Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.CN(C=O)C.C(Cl)(=O)[C:15]([Cl:17])=O.[N+](=C)=[N-]>C(Cl)Cl.CCOCC>[Cl:17][CH2:15][C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:8]
Reactant: O=C(O)c1ccoc1
Reactant: O=C(Cl)C(=O)Cl
Agent: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CCl)c1ccoc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under N2, 3-furoic acid (25 g, 0.22 mmol) was dissolved in CH2Cl2 (200 mL) and DMF (few drops) then oxalyl chloride (23.9 mL, 0.27 mmol) was added at 0° C. The resulting solution was stirred at 0° C. for 15 min. and at r.t. for 30 min. The solvent was evaporated. To the acid chloride (3.1 g, 24 mmol) in Et2O (20 mL) at r.t. was added an ethereal solution of diazomethane until the reaction was completed by T.L.C. The reaction mixture was cooled to 0° C. and HCl (g) was bubbled in for 20 min.. Excess HCl (g) was removed by bubbling N2 into the solution for 2 h. The resulting solution was washed with a saturated solution of NaHCO3 (2×), brine, dried over MgSO4 and then concentrated. Flash chromatography of the residue with hexane:EtOAc 9:1 as eluent afforded the title compound as a white solid.
Reaction SMILES: [OH:1][CH:2]([CH2:15][NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][C:6]=1I.[C:21]1([C:27]#[CH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOCC>C(N(CC)CC)C.C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH2:1].[OH:1][CH:2]([CH2:15][NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][C:6]=1[C:28]#[C:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)NCC(O)COc1ccc(C(N)=O)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)NCC(O)COc1ccc(C(N)=O)cc1C#Cc1ccccc1
Product: O
Yield: 65.2 %

Procedure:
A solution of 3.75 g (9.57 mmoles) of 4-(2-hydroxy-3-[(1,1-dimethylethyl)amino]propoxy]-3-iodobenzamide, 1.6 ml (14.35 mmole) of phenylacetylene, 0.036 g (0.048 mmole) of (Ph3P)2PdCl2 and 0.018 g (0.0957 mmole) of copper (I) iodide in 20 ml of triethylamine and 10 ml of THF (which had been deoxygenated by admission of N2) was stirred at 25° C. under N2 for one hour. It was heated at 60° for 3 hr. The precipitate which formed on cooling was collected by filtration and dried in vacuo. A fumarate salt was prepared in MeOH solvent and ether was added. A total of 3.0 g was collected by filtration in two crops. The solid was stirred with dilute NaOH and the crystalline free base was collected by filtration. The solid was recrystallized from CH3CN to give 1.2 g of crystalline 4-[2-hydroxy-3-[(1,1 -dimethylethyl)amino]propoxy]-3-(phenylethynyl)benzamide hydrate (4:1), mp 167°-169° C.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([NH:21]C(=O)OC(C)(C)C)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[CH:13]=3)[CH:6]=[CH:5][N:4]=1.[ClH:30].C(OCC)C>ClCCl.O1CCOCC1>[ClH:30].[NH2:21][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[CH:13]=2)[CH:18]=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([N:2]([CH3:1])[CH3:29])[N:8]=2)[CH:10]=1
Reactant: COc1ccc2cc(-c3ccnc(N(C)C)n3)cc(NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2cc(-c3ccnc(N(C)C)n3)cc(N)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl (3-(2-(dimethylamino)pyrimidin-4-yl)-7-methoxynaphthalen-1-yl)carbamate (140) (261 mg, 0.66 mmol) in dichloromethane (5 ml) was added 4 M hydrochloric acid in dioxane (2 ml). The mixture was stirred at room temperature for 24 hours. Diethylether (100 ml) was added and the solid filtered off and dried under vacuum to give 4-(4-amino-6-methoxynaphthalen-2-yl)-N,N-dimethylpyrimidin-2-amine (141) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1CCN2C(=NCCC2)CC1.O>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]([C:9]#[N:10])=[C:6]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1
Reactant: Oc1ccccc1
Reactant: CSc1nc(N)nc(Br)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: COCCOC
Product: CSc1nc(N)nc(Oc2ccccc2)c1C#N
Reaction time: 16 h
Yield: 75.9 %

Procedure:
To a stirred suspension of 500 mg (2.04 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile in 5 ml DME were added 192 mg (2.04 mmol) phenol and 0.31 ml (2.04 mmol) DBU and stirring continued for 16 hours at room temperature. 15 ml water was then added and the resulting crystals collected by filtration and triturated in hexane to afforded 400 mg (76%) 2-amino-4-methylsulfanyl-6-phenoxy-pyrimidine-5-carbonitrile as a light yellow crystalline solid. EI-MS m/e (%): 258 (M+, 100).
