Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9](=[O:23])[N:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)O1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:7]1[CH:6]=[CH:5][N:4]2[C:9](=[O:23])[N:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=[C:3]2[C:2]=1[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(Br)c(Cl)ccn12
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: Cc1ccccc1
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccncc3)c(Cl)ccn12
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 20 %

Procedure:
To a suspension of 8-bromo-7-chloro-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (389 mg, 0.955 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (783 mg, 3.823 mmol) in toluene (7 mL) and 2.0 M aqueous sodium carbonate (2.1 mL) was added (Ph3P)4Pd (165 mg, 0.143 mmol) in one portion, and the resulting yellow mixture was vigorously stirred under argon in a 100° C. oil bath for 2.5 h. HPLC/MS indicated that about 20% of the title compound had formed. Additional (Ph3P)4Pd (50 mg, 0.043 mmol) was added, and the reaction mixture was stirred at 100° C. under argon for 3.5 h more. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The EtOAc phase was washed with water, then saturated aqueous NaCl, dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel (12 g) column chromatography eluting with a gradient of EtOAc (0-100%) in hexanes to obtain the title compound as a yellow foam (169 mg). HPLC/MS: retention time=2.04 min, [M+H]+=406.
Reaction SMILES: O[CH:2]1[CH:7]([C:8](=[S:11])[NH:9][CH3:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4][C:3]1([CH2:22][O:23][CH3:24])[CH2:19][O:20][CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:24][O:23][CH2:22][C:3]1([CH2:19][O:20][CH3:21])[CH:2]=[C:7]([C:8](=[S:11])[NH:9][CH3:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4]1
Reactant: CNC(=S)C1c2cc([N+](=O)[O-])ccc2OC(COC)(COC)C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=S)C1=CC(COC)(COC)Oc2ccc([N+](=O)[O-])cc21
Yield: 21.1 %

Procedure:
A mixture of 550 mg of 3,4-dihydro-3-hydroxy-2,2-bis(methoxymethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carbothioamide, 0.16 g of p-toluenesulfonic acid monohydrate and 8 ml of toluene was refluxed with heating for 1.5 hours. Toluene was added to the mixture. After it was washed with water and dried, the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 110 mg of oily 2,2-bis(methoxymethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carbothioamide.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH2:2]1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)Cl>[Br:21][C:12]1[C:7]([O:6][C@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[N:8][C:9]([NH2:13])=[N:10][CH:11]=1
Reactant: Nc1nccc(O[C@H]2CCOC2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1ncc(Br)c(O[C@H]2CCOC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-amine (intermediate 62, 33 mg, 0.182 mmol) was dissolved in DCM (4 ml), treated with NBS (35.7 mg, 0.200 mmol) and stirred at 25° C. for 1 h. The reaction solution was diluted in DCM and washed with NaOH (1 M in water) and brine. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to obtain the title compound as a white solid. (UPLC-MS 3) tR 0.67 min; ESI-MS 260.1, 262.0 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([CH2:11][N+:12]([O-])=O)[CH2:7][CH2:8][CH2:9][CH3:10])C.[H][H]>CO.[Ni]>[CH2:7]([CH:6]1[CH2:11][NH:12][C:4](=[O:3])[CH2:5]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCC(CC(=O)OCC)C[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CCCCC1CNC(=O)C1
Yield: 90.7 %

Procedure:
To a solution of 3-nitromethylheptanoic acid ethyl ester (10 g, 49.2 mmol) in methanol (100 mL) under argon was added Raney Ni (5 g). The mixture was stirred under 50 psi of hydrogen for 48 h, flushed with argon, filtered through a Celite pad, and concentrated under vacuum to afford 4-butylpyrrolidin-2-one as a colorless oil (6.3 g, 91%). MS(ES) m/e 142 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][S:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26]([Cl:32])=[CH:27][CH:28]=3)[N:23]=2)[CH:15]=1)[S:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=O)[NH2:2].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.Cl>C1COCC1>[Cl:32][C:26]1[CH:25]=[C:24]2[C:29]([CH:30]=[CH:31][C:22]([CH2:21][O:20][C:16]3[CH:15]=[C:14]([CH:7]([S:6][CH2:5][CH2:4][C:1]#[N:2])[S:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:19]=[CH:18][CH:17]=3)=[N:23]2)=[CH:28][CH:27]=1
Reactant: NC(=O)CCSC(SCCC(=O)O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#CCCSC(SCCC(=O)O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To the amide acid (Example 17) (2.788 g, 3.63 mmoles) in THF (40 mL) at -23° C., pyridine (2.2 mL, 7.5 equiv.) and trifluoroacetic anhydride (1.1 mL, 2.2 equiv.) were added. After one hour of stirring at 0° C., 10% HCl was added, the mixture was extracted with EtOAc, dried over sodium sulfate and evaporated. Flash chromatography on silica with EtOAc:toluene:AcOH 30:70:1 afforded 1.447 g of the title compound.
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)[CH2:15][C:16]([CH3:18])=[O:17].[OH-].[Na+].Cl>O>[O:17]=[C:16]1[CH2:18][CH:10]([C:11]([OH:13])=[O:12])[CH2:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15]1
Reactant: O=C(O)C=CC(=O)c1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1C=C(c2ccccc2)CC(C(=O)O)C1

