Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:16]=[N:17][C:18](Cl)=[N:19][CH:20]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[Br:14][C:15]1[CH:16]=[N:17][C:18]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[N:19][CH:20]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Temperature: 150 °C
Yield: 96.3 %

Procedure:
In a microwave vial were mixed: 1,1-dimethylethyl 1-piperazinecarboxylate (110 mg, 0.589 mmol, available from Fluke), 5-bromo-2-chloropyrimidine (95 mg, 0.491 mmol, available from Lancaster) and DIPEA (0.112 mL, 0.638 mmol) in tert-butanol (2 mL). The reaction was stirred and heated in an Emrys Optimizer microwave at 150° C. for 0.5 hr. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL) and the organic layer washed with brine (20 mL) before being dried through an hydrophobic frit and concentrated to yield the desired product (162.3 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[NH2:23][N:24]1[CH2:28][CH:27]([CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[O:26][C:25]1=[O:36]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:23][N:24]3[CH2:28][CH:27]([CH2:29][N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[O:26][C:25]3=[O:36])=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: NN1CC(CN2CCOCC2)OC1=O
Product: O=C(NN1CC(CN2CCOCC2)OC1=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 3-amino-5-(4-morpholinylmethyl)-2-oxazolidinone (CAN 43056-63-9) as starting materials; LC-MS (UV peak area/ESI) 97.7%, 515.1292 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[NH2:8].[CH3:10][O:11][C:12]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:13]=1[C:14](O)=O>>[CH3:10][O:11][C:12]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:13]=1[C:14]1[N:1]=[C:2]2[C:3](=[O:9])[NH:4][NH:5][CH:6]=[C:7]2[N:8]=1
Reactant: Nc1cn[nH]c(=O)c1N
Reactant: COc1cc(N)ccc1C(=O)O
Product: COc1cc(N)ccc1-c1nc2c[nH][nH]c(=O)c-2n1

Procedure:
Prepared analogously to Example 1 from 4,5-diamino-2H-pyridazin-3-one and 2-methoxy-4-amino-benzoic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH:40]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)[CH2:39][CH2:38]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13](=[O:14])[N:46]1[CH2:45][CH2:44][CH:43]([C:40]2[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=2)[CH2:48][CH2:47]1)[CH3:2]
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: c1cc(C2CCNCC2)ccn1
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(c3ccncc3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 170 mg (1.04 mmol) 1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([Si:17]([C:20]1[C:25]([F:26])=[CH:24][N:23]=[C:22]([F:27])[C:21]=1[Cl:28])([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].[F:29][C:30]1[C:35]([C:36](N(OC)C)=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=1>C1COCC1>[Si:17]([C:20]1[C:21]([Cl:28])=[C:22]([F:27])[N:23]=[C:24]([C:36]([C:35]2[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:37])[C:25]=1[F:26])([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:19])[CH3:18]
Reactant: CON(C)C(=O)c1cccnc1F
Reactant: CC(C)(C)[Si](C)(C)c1c(F)cnc(F)c1Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)c1c(F)c(C(=O)c2cccnc2F)nc(F)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of diisopropylamine (52.41 g, 72.59 mL, 517.9 mmol) in THF (967.3 mL) was cooled to −20° C. n-BuLi (2.5M in hexane) (198.5 mL of 2.5 M, 496.3 mmol) was added dropwise over 15 minutes via cannula maintaining the internal temperature below −15° C. The solution was warmed to 0° C. then immediately re-cooled to −90° C. A solution of tert-butyl-(3-chloro-2,5-difluoro-4-pyridyl)-dimethyl-silane (113.84 g, 431.6 mmol) in THF (85.35 mL) was added dropwise over 20 min via cannula at such a rate that the internal temperature was kept below −85° C. During addition the solution first changed to bright yellow then slowly became an orange coloured suspension. The reaction mixture was stirred at −85° C. for 1 h. A solution of 2-fluoro-N-methoxy-N-methylpyridine-3-carboxamide (91.40 g, 496.3 mmol) in THF (85.35 mL) was added dropwise over 15 minutes via cannula at such a rate that the internal temperature was kept below −80.7° C. (ideally below −85° C.). The mixture turned dark orange brown after the addition. The mixture was stirred at −85° C. for 90 minutes after which time Lc/Ms indicated the reaction was complete. The cooling bath was removed and the mixture warmed to −50° C. Saturated ammonium chloride solution (400 mL) was added and the mixture allowed to warm up to RT. The mixture was diluted with ethyl acetate (1.5 L). The aqueous phase was separated and extracted with more ethyl acetate (300 ml). The combined organics were washed with brine (300 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to a brown oil. The crude was purified on silica gel (CombiFlash Companion XL, 1.5 kg column, 0.5-10% ethyl acetate in petroleum ether, 0-50% ethyl acetate in petroleum ether). This gave the title compound as a yellow oil which solidified on standing (159.6 g, 95%); 1H NMR (CDCl3) 0.60 (6H, d), 1.07 (9H, s), 7.47 (1H, m), 8.33 (1H, m), 8.52 (1H, m); 19F NMR (decoupled) −107.2, −72.4, −61.8; MS ES (+) 387.04 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:16]([S:20](Cl)(=[O:22])=[O:21])[CH2:17][CH2:18][CH3:19]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:20]([CH2:16][CH2:17][CH2:18][CH3:19])(=[O:22])=[O:21])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: CCCCS(=O)(=O)Cl
Product: CCCCS(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C)cc1

