Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]1([CH2:42][CH2:43][OH:44])[O:40][CH3:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:51](Cl)([C:54]1[CH:60]=[CH:59][C:57]([CH3:58])=[CH:56][CH:55]=1)(=[O:53])=[O:52]>C(Cl)Cl>[CH3:58][C:57]1[CH:59]=[CH:60][C:54]([S:51]([O:44][CH2:43][CH2:42][C@@:10]2([O:40][CH3:41])[C@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:13]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:11]2)(=[O:53])=[O:52])=[CH:55][CH:56]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CO[C@@]1(CCO)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@@]1(CCOS(=O)(=O)c2ccc(C)cc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 50 °C
Yield: 54.7 %

Procedure:
2-((2S,3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-2-methoxytetrahydro-2H-pyran-2-yl)ethanol (8) (0.46 g, 0.77 mmol) was dissolved in CH2Cl2 (2 mL). Pyridine (0.31 mL, 3.85 mmol) and TsCl (0.29 g, 1.54 mmol) were added and the reaction mixture was heated at 50° C. for 18 h. Additional TsCl (0.05 g, 0.26 mmol) was then added and the reaction mixture was heated at 50° C. for another 4 hours. The mixture was concentrated onto celite and chromatographed over SiO2, (ISCO system, 0-40% EtOAc/hexanes) to provide an oil (0.317 g, 55%). 1H NMR (300 MHz, CDCl3) δ ppm: 7.66 (d, J=8.4 Hz, 2H), 7.14-7.32 (m, 22H), 4.77-4.89 (m, 4H), 4.46-4.57 (m, 4H), 3.86-4.07 (m, 1H), 3.48-3.64 (m, 4H), 3.31 (d, J=9.3 Hz, 1H), 3.17 (s, 3H), 2.36 (s, 3H), 2.13 (t, J=8.1 Hz, 1H). LC/MS tR=3.37 min, calcd for C44H48O9S: 752.3, found 775.2 (M+Na)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@@H:22]4[NH:27][S:28]([CH2:31][C:32]([O:34]CC)=[O:33])(=[O:30])=[O:29])=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@@H:22]4[NH:27][S:28]([CH2:31][C:32]([OH:34])=[O:33])(=[O:29])=[O:30])=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCOC(=O)CS(=O)(=O)N[C@H]1CCc2c(-c3nnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NS(=O)(=O)CC(=O)O)s2)cc1C#N
Reaction time: 3 h
Yield: 10.8 %

Procedure:
Prepared using General Procedure 15: To a stirred solution of (S)-ethyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate (75 mg, 0.8 mmol) in MeOH (4 mL) was added 6N NaOH (0.12 mL). After 3 h, the crude reaction was concentrated then partitioned between DCM/IPA and 1N HCl. The organic layer was dried over MgSO4 and concentrated to give 43 mg (60%) of (S)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid 40 as light yellow solid. LCMS-ESI (m/z) calculated for C23H22N4O5S2: 498.1; found 499.1 [M+H]+, tR=3.34 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:19]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=2)(=[O:25])=[O:24])COC)[C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[N:6][CH:7]=1.O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=2)(=[O:24])=[O:25])[C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[N:6][CH:7]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A mixture of 2-{5-Chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-benzoic acid (150 mg, 0.27 mmol) in 3 ml of 4M HCl in dioxane and 1 mL of water was refluxed for 2 hours. After cooling to room temperature the mixture was concentrated and then diluted with water. Sodium bicarbonate was added until pH was 6. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was further purified via flash column (70% ethyl acetate in hexane) to afford 60 mg of title compound as an off white solid. MS: (M+H)/z=519.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>FC(C1C=CC=CC=1)(F)F>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:17])=[CH:4][C:3]=1[F:9]
Reactant: Cc1ccc(Br)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: Fc1cc(CBr)ccc1Br
Temperature: 85 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
To a solution of 1-bromo-2-fluoro-4-methylbenzene (2.5 g, 13.3 mmol) in trifluoromethyl benzene (25 mL) was a mixture of NBS (2.35 g, 13.3 mmol) and AIBN (945 mg, 6.7 mmol) in five portions at 85° C. for 30 min. The mixture was stirred at 85° C. for 3 h. The insoluble was filtered off and the filtrate was evaporated to afford 1-bromo-4-(bromomethyl)-2-fluorobenzene (2.7 g, 77%) as light yellow oil, which was used directly for next step.
