Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:7](=O)[CH2:8][O:9][CH3:10])[C:3](OC)=[O:4].C(O)(=O)C.[CH:16]([NH2:18])=[NH:17].C[O-].[Na+]>CO>[CH3:1][C:2]1[C:3]([OH:4])=[N:17][CH:16]=[N:18][C:7]=1[CH2:8][O:9][CH3:10]
Reactant: COCC(=O)C(C)C(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COCc1ncnc(O)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a solution of methyl 2-methyl-4-(methyloxy)-3-oxobutanoate (Intermediate 47, 1.01 g, 6.31 mmol) in methanol (7 mL) was added formamidine acetate (0.722 g, 6.94 mmol) and 25% sodium methoxide in MeOH (3.0 mL, 6.31 mmol) and the resulting mixture was heated under reflux for 2 hours, cooled to room temperature and left to stand overnight. The reaction mixture was evaporated under reduced pressure. The residue was diluted with water, adjusted to pH 7 using aqueous 2M HCl solution and extracted with chloroform (×3). The chloroform layers were combined, dried under magnesium sulfate and evaporated under reduced pressure to give the title compound as a white solid (597 mg);
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH3:5][N:6]([N:8]=[N:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15](OC)=[O:16])[CH3:7].O>C1COCC1>[CH3:7][N:6]([N:8]=[N:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]([NH:4][CH2:3][CH2:1][OH:2])=[O:16])[CH3:5]
Reactant: NCCO
Reactant: COC(=O)c1sccc1N=NN(C)C
Solvent: O
Solvent: C1CCOC1
Product: CN(C)N=Nc1ccsc1C(=O)NCCO
Temperature: 25 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
To an ice cold (0-5° C.) solution of ethanol amine (5 mL) in THF (5 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]thiophene-2-carboxylate (500 mg) in THF (5 mL) for 5 min and stirred at rt for 20 h. The solution was poured into ice cooled water and the solution was extracted with ethyl acetate (3×50 mL). The combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product, which was recrystallized from chloroform-hexane gave the product as a pale orange color solid (430 mg, 77%), mp 118-122° C. IR (neat) νmax, 3397, 3278, 2926, 1621, 1353, 1298, 1220, 1083, 1007, 882, 775 cm−1;
Reaction SMILES: [NH2:1][C:2]1[N:6](C(OC(C)(C)C)=O)[N:5]=[C:4]([CH2:14][CH2:15][C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.FC(F)(F)C(O)=O>N1C=CC=CC=1>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([CH2:15][CH2:14][C:4]3[CH:3]=[C:2]([NH:1][C:36](=[O:37])[C:35]4[CH:34]=[CH:33][C:32]([N:29]5[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]5)=[CH:40][CH:39]=4)[NH:6][N:5]=3)=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)n1nc(CCc2ccc3c(c2)OCO3)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: CN1CCN(c2ccc(C(=O)Nc3cc(CCc4ccc5c(c4)OCO5)n[nH]3)cc2)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a stirred solution of tert-butyl 5-amino-3-(2-benzo[1,3]dioxol-5-ylethyl)pyrazole-1-carboxylate (229 mg, 0.69 mmol, 1.0 eq) in pyridine (5 ml) at 5° C. was added 4-(4-methylpiperazin-1-yl)benzoyl chloride (181 mg, 0.76 mmol, 1.1 eq). The reaction mixture was stirred to 60° C. for 24 h. After this time, the mixture was concentrated and redissolved in DCM (10 ml). Trifluoroacetic acid (464 μl, 6.25 mmol, 8.25 eq) was added and the reaction mixture stirred for 2 h at 25° C. The reaction mixture was then concentrated. The crude product was purified by reverse-phase prep. HPLC (basic) using a 30-50% gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were combined and evaporated to afford the title compound as a white solid. (12 mg, 4%); 1H NMR (300.132 MHz, DMSO) δ 2.28 (s, 3H), 2.49 (t, 2H), 2.89 (s, 2H), 3.31-3.37 (m, 8H), 6.01 (s, 2H), 6.43 (s, 1H), 6.74 (d, 1H), 6.86 (d, 2H), 7.01 (d, 2H), 7.94 (d, 2H), 10.36 (s, 1H), 12.11 (s, 1H); MS: m/z 434 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH:19]([CH3:20])[CH2:18][O:17][CH2:16][CH:15]3[CH3:21])[N:11]=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:33]([C:36]1[CH:37]=[C:38]([NH:42][C:43](=O)[O:44]C2C=CC=CC=2)[CH:39]=[CH:40][CH:41]=1)(=[O:35])[NH2:34]>>[CH3:21][CH:15]1[CH2:16][O:17][CH2:18][CH:19]([CH3:20])[N:14]1[C:12]1[N:11]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[NH:31][CH3:32])=[CH:24][CH:23]=2)[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:43]([NH:42][C:38]3[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=3)[C:33]([NH2:34])=[O:35])=[O:44])=[CH:7][CH:6]=2)[N:13]=1
Reactant: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3C(C)COCC3C)n2)cc1
Reactant: NC(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(NC(=O)Nc4cccc(C(N)=O)c4)cc3)nc(N3C(C)COCC3C)n2)cc1
Yield: 4.1 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 7 using 1-(4-(4-(4-aminophenyl)-6-(3,5-dimethylmorpholino)-1,3,5-triazin-2-yl)phenyl)-3-methylurea and phenyl 3-carbamoylphenylcarbamate. Yield 56 mg, 4.1% yield.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[C:10]([CH3:16])[CH:9]=2)[N:4]=1.O[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[F:18][C:2]([F:17])([F:1])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[C:10]([CH3:16])[CH:9]=2)[N:4]=1
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1O
Reactant: OCCCCc1cccnc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCCc1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.2 %

