Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-])=O>[Pd].C(O)C>[NH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([N:2]([CH3:14])[CH3:1])=[O:13]
Reactant: CN(C)C(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CN(C)C(=O)c1ccccc1N
Reaction time: 12 h
Yield: 98.8 %

Procedure:
A mixture of N,N-dimethyl-2-nitrobenzamide (4.76 g, 24.5 mmol) and 10% palladium on carbon (470 mg) in 100 mL of ethanol was stirred under hydrogen at atmospheric pressure for approximately 12 hours. The mixture was filtered and concentrated to dryness to give 2-amino-N,N-dimethylbenzamide (4 g, 24.2 mmol), m.p. 53°-54° C.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:2]([N:6]([C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:7])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NN
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(N)C(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of t-butylhydrazine hydrochloride (1 g, 0.008M) in toluene (30 ml) at room temperature was added dropwise a 50% aqueous solution of sodium hydroxide (0.64 g, 0.008M). After 15 min., the reaction mixture was cooled to 5° C. and a solution of benzoyl chloride (1.12 g, 0.008M) in toluene (5 ml) and a solution of aqueous 50% sodium hydroxide (0.64 g, 0.008M) were added dropwise simultaneously from separate addition funnels while maintaining the temperature at or below 10° C. Following the addition, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction was diluted with hexane and the solid N'-t-butyl-N'-benzoylhydrazine was isolated by filtration.
Reaction SMILES: [C:1]1([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1(C)[CH:17]=CC(S(O)(=O)=O)=C[CH:13]=1>CC(C)=O>[CH3:13][C:12](=[N:11][NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[CH3:17]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NNS(=O)(=O)c1ccccc1
Solvent: CC(C)=O
Product: CC(C)=NNS(=O)(=O)c1ccccc1
Temperature: 20 °C

Procedure:
A four neck flask (1 liter) equipped with a thermometer, a reflux condenser and a stirrer was charged with 86 g (0.5 mol) of benzenesulfonohydrazide, 0.95 g (0.005 mol) of p-toluenesulfonic acid and 700 ml of acetone and then heated under reflux for about 5 hours. The reaction liquid was cooled down to 20° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby white crystal was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Br:15].I[C:17]1[CH:18]=[C:19]([C:23]2[C:28]3[S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:27]=3[CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>[Cu].C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Br:15])[C:21]1[CH:22]=[CH:17][CH:18]=[C:19]([C:23]2[C:28]3[S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:27]=3[CH:26]=[CH:25][CH:24]=2)[CH:20]=1
Reactant: Ic1cccc(-c2cccc3c2sc2ccccc23)c1
Reactant: Brc1ccccc1Nc1ccccc1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Brc1ccccc1N(c1cccc(-c2cccc3c2sc2ccccc23)c1)c1ccccc1Br
Temperature: 200 °C
Yield: 46.9 %

Procedure:
Bis(2-bromophenyl)amine (7.15 g, 21.86 mmol), 4-(3-iodophenyl)dibenzo[b,d]thiophene (9.29 g, 24.05 mmol), copper (0.695 g, 10.93 mmol), and K2CO3 (6.04 g, 43.7 mmol) were added into a 50 mL flask. The neat solids were heated at 200° C. for 36 hours. The mixture was then cooled. DCM (250 mL) was added to solubilize the organic products. The solution was filtered through a pad of Celite® and washed several times with DCM. The crude material was purified via column chromatography using hexane/DCM (85/15). The product collected from the column was triturated with methanol and filtered to afford 2-bromo-N-(2-bromophenyl)-N-(3-(dibenzo[b,d]thiophen-4-yl)phenyl)aniline (6.0 g, 10.25 mmol, 46.9% yield) as a yellowish powder.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]2)=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: CCCN1CCC(CN)CC1
Product: CCCN1CCC(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)CC1
