Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:24])=O>O1CCCC1>[Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:24])=[O:5]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Cl)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (157 mg, 0.705 mmol) produced in Example C61(v) in tetrahydrofuran (5 mL) were added N,N-dimethylformamide (20 μL) and oxalyl chloride (103 μL, 1.17 mmol), and the mixture was stirred at room temperature for 1.5 hr. The solvent was concentrated under reduced pressure to give 2-chloro-3-(1-cyano-1-methylethyl)benzoyl chloride. The present compound was dissolved in dimethylacetamide (5 mL), N-[5-(5-amino-2-methylphenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.587 mmol) produced in Example C47(i) was added, and the mixture was stirred at room temperature for 20 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and filtered through a pad filled with silica gel. The solvent was concentrated under reduced pressure, and the obtained the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→70/30), and recrystallized from ethyl acetate and tetrahydrofuran to give the title compound (204 mg, 64%) as white crystals.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:24])[CH2:4][C:5]1([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.I([O-])(=O)(=O)=[O:26].[Na+]>CC(C)=O.O.C(Cl)Cl>[OH:1][NH:2][C:3](=[O:24])[CH2:4][C:5]1([S:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][CH:12]=2)=[O:26])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(CC1(Sc2ccc(Oc3ccccc3)cc2)CCCC1)NO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C(CC1(S(=O)c2ccc(Oc3ccccc3)cc2)CCCC1)NO
Yield: 31.8 %

Procedure:
A solution of N-hydroxy-2-[1-(4-phenoxyphenylthio)-cyclopent-1-yl]-acetamide (45 mg) in acetone (4 ml) was treated with sodium periodate (260 mg) in water (2 ml). Over the course of 24 hours, two additional portions of sodium periodate (260 mg) were added. After complete disappearance of starting material the solution was diluted with methylene chloride, filtered, dried, and the solvent evaporated under reduced pressure. Preparative TLC on silica gel and elution with 10% methanol/methylene chloride gave N-hydroxy-2-[1-(4-phenoxyphenylsulfinyl)-cyclopent-1-yl]-acetamide (15 mg), PMR (CDCl3) 7.64 (d,2H), 7.44 (t,2H), 7.30-7.05 (m,5H), 2.97 (d,1H), 2.53 (d,1H), 2.15-1.65 (m,8H).
Reaction SMILES: [CH:1]([Cl:4])([Cl:3])[Cl:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].[OH-].[K+]>CN(C=O)C.CO>[Cl:2][C:1]([Cl:4])([Cl:3])[CH:10]([C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH3:5])[CH:8]=1)[OH:11]
Reactant: ClC(Cl)Cl
Reactant: COc1cccc(C=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cccc(C(O)C(Cl)(Cl)Cl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 1.8 mL (22.5 mmol) of chloroform in 10 mL DMF was added 1.4 g (10 mmol) of 3-methoxybenzaldehyde. The reaction mixture was chilled to 0° C. and a solution of 0.40 g (7 mmol) of potassium hydroxide in 1.8 mL of methanol was added. The reaction mixture was stirred for 3 h at 0° C., then quenched by addition of 1 mL of 1 N hydrochloric acid. The reaction mixture was adjusted to pH=7, then extracted with EtOAc. The organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:10](=[O:16])[C@@H:9]([CH2:17][C:18]([OH:20])=[O:19])[O:8][C@H:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:6]=2[CH:28]=1.[C:29]([O:35][CH2:36]Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].C(N(CC)CC(C)C)C(C)C.O>CN(C)C=O.C(OCC)(=O)C>[C:29]([O:35][CH2:36][O:19][C:18](=[O:20])[CH2:17][C@H:9]1[O:8][C@H:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[C:6]2[CH:28]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]([CH2:12][CH:13]([CH3:14])[CH3:15])[C:10]1=[O:16])(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC(C)CN1C(=O)[C@@H](CC(=O)O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Agent: CCN(CC(C)C)CC(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CN1C(=O)[C@@H](CC(=O)OCOC(=O)C(C)(C)C)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (10 ml) was dissolved trans- 7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (0.5 g) obtained in Example 2. To the solution were added pivaloyloxymethyl chloride (0.43 ml), N,N-diisobutyl ethylamine (0.52 ml) and KI (0.2 g). The mixture was stirred at room temperature overnight. To the reaction mixture were added water (100 ml) and ethyl acetate (100 ml), followed by extraction. The ethyl acetate layer was washed with an aqueous solution of potassium hydrogensulfate, an aqueous solution of sodium hydrogencarbonate and water, successively, which was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1) to afford trans-7-chloro-5-(2-chlorophenyl)-1-isobutyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid pivaloyloxymethyl ester (0.55 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH2:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.CO>CCOCC>[O:19]=[C:13]([NH:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C1CCC(=O)O1
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: CO
Solvent: CCOCC
Product: O=C(O)CCC(=O)NCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.2 %