Procedure:
To a suspension of 0.44 g (1.8 mmol) of 4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol, 0.25 g (1.66 mmol) of 3-(4-hydroxybutyl)-pyridine, and 0.52 g (1.99 mmol) of triphenylphosphine in 30 ml of methylene chloride under nitrogen at 0° C. was added dropwise a solution of 0.35 g (1.97 mmol of DEAD in methylene chloride, and the resulting mixture was allowed to warm to room temperature. After adding 70 mg of triphenylphosphine, the mixture was stirred at room temperature for 2 days. The solution was concentrated in vacuo and the residue was purified by MPLC (26 id Kieselgel 60 column; hexane/ethyl acetate 3:1) to yield 0.56 g (86.1%) of 3-[4-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-butyl]-pyridine, as a pale yellow oil.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8])(=O)=O.[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OCCC(F)(F)F)cc1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 3,3,3-trifluoropropyl tosylate (4.057 gm; 15.12 mmol), 3-hydroxybenzaldehyde (1.85 gm; 15.12 mmol), and K2CO3 (4.15 gm; 30.0 mmol) in DMF (80 mL) and heat at 100° C. After 18 hours, cool to room temperature, dilute with water (200 mL) and extract with dichloromethane (2×200 mL). Combine organic extracts and wash sequentially with water (100 mL), 0.1 M NaOH (2×100 mL), saturated sodium bicarbonate (100 mL) and saturated brine (100 mL), dry (MgSO4), and concentrate. Chromatography on silica gel (0-20% ethyl acetate in hexane) to give the title product.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([OH:16])[CH:9]=1)(C)(C)C.[C:19]1([CH2:25][CH2:26][CH2:27]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[OH:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([O:16][CH2:27][CH2:26][CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1
Reactant: BrCCCc1ccccc1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C#N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CO)cc1OCCCc1ccccc1
Reaction time: 14 h