Yield: 36.7 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.239 g, 1.0 mmol) and 4-aminomethyl-1-propylpiperidine (0.312 g, 2.0 mmol) according to the procedure used for Example 2 to give 0.145 g of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([CH:20]=O)[CH:16]=[N:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28].N1CCCCC1.Cl>C(O)C>[CH3:1][N:2]([CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([CH:20]=[C:26]3[S:22][C:23](=[O:28])[NH:24][C:25]3=[O:27])[CH:16]=[N:17]2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CSC(=O)N1
Reactant: CN(Cc1ccc2cc(C=O)cnc2c1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(Cc1ccc2cc(C=C3SC(=O)NC3=O)cnc2c1)c1ccccc1
Yield: 60.3 %

Procedure:
The above 7-(methylphenylamino)methylquinoline-3-carbaldehyde (222 mg, 0.8 mmol), 2,4-thiazolidinedione (105 mg, 0.8 mmol.), and piperidine (0.065 mL, 0.66 mmol) were suspended in ethanol (8 mL), and the mixture was heated under reflux overnight. The reaction mixture was cooled in an atmospheric condition, and to this was added 1N hydrochloric acid to adjust the solution to pH 1-2. The mixture was extracted with chloroform after addition of water (10 mL), washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=20/1), to give the desired compound as yellow crystalline powder (181 mg, yield: 60%).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:13][CH2:14][O:15][CH2:16][C:17]([O:19]C(C)(C)C)=O)[CH:12]=[CH:11][N:10]=[CH:9]1.C(N(C(C)C)CC)(C)C.[CH2:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH:34]1[NH:42][C:43]1[N:44]=[CH:45][C:46]2[CH2:52][NH:51][CH2:50][CH2:49][C:47]=2[N:48]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH:34]1[NH:42][C:43]1[N:44]=[CH:45][C:46]2[CH2:52][N:51]([C:17](=[O:19])[CH2:16][O:15][CH2:14][CH2:13][N:8]3[CH:12]=[CH:11][N:10]=[CH:9]3)[CH2:50][CH2:49][C:47]=2[N:48]=1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Reactant: CC(C)(C)OC(=O)COCCn1ccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COCCn1ccnc1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
Add trifluoroacetic acid (2 mL) dropwise to a solution of tert-butyl 2-(2-imidazol-1-ylethoxy)acetate (0.375 g; 1.0 equiv; 1.66 mmoles) in dichloromethane (10 mL). Stir at room temperature for 4 hours and then concentrate the mixture. Redissolve the remaining residue in dimethylformamide (5 mL) and add diisopropylethylamine (1.45 mL; 5 equiv; 8.31 mmoles) followed by N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.44 g; 1.0 equiv; 1.65 mmoles). Add O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.69 g; 1.1 equiv; 1.81 mmoles) and stir at room temperature for 16 hours. Pour the reaction mixture into saturated aqueous sodium bicarbonate solution (200 mL) and extract with dichloromethane (2×200 mL). Wash the combined organic extracts with saturated aqueous sodium bicarbonate solution (100 mL), dry over sodium sulfate, filter, and concentrate to give the crude product. Purify this residue by column chromatography (0 to 20% methanol in dichloromethane) to afford 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-2-[2-(1H-imidazol-1-yl)ethoxy]ethanone (0.152 g; 22%) as a light brown solid: MS (m/z): 419(M+1).
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C:17]([F:26])([F:25])[C:18]1[N:23]=[CH:22][C:21](O)=[CH:20][N:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][C:21]1[CH:20]=[N:19][C:18]([C:17]([F:26])([F:25])[F:16])=[N:23][CH:22]=1)(=[O:10])=[O:11]
Reactant: Oc1cnc(C(F)(F)F)nc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=S(=O)(Oc1cnc(C(F)(F)F)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Triflic anhydride (1.01 mL, 6.0 mmol) was added dropwise to a stirred mixture of 2-(trifluoromethyl)pyrimidin-5-ol (prepared according to U.S. Pat. No. 4,558,039) (0.82 g, 5.0 mmol), toluene (10 mL) and aqueous tripotassium phosphate (30% by weight, 10 mL) at ice-bath temperature (Frantz et al., Organic Letters, 2002, 4(26), 4717-4718). When the addition was complete the ice-bath was taken away and the solution was stirred at ambient temperature for 30 minutes. The clear phases were separated and the organic layer was washed with water, then brine. Drying of the organic phase over anhydrous sodium sulfate, filtration and concentration by rotary evaporation at room temperature afforded 2-(trifluoromethyl)-pyrimidine-5-yl trifluoromethanesulfonate as a colourless oil (1.38 g, 93%). B.p. 75-77° C. (10 mbar).
