Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Br)cc2)cc1-c1c(Br)cnn1C
Yield: 72.7 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.032 g, 0.11 mmol) was treated with 4-bromophenyl isocyanate (0.022 g, 0.11 mmol, 1.0 equiv.) in CH2Cl2 (2 mL), in a similar manner as described in Example 1.2 to afford Compound 5 (0.040 g, 0.08 mmol, 75%) as a white solid. LCMS m/z (%)=479 (M+H79Br79Br, 51), 481 (M+H79Br81Br, 100), 483 (M+H81Br81Br, 50). 1H NMR (400 MHz, acetone-d6) δ: 8.22 (s, 1H), 8.14 (s, 1H), 7.68 (dd, J=2.7, 9.0 Hz, 1H), 7.48-7.54 (m, 3H), 7.39-7.46 (m, 3H), 7.14 (d, J=9.0 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:5].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4](=[O:5])[C:6](=[CH:17][N:18]([CH3:20])[CH3:19])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CC(=O)c1ccccc1Cl
Reactant: COC(OC)N(C)C
Product: COC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 57.7 %

Procedure:
A mixture of methyl 2-chlorobenzoylacetate (Acros; 266 mg, 1.25 mmol) and N,N-dimethylformamide dimethylacetal (161 mg, 1.35 mmol) was stirred at rt under N2 for 2 weeks. The reaction was then concentrated in vacuo and the residue was adsorbed on silica gel and chromatographed. Elution with 3:1 EtOAc/hexanes afforded 193 mg of the title compound as a yellow solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: CN1CCNCC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(c2ccc(C#N)cc2)CC1
Temperature: 120 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a solution of 4-fluorobenzonitrile (2.0 g) and 1-methylpiperazine (2.5 g) in dimethylsulfoxide (30 ml) was added potassium carbonate (4.6 g), and the solution was stirred for 1 hour at 120° C. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide 4-(4-methylpiperazin-1-yl)benzonitrile (2.34 g). This compound (1.1 g) was used according to an analogous synthetic method to Preparation Example 16 to provide the title compound (1.1 g).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][C:15]1[O:19][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH2:26][CH2:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>O1CCCC1>[CH3:14][C:15]1[O:19][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH2:26][CH2:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[CH:5][C:3]#[N:4])=[CH:31][CH:30]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=CC#N)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.4 %

Procedure:
Sodium hydride (60% in oil, 2.0 g) was added, in small portions at 0° C. a solution of diethyl cyanomethylphosphonate (8.2 g) in tetrahydrofuran (150 ml). The mixture was stirred for about 15 minutes, to which was added 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (13.0 g), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off to leave 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]cinnamonitrile (11.8 g, 85%). The product was recrystallized from ethyl acetate--hexane to give colorless needles, m.p.112°-113° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1.C(N(CC)CC)C.[C:21](#[N:24])[CH:22]=[CH2:23]>CO>[O:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH:4]([CH2:3][CH2:2][NH:1][CH2:23][CH2:22][C:21]#[N:24])[CH2:5]1
Reactant: NCCC1COc2ccccc2C1
Reactant: C=CC#N
Solvent: CO
Solvent: CCN(CC)CC
Product: N#CCCNCCC1COc2ccccc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
17.7 g (0.1 mol) of 3-(2-aminoethyl)chroman are dissolved in 100 ml of methanol, and then 10.5 g (0.1 mol) of triethylamine and 5.84 g (0.11 mol) of acrylonitrile are added to the solution. The reaction mixture is stirred for 15 hours at room temperature and then concentrated under a water-jet vacuum. The residue is taken up in diethyl ether and washed neutral with ice-water. The ethereal phase is dried over potassium carbonate and concentrated by evaporation. N-[2-(chroman-3-yl)ethyl]-N-(2-cyanoethyl)-amine is thus obtained in the form of a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:38][CH:37]=3)[CH:19]=[CH:20][C:21]=2[CH2:22][CH2:23][CH2:24][N:25]2C(=O)C3C(=CC=CC=3)C2=O)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:38][CH:37]=3)[CH:19]=[CH:20][C:21]=2[CH2:22][CH2:23][CH2:24][NH2:25])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc(CCCN3C(=O)c4ccccc4C3=O)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(CCCN)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Yield: 76.7 %