Procedure:
A solution of 15.0 g (85.6 mmol) of (3-(trifluoromethyl)phenyl)methylamine in ether (40 ml) was added dropwise to a suspension of 7.5 g (85.6 mmol) of succinic anhydride in ether (450 ml) within 30 min. The mixture was then stirred for 72 h at room temperature. The deposit obtained was filtered and dried. After column chromatography (EE/MeOH 1:1) of the residue, 10.4 g (37.8 mmol, 44%) of 4-oxo-4-(3-(trifluoromethyl)benzylamino)butyric acid were obtained.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10](O)[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.Cl>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[C:10](=[C:10]3[C:9]4[CH:8]=[C:7]([CH3:16])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]=4[O:12][C:11]3=[O:14])[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2=C1C(=O)Oc2c1cc(C)cc2C(C)(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
22 g of 7-tert-butyl-3-hydroxy-5-methyl-3H-benzofuran-2-one (prepared as described in Example 2 of U.S. Pat. No. 5,614,572) are introduced in 50 ml of toluene as initial charge and admixed with 3 drops of DMF and 15 ml of thionyl chloride. The solution is then gradually heated to 100° C. so that the evolution of HCl and SO2 remains lively but still controllable. Thereafter the reaction mixture is stirred at 100° C. for a further 1 h. About 50 ml of liquid are subsequently distilled off to remove excess thionyl chloride. The residue is diluted with 160 ml of toluene and admixed at room temperature with 14 ml of triethylamine added dropwise. The thick red reaction mixture is then refluxed for 30 min. The precipitated triethylamine hydrochloride is filtered off after cooling to room temperature and the residue is concentrated in a rotary evaporator to an oily consistency. The isoxindigo is crystallized out by addition of 200 ml of acetonitrile, filtered off, washed with acetonitrile and dried to leave 11.6 g (57% of theory) of 7,7′-di-tert-butyl-5,5′-dimethyl[3,3′]bibenzofuranylidene-2,2′-dione of the formula:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6]1.[C:25]12[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=1)[NH:30]C(=O)O[C:26]2=[O:27]>>[NH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:25]=1[C:26]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][CH:8]([O:11][CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:10]1)=[O:27]
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: Nc1ccccc1C(=O)NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 66 %