Reaction SMILES: CN(C)C(=N[C:6](=O)[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([O:15]C)=[N:9][C:8]=1[CH3:17])C.Cl.NO.[OH-].[Na+].[C:25](O)(=O)[CH3:26]>O1CCOCC1.O>[CH2:13]([C:11]1[C:10](=[O:15])[NH:9][C:8]([CH3:17])=[C:7]([C:6]2[CH:6]=[C:7]([CH:12]=[CH:25][CH:26]=2)[C:8]#[N:9])[CH:12]=1)[CH3:14]
Reactant: CC(=O)O
Reactant: CCc1cc(C(=O)N=C(C)N(C)C)c(C)nc1OC
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(-c2cccc(C#N)c2)c(C)[nH]c1=O
Temperature: 90 °C
Reaction time: 0.58 h
Yield: 81 %

Procedure:
In a round bottom flask under a nitrogen atmosphere a mixture of N-(1-dimethylaminoethylidene)-5-ethyl-6-methoxy-2-methylnicotinamide (synthesized on 1.00 mmol scale), hydroxylamine hydrochloride (83.4 mg, 1.2 mmol), sodium hydroxide (48 mg, 1.2 mmol) and glacial acetic acid (1.4 mL) is treated with water (0.7 mL) and 1,4-dioxane (1 mL). The resulting dark mixture is stirred at 90° C. for 35 min. The reaction mixture is partitioned between water and ethyl acetate. The mixture is treated with excess solid sodium bicarbonate, the ethyl acetate layer is separated and the aqueous layer is extracted with 4 further portions of ethyl acetate. The combined ethyl acetate layer is dried over magnesium sulfate and evaporated to give a black residue that is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane. Fractions containing the product are combined, evaporated and re-purified by flash chromatography on a 5-gram silica gel cartridge by elution with heptane:dichloromethane (49:1). Fractions containing the product are combined and the solvent evaporated to give 3-ethyl-2-methoxy-6-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine (189 mg, 81% yield, from Steps 1 and 2 above) as a white solid. MS: m/e=234 (M+H); 1H NMR (CDCl3, δ, ppm): 8.01 (1H, s), 4.01 (3H, s), 2.81 (3H, s), 2.60 (2H, q), 2.46 (3H, s), 1.23 (3H, t).
Reaction SMILES: BrC1C(CBr)=C(C(OC(C)(C)C)=O)N2C(=O)C(NC=O)[C@H]2S1=O.[Br:24][CH:25]1[C:30]([CH2:31][Br:32])=[C:29]([C:33]([O:35]C(C)(C)C)=[O:34])[N:28]2[C:40](=[O:52])[CH:41]([NH:42][C:43](=[O:51])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C@H:27]2[S:26]1=[O:53]>FC(F)(F)C(O)=O>[Br:24][CH:25]1[C:30]([CH2:31][Br:32])=[C:29]([C:33]([OH:35])=[O:34])[N:28]2[C:40](=[O:52])[CH:41]([NH:42][C:43](=[O:51])[CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C@H:27]2[S:26]1=[O:53]
Reactant: CC(C)(C)OC(=O)C1=C(CBr)C(Br)S(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Agent: CC(C)(C)OC(=O)C1=C(CBr)C(Br)S(=O)[C@@H]2C(NC=O)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)=C(CBr)C(Br)S(=O)[C@H]12
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
The reference compound IV in the HPLC analysis was prepared as follows: 1 g (1.8 mmol) of t-butyl 2-bromo-3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate 1-oxide [prepared by the procedure of Step C of Example II] was dissolved in 15 ml of trifluoroacetic acid and after standing for 15 minutes at room temperature, the solution was evaporated to dryness. The residue was dissolved in methylene chloride and the solution was again evaporated to dryness. The residue was treated with diethyl ether and the product was isolated by filtration and was washed with diethyl ether and hexane to obtain 0.8 g (88% yield) of 2-bromo-3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylic acid 1-oxide.