Procedure:
An 800 L still is charged with 53.9 kg (306 mol) of 3-benzoylacrylic acid. The 800 n still is charged with 41 kg (315 mol) of ethyl acetoacetate. The still is charged with 150 L of water. The agitator is started on the still. The still is charged with 56 kg (1475 mol) of 50% sodium hydroxide, followed by 20 L of water. The resulting solution is agitated, and the temperature of the contents is maintained at 45°-50° C. for 16 to 18 hours after the addition of the sodium hydroxide. The solution in the still is then refluxed for 20 to 24 hours (~100° C.). An 800 L reactor is charged with 140 L of water and 90.6 kg (1100 mol) of concentrated hydrochloric acid followed by 20 L of water, and the agitator is started. The reaction mixture in the still is cooled to 25°-40° C. The still is vented through the condenser to an atmospheric scrubber. The cooled solution in the still (25°-40° C.) is added to the diluted hydrochloric acid solution in the reactor at a rate of about 2-4 L/minute. The still is charged with 100 L of water, and this is transferred to the reactor. The resulting slurry in the reactor is agitated at 25°-40° C. for about 2 to 4 hours. The solid product in the reactor is filtered onto a centrifuge. The reactor is charged with 100 L water, and the water is directed to the cake on the centrifuge. The mother liquors and washes are discarded. The still is charged with 100 L water, the water is directed over the filter-cake, and the filtrate is discarded. The product wet cake from the centrifuge is returned to the still followed by 400 L of water, and the slurry is agitated for 2 to 4 hours. The solid product is filtered onto a centrifuge. The still and filter-cake are washed with 200 L of water. The filtrates are discarded. The water wet 5-oxo-3-phenyl-3-cyclohexenecarboxylic acid is transferred to a vacuum tray dryer and dried at 80°±5° C. for at least 24 hours using the best available vacuum to yield 62.5 kg of an off-white to pale yellow solid; mp 140°-160° C. (average of 2 determinations). The dry product is stored in plastic lined drums.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-])=O>[Fe].C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(c1ccccc1)c1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc(C(=O)c2ccccc2)ccc1N1CCCCC1
Reaction time: 2 h

Procedure:
A solution of 6.5 g. of 3-nitro-4-piperidino-benzophenone in 80 ml. of glacial acetic acid is added dropwise into a well stirred mixture of 5.3 g. of iron powder and 25 ml. of glacial acetic acid. The reaction mixture is kept at 80° to 90° C for about 2 hours. During this period the reaction takes place completely. The heterogeneous reaction mixture is cooled, filtered, and the filtrate is evaporated under reduced pressure. The residue is dissolved in water and the solution is rendered alkaline. This mixture is extracted with benzene, the benzene solution is washed with water until neutral, dried over anhydrous magnesium sulphate, filtered through a column filled with silica gel, and evaporated under reduced pressure. This way 4.5 g. of a solid, crystalline substance are obtained. The physical constants of the product are the same as given in Example 10.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([O:11]CC)=O.O.[NH2:15][NH2:16]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([NH:15][NH2:16])=[O:11]
Reactant: CCOC(=O)CCc1ccccn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CCc1ccccn1