Reaction SMILES: [CH2:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:5][C:4](=[O:12])[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:27][CH2:28][CH2:29]Cl)=[CH:22][CH:21]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)=[CH:27][CH2:28][CH2:29][N:9]2[CH2:10][CH2:11][C:6]3([O:5][C:4](=[O:12])[N:3]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:2]3=[CH2:1])[CH2:7][CH2:8]2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(C(=CCCCl)c2ccc(F)cc2)cc1
Reactant: C=C1N(c2ccccc2)C(=O)OC12CCNCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: C=C1N(c2ccccc2)C(=O)OC12CCN(CCC=C(c1ccc(F)cc1)c1ccc(F)cc1)CC2
Reaction time: 12 h
Yield: 83.5 %

Procedure:
A mixture containing 8.4 g of 4-methylene-2-oxo-3-phenyl-1-oxa-3,8-diazaspiro[4,5]decane, 18.4 g of 4,4-bis(4-fluorophenyl)-3-butenyl chloride, 0.3 g of potassium iodide, 9.2 g of anhydrous potassium carbonate and 81 ml of methyl isobutyl ketone is mildly refluxed under argon while stirring for 12 hours. After cooling down and filtering off the inorganic salts, the precipitate is washed with methyl isobutyl ketone, the filtrate is washed with water to neutral, dried over anhydrous magnesium sulfate, then the solvent is evaporated under reduced pressure. After triturating the evaporation residue with n-hexane, the precipitate is filtered and recrystallized from ethanol to give the title compound in 83.5% yield, m.p.: 136.5°-137.5° C.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH:28]1([S:31]([O-:33])=[O:32])[CH2:30][CH2:29]1.[Na+].CNCCNC>CS(C)=O>[CH:28]1([S:31]([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][O:7][CH2:8][C@@H:9]3[CH2:11][C@@H:10]3[CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=4)[CH2:14][CH2:13]3)=[CH:4][CH:3]=2)(=[O:33])=[O:32])[CH2:30][CH2:29]1
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(Br)cc3)CC2)nc1
Reactant: O=S([O-])C1CC1
Agent: CNCCNC
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(S(=O)(=O)C4CC4)cc3)CC2)nc1
Temperature: 120 °C

Procedure:
The product of example 54 (step A) (100 mg, 0.2 mmol), sodium cyclopropanesulfinate (36 mg, 0.28 mmol), copper (I) trifluoromethanesulfonate benzene complex (6 mg, 0.012 mmol), and N,N′-dimethylethylenediamine (2 mg, 0.02 mmol) were dissolved in DMSO (1 mL), and the solution was heated at 120° C. The solution was partitioned between water and Et2O. The aqueous layer was extracted with Et2O. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography (2/1 EtOAc/hexanes) to provide the title compound. MS (ESI) m/z 456 [M+H]+. GPR119 Human EC50: 1.2 nM
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.[H-].[Na+]>CCOCC.CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:10]#[N:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: N#CC1(c2ccc(Cl)c(Cl)c2)CCOCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3,4-Dichlorophenylacetonitrile (10.00 g, 53.8 mmol) and bis(2-bromoethyl)ether (12.5 g, 53.8 mmol) were dissolved in ether and added dropwise via addition funnel to a suspension of NaH (60% dispersion in mineral oil; 6.45 g, 161 mmol) in 1-methylpyrrolidone (108 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and was then allowed to warm to ambient temperature. The reaction was then quenched with water. 5N HCl was added, and the reaction mixture was diluted with 200 mL of diethyl ether, added to a separatory funnel, washed 2 times with 100 mL of ether, separated, dried over Na2SO4, and concentrated in vacuo to give the purified title compound (7.97 g) after flash chromatography.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([C:15](=O)[CH3:16])=[CH:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1)[CH2:2][CH3:3].Cl.[NH2:19][OH:20].N1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:1]([O:4][C:5]1[C:6]([C:15](=[N:19][OH:20])[CH3:16])=[CH:7][C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1)[CH2:2][CH3:3]
