Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.COC(=O)/[CH:7]=[CH:8]/[C@H:9]1[CH2:14][O:13][CH2:12][C@@H:11]([C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=2)[N:10]1[C:24](=[O:28])[CH2:25]C=C>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(N(CC)CC)C>[F:21][C:19]1[CH:20]=[C:15]([C@@H:11]2[CH2:12][O:13][CH2:14][C@@H:9]3[CH:8]=[CH:7][CH2:25][C:24](=[O:28])[N:10]23)[CH:16]=[C:17]([F:23])[C:18]=1[F:22]
Reactant: C=CCC(=O)N1[C@@H](/C=C/C(=O)OC)COC[C@H]1c1cc(F)c(F)c(F)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC=C[C@H]2COC[C@@H](c3cc(F)c(F)c(F)c3)N12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.3 %

Procedure:
Grubbs catalyst second generation (285 mg) was added to a dichloromethane solution (100 mL) of (E)-3-[(3S,5R)-4-(3-butenoyl)-5-(3,4,5-trifluorophenyl)morpholin-3-yl]acrylic acid methyl ester (1.24 g). The resulting reaction solution was heated under reflux for 1.5 hr in nitrogen atmosphere. The reaction solution was cooled to room temperature, and triethylamine (3 mL) was added thereto. The resulting reaction solution was stirred for 10 min and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to give 250 mg of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:11][CH3:12])=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:3]1[C:4]2[C:9](=[CH:8][C:7]([O:11][CH3:12])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1])[CH3:21]
Reactant: COc1ccc2[nH]c(C)cc2c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)cc2cc(OC)ccc21
Reaction time: 0.5 h

Procedure:
To a solution of 2-methyl-5-methoxylindole (5.10 g, 31.6 mmol) in DMF (200 mL) is added sodium hydride (60%, 1.9 g, 47.4 mmol) at 0˜5° C., stirred for 30 min, ethyl 2-bromoacetate (8.35 g, 50 mmol) is added. After 2 hr at room temperature, the reaction is quenched by water, extracted with ether. Combined organic layers are washed with water and brine, dried over sodium sulfate. Concentration yields the crude title product, which is used for next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([O:13]C)=[O:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=[O:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1n[nH]c2ncc(Br)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1n[nH]c2ncc(Br)cc12
Temperature: 90 °C
Yield: 92.6 %

Procedure:
A suspension of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (XVII) (70 mg, 0.27 mmol) in aqueous 1N NaOH solution (20 mL) was heated at 90° C. for 3 h until the solution became clear. The solution was then cooled to 0° C. and acidified with a 10% HCl solution. The solids formed were filtered, washed with cold water and dried at room temperature under vacuum to give 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (XVIII) as a white solid (60 mg, 0.25 mmol, 92% yield). 1H NMR (CDCl3) δ ppm 8.58 (d, J=3.01 Hz, 1H), 8.66 (d, J=3.01 Hz, 1H); ESIMS found for C7H4BrN3O2 m/z 242.1 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([CH2:32][OH:33])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[CH2:36](I)[CH3:37].C(O)C>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([CH2:32][O:33][CH2:36][CH3:37])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1ccc(CC(=O)NC(CO)c2ccccc2N2CCCCC2)cc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1
Reaction time: 1 h