Procedure:
The title compound was prepared according to general procedure for sulfonylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using butane sulfonyl chloride (72 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]butane-1-sulfonamide (0.026 g).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.NC(C)(C)C[C:22]1[CH:34]=[CH:33][C:25]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:24][CH:23]=1>>[OH:1][C@@H:2]([CH2:3][N:11]([C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:33][CH:34]=1)[CH2:10][CH:18]([CH3:6])[CH3:17])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(N)Cc1ccc(Oc2ccccn2)cc1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(Oc2ccccn2)cc1

Procedure:
Titled compound was prepared substantially in accordance with Example 118 from (S)-4-(oxiranylmethoxy)-9H-carbazole (0.375 g) and 2-(4-(2-amino-2-methylpropyl)phenoxy)pyridine (0.496 g) to yield product (0.26 g) after purification. NMR.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc3cc[nH]c23)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc3cc[nH]c23)CC1
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A mixture of 4-(1H-indol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester XVII (700 mg, 2.3 mmol) and 10% Pd/C (70 mg) in ethanol (75 mL) was placed under H2 atmosphere on the parr shaker at 50 psi, and was shaken overnight. The reaction mixture was filtered through a plug of celite capped with a glass filter. The filtrate was concentrated to afford (680 mg, 95%) of 4-(1H-indol-7-yl)-piperidine-1-carboxylic acid tert-butyl ester XVIII.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:18])[NH:12][C@H:13]([CH2:16][OH:17])[CH2:14][CH3:15])[N:10]=2)[CH2:3]1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C)C=O>[Si:19]([O:17][CH2:16][C@@H:13]([NH:12][C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:5][CH:2]([OH:1])[CH2:3]2)[S:7][CH:8]=1)=[O:18])[CH2:14][CH3:15])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC[C@@H](CO)NC(=O)c1csc(N2CC(O)C2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(1S)-1-(hydroxymethyl)-propylcarbamoyl]-1,3-thiazol-2-yl}azetidine (940 mg, 3.50 mmol) (obtained as described in Reference Example 34(3)) in dimethylformamide (47 ml) were added t-butyldimethylsilyl chloride (633 mg, 4.20 mmol) and imidazole (286 mg, 4.20 mmol) in an ice bath, and the reaction mixture was stirred at room temperature for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:3) as the eluant to afford 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)propylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (1.00 g, yield 74%) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:4][N:5]([CH3:15])[C:6]=1[NH:7]C(=O)OC(C)(C)C.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.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:16]([C:3]1[C:2]([C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)=[C:6]([NH2:7])[N:5]([CH3:15])[N:4]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: Cn1nc(C(C)(C)C)c(Br)c1NC(=O)OC(C)(C)C
Reactant: OB(O)c1cccnc1
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: CCO
Product: Cn1nc(C(C)(C)C)c(-c2cccnc2)c1N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