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-2-hydroxy-benzonitrile from step 2 (50 mg, 0.19 mmol) was dissolved in DMF (1 ml) and treated with phenylpropylbromide (29 μl, 0.19 mmol). Cs2CO3 (68 mg, 0.21 mmol) was then added and the reaction mixture stirred at room temp. for 14 hours. The mixture was filtered and washed with DMF (3×10 mL). The solvent was removed in vacuo and the residue was purified by flash chromatography (10% EtOAc/Hexane) to yield desired product.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([O:9][C:10](=[O:32])[NH:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][O:30][NH2:31])([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([O:9][C:10](=[O:32])[NH:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[C:16]1[CH2:29][O:30][N:31]=[C:2]([CH3:4])[CH3:1])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCCn1c(CON)nc2c(N)nc3ccccc3c21
Reactant: CC(C)=O
Solvent: CO
Product: CC(C)=NOCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetone (20 mL) was added to a solution of tert-butyl[3-(4-amino-2-aminooxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate (3.6 g) in methanol (70 mL). The reaction mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure to provide 4.12 g of tert-butyl[3-(4-amino-2-isopropylideneaminoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate as a light yellow foam.
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.C[O:8][C:9](=O)[CH:10]([CH3:25])[CH2:11][NH:12][C:13]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:24][O:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([NH:12][CH2:11][CH:10]([CH3:25])[C:9]([NH2:2])=[O:8])[CH:22]=1
Reactant: [NH4+]
Reactant: COC(=O)C(C)CNc1cc(OC)c2ccccc2n1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(NCC(C)C(N)=O)nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
A slurry of ammonium chloride (0.38 g, 7.11 mmol) in dry methylene chloride (20 mL) at 0° C. was treated with trimethylaluminum (1 eq, 7.11 mmol, 3.6 mL of a 2M solution in toluene). The mixture was allowed to warm to room temperature over a period of two hours, at which time a solution of 3-(4-methoxy-quinolin-2-ylamino)-2-methyl-propionic acid methyl ester (0.33 eq, 2.37 mmol, 0.65 g) in dry methylene chloride (5 mL) was added. The solution stirred at room temperature for two hours, then was quenched slowly by addition of concentrated HCl (1 mL). After stirring for an additional 30 minutes, the mixture was diluted with 10% NaOH (30 mL) and brine (20 mL) and extracted into methylene chloride. The organic extracts were dried over Na2SO4, filtered and concentrated to an oil. Purification via column chromatography on silica (95:5 methylene chloride/methanolic ammonia) provided the product (0.29 g, 48%) as a white solid. [M+H]+ 260.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18]>CN(C)C=O.O>[CH2:18]([N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: C=CCCCCCCBr
Reactant: O=C1NC(=O)C2CC12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCCCCN1C(=O)C2CC2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (0.11 g) was added to a solution of 3-azabicyclo[3.1.0]hexane-2,4dione (0.3 g) and 7-octenyl bromide (0.52 g) in dimethylformamide (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (15 ml) and then extracted with toluene (20 ml). The organic extract was washed with water (15 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by Kugelrohr distillation (boiling point 130-140° C. @ 0.1 mmHg) to give the title compound as a colourless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])#[N:2].[C:23]([CH:26]=[C:27]=[O:28])(=[O:25])[CH3:24]>CCOC(C)=O>[C:1]([C:3]1[CH:8]=[C:7]([NH:9][C:27](=[O:28])[CH2:26][C:23](=[O:25])[CH3:24])[CH:6]=[CH:5][C:4]=1[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])#[N:2]
Reactant: CCCCCCN(CCCCCC)c1ccc(N)cc1C#N
Reactant: CC(=O)C=C=O
Solvent: CCOC(C)=O
Product: CCCCCCN(CCCCCC)c1ccc(NC(=O)CC(C)=O)cc1C#N
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a solution of 2-cyano-N1,N1-dihexylbenzene-1,4-diamine (1.55 g, 5.14 mmol) in EtOAc (30 mL) was added acetyl ketene (0.52 g, 6.19 mmol) with stirring and the mixture was stirred at 80° C. overnight. The mixture was then cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as yellow oil (1.47 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](OS(C(F)(F)F)(=O)=O)[N:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:20][C:21]1[N:22]=[C:23]([CH3:26])[S:24][CH:25]=1>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:20][C:21]3[N:22]=[C:23]([CH3:26])[S:24][CH:25]=3)[N:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc(N)cs1
Reactant: O=S(=O)(Oc1nccc2ccc(Cl)nc12)C(F)(F)F
Product: Cc1nc(Nc2nccc3ccc(Cl)nc23)cs1

Procedure:
The title compound, MS: m/e=277.0/279.1 (M+H+), was prepared in accordance with the general method of example 1 from trifluoro-methanesulfonic acid 2-chloro-[1,7]naphthyridin-8-yl ester (Example G) and 4-amino-2-methylthiazole (Example F).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:30])[C:28]=1[CH3:29].[H-].[Na+]>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:30])[C:28]=1[CH2:29][C:2]1[C:11]2[C:6](=[C:7]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1
Reactant: COc1ccc2c(Cl)nncc2c1C#Cc1ccncc1
Reactant: Cc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#Cc1ccncc1
Yield: 40.4 %

Procedure:
Operating analogously to what described in example 15 starting from 1-chloro-6-methoxy-5-pyridin-4-ylethynyl-phthalazine (1.38 g, 4.66 mmoles), prepared as described in example 142, 3,5-dichloro-4-methylpyridine (1.887 mg, 11.65 mmoles), DMF (20 ml), NaH (466 mg, 11.65 mmoles), 793 mg of the title compound were obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[SH:10][CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][S:10][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: OCCS
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(SCCO)cc1