Procedure:
Ethyl 2-ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate (0.64 g, 1.4 mmol) is added with stirring at ambient temperature to sodium hydride (0.061 g, 1.4 mmol) (55% in oil) in absolute tetrahydrofuran (6.4 ml). The mixture is stirred for 1 hour, then ethyl iodide (0.113 ml, 1.4 mmol) is added and the mixture is stirred for a further 16 hours at ambient temperature. Then ethanol (2 ml) is added and the mixture is evaporated down in vacuo. The evaporation residue is partitioned between chloroform and water. The organic phase is washed twice with water, dried, filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/acetone=17/3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].[N:14]([C:17]1[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=1)=[C:15]=S.Cl.CN(C)CCCN=C=NCC.CN(C)C>O1CCCC1.C(OCC)(=O)C.O>[NH2:8][C:4]1[C:3]2[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:15]([NH:14][C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)=[N:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(N)c1NCCCO
Reactant: COc1ncc(N=C=S)c(OC)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ncc(Nc2nc3cccc(N)c3n2CCCO)c(OC)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
To a solution of 3-[(2,6-diaminophenyl)amino]propan-1-ol (Reference Example 115; 363 mg, 2.00 mmol) in tetrahydrofuran (5.0 mL) was added 5-isothiocyanato-2,4-dimethoxypyrimidine (440 mg, 2.20 mmol) portionwise at room temperature. After stirring for 2 hr, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (422 mg, 2.20 mmol) and trimethylamine (0.331 mL, 2.40 mmol) was added. The mixture was warmed to 50° C. and stirred for additional 3 hr. Water and ethyl acetate were added to the mixture and the insoluble materials were filtered off. The filtrate was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 0-15% methanol/ethyl acetate gradient mixture. The filtrate was concentrated in vacuo to give the title compound (99 mg, 0.287 mmol, 14%) as a pale yellow amorphous.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][C:30]([N:29]([CH3:33])[CH3:28])=[O:31])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Nc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 5.7 %

Procedure:
To a solution of 1-Boc-4-(2-aminophenyl)-piperazine (270 mg, 1.0 mmol) and Et3N (400 microliter, 2.89 mmol) in 10 mL of CH2Cl2 was added dimethylcarbamyl chloride (135 microliter, 1.48 mmol). After stirring for about 1 hour, DMAP (10 mg) was added. After stirring for about 3 days, another 800 microliter of Et3N and 270 microliter of dimethylcarbamyl chloride were added. After stirring overnight, the solution was diluted with EtOAc, washed with 1 M HCl (2×), saturated sodium bicarbonate, water and brine, and then dried (Na2SO4), filtered and concentrated. Purification by silica gel chromatography (35 g SiO2, 20 to 50% EtOAc/hexanes, over 30 minutes at 35 mL/min) afforded about 20 mg (0.057 mmol, 6%) of the tide compound as a white solid. LRMS: 349.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:32][CH3:33])=[C:19]([CH2:23][N:24]4[CH2:27][CH:26]([C:28]([O:30]C)=[O:29])[CH2:25]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:32][CH3:33])=[C:19]([CH2:23][N:24]4[CH2:25][CH:26]([C:28]([OH:30])=[O:29])[CH2:27]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(CN2CC(C(=O)OC)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
To a solution of crude methyl 1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylate (D13) (54 mg) in isopropanol (3 mL) and water (3 mL) was added sodium hydroxide (50 mg). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with 2N HCl till pH ˜6.0. The mixture was extracted with EA/THF for 3 times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated and the residue was purified by Mass Directed AutoPrep (basic conditions) to give 1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-3-azetidinecarboxylic acid (E4) (10 mg) as a TFA salt (off-white solid). δH (DMSO-d6, 400 MHz): 1.09 (3H, t), 1.35 (6H, d), 2.89 (2H, m), 3.61 (2H, m), 4.28 (3H, br. s.), 4.53 (2H, m), 4.84 (1H, m), 7.38 (1H, d), 7.44 (1H, m), 7.58 (2H, m), 7.96 (1H, dd), 8.10 (1H, d), 13.06 (1H, br s). δF (DMSO-d6, 376 MHz): −73.4. MS (ES): C24H26ClN3O3S requires 471. found 472.1 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]O)=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:30]N1C(=O)CCC1=O>ClCCl>[Cl:30][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: OCCCc1ccncc1
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClCCCc1ccncc1
Reaction time: 8 h
Yield: 78.8 %