tert-Butyl (4-bromo-3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbamate (Intermediate I, 1.7 g, 5.12 mmol), pyridine-3-boronic acid (1.26 g, 10.23 mmol), and Pd(PPh3)4 (295 mg, 0.26 mmol) were dissolved in ethanol (25 mL), and Na2CO3 (2 M aqueous solution, 25 mL) was added. The mixture was degassed for 10 min. The reaction mixture was then heated to 80° C. for 16 h. The mixture was diluted with ethyl acetate, the solid was filtered off, and the filtrate was treated with TFA (5 mL). The mixture was stirred for 30 min before being concentrated under reduced pressure. The crude was dissolved in methanol and filtered though a C8-silica plug. HPLC purification with gradient elution from 5 to 60% acetonitrile in water afforded 300 mg (25%) of the title compound. 1H NMR (300 MHz, CD3OD) δ 8.73 (d, 1H), 8.64 (s, 1H), 8.14 (d, 1H), 7.81 (dd, 1H), 3.73 (s, 3H), 1.20 (s, 9H). ES-MS m/z 231.2 (MH+); HPLC RT (min) 0.23.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([O:11][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:2]([CH3:1])[CH:7]=1)(=[O:9])[CH3:10]
Reactant: COC(=O)CBr
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(C)=O)cc1C
Reaction time: 66 h

Procedure:
A mixture of 4-hydroxy-3-methylacetophenone (5 g), methyl bromoacetate (3.70 ml) and anhydrous potassium carbonate (5.52 g) in acetone (100 ml) was stirred for 66 hours. The mixture was filtered and the filtrate evaporated to give an oil which crystallised on standing giving methyl 4-acetyl-2-methylphenoxyacetate, 7.2 g: m.p. 51°-53° C.; NMR (d6DMSO) δ 7.79 (1H, s), 7.77 (1H, d), 6.94(1H,d), 4.93 (2H, s), 3.71 (3H, s), 2.50 (3H, s+DMSO), 2.24 (3H, s).
Reaction SMILES: [CH2:1]([NH2:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:7][C:8]1[C:9](Cl)=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1>CO>[Br:7][C:8]1[C:9]([NH:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1
Reactant: CC(C)(C)CN
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CO
Product: CC(C)(C)CNc1nc(Cl)ncc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.5 %

Procedure:
Neopentylamine (30 ml, 0.255 mol) is added dropwise at 0° C. over 20 min to a soln. of 5-bromo-2,4-dichloropyrimidine (29.17 g, 0.128 mol) in MeOH (230 ml). After stirring for 20 min at 0° C., the mixture is warmed to room temperature, stirred for 3 h, and evaporated. The residue is suspended in 300 ml of EtOAc, washed with sat. aq. NaHCO3 soln. (80 ml) and brine (80 ml), dried (MgSO4), and evaporated. The residue is chromagraphed on silica gel column (800 g of silica gel; hexane/EtOAc 5:1) to give the product (A) (32.64 g, 92%). White crystals. 1H-NMR (400 MHz, CDCl3) δ 1.00 (s), 3.36 (d, J=8.0), 5.52-5.61 (br. s), 8.12 (s). Rf 0.48 (hexane/EtOAc 5:1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32]Br.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32][N:9]1[CH:10]([C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:11][CH2:12][CH2:13][CH:8]1[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Clc1cccnc1C1CCCC(c2ncccc2Cl)N1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C#N)ccc1CN1C(c2ncccc2Cl)CCCC1c1ncccc1Cl
Yield: 82.3 %