Procedure:
In a 50 mL three-necked flask under a nitrogen atmosphere, equipped with a magnetic stirrer, 900 mg (1.46 mmol) of ethyl 3″-tert-butyl-4″-diethylamino-4′-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propyl]-[1,1′;3′,1″]terphenyl-4-carboxylate and 292 mg (5.8 mmol) of hydrazine hydrate are placed in 20 mL of ethanol. The reaction medium is heated to the reflux point of the ethanol for 20 hours and then filtered; the filtrate obtained is evaporated and then purified directly on a column of silica (eluent: 94/6 dichloromethane/methanol) to give, after evaporation of the purest fractions, 545 mg of ethyl 3″-tert-butyl-4′-(3-aminopropyl)-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate (yield=77%) in the form of a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:18]1([CH:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:33]1([CH:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCCCCC(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCCCCC(c1ccccc1)c1ccccc1

Procedure:
Batch size: 2.7 g (18.0 mmol) 3-(3-pyridyl)-acrylic acid, 5 ml (57.9 mmol) oxalyl chloride, 3.9 ml (28.0 mmol) TEA and 4.0 g (14,0 mmol) 8,8-diphenyloctylamine.
Reaction SMILES: CCO/N=C(\C(N[C@@H]1C(=O)N2C(C([O-])=O)=C(SC3SC=C(C4C=C[N+](C)=CC=4)N=3)CS[C@H]12)=O)/C1N=C(NP(O)(O)=O)SN=1.[Na+:44].[O:45]=[C:46]1[N:52]2[CH2:53][C@@H:48]([CH2:49][CH2:50][C@@H:51]2[C:54]([NH-:56])=[O:55])[N:47]1[O:57][S:58]([OH:61])(=[O:60])=[O:59].N[C@H](C(O)=O)CCCNC(=N)N.ClCCCCC=CC(=C)C.[Al]>>[CH2:49]1[C@H:48]2[N:47]([O:57][S:58]([O-:61])(=[O:60])=[O:59])[C:46](=[O:45])[N:52]([CH2:53]2)[C@H:51]([C:54]([NH2:56])=[O:55])[CH2:50]1.[Na+:44]
Reactant: [NH-]C(=O)[C@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Agent: C=C(C)C=CCCCCCl
Agent: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(Sc3nc(-c4cc[n+](C)cc4)cs3)CS[C@H]12)c1nsc(NP(=O)(O)O)n1
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Product: NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)[O-]
Reaction time: 0.62 h

Procedure:
Ceftaroline fosamil, trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide sodium salt (Form I) and L-Arginine were blended in a twin shell blender (Patterson-Kelly) for times ranging from 15 to 60 minutes. The blend was subsequently weighed into vials and the vials were stoppered (with or without nitrogen), sealed and stored at different conditions to monitor stability. Packaging components used were 20 ml Type I glass vial, Gray chlorobutyl-isoprene stopper and Blue Aluminum tear-off seal.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[S:5][CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[CH:20]=O.Cl.[NH2:23][OH:24].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[S:5][CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[CH:20]=[N:23][OH:24]
Reactant: COc1cccc2c1SC(c1ccccc1)C(C=O)=C2Cl
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1SC(c1ccccc1)C(C=NO)=C2Cl