Procedure:
Using the method similar to that in Reference Example 1 and using 1-(3-aminopropyl)-4-diphenylmethoxypiperidine instead of 4-methoxybenzylamine and starting from isatoic anhydride (2.87 g), the title compound (6.19 g, 66%) was synthesized. This product was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[C:12]2[C:19]([CH3:20])=[CH:18][S:17][C:13]=2[N:14]=[CH:15][N:16]=1.[H-].[Na+].[CH3:23]I.O>CN(C)C=O>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[N:10]([C:11]1[C:12]2[C:19]([CH3:20])=[CH:18][S:17][C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:23]
Reactant: Cc1csc2ncnc(NC3Cc4ccccc4C3)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc2ncnc(N(C)C3Cc4ccccc4C3)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A compound of the above Example 1, 4-(2-indanylamino)-5-methylthieno[2,3-d]pyrimidine (29 mg, 0.10 mmol), was dissolved in dry dimethylformamide (0.5 ml), to which sodium hydride (4.4 mg, 0.11 mmol) was added. After the mixture was stirred at room temperature for 10 minutes, methyl iodide (7.0 μl, 0.11 mmol) was added to the reaction mixture, which was further stirred at room temperature for 30 minutes. Water was added to the reaction mixture, which was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (20 mg, 0.070 mmol) having the following physical properties:
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6](=O)[CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]3[NH:25][C:24]4[C:23](=[O:26])[N:22]([CH2:27][CH2:28][CH3:29])[C:21](=[O:30])[N:20]([CH2:31][CH2:32][CH3:33])[C:19]=4[N:18]=3)([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)#[N:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Si]([N:58]=[N+:59]=[N-:60])(C)(C)C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:30]=[C:21]1[N:20]([CH2:31][CH2:32][CH3:33])[C:19]2[N:18]=[C:17]([C:12]34[CH2:15][CH2:16][C:9]([CH2:8][CH2:7][C:6]5[N:5]([CH2:4][CH2:3][C:1]#[N:2])[N:60]=[N:59][N:58]=5)([CH2:14][CH2:13]3)[CH2:10][CH2:11]4)[NH:25][C:24]=2[C:23](=[O:26])[N:22]1[CH2:27][CH2:28][CH3:29]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CCC(=O)NCCC#N)(CC3)CC4)nc2n(CCC)c1=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCc5nnnn5CCC#N)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 24 h
Yield: 3.8 %

Procedure:
A solution of N-(2-cyano-ethyl)-3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionamide (500 mg, 1.06 mmol, 1.0 eq), Ph3P (2.0 eq, 2.13 mmol, 560 mg), TMSN3 (2.0 eq, 2.13 mmol, 245 mg), and DEAD (2.0 eq, 2.13 mmol, 371 mg) in THF (10 ml) was stirred at rt for 24 h. The reaction vessel was re-charged with the reagent cocktail (2.0 eq, 2.13 mmol) and stirring was continued for an additional 24 h. The reaction was quenched by the addition of a 5% aqueous solution of (NH4)2Ce(NO3)6 and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated in vacuo to afford a viscous orange oil. A portion of the material was purified by preparative LC to afford 20 mg of pure material. MS: 494 (MH+).
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:20]=[C:19]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27]([C:31](=[O:34])[NH:32][CH3:33])[CH:26]=[CH:25]3)[CH:18]=[CH:17][N:16]=1)[C:3](=O)[O:4]C1C=CC([N+]([O-])=O)=CC=1.[NH3:35]>CN(C)C=O>[CH3:33][NH:32][C:31]([N:27]1[C:28]2[C:24](=[CH:23][C:22]([O:21][C:19]3[CH:18]=[CH:17][N:16]=[C:15]([N:2]([CH3:1])[C:3]([NH2:35])=[O:4])[CH:20]=3)=[CH:30][CH:29]=2)[CH:25]=[CH:26]1)=[O:34]
Reactant: N
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C)C(=O)Oc4ccc([N+](=O)[O-])cc4)c3)ccc21
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(N(C)C(N)=O)c3)ccc21
Temperature: 25 °C
Reaction time: 10.5 h
Yield: 48 %

Procedure:
4-Nitrophenyl N-methyl-(4-(1-methylcarbamoyl-indol-5-yloxy)pyridin-2-yl)carbamate (105 mg, 0.228 mmol) was dissolved in N,N-dimethylformamide (2.5 ml); aqueous ammonia (0.5 ml, 28.0%) was added thereto; the reaction mixture was stirred at room temperature for 10.5 hours. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crystals were suspended in ethanol:diethyl ether=1:1 (6 ml), filtered off, washed with diethyl ether, and dried to yield the title compound (37 mg, 0.11 mmol, 48%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2].[Cl:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:26][CH2:25][O:24][CH2:23][CH2:22][Cl:21])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCOCCCl
Reaction time: 24 h
Yield: 72 %