Reaction SMILES: [CH2:1]([C:3]1[C:19]([F:20])=[CH:18][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[F:17])=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2].C(Cl)(=O)C(Cl)=O.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][C:30]1=[O:35].C(N(C(C)C)CC)(C)C.Cl>ClCCl.CN(C)C=O>[CH2:1]([C:3]1[C:19]([F:20])=[CH:18][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([N:32]3[CH2:33][CH2:34][NH:29][C:30](=[O:35])[CH2:31]3)=[O:14])=[CH:10][C:9]=2[F:17])=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(OC)c(Oc2ccc(C(=O)O)cc2F)cc1F
Reactant: O=C1CNCCN1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(OC)c(Oc2ccc(C(=O)N3CCNC(=O)C3)cc2F)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoic acid (55 mg, 0.18 mmol; which may be prepared as described in D2) in dichloromethane (1.8 mL) under Argon cooled at 0° C. were added oxalyl chloride (2M in dichloromethane, 135 μL, 0.27 mmol) and a drop of N,N-dimethylformamide. The mixture was allowed to come to room temperature over 2 hours, and then piperazin-2-one (20 mg, 0.20 mmol) followed by diisopropylethylamine (93 μL, 0.53 mmol) were added. The reaction mixture was cooled to 0° C. and a solution of 1N HCl was added. After stirring a few minutes, dichloromethane was added and the aqueous layer (pH 7) was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtrated and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel, using dichloromethane/methanol (95:5) as eluent. The title product was obtained as a yellow oil (38 mg, 55%).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].C(O)(=O)[CH:14]([CH2:16][C:17](O)=O)[OH:15].S(=O)(=O)(O)O.CN(C)C1C=C2C(C=CC(=O)O2)=CC=1>>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]2[C:7]([CH:17]=[CH:16][C:14](=[O:15])[O:10]2)=[CH:8][CH:9]=1)[CH3:12]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: CCN(CC)c1cccc(O)c1
Agent: CN(C)c1ccc2ccc(=O)oc2c1
Agent: O=S(=O)(O)O
Product: CCN(CC)c1ccc2ccc(=O)oc2c1

Procedure:
m-Diethylaminophenol 7.4g, malic acid 6.0g and 85% sulfuric acid 12.0ml were treated as for the 7-dimethylamino-coumarin, although the alumina column cut could not be induced to crystallize. It was rechromatographed, eluting first with benzene thoroughly, and then developing with dichloromethane. After two crystallizations from cyclohexane, cream colored crystals 0.5g (5%), m.p. 87.5°-88.0° were obtained, found C 71.94; H 7.09; N 6.35; C13H15NO2 requires C 7.19; H 6.92; N 6.45%.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=O)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].Cl.[CH3:14][NH:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>ClC(Cl)C>[C:9]([O:8][CH2:7][CH:6]([N:15]([CH3:14])[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: CC(=O)OCC(=O)COC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(=O)OCC(COC(C)=O)N(C)CC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 17 %

Procedure:
To a solution of 3-(acetyloxy)-2-oxopropyl acetate (4.54 g, 26 mmol) in dichloroethane (75 ml) was added tert-butyl 2-(methylamino)acetate HCl. After stirring for 10 minutes sodium triacetoxyborohydride (8.3 g, 39 mmol) was added and stirring was continued for 18 hours and monitored by TLC (1:1heptane:EtOAc). The reaction was quenched by the addition of saturated sodium hydrogen carbonate solution and the crude product was extracted into dichloromethane. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. The title compound was purified by silica column chromatography eluting with 0-20% EtOAc:Hept to yield the title compound (1.32 g, 17% yield). 1H NMR (250 MHz, CHLOROFORM-d) δ 4.07-4.33 (4H, m), 3.34 (2H, s), 3.23 (1H, t, 5.9 Hz), 2.49 (3H, s), 1.99-2.19 (6H, m), 1.33-1.55 (9H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[CH2:16]O.P(Br)(Br)[Br:19]>C1COCC1>[Br:19][CH2:16][C:4]1[C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[C:5]=1[CH3:15]
Reactant: BrP(Br)Br
Reactant: COc1c(C)c(CO)c(OC)c(OC)c1OC
Solvent: C1CCOC1
Product: COc1c(C)c(CBr)c(OC)c(OC)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 161.9 %

Procedure:
To a solution of 2,3,4,5-tetramethoxy-6-methylphenylmethanol (44.4 g) in THF (200 ml) was dropwise added phosphorus tribromide (29.8 g) with cooling with ice. After being stirred for 1 hr, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo to yield the entitled compound (54.4 g) as an oil.