Procedure:
To a stirring 5 mL EtOH solution of 0.58 g (3.2 mmol) of ethyl 3-(2-pyridinyl)propanoate (4), prepared as described above in Example 4, was added 0.32 g (6.5 mmol) of hydrazine hydrate. The reaction was heated at reflux for three weeks. Although the reaction was still incomplete, the solvent was removed under vacuum. The resulting gum was triturated with diethyl ether (Et2O). The product remained a gum. The yield of 3-(2-pyridyl)propanoic acid, hydrazide (5) was 0.22 g (42%). This product was used immediately in the manner described in Example 6 below.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[F:27][C:28]1[CH:29]=[C:30]([NH:34][NH2:35])[CH:31]=[CH:32][CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([N:34]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N(C)C)c2)ccc1=O
Reactant: NNc1cccc(F)c1
Product: CN(C)S(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(F)c3)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzenesulfonamide (A-12) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=440.2 (M+H)+
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[CH3:34][C:35]1[C:39]([Sn](CCCC)(CCCC)CCCC)=[CH:38][O:37][N:36]=1.C(OCC)(=O)C.O>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:5](=[O:19])[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[O:21])=[CH:3][C:2]=1[C:39]1[C:35]([CH3:34])=[N:36][O:37][CH:38]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1conc1C
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: Cc1nocc1-c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 100 °C
Reaction time: 24 h

Procedure:
5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (25 mg, 0.042 mmol), tetrakis(triphenylphosphine) palladium (2.5 mg, 0.0022 mmol) and 3-methyl-4-(tributylstannyl)isoxazole [synthesized as described by D. Uchiyama in Heterocycles, 43, 6, 1301, 1996] (32 mg, 0.086 mmol) were mixed in DME (0.45 ml) in an argon filled vial. The vial was closed and heated with stirring at 100° C. for 24 h. The reaction mixture was poured into a mixture of ethyl acetate and water. The mixture was shaken, the water phase was removed and the organic phase was dried over sodium sulphate. The product was purified by preparative HPLC. Yield: 12 mg, 0.022 mmol (52%).
Reaction SMILES: [CH:1]([NH:3][C:4]([CH3:14])([CH3:13])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:2].[C:15](Br)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH:1]([NH:3][C:4]([CH3:14])([CH3:13])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:15](=[O:17])[CH3:16])=[CH:9][CH:8]=1)=[O:2]
Reactant: CC(=O)Br
Reactant: CC(C)(CCc1ccccc1)NC=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc(CCC(C)(C)NC=O)cc1
Temperature: 25 °C

Procedure:
N-Formyl-3-phenyl-1, 1-dimethylpropanamine (115 g) was dissolved in 1,2-dichloroethane (850 ml) at 0° C. Acetyl bromide (116 ml) was added followed by the portionwise addition of aluminum chloride (263 g) over 0.5 h. At the end of addition the mixture was allowed to warm to room temperature and then refluxed for 1h. The hot solution was poured onto crushed ice (3 Kg) and the mixture extracted with chloroform. The chloroform extracts were washed with water, sodium bicarbonate and dried (MgSO4). Evaporation of the solvent gave an oil of which 25 g was chromatographed on Kieselgel 60 (1 Kg). Elution with 1% methanol-chloroform gave the title compound as an oil (18 g). τ(CDCl3) 8.6 (6H, s) 8.4-7.75 (2H, m), 7.45 (3H, s), 7.5-7.05 (2H, m), 3.0-4.0 (1H, broad), 2.7 (2H, d, J=8 Hz), 2.15 (2H, d, J=8 Hz) 1.2 (1H, d, J=5 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[C:4]([O:13][CH3:14])[CH:3]=1.C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[Cl:22][CH2:23][C:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[C:4]([O:13][CH3:14])[CH:3]=1)=[O:25]
Reactant: O=C(Cl)CCl
Reactant: COc1cc(N)ccc1-c1cnco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)CCl)ccc1-c1cnco1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1D (500 mg, 2.63 mmol) and triethylamine (370 μL, 2.89 mmol) in dichloromethane (13.0 mL), was added chloroacetyl chloride (0.23 mL, 2.89 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min. and then at RT for 4 h. The mixture eas diluted with dichloromathane, washed with water, brine, and dried over Na2SO4. The mixture was filtered through celite and concentrated in vacuo to give 2A as a yellow solid. LC/MS: ret. timeA=3.123 min., MS (M+H)+=267.
Reaction SMILES: COC[N:4]1[C:8]2=[N:9][C:10]([N:13]3[CH2:18][CH2:17]O[CH2:15][CH2:14]3)=[CH:11][CH:12]=[C:7]2[N:6]=[C:5]1[C:19]1[S:20][C:21]2[C:27]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:26][CH:25]=[C:24]([O:34][CH3:35])[C:22]=2[N:23]=1.Cl>>[CH3:35][O:34][C:24]1[C:22]2[N:23]=[C:19]([C:5]3[NH:4][C:8]4=[N:9][C:10]([N:13]5[CH2:18][CH2:17][CH2:15][CH2:14]5)=[CH:11][CH:12]=[C:7]4[N:6]=3)[S:20][C:21]=2[C:27]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:26][CH:25]=1
Reactant: COCn1c(-c2nc3c(OC)ccc(N4CCOCC4)c3s2)nc2ccc(N3CCOCC3)nc21
Agent: Cl
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4ccc(N5CCCC5)nc4[nH]3)nc12