Procedure:
3-(4-Pyridyl)-1-propanol (2.68 g, 19.3724 mmol) was dissolved in dichloromethane (100 ml), triphenylphosphine (5.6 g. 21.3096 mmol) was added, and then N-chlorosuccinimide (2.6 g, 19.3724 mmol) was gradually added while cooling on ice prior to stirring overnight. After distilling off the solvent under reduced pressure, the residue was dissolved in ethyl acetate and extracted with 1N hydrochloric acid. Upon neutralization with saturated bicarbonate water, the mixture was extracted with ethyl acetate, washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (2,375 g, 15.2605 mmol, 78.77%) as a yellowish-brown oil. This was used without further purification for the following reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C1COCC1.CN(C=O)C.[CH3:37][C:38]([OH:42])([C:40]#[CH:41])[CH3:39]>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.[Cu]I>[NH2:20][C:17]1[O:18][CH2:19][C@:15]2([C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:41]#[C:40][C:38]([CH3:39])([OH:42])[CH3:37])[CH:3]=3)[O:8][C:9]3[C:14]2=[CH:13][C:12]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:11][CH:10]=3)[N:16]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(Br)cc12
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 110 °C

Procedure:
Combined (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (99 mg, 0.242 mmol), tetrakis(triphenylphosphine)palladium (28.0 mg, 0.024 mmol), copper(i) iodide (4.61 mg, 0.024 mmol) and THF (969 μL, 0.242 mmol) and DMF (969 μL, 0.242 mmol). Added DIPA (679 μL, 4.85 mmol) then 2-methylbut-3-yn-2-ol (118 μL, 1.211 mmol) and flushed the reaction tube with argon. Sealed and heated at 110° C. for 2 hours. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 25-g SNAP column, eluting with 0-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH to give (S)-4-(2′-amino-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yl)-2-methylbut-3-yn-2-ol as a white solid after evaporation from DCM/hexane.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:15]([F:16])=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[C:18]=2[F:26])[N:13]=[C:12]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH:11]=1>ClCCCl>[NH2:9][C:10]1[C:15]([F:16])=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[C:18]=2[F:26])[N:13]=[C:12]([C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:11]=1[Br:1]
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)cc(N)c2F)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Product: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(Br)c(N)c2F)c1F
Temperature: 23 °C
Reaction time: 72 h
Yield: 89.6 %

Procedure:
N-Bromosuccinimide (NBS; 580 mg, 3.3 mmol, 1.1 equiv) was added to a stirred suspension of benzyl 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate (1.2 g, 3.0 mmol, 1.0 equiv) in 1,2-dichloroethane (15 mL) at 23° C. The resulting bright yellow mixture was stirred at 23° C. for 72 h. The brown reaction mixture was concentrated by N2 stream and the residue was purified by silica gel column chromatography (eluting with 29% EtOAc/hexane) to afford the desired product, benzyl 4-amino-3-bromo-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate as a tan powder (1.3 g, 93%): mp 144-146° C.; IR (thin film) 3370 (s), 3225 (w), 3190 (w), 3093 (w), 3066 (w), 3037 (w), 2948 (w), 1731 (s), 1616 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.47 (m, 2H), 7.41-7.33 (m, 3H), 7.26-7.22 (m, 2H), 5.42 (s, 2H), 4.98 (br s, 2H), 3.96 (d, J=1 Hz, 3H); ESIMS m/z 485 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][O:14][C:15]([N:17]=[C:18]=[S:19])=[O:16]>CC(C)=O>[CH3:13][O:14][C:15]([NH:17][C:18](=[S:19])[NH:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])=[O:16]
Reactant: CSc1ccc([N+](=O)[O-])c(N)c1
Reactant: COC(=O)N=C=S
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1cc(SC)ccc1[N+](=O)[O-]
Reaction time: 120 h

Procedure:
1.5 G. 2-amino-4-methylthio-1-nitrobenzene in 30 ml. acetone is treated with 2.5 g. methoxy carbonyl isothiocyanate. After five days the mixture is stripped under vacuum and the residue triturated with methanol yielding 1-(3-methoxycarbonyl-2-thioureido)-5-methylthio-2-nitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[C:16]([F:24])[CH:15]=3)=[CH:12][CH:13]=[C:8]2[N:7]=[N:6]1.[OH-].[Na+].Cl>CO.C1COCC1.O>[Cl:1][C:2]1[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[C:16]([F:24])[CH:15]=3)=[CH:12][CH:13]=[C:8]2[N:7]=[N:6]1
Reactant: COC(=O)c1ccc(-c2ccc3nnn(Cc4c(F)ccc(F)c4Cl)c3n2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2ccc3nnn(Cc4c(F)ccc(F)c4Cl)c3n2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.5 %