Procedure:
As in example 10 but starting with 1 g 4-chloro-3-formyl-8-methoxy-thioflav-3-ene in 1.5 ml DMF. 220 mg hydroxylamine hydrochloride dissolved in 2 ml DMF are added. After 11/2 hours of reflux, the solution is cooled at room temperature before the addition of 20 ml of water. After extraction with CH2Cl2 a gum is obtained which is purified by column chromatography on silicagel using n-hexane/acetone 9:1 as eluant. Pure 4-chloro-3-hydroxyiminomethyl-8-methoxy-thioflav-3-ene is obtained as a yellow solid. TLC (SiO2, n-hexane/acetone 4:1): Rf =0.15.-NMR (90 MHz, CDCl3): δ(ppm)=3.76 (s, 3H, OCH3), 5.5 [s, 1H, H-C(2)], 6.76-7.69 [m, 3H, H-C(5,6,7)], 7.17 [s, 5H, H-C(2',3',4',5',6')], 8.53 [s, 1H, CH=N], 11.4 [s, 1H, OH].-M.p. 190°-203° C. (n-hexane/toluene).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[NH:13][N:12]=[C:11]([O:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([O:24][CH3:25])[N:16]=2)[CH:10]=1.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27].Cl>C(OCC)(=O)C>[CH2:26]([NH:28][C:29]([N:13]1[C:9]([CH3:8])=[CH:10][C:11]([O:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([O:24][CH3:25])[N:16]=2)=[N:12]1)=[O:30])[CH3:27]
Reactant: CCN=C=O
Reactant: COc1ccc([N+](=O)[O-])c(Oc2cc(C)[nH]n2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2nc(OC)ccc2[N+](=O)[O-])cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
Triethylamine (0.22 g, 2.2 mmol) was added to a solution of 5-methyl-3-(6-methoxy-3-nitropyridin-2-yloxy)pyrazole (0.5 g, 2.0 mmol) in ethyl acetate (10 ml), and the mixture was cooled to 0° C. Ethyl isocyanate (0.16 g, 2.2 mmol) was added, and the mixture was stirred at an ambient temperature for 30 minutes. The mixture was allowed to have room temperature. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/6), to give a yellow viscous substance of N-ethyl-5-methyl-3-(6-methoxy-3-nitropyridin-2-yloxy)pyrazole-1-carboxamide (0.38 g, yield: 59.8%). 1H-NMR (CDCl3, TMS, ppm): δ 1.24 (t, J=7.3 Hz, 3H), 2.65 (d, J=0.8 Hz, 3H), 3.40 (dq, J=1.4 and 7.3 Hz, 2H), 3.84 (s, 3H), 6.02 (q, J=0.8 Hz, 1H), 6.57 (dd, J=3.5 and 8.8 Hz, 1H), 7.05 (br s, 1H), 8.41 (dd, J=3.5 and 8.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2[C:14]3[N:15]([N:19]=[C:20]([NH:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH:24]4[F:29])[N:21]=3)[CH:16]=[CH:17][CH:18]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:33]1[O:34][C:35]([CH3:38])=[N:36][N:37]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2[C:14]3[N:15]([N:19]=[C:20]([NH:22][CH:23]4[CH2:28][CH2:27][N:26]([C:33]5[O:34][C:35]([CH3:38])=[N:36][N:37]=5)[CH2:25][CH:24]4[F:29])[N:21]=3)[CH:16]=[CH:17][CH:18]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: FC1CNCCC1Nc1nc2c(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cccn2n1
Reactant: Cc1nnc(Br)o1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(N2CCC(Nc3nc4c(-c5cc(C(F)(F)F)cc(C(F)(F)F)c5)cccn4n3)C(F)C2)o1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A solution of 8-(3,5-bis(trifluoromethyl)phenyl)-N-(3-fluoropiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (example 269b, 68 mg, 152 μmol), 2-bromo-5-methyl-1,3,4-oxadiazole (32.2 mg, 198 μmol) and diisopropylethylamine (39.3 mg, 53.1 μL, 304 μmol) dissolved in dry dioxane (2 mL) was stirred at 70° C. for 12 hours and then at 110° C. for 1 hour. Further diisopropylethylamine (39.3 mg, 53.1 μL, 304 μmol) and 2-bromo-5-methyl-1,3,4-oxadiazole (32.2 mg, 198 μmol) were added and heated to 110° C. for another hour. The solvent was evaporated and the residue directly purified by flash chromatography (silica gel, 70 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane). The title compound was obtained as colorless oil (46 mg, 57%) as a mixture of cis- and trans-isomers.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:36]([N:38]([CH2:42][CH2:43][O:44][Si](C(C)(C)C)(C)C)[CH:39]([CH3:41])[CH3:40])=[O:37])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OCCN(C(C)C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N=1)=O>>[CH2:1]([O:8][C:9]1[C:10]([C:36]([N:38]([CH2:42][CH2:43][OH:44])[CH:39]([CH3:41])[CH3:40])=[O:37])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[C:24]([C:32]([F:33])([F:34])[F:35])[CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO)C(=O)c1nc(CC2(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-(Benzyloxy)-2-((1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methyl)-6-hydroxy-N-(2-hydroxyethyl)-N-isopropylpyrimidine-4-carboxamide (464) was synthesized form 5-(benzyloxy)-2-((1-(3,5-bis(trifluoromethyl)phenyl)cyclopentyl)methyl)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-hydroxy-N-isopropylpyrimidine-4-carboxamide (463) following the procedure described 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (246).
Reaction SMILES: C([O:8][C:9](=[O:35])[C@@H:10]([O:17][C:18](=[O:34])[CH:19]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:27]([CH:19]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18]([O:17][C@@H:10]([CH2:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)[C:9]([OH:35])=[O:8])=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O[C@@H](Cc1c[nH]cn1)C(=O)OCc1ccccc1)C(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O[C@@H](Cc1c[nH]cn1)C(=O)O)C(Cc1ccccc1)Cc1ccccc1
Yield: 96.7 %