Procedure:
0.07 g 3-Methoxymethyl-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-5-morpholin-4-yl-3H-imidazo[4,5-b]pyridine (0.15 mmol) was treated with 5N HCl (2 ml) at 90° C. for 1.5 h. The reaction mixture was concentrated, taken up in water (3 ml) and adjusted to pH 10 with ammonium hydroxide (25%), whereupon a precipitation formed. The precipitation was filtered and the crystals were triturated in hot ethanol. After drying in vacuo 0.025 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-5-pyrrolidin-4-yl-3H-imidazo[4,5-b]pyridine (39%) was obtained as a yellow solid; M.p.: 264–268° C.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[N:7]2)(=[O:32])=[O:33])=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc2c(C3CCCC3)n[nH]c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(=O)(=O)n2nc(C3CCCC3)c3ccccc32)cc1
Reaction time: 12 h
Yield: 45.7 %

Procedure:
Combine 3-Cyclopentyl-1H-indazole (2.168 g 11.640 mmole) with triethylamine (3.526 g, 34.92 mmoles) in 50 mls of dichloromethane. Dissolve 4-Chlorosulfonyl-benzoic acid methyl ester (4.085 g, 17.460 mmole) in dichloromethane 50 ml and add drop wise to solution at 0° C. Stir the reaction is for 12 hrs. Dilute the reaction and wash with NaHCO3. Dry organic layer over MgSO4 and concentrate. Purify the residue via column chromatography with a mixture of ethyl acetate and hexanes to isolate 2.046 g (Yield=48.5%) of the title compound: MS ES+385.3.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([NH:12][CH:13]([C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24](O)=[O:25])[CH2:14][C:15](=[O:21])[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[N:9]2)=[CH:4][CH:3]=1.C(O)C>O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:13]([CH2:14][C:15](=[O:21])[CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[C:22]4[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:24]3=[O:25])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CCC(=O)CC(Nc1ccc2ccc(Cl)nc2n1)c1ccccc1C(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)CCC(=O)CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 35 °C
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
A solution of 2-{1-[(7-chloro-1,8-naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid (74.9 kg, 175.9 mol), (1S, 2R)-ephedrine hemihydrate (32.5 kg, 186.5 mol), 200 proof ethanol (290 Kg) and water (17 L) were stirred and heated to about 35° C. for 35 minutes. The solution was filtered and then cooled to about 20° C. until the onset of crystallization. The reaction was further cooled to 0-5° C. for about 2 hours. The intermediate ephedrine salt was filtered and washed with a cold (0-5° C.) solution of 200 proof ethanol (206 Kg) and water (10 L). The ephedrine salt was dissolved in 377 L of dichloromethane and stirred with 125 L water and 9.7 kg 37% hydrochloric acid. The aqueous layer was removed. The organic layer was washed with water (125 L). The organic layer was distilled to 60% of the original volume. Carbonyldiimidazole was dissolved in CH2Cl2 (128 L) and slowly transferred to the reaction solution. The reaction was complete after 20 minutes. The reaction was washed two times with water (250 L each). The CH2Cl2 solution was distilled atmospherically, the volume being replaced with of 200 proof ethanol (500 Kg). The ethanol solution was cooled at a rate of 20±5° C. per hour to 0-5° C. The solution was then held at 0-5° C. for 16 hours. The product was filtered and washed with 200 proof ethanol (100 kg). The product was dried for 16 hours under vacuum at 60° C. This afforded 26.0 Kg of (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone as a white solid (36% yield). 1H-NMR: δ 8.87 (d, J=8.8, 1H), 8.61 (m, 2H), 7.93 (d, J=7.0, 1H), 7.74 (m, 4H), 6.05 (m, 1H), 3.62 (m, 1H), 3.28 (dd, J=7.0, 17.2, 1H), 2.42 (m, 2H), 1.35 (m, 3H), 0.79 (d, J=6.2, 6H); Cl (MS) M+1 at 408, 100%; [α]D20=+135° (c=1, dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9](C(=O)C)[CH2:10][CH2:11][N:12]=2)=[C:6](Cl)[N:5]([NH2:17])[CH:4]([CH3:18])[N:3]=1.[CH3:19][OH:20]>>[Cl:1][C:2]1[C:7]([C:8]2[NH:9][CH2:10][CH2:11][N:12]=2)=[C:6]([O:20][CH3:19])[N:5]([NH2:17])[CH:4]([CH3:18])[N:3]=1
Reactant: CO
Reactant: CC(=O)N1CCN=C1C1=C(Cl)N(N)C(C)N=C1Cl
Product: COC1=C(C2=NCCN2)C(Cl)=NC(C)N1N
Yield: 80 %