Reactant: CCCOc1cc2c(cc1C(C)=O)CCCC2
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCOc1cc2c(cc1C(C)=NO)CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
1-(3-Propoxy-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone (8.88 g, 38.2 mmol) was dissolved in a mixed solvent of chloroform (20 ml) and methanol (80 ml). Hydroxylamine hydrochloride (4.05 g, 58.2 mmol) and pyridine (9.46 ml, 117 mmol) were added to the solution and stirred for 16 hours while heating under reflux. The reaction mixture was cooled to room temperature, and then concentrated to dryness under reduced pressure. 2N hydrochloric acid (30 ml) and water were added to the residue, followed by extraction using dichloromethane. The thus-obtained organic layer was concentrated to dryness under reduced pressure, and the residue was then purified using silica gel column chromatography (n-hexane:ethyl acetate=5:1). The purified product was concentrated to dryness under reduced pressure, giving a pale yellow powder of 1-(3-propoxy-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone oxime (8.87 g, yield: 94%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CSc1ccc(O)cc1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CSc1ccc(OCCC(C)C)cc1
Temperature: 25 °C

Procedure:
To stirred solution of (4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, 10 mmol), K2CO3(anhydrous, 10 g) and 1-bromo-3-methyl butane (3 g, excess) was added in boiling acetone. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. The reaction mixture was filtered and concentrated. The residue obtained was extracted with chloroform; washed well with water and concentrated. The crude product obtained was taken to next step with out purification. Yield 2.7 g (94%); (M+H)+ 283.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24].[C:27](Cl)(=[O:29])[CH3:28]>>[C:27]([N:20]1[CH2:21][CH2:22][CH:17]([NH:16][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:6]([Cl:26])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[C:10]([N+:23]([O-:25])=[O:24])[CH:11]=2)=[O:15])[CH2:18][CH2:19]1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CC(=O)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 199 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(piperidin-4-yl)thiophene-2-carboxamide (0.2 g, 0.46 mmol) and acetyl chloride (53.0 mg, 0.69 mmol). The title compound was obtained as a solid (75 mg, 35% yield). 1H NMR (400 MHz, d6-DMSO) δ:8.98 (2H, m), 8.67 (1H, m), 8.48 (1H, s), 4.28 (1H, m), 3.89 (1H, m), 3.80 (1H, m), 3.61 (1H, m), 3.13 (1H, m), 2.70 (1H, m), 2.00 (3H, s), 1.83 (1H, m), 1.76 (1H, m), 1.41 (1H, m), 1.28 (1H, m). MS m/z: 473.23, 475.25 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:8]3=[N:13][S:14][N:15]=[C:7]3[CH:6]=[CH:5][C:4]=2[N:3]=1.[N+:16]([O-])([O-:18])=[O:17].[K+]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:8]3=[N:13][S:14][N:15]=[C:7]3[C:6]([N+:16]([O-:18])=[O:17])=[CH:5][C:4]=2[N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1nc2ccc3nsnc3c2nc1O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2nsnc12
Temperature: 0 °C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