Reaction SMILES: [CH2:1]1COC[CH2:2]1.C([Mg]Br)C.[C:10]1([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[NH4+].[Cl-].O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:10]1([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[C:22]2([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:2][CH2:1]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C([C@@H]1CCCN1Cc1ccccc1)N1CCCC1
Reactant: C1CCOC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Mg]Br
Solvent: O
Product: c1ccc(CN2CCC[C@H]2C2(N3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a stirred solution of THF (50 mL) cooled to −78° C. was added ethyl magnesium bromide (11.6 mL, 34.8 mmol) followed by titanium(IV) isopropoxide (2.042 mL, 6.96 mmol) and then (2S)-1-(phenylmethyl)-2-(1-pyrrolidinylcarbonyl)pyrrolidine (1.619 g, 6.96 mmol). The mixture was allowed to warm to room temperature and stir for 2 h, and was then checked by LCMS. Greater than 40% of the starting material remained, and so the mixture was stirred overnight, and then checked by LCMS again. Greater than 20% of the starting material remained, and therefore an additional portion of ethyl magnesium bromide (5.8 mL, 17.4 mmol) was added, and the mixture was allowed to stir for 2 h and was checked by LCMS again. Greater than 5% of the starting material remained, and an additional portion of ethyl magnesium bromide (2.32 mL, 6.96 mmol) was added and the mixture was allowed to stir for 2 h. When the reaction was complete as determined by LCMS, the reaction mixture was diluted with sat. aq. NH4Cl (150 mL) and water (50 mL), and the resulting white solid precipitate was filtered off. The pH of the filtrate was adjusted to >12 with 6 N aq. NaOH. The aqueous solution was extracted with Et2O (3×100 mL), and the combined organic layers were dried over MgSO4 and concentrated in vacuo. This crude product was purified by flash chromatography (Combiflash, 0-100% ethyl acetate/hexanes, 1% triethylamine) to provide (2S)-1-(phenylmethyl)-2-[1-(1-pyrrolidinyl)cyclopropyl]pyrrolidine (1.0837 g, 57%). LCMS: (M+H)+: 271.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:20][CH:19]([CH2:21][NH:22]C(=O)OC(C)(C)C)[CH2:18]3)[CH:14]=[C:13]([NH:30][C:31]3[CH:36]=[N:35][CH:34]=[CH:33][N:32]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:22][CH2:21][CH:19]1[CH2:18][N:17]([C:15]2[N:16]=[C:11]([NH:10][C@H:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH3:9])[N:12]=[C:13]([NH:30][C:31]3[CH:36]=[N:35][CH:34]=[CH:33][N:32]=3)[CH:14]=2)[CH2:20]1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(CNC(=O)OC(C)(C)C)C2)n1)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(CN)C2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
80 mg of t-butyl (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methylcarbamate was dissolved in 4 ml of dichloromethane, and 0.8 ml of trifluoroacetic acid was added thereto, and the mixture solution was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 63 mg of the objective compound as a brown amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH:11]([CH3:13])[CH3:12])=[C:5]([N+:14]([O-])=O)[CH:4]=1.Cl[Sn]Cl.[BH4-].[Na+]>C1COCC1.CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH:11]([CH3:13])[CH3:12])=[C:5]([CH:4]=1)[NH2:14]
Reactant: COc1ccc(C#CC(C)C)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C#CC(C)C)c(N)c1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4-methoxy-1-(3-methylbut-1-ynyl)-2-nitrobenzene (Compound 134, 2.97 g, 13.6 mmol) in THF (45 ml) and EtOH (15 ml) at 0° C. was added SnCl2 (12.9 g, 68 mmol), followed by NaBH4 (3.1 g, 81.6 mmol) in three equal portions with one hour between each addition. The reaction was stirred at 0° C. for a total of 3.5 h and was quenched with aqueous ammonia, filtered through a pad of Celite, extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→20% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:27]=CC=1CC(O)=O)[CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][NH:18][C:19](=O)[CH2:20][CH2:21][C:22]([CH3:25])([OH:24])[CH3:23])[CH:13]=[CH:14][CH:15]=1)(O)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+].C1C[O:46][CH2:45][CH2:44]1>>[OH:46][CH2:45][C:44]1[CH:27]=[C:7]([CH:6]=[CH:5][C:4]=1[CH2:1][OH:2])[CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:25])([OH:24])[CH3:23])[CH:13]=[CH:14][CH:15]=1
Reactant: C1CCOC1
Reactant: CC(C)(O)CCC(=O)NCCc1cccc(OCc2ccc(CC(=O)O)c(CC(=O)O)c2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CC(C)(O)CCCNCCc1cccc(OCc2ccc(CO)c(CO)c2)c1
Reaction time: 1 h

Procedure:
350 mg (0.76 mmol) of 5-{[3-(3,4-bis-carboxymethylbenzyloxy)phenyl]ethylamino}-5-oxo-2-methylpentan-2-ol are dissolved in 10 ml of anhydrous THF and then 120 mg of lithium aluminium hydride (3.1 mmol) are added in two equal portions. After heating under reflux for 4 hours, the reaction medium is cooled and then sequentially treated with 120 l of water, 120 l of a 15% NaOH solution and then 360 l of water. After stirring for 1 hour, the reaction medium is filtered, concentrated and then purified by chromatography on a silica gel. A colourless oil is obtained (m=280 mg; Y=95%).