Procedure:
A mixture of 6.0 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester, 25 ml of bis(2-chloroethyl)ether and 2.2 g of anhydrous potassium carbonate in 150 ml of anhydrous acetone was stirred at reflux. After 24 hours, 2 g of potassium iodide and 50 ml of anhydrous dimethylformamide were added and reflux was continued. After 50 hours, 2.2 g of potassium carbonate and 2 g of potassium iodide were added and after 77 hours, 2.0 g of potassium carbonate was added. After a total reflux time of 108 hours, the reaction mixture was concentrated in vacuo and the residue was purified by high pressure liquid chromatography using 25% ethyl acetate-hexane to give 5.96 g (72% yield) of [4-acetyl-3-[2-(2-chloroethoxy)ethoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][CH3:18])[CH:10]=1)=[O:2].[CH2:19]1[CH2:23]OC[CH2:20]1>>[CH:20]1([CH:1]([OH:2])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][CH3:18])[CH:10]=2)[CH2:19][CH2:23]1
Reactant: COc1cc(-c2cnccc2C=O)ccc1C#N
Reactant: C1CCOC1
Product: COc1cc(-c2cnccc2C(O)C2CC2)ccc1C#N
Temperature: -36 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-formylpyridin-3-yl)-2-methoxybenzonitrile (100 mg, 0.42 mmol) in THF (4 mL) at −36° C. was added 0.5M c-PrMgCl in THF (2.27 mL, 1.13 mmol) dropwise and the mixture was stirred at −36° C. for 1 hr. The mixture was quenched with water at −36° C., silica gel was added, and the mixture was concentrated in vacuo. The residue was purified by silica chromatography eluting with a 40 to 100% EtOAc-heptane gradient. The product obtained was re-purified by Xbridge C18 eluting with a 10 to 100% acetonitrile-water gradient to give 4-(4-(cyclopropyl(hydroxy)methyl)pyridin-3-yl)-2-methoxybenzonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.13-−0.05 (m, 1H), 0.20-0.29 (m, 1H), 0.29-0.41 (m, 2H), 0.91-1.06 (m, 1H), 3.95 (s, 3H), 4.16 (dd, J=6.6, 4.3 Hz, 1H), 5.39 (d, J=4.5 Hz, 1H), 7.12 (dd, J=7.8, 1.3 Hz, 1H), 7.27 (d, J=1.3 Hz, 1H), 7.66 (d, J=5.3 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 8.42 (s, 1H), 8.62 (d, J=5.3 Hz, 1H). HRMS: (ESI) m/z 281.1280 [(M+H)+ Calcd for C17H16N2O2 281.1290].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH2:11][CH2:12][CH:13]=O)=[O:9])[NH:5][C:6]=1[Br:7]>CS(O)(=O)=O.CCOCC>[Br:7][C:6]1[NH:5][C:4]2[C:8](=[O:9])[NH:10][CH2:11][CH:12]=[CH:13][C:3]=2[C:2]=1[Br:1]
Reactant: O=CCCNC(=O)c1cc(Br)c(Br)[nH]1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: O=C1NCC=Cc2c1[nH]c(Br)c2Br
Yield: 67.4 %