Procedure:
Using General Procedure A: 3,3″-dichloro-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (304 mg, 0.987 mmol), 2-bromomethyl-5-cyano-benzoic acid methyl ester (351 mg, 1.38 mmol), KI (32.7 mg, 0.197 mmol), DIPEA (0.34 mL, 1.97 mmol), and DMF (5 mL) were stirred at 60° C. for 3 h. Purification of the crude material by flash chromatography on silica gel (CH2Cl2/MeOH, 98:2) afforded 5-cyano-2-(3,3″-dichloro-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester (391 mg, 82%) as a yellow oil. 1H NMR (CDCl3) δ 1.63-1.78 (m, 3H), 2.01-2.14 (m, 1H), 2.18-2.38 (m, 2H), 3.87 (s, 3H), 3.95 (s, 2H), 4.52 (dd, 2H, J=11.4, 1.6 Hz), 6.89 (dd, 2H, J=8.4, 4.9 Hz), 7.38-7.48 (m, 3H), 7.57 (d, 1H, J=1.7 Hz), 8.22-8.32 (m, 3H).
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][C:8](=[O:21])[CH2:9][CH:10](O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH:10]2[O:22][C:6](=[O:5])[CH2:7][C:8](=[O:21])[CH2:9]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)CC(=O)CC(O)CCc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(=O)OC(CCc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
To a stirred solution of 7-(4-Fluoro-phenyl)-5-hydroxy-3-oxo-heptanoic acid tert-butyl ester (0.64 g, 2.06 mmol) in dry DCM was added TFA (0.24 g, 2.1 mmol) at 0° C. The resultant clear solution was stirred at rt for 16h. Removal of the volatile components under reduced pressure afforded the product 6-[2-(4-Fluoro-phenyl)-ethyl]-dihydro-pyran-2,4-dione as a white solid (0.32g, 66%). 1H NMR (300 MHz, CDCl3) δ1.8-2.2 (m, 2H), 2.25-2.55 (m, 2H), 2.65-2.95 (m, 2H), 3.55 (dd, ˜1H, J=10), 4.25-4.40(m, ˜0.5H), 4.6-4.7 (m, ˜0.5 H), 5.2 (s, ˜0.5 H), 6.90-7.05 (m, 2H), 7.1-7.2 (m, 2H), 10.8 (br, ˜0.5H). ESMS calcd (C13H13FO3): 236.1; found: 237.1 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=4)=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.[C:26](O)(=[O:30])[C@H:27]([CH3:29])[OH:28].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([CH2:24][NH:25][C:26](=[O:30])[C@@H:27]([OH:28])[CH3:29])=[CH:22][CH:23]=4)=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: NCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1
Reactant: C[C@H](O)C(=O)O
Agent: F[B-](F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](O)C(=O)NCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1
Reaction time: 0.25 h

Procedure:
1-{4-[1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yl]phenyl}methanamine (19 mg, 0.055 mmol), L-lactic acid (9.9 mg, 0.11 mmol, 2 equiv), N,N-diisopropylethylamine (48 μL, 0.27 mmol, 5 equiv) and (1H-benzotriazol-1-yloxy) (tripyrrolidin-1-yl) phosphonium tetrafluoroborate (43 mg, 0.082 mmol, 1.5 equiv) were combined in dichloromethane (1.5 mL) and stirred for 15 minutes. The mixture was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (95:5 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 8.33 (1H, t, J=6.9 Hz), 8.30 (1H, d, J=8.5 Hz), 7.51 (1H, d, J=8.7 Hz), 7.36-7.32 (4H, m), 4.72 (2H, d, J=7.2 Hz), 4.41-4.33 (2H, m), 4.08-4.03 (1H, m), 1.46-1.38 (1H, m), 1.27 (3H, d, J=6.6 Hz), 0.60-0.55 (2H, m), 0.53-0.50 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 419.1700 [(M+H)+; calculated for C21H22F3N4O2: 419.1689].
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])=[O:7])=[N:15][CH:16]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Br)cn1)c1ccccc1[N+](=O)[O-]
Yield: 77.9 %