Reaction SMILES: N([O:3][C:4](C)(C)[CH3:5])=O.ON1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17]C=C2C1=O.C1(=NO)CCCC1.[N+](C1CCCC1)([O-])=O.C1(=O)CCCC1>C(O)(=O)C.C1CCCC1>[C:4]([O:14][CH:13]1[CH2:12][CH2:15][CH2:16][CH2:17]1)(=[O:3])[CH3:5]
Reactant: CC(C)(C)ON=O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=[N+]([O-])C1CCCC1
Agent: ON=C1CCCC1
Solvent: O=C1CCCC1
Solvent: CC(=O)O
Solvent: C1CCCC1
Product: CC(=O)OC1CCCC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Cyclopentane (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that cyclopentanone oxime, nitrocyclopentane, cyclopentanone, and cyclopentyl acetate were formed in yields of 4%, 2%, 3%, and less than 1%, respectively.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([F:31])[CH:25]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.C(OCC)(=O)C>CS(C)=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH3:23])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:25][C:26]=1[F:31]
Reactant: [C-]#N
Reactant: CSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)c(F)c3)c[nH]c12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)c(F)c3)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
0.38 g (5.90 mmol) of potassium cyanide was added to 1.30 g (2.95 mmol) of the compound from Example 110A in 27 ml of DMSO. The mixture was stirred at 80° C. for 3 h, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were freed of solvent, and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 0.95 g (86% of theory) of the target compound was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:55][N:56]1[CH2:61][CH2:60][CH:59]([OH:62])[CH2:58][CH2:57]1.Cl>CCOC(C)=O.CN(C=O)C.C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([NH:55][N:56]2[CH2:61][CH2:60][CH:59]([OH:62])[CH2:58][CH2:57]2)=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: NN1CCC(O)CC1
Reactant: N#Cc1ccc(-c2cc(C(=O)O)cnc2OCC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2cc(C(=O)NN3CCC(O)CC3)cnc2OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a 5 mL round-bottomed flask, the above prepared 5-(4-cyano-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (0.050 g, 155 μmol, Eq: 1.00) was combined with THF (1 mL) and DMF (1 mL) to give a colorless solution. TBTU (74.7 mg, 233 μmol, Eq: 1.5) and N,N-diisopropyl-ethylamine (100 mg, 135 μL, 776 μmol, Eq: 5) were added. The reaction mixture was stirred for 10 min at RT, then 1-aminopiperidin-4-ol (21.6 mg, 186 μmol, Eq: 1.2, CAN 79414-82-7) was added and the reaction mixture kept at RT overnight. Pouring into 25 mL 1 M HCl, extraction with EtOAc (2×50 mL), washing with 1 M NaOH, drying over Na2SO4 and evaporation of all solvents in vacuo, followed by stirring for 15 min with 3 mL of heptane containing 3 drops of EtOAc, generated 51 mg of the title compound as white solid; MS (EI) 421.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[CH:3]=1.Cl.[NH2:11][CH:12]([CH3:22])[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:8][C:6]1[CH:7]=[C:2]([NH:11][CH:12]([CH3:22])[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH:3]=[C:4]([CH3:9])[N:5]=1
Reactant: Cc1cc(Cl)cc(C)n1
Reactant: CC(N)CNC(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(NC(C)CNC(=O)OC(C)(C)C)cc(C)n1
Temperature: 110 °C
Yield: 120.3 %

Procedure:
A mixture of 4-Chloro-2,6-dimethylpyridine (131 mg, 0.925 mmol), tert-butyl 2-aminopropylcarbamate hydrochloride (151 mg, 0.717 mmol), cesium carbonate (750 mg, 2.302 mmol), and anhydrous 1,4-dioxane (3 ml) was treated with tris(dibenzylideneacetone)dipalladium(0) (39 mg, 0.043 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (74 mg, 0.128 mmol) under an atmosphere of argon. The mixture was heated at 110° C. for 8 hours, allowed to reach room temperature and filtered. The filter residue was washed with DCM, the combined filtrates were evaporated. The residue was purified by column chromatography using a gradient of methanol (1-10%) in dichloromethane to yield 241 mg of a yellow oil. MS (ESI) m/z=280.2.