Procedure:
3.2 g (6.83 mmol) of (S)-α-(dibenzylacetoxy)imidazole-4-propionic acid benzyl ester in 150 ml of methanol were hydrogenated at room temperature for 2 hours in the presence of 660 mg of palladium-on-carbon. The catalyst was filtered off and the filter residue was washed several times with a 1:1 mixture of methylene chloride and methanol. The solution was concentrated under reduced pressure until crystallization occurred. Recrystallization of the crystallizate from methylene chloride/methanol yielded 2.5 g (96%) of (S)-α-(dibenzylacetoxy)imidazole-4-propionic acid, melting point 210°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:40][C:37]3[C:38]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3cccc(F)c3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]2[CH:11]=[C:12](Br)[C:13]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:14][C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.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>[CH2:1]([O:3][C:4]([C:6]1[N:10]2[CH:11]=[C:12]([C:29]3[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][C:30]=3[Cl:32])[C:13]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:14][C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(CNC(=O)OC(C)(C)C)c(Br)cn12
Reactant: OB(O)c1ccc(Cl)cc1Cl
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: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(CNC(=O)OC(C)(C)C)c(-c3ccc(Cl)cc3Cl)cn12
Temperature: 150 °C
Yield: 79.8 %

Procedure:
In a sealed tube, a mixture of 6-bromo-7-(tert-butoxycarbonylamino-methyl)-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (1.4 g, 3.52 mmol), 2,4-dichloro-benzeneboronic acid (1.01 g, 5.29 mmol), Pd(PPh3)4 (203 mg, 0.18 mmol) and Na2CO3 (2.0 M solution in water, 6.2 mL) in DME (20 mL) was heated at 150° C. for 17 min under microwave irradiation. The reaction mixture was cooled to RT, diluted in AcOEt (400 mL) and washed with a 2.0 M aqueous Na2CO3 solution (2×200 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→2:8) to yield the title compound (1.39 g, 2.81 mmol, 80%). MS: 464 [M+1]+; HPLC: AtRet=2.31; TLC: RF 0.47 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[CH3:15].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:50]([N:57]1[CH2:61][CH2:60][C@@H:59]([NH2:62])[CH2:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:50]([N:57]1[CH2:61][CH2:60][C@@H:59]([NH:62][C:2]2[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=2[CH3:15])[CH2:58]1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CCOC(=O)/C=C/c1cnc(Br)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(C)c1
Temperature: 100 °C
Yield: 54.1 %

Procedure:
To a solution of ethyl (2E)-3-(6-bromo-5-methyl-3-pyridyl)acrylate (500 mg) in dioxane (5 mL) was added palladium(II) acetate (41.6 mg) and 2′-(dicyclohexylphosphino)-N,N-dimethyl-2-biphenylamine (109 mg) and cesium carbonate (843 mg), and (3R)-(−)-1-benzyl-3-aminopyrrolidine (359 mg). The mixture was heated at 100° C. for 18 hours. The resulting mixture was poured into sat.NH4Cl aqueous solution and extracted with AcOEt. The organic layer was washed with sat. NH4Cl aq solution, water, and brine, and dried over Na2SO4. The solvent was removed in vacuo and residual brown oil was purified by preparative thin layer chromatography (chloroform:methanol=90:10) to give ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylate (366 mg) as pale yellow oil.
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-])=O)=[CH:40][C:39]=1[S:47]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:48]>>[NH2:44][C:41]1[CH:42]=[CH:43][C:38]([Cl:37])=[C:39]([S:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:48])[CH:40]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)c2ccccc2)c1
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Nc1ccc(Cl)c(S(=O)c2ccccc2)c1
Yield: 89 %

Procedure:
Following the procedure described in Example 2 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of (2-chloro-5-nitrophenyl)-phenyl sulfoxide, the title compound is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=C[C:5]([C@@H:8](CNC(C)C)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][CH:24]=[C:25]([NH:26]C(=O)CCC)[C:18]=34)[CH2:13][CH2:12]2)=O)=[CH:4][CH:3]=1.C(O[C:41](=[O:43])[CH3:42])(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.N1C=CC=CC=1.CO.[Li+].[OH-]>[CH2:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[NH:23][CH:24]=[C:25]([NH:26][C:41](=[O:43])[CH3:42])[C:18]=23)[CH2:13][CH2:12]1)[C:8]1[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: CCCC(=O)Nc1c[nH]c2nccc(N3CCN(C(=O)[C@H](CNC(C)C)c4ccc(Cl)cc4)CC3)c12
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1c[nH]c2nccc(N3CCN(Cc4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
4-(4-Benzylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-amine (0.35 g, 1.14 mmol, see Example 25) was placed in DCM (2 mL) and pyridine (1 mL). Acetic anhydride (0.129 mL, 1.37 mmol) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then diluted with MeOH (5 mL), and 3M LiOH (0.5 mL) was added. The reaction was stirred for 10 minutes and then poured into saturated Na2CO3 and extracted into DCM. The organic fractions were combined, dried, filtered and concentrated to give a crude residue that was purified by column chromatography (500:8-500:20 DCM:MeOH) to give N-(4-(4-benzylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (0.35 g, 88.0% yield).