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1CC([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=O)C.C(C1C=CC=C(C(C)C)C=1CC(O)=O)(C)C.[CH:49]1[C:62]2[CH:61]([C:63](O)=[O:64])[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[O:54][C:53]=2[CH:52]=[CH:51][CH:50]=1>>[CH:59]1[C:60]2[CH:61]([C:63]([C:16]3[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=3)=[O:64])[C:62]3[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=3)[O:54][C:55]=2[CH:56]=[CH:57][CH:58]=1
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Agent: CC(C)c1cccc(C(C)C)c1CC(=O)O
Product: CC(C)c1ccc(C(=O)C2c3ccccc3Oc3ccccc32)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with xanthene-9-carboxylic acid, mp 180°-181° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:44]=[CH:43][C:16]([CH2:17][N:18]([CH2:32][C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=[CH:35][CH:34]=3)[C:19]3[CH:31]=[CH:30][C:22]4[O:23]C(C)(C)[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O[Li].O.[ClH:48].[Na+].[Cl-]>O1CCOCC1.O>[ClH:48].[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:44]=[CH:43][C:16]([CH2:17][N:18]([CH2:32][C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=[CH:35][CH:34]=3)[C:19]3[CH:31]=[CH:30][C:22]([OH:23])=[C:21]([CH:20]=3)[C:26]([OH:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3cccc4ccccc34)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3cccc4ccccc34)c3ccc(O)c(C(=O)O)c3)cc2)cc1
Temperature: 80 °C
Yield: 51 %

Procedure:
To a solution of 6-[{4-[(4-butylphenyl)ethynyl]benzyl}(1-naphthylmethyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (72 mg, 0.12 mmol) in dioxane (2 ml) was added a solution of LiOH hydrate (25 mg, 0.60 mmol) in water (0.2 mL). The reaction mixture was heated at 80° C. for 2 hrs. Then a solution of HCl in dioxane (1 mL, 4N) and a saturated aqueous solution of NaCl (5 mL) were added and extracted with Et2O (2×10 mL). The combined organic layers were dried over Na2SO4 and the solvents were removed under reduced pressure. The residue was dissolved in a solution of HCl in Et2O (1 mL, 1N) and DCM (1 mL). Evaporation of the solvent under reduced pressure gave 41 mg (51%) of the title compound as a beige foam. HPLC, Rt: 5.8 min (purity: 82.7%). LC/MS, M+(ESI): 540.3, M−(ESI): 538.3. 1H NMR (CD3OD) δ: 7.97 (m, 3H), 7.72 (m, 1H), 7.58-7.41 (m, 11H), 7.23 (d, J=8.3 Hz, 2H), 6.92 (d, J=9.0 Hz, 1H), 5.42 (s, 2H), 5.11 (s, 2H), 2.67 (t, J=7.5 Hz, 2H), 1.64 (m, 2H), 1.38 (m, 2H), 0.98 (t, J=7.4 Hz, 3H).