Procedure:
5 g of 4-fluorobenzonitrile was used in Procedure Q with 2-mercaptoethanol to afford 4-(2-hydroxyethylthio)benzonitrile. 900 mg of 4-(2-hydroxyethylthio)benzonitrile was reacted via Procedure T to give 4-(2-hydroxyethylthio)benzoic acid. 1.0 g of 4-(2-hydroxyethylthio)benzoic acid was reacted via Procedure R to give 4-(2-hydroxyethylsulfonyl)benzoic acid. 80 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-hydroxyethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxyethylsulfonyl)benzamide. MS (Q1) 417.0 (M)+.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([C@H:4]([C@@H:6]([C@@H:8](CO)[OH:9])[OH:7])[OH:5])[OH:3]>O.C(O)C>[CH2:1]([OH:12])[C@@H:2]([C@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Solvent: CCO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Yield: 119.7 %

Procedure:
The procedure of Example 1 was repeated except that 300 mg of mannitol was dissolved in a mixture of 10 mg of water and 10 mg of ethanol, the solution was subjected to wet granulation, and the resulting wet granules were dried and used as the sugar alcohol, not 300 mg of xylitol, to obtain an inventive rapidly disintegrating formulation tablet.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:19]=[CH:18][CH:17]=[C:11]2[C:12]([O:14][C:15](=[O:16])[C:10]=12)=O.Cl.[NH2:21][CH:22]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:23]1=[O:24]>CN(C=O)C>[O:24]=[C:23]1[CH:22]([N:21]2[C:15](=[O:16])[C:10]3[C:11](=[CH:17][CH:18]=[CH:19][C:9]=3[OH:8])[C:12]2=[O:14])[CH2:28][CH2:27][C:26](=[O:29])[NH:25]1
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C1OC(=O)c2c(O)cccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2C(=O)c3cccc(O)c3C2=O)C(=O)N1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Triethylamine (2.70 mL, 19.4 mmol) was added to a mixture of 3-hydroxyphthalic anhydride (3.00 g, 18.3 mmol) and rac-α-aminoglutarimide hydrochloride (3.01 g, 18.3 mmol) in DMF (60 mL). The reaction mixture was heated to 90° C. overnight, then cooled to room temperature and the solvent was evaporated under vacuum. The residue was stirred in CH2Cl2 (100 mL) for 30 min and the solvent was removed under vacuum. The residue was stirred in water (120 mL) for 2 h and the resulting solid was filtered, washed with water (50 mL) and dried. 1,4-Dioxane (200 mL) was added, and the resulting suspension was stirred for 16 h and filtered; the insoluble material was reserved. The filtrate was treated with decolorizing carbon (2 g) and heated to reflux for 1 h. After cooling to 50° C., the reaction mixture was filtered through Celite and the filter was washed with additional 1,4-dioxane (50 mL). The filtrate was combined with the insoluble precipitate and evaporated to dryness. The resulting solid was triturated with ethyl acetate (100 mL), filtered and dried to give 2-(2,6-dioxo-piperidin-3-yl)-4-hydroxy-isoindole-1,3-dione, 4.18 g, in 56% yield; 1H NMR (DMSO-d6) δ 1.99-2.06 (m, 1H), 2.45-2.61 (m, 2H), 2.82-2.96 (m, 1H), 5.08 (dd, J=12.6 Hz, J=5.3 Hz, 1H), 7.23-7.33 (m, 2H), 7.66 (dd, J=8.2 Hz, J=7.2 Hz, 1H), 1.10 (s, 1H), 1.19 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][Si](C)(C)C)[CH:15]=3)[C:10]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[N:9]2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=3)[C:10]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C(=O)c1nn(-c2ccnc(N)n2)c2cc(C#C[Si](C)(C)C)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc2c(C(=O)N(C)C)nn(-c3ccnc(N)n3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-N,N-dimethyl-6-[2-(trimethylsilyl)ethynyl]indazole-3-carboxamide (250 mg, 0.66 mmol) in methanol (5 mL) and DCM (10 mL) was added K2CO3(182.57 mg, 1.32 mmol). The reaction mixture was stirred for 1 hr and then filtered by suction filtration. The precipitate was washed with DCM and methanol and the filtrate was concentrated in vacuo to give the title intermediate: 1H NMR (250 MHz, DMSO) delta 3.08 (3H, s), 3.29 (3H, br. s.), 4.42 (1H, s), 7.06 (1H, d, J=5.63 Hz), 7.14 (2H, br. s.), 7.41-7.48 (1H, m), 7.97 (1H, d, J=8.22 Hz), 8.31 (1H, d, J=5.48 Hz), 9.04 (1H, s); LC-MS: m/z=+307.00 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]([F:16])([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:5]2.C[Mg]Br.[F:20][C:21]([Si](C)(C)C)([F:23])[F:22].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([C:21]([F:23])([F:22])[F:20])([OH:11])[C:6]([F:16])([S:12]([CH3:15])(=[O:13])=[O:14])[CH2:5]2
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CS(=O)(=O)C1(F)Cc2cc(Cl)ccc2C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Mg]Br
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)C1(F)Cc2cc(Cl)ccc2C1(O)C(F)(F)F