Reaction SMILES: [CH2:1]([N:3]([CH:19]1[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]1)[C:4]1[C:5]([CH3:18])=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7]([O:9]C)=[O:8])[CH3:2].[OH-].[Na+].Cl>CO>[CH2:1]([N:3]([CH:19]1[CH2:24][CH2:23][N:22]([CH:25]([CH3:26])[CH3:27])[CH2:21][CH2:20]1)[C:4]1[C:5]([CH3:18])=[C:6]([CH:11]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:13]=1)[C:7]([OH:9])=[O:8])[CH3:2]
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1CCN(C(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)O)c1C)C1CCN(C(C)C)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-{ethyl[1-(propan-2-yl)piperidin-4-yl]amino}-2-methyl-5-(trifluoromethyl)benzoate (220 mg, 0.569 mmol) in methanol (4 mL) was added aq. NaOH (5M, 170 ul, 0.854 mmol). The reaction mixture was stirred at 50° C. for 2 hours. After cooling to 23° C. HCl (2 M) was added to the mixture. The mixture was acidified to pH=5 and was concentrated in vacuo to give the titled compound as crude products (510 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:13][O:12][C:10](=[O:11])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([NH:2][CH2:1][C:23](=[O:26])[CH:24]=[CH2:25])=[CH:8][CH:7]=1
Reactant: CNc1ccc(CC(=O)OC)cc1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)CNc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl (4-methylaminophenyl)acetate (4.00 g, 22.3 mmol) and N,N-diisopropylethylamine (7.78 mL, 44.6 mmol) in DCM (20.0 mL) at 0° C. was slowly added 2-propenoyl chloride (2.18 mL, 26.8 mmol). The reaction mixture was stirred at room temperature for 2 h and then saturated aqueous sodium bicarbonate (20.0 mL) was added. This mixture was extracted with DCM (10 mL) and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used in the next reaction without further purification.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl.[NH2:5][C:6]1[N:11]=[C:10]([OH:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=2)=[C:8]([CH3:22])[N:7]=1>CN(C=O)C.CS(C)=O>[NH2:5][C:6]1[N:11]=[C:10]([OH:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:1]#[N:2])=[CH:16][CH:15]=2)=[C:8]([CH3:22])[N:7]=1
Reactant: [C-]#N
Reactant: Cc1nc(N)nc(O)c1Cc1ccc(CCl)cc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1nc(N)nc(O)c1Cc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium cyanide (2 g) was added to a solution of the product from step (ii) in DMF (20 ml) and DMSO (10 ml) and the mixture stirred at rt for 18 h. The mixture was flushed with nitrogen for 20 min, then diluted with brine (80 ml), stirred for 10 min and the precipitate filtered, washed with water then ether and dried to afford the subtitle compound, 2.46 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N:17]4[CH:21]=[CH:20][CH:19]=[N:18]4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.CCO.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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.O>[N:17]1([C:13]2[CH:12]=[C:11]([C:8]3[N:5]4[CH:6]=[CH:7][C:2]([C:24]5[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=5)=[CH:3][C:4]4=[N:10][CH:9]=3)[CH:16]=[CH:15][CH:14]=2)[CH:21]=[CH:20][CH:19]=[N:18]1
Reactant: OB(O)c1cccnc1
Reactant: Clc1ccn2c(-c3cccc(-n4cccn4)c3)cnc2c1
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: O
Solvent: COCCOC
Solvent: CCO
Product: c1cncc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)c1

Procedure:
7-Chloro-3-(3-pyrazol-1-yl-phenyl)-imidazo[1,2-a]pyridine (Intermediate AA) (1 eq, 0.214 mmol, 70 mg) and 3-pyridine boronic acid (1 eq, 0.214 mmol, 26.1 mg) are dissolved in DME (3 ml), EtOH (1 ml) and water (1.5 ml) and Na2CO3 (2 eq, 0.427 mmol, 53.0 mg) is added. Pd(PPh3)4 (0.06 eq, 0.01 mmol, 15 mg) is added and the reaction mixture is heated using microwave radiation at 120° C. for 15 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 8:2 DCM/MeOH to yield 3-(3-pyrazol-1-yl-phenyl)-7-pyridin-3-yl-imidazo[1,2-a]pyridine as a light brown solid; [M+H]+=338