Procedure:
To a solution of Example 17 (0.300 g, 0.725 mmol) in methanol (1 ml), THF (2 ml), sodium hydroxide (0.150 g, 3.75 mmol) in water (1 ml) was added and stirred at RT. After 12 h, the pH was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as a pale brown solid (0.120 g, 41%). M.P.: 211-213° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.65 (d, J=8.8 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.02 (m, 2H), 7.83 (t, J=7.4 Hz, 1H), 7.60 (dt, J=9.1, 4.8 Hz, 1H), 7.46 (dt, J=9.0, 4.0 Hz, 1H), 6.11 (s, 2H). MS (m/z): 418.70 (M+).
Reaction SMILES: [C:1]12([CH:11]([NH:15][CH3:16])[C:12]([OH:14])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH3:50]/[C:51](=[CH:57]\[C@@H:58]([N:62]([CH3:71])[C:63](=[O:70])[C@H:64]([C:66]([CH3:69])([CH3:68])[CH3:67])[NH2:65])[CH:59]([CH3:61])[CH3:60])/[C:52]([O:54][CH2:55][CH3:56])=[O:53].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]12([C@@H:11]([NH:15][CH3:16])[C:12]([NH:65][C@H:64]([C:63]([N:62]([CH3:71])[C@@H:58]([CH:59]([CH3:61])[CH3:60])/[CH:57]=[C:51](\[CH3:50])/[C:52]([O:54][CH2:55][CH3:56])=[O:53])=[O:70])[C:66]([CH3:69])([CH3:68])[CH3:67])=[O:14])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](N)C(C)(C)C
Reactant: CNC(C(=O)O)C12CC3CC(CC(C3)C1)C2
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](NC)C12CC3CC(CC(C3)C1)C2)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To adamantan-1-yl-methylamino-acetic acid (0.447 g, 2.0 mmol, from Reference Example 6) in dichloromethane (17 mL) is added PyBOP (1.04 g, 2.0 mmol). After 15 min ethyl (2E,4S)-2,5-dimethyl-4-[methyl(3-methyl-L-valyl)amino]hex-2-enoate (0.625 g, 2.0 mmol, WO 99/32509) in dichlormethane (5 mL) is added, followed by diisopropylethylamine (0.75 mL, 4.3 mmol). This is stirred at room temperature overnight. The reaction mixture is evaporated in vacuo and the residue treated with ethyl acetate and water. The ethyl acetate layer is dried over sodium sulfate and purified by hplc. The two diastereomers are partially separated. The first isomer is assigned the SSS configuration and contained 33.4% of the RSS isomer. MS: m/z 518.3 (M+1). The second isomer is assigned the RSS configuration and contained 8.9% of the SSS isomer. MS: m/z 518.3 (M+1).
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=[C:13]2[O:21]C)[CH2:9]1)(C)(C)C.ClC1[S:26][C:27]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=2[N:29]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[F:34][C:32]1[CH:31]=[CH:30][C:28]2[N:29]=[C:6]([NH:7][C@H:8]3[CH2:9][C@H:10]([N:12]4[C:16]5=[N:17][CH:18]=[CH:19][CH:20]=[C:15]5[NH:14][C:13]4=[O:21])[CH2:11]3)[S:26][C:27]=2[CH:33]=1
Reactant: COc1nc2cccnc2n1[C@H]1C[C@H](NC(=O)OC(C)(C)C)C1
Reactant: Fc1ccc2nc(Cl)sc2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c2cccnc2n1[C@H]1C[C@H](Nc2nc3ccc(F)cc3s2)C1
Temperature: 90 °C