Procedure:
If 5-chloro-2-fluoro-2-methanesulfonylindan-1-one is, instead of methylmagnesium bromide, reacted with trifluoromethyltrimethylsilane and tetrabutylammonium fluoride in tetrahydrofuran, 5-chloro-2-fluoro-2-methyanesulfonyl-1-trifluoromethylindan-1-ol of molecular weight 332.7 (C11H9CIF4SO3); MS (ESI): 333.20 (MH+) is obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([Cl:16])=[O:12]
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2ccccc2s1
Yield: 23 %

Procedure:
Benzothiophene-2-carboxylic acid was treated with 1.5 equivalents of oxalyl chloride in dichloromethane in the presence of a catalytic amount of DMF to form benzothiophene-2-carbonyl chloride. Following procedures described for Example 1 and substituting this acyl chloride for 3-trifluoromethylbenzoyl chloride, compound 77 was prepared in 23% yield.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO>C(Cl)Cl.[O-2].[Mn+2].O=[Mn]=O>[N:1]1([C:7]2[C:8]3[N:16]=[C:15]([CH:17]=[O:18])[CH:14]=[CH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCc1ccc2ncnc(N3CCCCC3)c2n1
Agent: O=[Mn]=O
Agent: [Mn+2]
Agent: [O-2]
Solvent: CO
Solvent: ClCCl
Product: O=Cc1ccc2ncnc(N3CCCCC3)c2n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
[4-(1-piperidinyl)pyrido[3,2-d]pyrimidin-6-yl]methanol (Intermediate 1.6) (3.95 g; 16.2 mmol; 1.00 eq.) was dissolved in DCM (160 mL). The solution was cooled down to 0° C. and manganese oxide (16.5 g; 0.162 mol; 10 eq.) was added. The reaction was stirred 5 min at 0° C. then overnight at rt. To complete the conversion, MnO2 was added after 12 hours and 20 hours (two batches of 4.96 g; 48.48 mmol; 3 eq.). After 20 hours, the reaction was complete. MeOH (100 mL) was added and the mixture was filtered through Celite, and widely rinsed with DCM/MeOH 1:1 mixture. Solvents were removed under reduced pressure to give 4-(1-piperidinyl)pyrido[3,2-d]pyrimidine-6-carbaldehyde (Intermediate 1.7). This product was used in the next step without further purification. Amount: 4.1 g; Formula: C13H14ON4; HPLC Purity: 58.84%; LC-MS: M/Z ESI: Rt (min) 1.53; 243.06 (M+1); HPLC (H2O TFA 0.1%-ACN TFA 0.05%): Rt (min); Area %=1.39; 58.84. 1H NMR (DMSO-d6) δ 9.95 (s, 1H), 8.52 (s, 1H), 8.16 (m, 2H), 4.46 (l, 4H), 1.70 (l, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[N+:16]([O-])([OH:18])=[O:17].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)=[N:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(Oc2ncc(Cl)cn2)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Oc2ncc(Cl)cn2)ccc1O
Yield: 53.5 %

Procedure:
A solution of 4-(5-chloro-2-pyrimidyloxy)phenol (1.4 g) in acetic acid (20 ml) was treated with fuming nitric acid (0.5 g) at 25° C. After 4 hours the mixture was poured into water and extracted with chloroform (2×100 ml). The chloroform extracts were dried (Mg2O4) and evaporated to a yellow solid which was chromatographed on silica gel (40 g). Elution with chloroform gave 4-(5-chloro-2-pyrimidyloxy)-2-nitrophenol (0.9 g) as pale yellow crystals.