Procedure:
10.0 g 4,6-dichloro-2-methyl-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine are boiled in 400 ml methanol for 48 hours under reflux. The solution is concentrated, and the residue mixed with warm tetrahydrofuran. The crystals are recrystallized from isopropanol/ether. 6.4 g (80%) of 4-chloro-6-methoxy-2-methyl-5-(2-imidazolin-2-yl)-aminopyrimidine is obtained as the hydrochloride, melting point 189° C. Melting point of the base 217°-219° C. (decomposition). 1H-NMR spectrum is DMSO-d6, delta values in ppm: 2.53 (s, CH3), 3.65 (s, N-CH2 --CH2 -N), 3.98 (s, OCH3), 8.66 (twice NH, deuterizable).
Reaction SMILES: C(N)C1C=CC=CC=1.[CH:9]1([CH2:12][CH2:13][NH2:14])[CH2:11][CH2:10]1.[F:15][C:16]1[CH:38]=[CH:37][C:19]([CH2:20][N:21]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][N:35]=3)[C:29](OC)=[O:30])[C:22]2=[O:36])=[CH:18][CH:17]=1>>[CH:9]1([CH2:12][CH2:13][NH:14][C:29](=[O:30])[C:28]2[CH:33]=[CH:34][N:35]=[C:26]([N:23]3[CH2:24][CH2:25][N:21]([CH2:20][C:19]4[CH:18]=[CH:17][C:16]([F:15])=[CH:38][CH:37]=4)[C:22]3=[O:36])[CH:27]=2)[CH2:11][CH2:10]1
Reactant: NCCC1CC1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Solvent: NCc1ccccc1
Product: O=C(NCCC1CC1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 70 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with 2-cyclopropylethanamine to react with methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate, N-(2-cyclopropylethyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 70% yield: mp 123-125° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.35 (d, J=5.1 Hz, 1H), 7.38 (dd, J=5.1, 1.2 Hz, 1H), 7.29-7.24 (m, 2H), 7.05-7.00 (m, 2H), 6.52 (br s, 1H), 4.44 (s, 2H), 4.05 (t, J=8.1 Hz, 2H), 3.55-3.49 (m, 2H), 3.37 (t, J=8.1 Hz, 2H), 1.54-1.47 (m, 2H), 0.77-0.64 (m, 1H), 0.53-0.45 (m, 2H), 0.11-0.02 (m, 2H); MS (ES+) m/z 383.3 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[O:12][CH:13]([CH3:15])[CH3:14].[CH3:16][O-:17].[Na+].O>O1CCOCC1.Cl>[CH:13]([O:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=1[O:17][CH3:16])([CH3:15])[CH3:14]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(OC(C)C)c(Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1nc(C(=O)O)ccc1OC(C)C
Temperature: 140 °C
Yield: 98.8 %

Procedure:
Methyl 6-chloro-5-isopropoxypicolinate (330 mg, 1.437 mmol) was dissolved in dioxane (12 mL) before a solution of sodium methoxide (5.75 mL of 0.5 M in MeOH, 2.87 mmol) was added. The reaction was heated under microwave irradiation at 140° C. for 1.5 hours. Water (52 μL, 2.9 mmol) was added and the reaction mixture was heated by microwave irradiation at 100° C. for 30 minutes. The reaction mixture was diluted with 1 N HCl solution (50 mL) and was extracted with ethyl acetate (2×50 mL). Organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide 5-isopropoxy-6-methoxypicolinic acid (300 mg, 98%) as a beige solid. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=8.1 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 4.72-4.61 (m, 1H), 4.06 (s, 3H), 1.45 (t, J=7.4 Hz, 6H). ESI-MS m/z calc. 211.1, found 211.9 (M+1)+; Retention time: 0.97 minutes (3 min run).