To a solution of 0,4 g (1,8 mmol) 7,8-dihydroxy-1,2,5-thiadiazolo(3,4-f)quinoxaline in 20 ml concentrated sulfuric acid was added at 0° C. 0,19 g (1,9 mmol) potassium nitrate. Stirring was continued at 0° C. for 30 min. and at 25° C. for 24 h. The reaction mixture was poured into 100 ml ice-water to give 0,34 g (71%) 7,8-dihydroxy-4-nitro-1,2,5-thiadiazolo(3,4-f)quinoxaline as a precipitate, m.p.>300° C. NMR (DMSO-d6) 12,3 (1H, broad s), 11.6 (1H, broad s), 8.43 (1H,s).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:24]([CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)O)[CH:8]=2)[N:3]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:15]1[CH2:16][CH2:17][N:12]([C:11]2[C:2]([NH2:1])=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:6][CH:5]=3)[CH2:13][CH2:14]1
Reactant: Nc1nc2ccc(-c3ccccc3C(O)C3CCOCC3)cc2cc1N1CCOCC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2ccc(-c3ccccc3CC3CCOCC3)cc2cc1N1CCOCC1
Temperature: 70 °C

Procedure:
(2-(2-Amino-3-morpholinoquinolin-6-yl)phenyl)(tetrahydro-2H-pyran-4-yl)methanol (0.085 g, 0.203 mmol, see Example 12) was dissolved in DCM (20 mL) and treated with triethylsilane (1.0 mL, 6.26 mmol) and TFA (2.0 mL, 26.9 mmol). The mixture was heated to 70° C. for 30 min after which analysis showed the reduction was complete. The solution was evaporated to dryness under reduced pressure. The crude was partitioned between water (10 mL), saturated sodium bicarbonate (10 mL) and DCM (20 mL). The organic layer was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (0-10% methanol in DCM gradient) gave the desired 3-morpholino-6-(2-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)quinolin-2-amine. MS (ESI, pos. ion) m/z: 404 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([S:28]([NH:31][NH2:32])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[O:21]=[C:19]([NH:32][NH:31][S:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:29])=[O:30])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=1
Reactant: NNS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)NNS(=O)(=O)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (200 mg, 0.7 mmol), benzenesulfono hydrazide (179.8 mg, 1.04 mmol) and HATU (397.02 mg, 1.04 mmol) dissolved in DMF (7.0 ml), N,N-diisopropylethylamine (DIPEA)(0.1819 ml, 1.04 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=2:1) and dried so that ivory (E)-tert-butyl 3-(3-oxo-3-(2-(phenylsulfonyl)hydrazinyl)prop-1-enyl)-1H-indole-1carboxylate was obtained (56.2 mg, 16.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([C:32]([O:34][CH3:35])=[O:33])([C:28]([O:30][CH3:31])=[O:29])[CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].FC(F)(F)C(O)=O.Cl>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]2[C:17]3[C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[CH2:15][C:14]([C:32]([O:34][CH3:35])=[O:33])([C:28]([O:30][CH3:31])=[O:29])[CH2:13][C:5]=2[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C(Cc1cc(OC)c(OC)c(OC)c1)(Cc1cc(OC)c(OC)c(OC)c1)C(=O)OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(C(=O)OC)Cc2cc(OC)c(OC)c(OC)c2-c2c(cc(OC)c(OC)c2OC)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Dissolved in 4 ml of dichloromethane were 200 mg (0.41 mmol) of dimethyl 1,3-bis(3,4,5-trimethoxyphenyl)propane-2,2-dicarboxylate. The solution was added with 0.4 ml of trifluoroacetic acid and 580 mg (1.25 mmol) of ferric perchlorate, followed by stirring at room temperature for 2 hours. After the reaction mixture was added with 2N-HCl and then dissolved in 20 ml of ethyl acetate, the water layer was removed. The organic layer was washed with water and then with saturated NaHCO3, and then was dried over anhydrous magnesium sulfate. The solvent was thereafter distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (silica gel: "MERCK #9385", 10 g, eluent: 1:1 mixed solvent of ethyl acetate and hexane), whereby 183 mg of the title compound were obtained as a colorless solid (yield: 92%).