Procedure:
A solution of 2-nitrobenzoyl chloride (3.70 g, 20 mmol, 1.0 equiv), 2-amino-5-bromopyridine (3.50 g, 1.0 equiv), pyridine (10 mL) in 25 mL of methylene chloride was stirred overnight. The volatile was evaporated, flash chromatography on silica gel gave N-(5-bromo-2-pyridinyl)-(2-nitro)phenylcarboxamide (5.02 g, 77%). MS found for C12H9BrN3O3 (M+H)+: 322.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.CCOCC>C(Cl)Cl>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,3-Dihydro-3-(RS)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one (500 mg, 1.98 mmole) and p-chlorobenzoyl chloride (255 μl, 2.00 mmole) were combined at room temperature in 30 ml of methylene chloride. The resulting solution was protected from moisture and stirred at room temperature overnight. The reaction mixture was diluted with 70 ml of methylene chloride and washed with sodium bicarbonate solution (sat.) and brine. The organic extracts were dried (MgSO4) and concentrated to give the crude product. Trituration with ether afforded the analytical sample as a white solid.
Reaction SMILES: [C:1]([CH:4]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH:5]([CH3:9])[CH2:6][C:7]#[N:8])(=O)[CH3:2].S(=O)(=O)(O)[OH:17]>C(O)(=O)C>[CH3:9][CH:5]1[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:1]([CH3:2])[NH:8][C:7](=[O:17])[CH2:6]1
Reactant: CC(=O)C(c1ccncc1)C(C)CC#N
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC1=C(c2ccncc2)C(C)CC(=O)N1
Reaction time: 4 h

Procedure:
To a 2.0 g portion of 4-acetyl-3-methyl-4-(4-pyridinyl)butanenitrile dissolved in 20 ml of acetic acid was added dropwise 3 ml of sulfuric acid whereupon an exothermic reaction ensued. The reaction mixture was stirred for 4 hours, the acetic acid was evaporated off in vacuo and to the remaining material was added 10 ml of water followed by basification with 35% aqueous sodium hydroxide solution. The alkaline solution was extracted four times with ethyl acetate; the combined extracts were dried over anhydrous magnesium sulfate; the ethyl acetate was distilled off in vacuo; and, the remaining white solid was recrystallized from acetonitrile to produce 2.0 g of 3,4-dihydro-4,6-dimethyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 184°-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:4][C:3]=1[O:20]C.B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:4][C:3]=1[OH:20]
Reactant: COc1cc(CN2C(=O)c3ccccc3C2=O)ccc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)c(O)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
2-{[4-Chloro-3-(methyloxy)phenyl]methyl}-1H-isoindole-1,3(2H)-dione (7.0 g, 23 mmol) was dissolved in CH2Cl2 (25 mL) and cooled to 0° C. Boron tribromide (1.0 M solution, 46 mL) was added slowly then the solution was warmed to RT and stirred for 4 h. The reaction was cooled to 0° C. and ice water (100 mL) and EtOAc (200 mL) were added. The aqueous layer was separated and extracted with EtOAc (2×200 mL). The organic extracts were combined, dried over Na2SO4, filtered, evaporated and triturated with hexanes to afford the title compound (6.5 g, 97%) as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 10.15 (s, 1H), 7.87 (d, 2H), 7.87 (ddd, 2H), 7.25 (d, 1H), 6.88 (d, 1H), 6.74 (dd, 1H), 4.66 (s, 2H). MS: m/z 286.0 (M−1).