Reaction SMILES: [N:1](/[C:4](=[CH:10]\[C:11]1[S:15][CH:14]=[N:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-]>C1(C)C=CC=CC=1>[S:15]1[C:11]2[CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:1][C:12]=2[N:13]=[CH:14]1
Reactant: CCOC(=O)/C(=C/c1cncs1)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2scnc2[nH]1
Temperature: 120 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
(Z)-ethyl 2-azido-3-(thiazol-5-yl)acrylate (9 g, 40.18 mmol) was dissolved in anhydrous toluene (100 mL), and the resulting reaction was allowed to stir for 2 hours at 120° C. The reaction mixture was concentrated and purified by column chromatograph on silica gel eluted with (petrol ether/acetic ester 15:1→10:1→8:1) to give the title compound (5 g, 63.5%) as an yellow solid. LCMS (M+H+) m/z: calcd. 196.03. found 196.9.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][C:5]([NH:15][CH2:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:28])[CH:26]=[CH2:27])[CH2:21][CH2:20]2)=[O:18])=[C:4]([O:29]C)[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][C:5]([NH:15][CH2:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:28])[CH:26]=[CH2:27])[CH2:21][CH2:20]2)=[O:18])=[C:4]([OH:29])[CH:3]=1
Reactant: C=CC(=O)N1CCN(C(=O)CNc2cc(-c3ccccc3Cl)c(Cl)cc2OC)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=CC(=O)N1CCN(C(=O)CNc2cc(-c3ccccc3Cl)c(Cl)cc2O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
To a solution of 1-(4-(2-(4-chloro-5-(2-Chlorophenyl)-2-methoxyphenylamino)acetyl)piperazin-1-yl)prop-2-en-1-one (70 mg, 0.147 mmol) in DCM (15 mL)-78° C. under argon, BBr3 (187 mg, 0.754 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was poured into ice water and extracted ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=40:1) to afford the desired product (15 mg, 24% yield). 1H NMR (400 MHz, DMSO-d6) δ: 10.08 (s, 1H), 7.53-7.51 (m, 1H), 7.41-7.37 (m, 2H), 7.30-7.28 (m, 1H), 6.84-6.77 (m, 2H), 6.48 (s, 1H), 6.12 (dd, J=2.4, 16.4 Hz, 1H), 5.70 (dd, J=2.0, 10.4 Hz, 1H), 5.24 (t, J=4.0 Hz, 1H), 3.90 (d, J=4.4 Hz, 2H), 3.56-3.49 (m, 8H). ESI-MS m/z: 434.2[M+H]+.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[S:13][C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH:18]=[C:17]4[C:33]3[N:38]=[C:37]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[C:41](=[O:46])[CH2:40]4)[CH:36]=[CH:35][CH:34]=3)=[N:11][N:10]=2)=CC=1.[OH-].[K+].COC1C=CC(CNC2SC(C3C=C4C(=CC=3)NC=C4C3N=C(N4CCN(C)C(=O)C4)C=CC=3)=NN=2)=CC=1.C(O)(C(F)(F)F)=O>O1CCOCC1.O>[NH2:8][C:9]1[S:13][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[C:17]3[C:33]2[N:38]=[C:37]([N:39]3[CH2:44][CH2:43][N:42]([CH3:45])[C:41](=[O:46])[CH2:40]3)[CH:36]=[CH:35][CH:34]=2)=[N:11][N:10]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(N5CCN(C)C(=O)C5)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Agent: COc1ccc(CNc2nnc(-c3ccc4[nH]cc(-c5cccc(N6CCN(C)C(=O)C6)n5)c4c3)s2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2cccc(-c3c[nH]c4ccc(-c5nnc(N)s5)cc34)n2)CC1=O
Temperature: 80 °C
Yield: 42.1 %

Procedure:
A glass microwave reaction vessel was charged with 4-(6-(5-(5-(4-methoxybenzylamino)-1,3,4-thiadiazol-2-yl)-1-tosyl-1H-indol-3-yl)pyridin-2-yl)-1-methylpiperazin-2-one (350 mg, 0.515 mmol) in p-dioxane (6 mL) followed by aq. 1 M KOH (2.5 mL, 2.500 mmol). The reaction was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 80° C. for 15 min. The mixture was diluted with H2O and extracted with DCM. The combined organic layers were dried, filtered and concentrated to give the crude product. MS (ESI, pos. ion) m/z: 526 (M+1). A glass microwave reaction vessel was charged with crude 4-(6-(5-(5-(4-methoxybenzylamino)-1,3,4-thiadiazol-2-yl)-1H-indol-3-yl)pyridin-2-yl)-1-methylpiperazin-2-one (271 mg, 0.516 mmol) and TFA (5.00 mL, 67.3 mmol). The reaction was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 40 min, then the solvent was removed. The residue was purified with RP-HPLC to give 4-(6-(5-(5-amino-1,3,4-thiadiazol-2-yl)-1H-indol-3-yl)pyridin-2-yl)-1-methylpiperazin-2-one (88.0 mg, 0.217 mmol, 42.1%). MS (ESI, pos. ion) m/z: 406 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.70 (1H, d, J=2.0 Hz), 8.79 (1H, d, J=1.6 Hz), 8.11 (1H, d, J=2.5 Hz), 7.71 (1H, dd, J=8.4, 1.8 Hz), 7.59 (1H, t, J=7.9 Hz), 7.50 (1H, d, J=8.6 Hz), 7.27 (2H, s), 7.22 (1H, d, J=7.4 Hz), 6.62 (1H, d, J=8.2 Hz), 4.12 (2H, s), 4.06 (2H, t, J=5.4 Hz), 3.58 (2H, t, J=5.3 Hz), 2.96 (3H, s).