Procedure:
To a glass microwave reaction vessel was added 3-(trans-3-aminocyclobutyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (intermediate 43, 0.1288 g, 0.465 mmol), 2-chloro-6-fluorobenzo[d]thiazole (0.087 g, 0.465 mmol), and diisopropylethylamine (0.283 ml, 1.627 mmol) in dry dimethylsulfoxide (1.549 ml). The vial was sealed and heated at 90° C. for 14 hours. It was allowed to cool to room temperature and the crude product purified by reverse-phase preparative HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in acetonitrile/water, gradient 10% to 90% over 12 min) to give the desired 3-(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (26.2 mg, 0.074 mmol, 15.86% yield). M+1: 355.99. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37-2.47 (m, 2 H) 3.25-3.34 (m, 1 H) 4.55 (d, J=5.28 Hz, 1 H) 5.20 (quin, J=8.41 Hz, 1 H) 6.99-7.12 (m, 2 H) 7.32 (dd, J=7.63, 1.17 Hz, 1 H) 7.41 (dd, J=8.80, 4.89 Hz, 1 H) 7.64 (dd, J=8.80, 2.74 Hz, 1 H) 8.00 (dd, J=5.18, 1.27 Hz, 1 H) 8.56 (d, J=6.06 Hz, 1 H) 11.15 (s, 1 H).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]3=[O:32])=[CH:18][C:17]=2[F:33])[CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[CH3:3][N:4]([CH:6]=[N:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]3=[O:32])=[CH:18][C:17]=2[F:33])[CH2:14][CH2:15]1)[CH3:5]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(N)CC3)c(F)c2)C(=O)O1
Solvent: Cc1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(N=CN(C)C)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 84 %

Procedure:
N,N-dimethylformamide dimethylacetal (0.8 ml) and 1.0 g of the (S)-N-{3-[4-(4-amino-piperidin-1-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (Compound No. 6) which was synthesized in Example 4 were added to toluene (10 ml) and the mixture was heated under reflux for 24 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was washed with hexane to remove excess dimethylacetal. The resulting precipitate was suspended in dichloromethane and the insolubles were separated by filtration. The filtrate was concentrated under vacuum to afford the title compound (985 mg) in a yield of 84%.
Reaction SMILES: C(OC(C1C(C=O)=NNC=1)=O)C.[N+:13]([C:16]1[C:17]([CH2:27][OH:28])=[N:18][N:19]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:20]=1)([O-:15])=[O:14]>[O-2].[Mn+4].[O-2].CC(C)=O>[N+:13]([C:16]1[C:17]([CH:27]=[O:28])=[N:18][N:19]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:20]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cn(C2CCCCO2)nc1CO
Agent: [Mn+4]
Agent: CCOC(=O)c1c[nH]nc1C=O
Agent: [O-2]
Solvent: CC(C)=O
Product: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]

Procedure:
By proceeding in a manner similar to Reference Example 6(a) above but (i) using [4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-methanol (663 mg, Reference Example 53) and manganese (IV) oxide (2.54 g) with acetone as the solvent, (ii) carrying out the reaction at 65° C. for 2 hours and (iii) subjecting the reaction product to flash silica chromatography eluting with a mixture of pentane and ethyl acetate (70:30, v/v), there was prepared 4-nitro-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-3-carbaldehyde (191 mg) as a pale yellow oil. LC-MS (Method H): RT=2.19 minutes, 248.24 (M+H+Na)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[OH:15])[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH3:11]>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:2]([O:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][C:14](=[O:15])[CH3:13])[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH3:11])(=[O:1])[CH3:3]
Reactant: CN1CCCC1Cc1ccc(O)c(O)c1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(CC2CCCN2C)cc1OC(C)=O

Procedure:
Allow 3.25 g of 2-(3,4-dihydroxybenzyl)-1-methylpyrrolidine to stand for 24 hours in 30 ml of acetic anhydride/pyridine 1:1. Concentrate the resulting reaction mixture under a vacuum and distil off the residue to obtain 3.5 g (76% of theory) of the title compound in the form of a yellowish oil (b.p. 135° to 140° at 0.005 mm of Hg) which, on standing, solidifies to a crystalline mass of m.p. 44° to 45°.