Reaction SMILES: [NH:1]([C:3](=[S:5])[NH2:4])[NH2:2].Cl[C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>N1C=CC=CC=1>[NH2:4][C:3]([NH:1][NH:2][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[S:5]
Reactant: NNC(N)=S
Reactant: CCOC(=O)CC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)NNC(N)=S
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.9 %

Procedure:
To a suspension of hydrazinecarbothioamide (15.0 g, 165 mmol) in pyridine (100 mL) was added dropwise ethyl 3-chloro-3-oxopropanoate (24.8 g, 165 mmol) over 30 min at 0° C., and the reaction solution was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and methanol was added to the residue. The resulting solid was filtered off, the filtrate was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, THF and saturated aqueous ammonium chloride solution. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over sodium sulfate, and concentrated. The residue was crystallized from ethyl acetate and isopropyl ether, and the obtained crystals were washed with isopropyl ether, and dried to give the title compound (14.2 g, 42%).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:32]
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2ccccc2Cl)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (70 mg, 0.206 mmol), (2-chlorophenyl)acetic acid (35.2 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at room temperature for overnight. LCMS showed reaction was completed. The reaction was poured into water, off-white solid formed. The solid was filtered to give 3-{1-[(2-chlorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28-3.30 (m, 2H), 3.94 (s, 3H), 4.02 (s, 2H), 4.32 (t, J=8.46 Hz, 2H), 7.31-7.37 (m, 2H), 7.40-7.45 (m, 2H), 7.46-7.49 (m, 1H), 7.53 (s, 1H), 8.15 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([OH:3])=O.C(Cl)(=O)[C:24]([Cl:26])=O.CN(C)C=O.Cl.O1CCOCC1>C(Cl)Cl>[CH2:16]([C@H:5]([CH2:4][C:1]([CH2:24][Cl:26])=[O:3])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CCl)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
The resultant acid from Example 23 (500 mg, 1.68 mmol) in CH2Cl2 (8 ml) at 0° C. was treated with oxalyl chloride (0.160 ml, 1.83 mmol) and dimethylformamide (0.0065 ml). After 2 h at 0° C., the solvent was evaporated and the residue was dissolved in ether (6 ml), cooled to 0° C. and treated with an ether solution of CH2N2. After 2 h at 0° C. the solvent was evaporated and the residue was dissolved in ether (6 ml), cooled to -10° C., and treated with 4.0M HCl/ dioxane (0.6 ml, 2.4 mmol). After 1 h the solvent was evaporated and the residue was chromatographed on silica gel with 10% ethyl acetate in hexane to afford 476.8 mg (83%) of a colorless oil. 1H NMR (CDCl3) δ7.08-7.40 (m,10H), 5.12 (d,1H), 5.08 (d,1H), 4.02 (s,2H), 3.30 (m,1H), 3.10 (dd,1H), 2.97 (dd,1H), 2.78 (dd,1H), 2.55 (dd,1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[NH2:7].[C:9]([CH:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:13](OC)=[O:14])(=O)[CH3:10]>C1(C)C(C)=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[C:3]([CH3:8])=[N:4][N:5]2[C:13]([OH:14])=[C:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:9]([CH3:10])=[N:7][C:6]=12
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Reactant: Cc1n[nH]c(N)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)Cc1c(C)nc2c(Cl)c(C)nn2c1O
Yield: 57.5 %

Procedure:
To a solution of 4-chloro-3-methyl-1H-pyrazol-5-amine (0.263 g, 2 mmol) and dimethyl 2-acetylsuccinate (1.3 g, 6 mmol) in xylene (50 mL) was added p-toluenesulfonic acid monohydrate (4 mg, 0.02 mmol). The reaction mixture was heated at reflux under a Dean-Stark trap for 2 hrs. The solid was filtered and washed by hexanes to afford (0.31 g, 58%) of the title compound. 1H-NMR (500 MHz, DMSO-d6) δ ppm 2.28 (s, 3H), 2.33 (s, 3H), 3.54 (s, 2H), 3.61 (s, 3H).