropanol (400 mL) is heated under reflux for 6 h, and the solution is concentrated to give 4-(3-bromoanilino)-triazolo[4,5-g]quinazoline hydrochloride (0.33 g, 63 %). 1H NMR (DMSO) δ12.01 (1H, brs), 9.86 (1H, s), 9.02 (1H, s), 8.63 (1H, s), 8.39 (1H, s), 8.13 (1H, dd, J=1.9, 1.5 Hz), 7.85 (1H, ddd, J=7.7, 1.9, 1.5 Hz), 7.56 (1H, ddd, J=8.0, 1.7, 1.5 Hz), 7.41 (1H t, J=7.8 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:17][N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][C:21](=[O:26])[CH2:22]2>>[CH3:17][N:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][C:21]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1)([OH:26])[CH2:22]2
Reactant: CN1C2CCC1CC(=O)C2
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Li]CCCC
Product: CN1C2CCC1CC(O)(c1ccc(C(F)(F)F)cc1)C2

Procedure:
The title compound was prepared from 4-bromobenzotrifluoride, n-butyllithium in hexanes (31.2 mL, 2.5M; 77.9 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-one (5 g, 36 mmol). Yield 6.2 g (60%) as a yellow solid, m.p. 189.2-190.5° C.