Procedure:
A solution of 12 (1.0 g, 3.3 mmol) in 10 mL of methanesulfonic acid was stirred at room temperature for 7 d. The reaction mixture was diluted with ether (500 mL), washed with sat. NaHCO3 (100 mL×3) and sat. NaCl (100 mL). The organic layer was dried (MgSO4) and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (CH2Cl2/MeOH 19:1) to give 13 (0.68 g, 80%) as a colorless solid: mp 170-175° C.; 1H NMR (CD3OD) d 3.57 (d, 2H, J=6.4), 6.01 (dt, 1H, J=10.1, 6.4), 6.65 (d, 1H, J=10.1); (DMSO-d6) d 3.46 (dd, 2H, J=6.4, 4.9), 6.03 (dt, 1H, J=10.0, 6.4), 6.54 (d, 1H, J=10.0), 7.75 (t, 1H, J=4.9), 13.04 (s, 1H); 13C NMR (CD3OD) d 39.6 (e), 100.2 (e), 108.4 (e), 126.4 (o), 126.7 (e), 126.8 (o), 127.0 (e), 164.6 (e); IR (nujol) 3184, 1639, 1603, 1541 cm−1; UV (CH3OH) lmax 288, 227 nm; MS, m/z (relative intensity) 308 (M++4, 30), 306 (M++2, 60), 304 (M+, 30), 225 (100), 200 (80), 182 (40), 170 (40); HRMS, calcd for C8H6N2OBr2 (M+) 303.8847, found 303.8833. Anal. Calcd for C8H6N2OBr2: C, 34.41; H, 1.98; N, 9.16; Found: C, 34.75; H, 2.09; N, 9.07.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:10])[CH3:9])[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.[OH-].[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:4]=2[CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(C)O)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(C)=O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)ethanol (38B, 130 mg, 0.277 mmol) was taken up in DCM (2.87 ml) and Dess-Martin periodinane (141 mg, 0.332 mmol) was added. The reaction was allowed to stir at rt for 1 hr. The reaction was diluted with DCM (8 ml) and 1N NaOH was added (15 ml) and the mixture was allowed to stir. The organic phase was separated and the aqueous was washed with DCM (20 ml×3). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give 1-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)ethanone (Intermediate 39B). The products were carried forward without purification. MS: [M+H]+ m/z 468.
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]([NH:8][CH:9]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:10](=[O:23])[CH2:11][O:12][C:13](=[O:22])[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])=[O:7])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl.CS(C)=O>[C:1]([S:4][CH2:5][C:6]([NH:8][CH:9]([CH2:24][C:25]([OH:27])=[O:26])[C:10](=[O:23])[CH2:11][O:12][C:13](=[O:22])[C:14]1[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=1[Cl:20])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(=O)NC(CC(=O)OC(C)(C)C)C(=O)COC(=O)c1c(Cl)cccc1Cl
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)SCC(=O)NC(CC(=O)O)C(=O)COC(=O)c1c(Cl)cccc1Cl
Temperature: 0 °C

Procedure:
The product 26 was dissolved in 10 ml of dry DCM, cooled to 0° C., and treated with 9 ml trifluoroacetic acid (TFA). The reaction was then removed from the ice bath and allowed to warm to ambient temperature over a period of one hour. Solvent was removed under reduced pressure, and the residue redissoved twice in DCM and evaporated to remove residual TFA. The crude product 13 was purified by reverse-phase high-pressure liquid chromatography to yield 101.9 mg (0.234 mmol, 32% from 25) of white hygroscopic powder. Expected MW=436.37, found 437 (M+1). This was dissolved in dimethylsulfoxide (DMSO) to yield a 50 mM stock solution.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:14][CH:11]1[CH2:13][CH2:12]1)=[O:6]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1cccc(Br)c1
Yield: 86.4 %

Procedure:
By the reaction in the same manner as in Example 45-(i) using 3-bromobenzoyl chloride (5.50 g) and cyclopropylamine (4.30 g), the title compound (5.20 g) was obtained as colorless needle crystals.
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.C(=O)(O)[O-].[Na+].[C:26](Cl)(Cl)=[S:27]>C(Cl)(Cl)Cl.CCCCCC>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:26]=[S:27])[C:14]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:13][C:5]=2[N:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1nc2cc(N3CCOCC3)c(N)cc2s1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CC(C)(C)c1nc2cc(N3CCOCC3)c(N=C=S)cc2s1
Reaction time: 10 h

Procedure:
To a cooled mixture of 143 g of 6-amino-2-tert-butyl-5-morpholinobenzothiazole and 168 g of sodium bicarbonate in 200 ml of CHCl3 is added 75 g of thiophosgene under stirring. The stirring is continued at ambient temperature for 10 hours. The solide are filtered off and the filtrate is evaporated. The solid thus obtained is dissolved in hexane and filtered through a silica gel column. The filtrate is evaporated to give 2-tert-butyl-6-isothiocyanato-5-[morpholin-4-yl]benzothiazole melting at 141°-143°.