Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][N:17]([C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[CH:29][CH:28]=3)[S:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:20])=[O:19])=[CH:13]2)=[CH:8][CH:7]=1)(=[NH:5])[NH2:4].Cl.[C:41](=[NH:46])(OCC)[CH3:42].C(N(CC)CC)C>C(O)C>[ClH:1].[ClH:1].[C:41]([N:36]1[CH2:37][CH2:38][CH2:39][N:33]([C:30]2[CH:31]=[CH:32][C:27]([N:17]([CH2:16][C:12]3[CH:11]=[CH:10][C:9]4[C:14](=[CH:15][C:6]([C:3](=[NH:4])[NH2:5])=[CH:7][CH:8]=4)[CH:13]=3)[S:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:20])=[O:19])=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)(=[NH:46])[CH3:42]
Reactant: CCOC(C)=N
Reactant: CCOC(=O)CS(=O)(=O)N(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(N2CCCNCC2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CS(=O)(=O)N(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(N2CCCN(C(C)=N)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.4 %

Procedure:
590 mg of ethyl [N-[(7-amidino-2-naphthyl)methyl]-N-[4-(hexahydro-1H-1,4-diazepin-1-yl)phenyl]sulfamoyl]-acetate dihydrochloride obtained in Example 6 was dissolved in 22 ml of ethanol, to which were added 680 mg of ethyl acetimidate hydrochloride and 555 mg of triethylamine, and stirred at room temperature for 15 hours. The reaction mixture was evaporated, and the resulting residue was purified through ODS column chromatography using an eluent solvent of ethanol/water (10/90). A small amount of 1 N hydrochloric acid was added to this, which was then freeze-dried to obtain 118 mg of ethyl [N-[4-(4-acetimidoylhexahydro-1H-1,4-diazepin-1-yl)phenyl]-N-[(7-amidino-2-naphthyl)methyl]-sulfamoyl]acetate dihydrochloride.
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[C:7]([O:11]C)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]([S:23][CH3:24])=[S:22])[CH2:17][CH2:16]1.O.C(=O)([O-])O.[Na+]>ClCCl.B(Br)(Br)Br>[OH:2][C:3]1[C:8]([OH:9])=[C:7]([OH:11])[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][N:18]([C:21]([S:23][CH3:24])=[S:22])[CH2:19][CH2:20]1
Reactant: COc1ccc(CCN2CCN(C(=S)SC)CC2)c(OC)c1OC
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CSC(=S)N1CCN(CCc2ccc(O)c(O)c2O)CC1
Reaction time: 8 h
Yield: 31.7 %

Procedure:
In 14 ml of dry dichloromethane was dissolved 1 ml of boron tribromide 9.3 ml of the resulting solution containing 665 mmol. of boron tribromide was chilled to -50° C. in a nitrogen atmosphere. To the chilled solution was dropwise added a solution of 0.73 g of methyl 4-{2-(2,3,4-trimethoxyphenyl)ethyl}-1-piperazinecarbodithioate in 25 ml ofdry dichloromethane for 15 min. The resulting mixture was left to reach room temperature, and then stirred overnight. To the mixture was added 3 ml of water, and further added a saturated aqueous sodium hydrogen carbonate solution until the mixture had pH 8. The mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and placed under reduced pressure to distill off the solvent, yielding 205 mg of the desired compound as a grayish powder, m.p. 156°-158° C. (decomp.), yield 31.5%.
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@@H:19]([C:38](O)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][C:93]([O:95][CH2:96][C:97]1[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=1)=[O:94]>CN(C=O)C.C(OCC)(=O)C>[C:43]([O:42][CH2:41][C@@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][S:17][CH2:18][C@H:19]([NH:20][C:21]([O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:37])[C:38]([NH:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][C:93]([O:95][CH2:96][C:97]1[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=1)=[O:94])=[O:39])(=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Reactant: NCCCCCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCCCC(=O)OCc1ccccc1)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (5R,9R)-9-(dodecanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylic acid (6, 1 eq) in DMF (0.2 M) was added DIEA (5 eq) and EDCI (1.3 eq) and HOBT (1.3 eq). The reaction was stirred at room temperature for 10 minutes, which was followed by adding benzyl 6-aminohexanoate hydrochloride (1.2 eq). The reaction mixture was then stirred at room temperature overnight. The mixture was diluted with ethyl acetate, and washed with saturated NaHCO3 solution, water and brine. The organic layer was dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give the title product.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:28]#[C:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:4][N:3]=1>CO.[Pd]>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH2:28][CH2:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:4][N:3]=1
Reactant: CCN(CC)CC#Cc1cnc(N)c2c(-c3ccc(NC(=O)Nc4cccc(C)c4)cc3)csc12
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCCc1cnc(N)c2c(-c3ccc(NC(=O)Nc4cccc(C)c4)cc3)csc12
Yield: 41.4 %

Procedure:
A mixture of Example 153 (185 mg, 0.53 mmol) and 10% Pd/C (37 mg) in MeOH (10 mL) was stirred under hydrogen (60 psi) for 16 h. The catalyst was removed by filtration through Celite, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography on silica gel to give the desired product (107 mg, 72%). 1H NMR (300 MHz, DMSO-D6) δ ppm 0.95 (t, J=7.1 Hz, 6H) 1.73-1.82 (m, 2H) 2.29 (s, 3H) 2.41-2.50 (m, 6H) 2.68-2.73 (m, 2H) 5.25 (s, 2H) 6.80 (d, J=7.5 Hz, 1H) 7.17 (t, J=7.8 Hz, 1H) 7.25 (d, J=8.5 Hz, 1H) 7.31 (s, 1H) 7.36 (d, J=8.5 Hz, 2H) 7.43 (s, 1H) 7.59 (d, J=8.5 Hz, 2H) 7.68 (s, 1H) 8.66 (s, 1H) 8.85 (s, 1H) MS (ESI(+)) m/e 488.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][C:3]=1[NH2:4].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:10]([S:9][C:6]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([CH:5]=1)[NH2:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cc(S)ccc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(SCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-5-mercaptoaniline (0.64 g) and benzyl bromide (0.52 mL) in N,N-dimethylformamide (10 mL) was added potassium carbonate (0.61 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=7/3) to give the title compound (0.37 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:9]=1[O:10][CH2:11][CH:12]1[CH2:14][CH2:13]1.[CH:31]1([CH2:34]Br)[CH2:33][CH2:32]1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:25]([CH2:34][CH:31]2[CH2:33][CH2:32]2)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:7]=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[C:9]=1[O:10][CH2:11][CH:12]1[CH2:13][CH2:14]1
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1CC1)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a suspension of NaH (37 mg, 50% suspension, 0.79 mmol) in 25 ml of DMF was slowly added a mixture of ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (300 mg, 0.719 mmol) and cyclopropylmethyl bromide (108 mg, 0.782 mmol) in 20 ml of DMF at 0° C. for 15 min under nitrogen atmosphere. Upon completion of the addition, the mixture was stirred for 15 min at 0° C. The reaction mixture was poured onto crushed ice and extracted with EtOAc (×2). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by Flash column Chromatography to give ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate in 62% yield. (0.210 g). 1HNMR (CDCl3): 7.69 (s, 4H); 7.41 (s, 1H); 7.21 (s, 1H); 4.19 (q, 2H); 3.63 (t, 1H); 3.41 (d, 2H); 1.94 (m, 1H); 1.78 (m, 1H); 1.27 (t, 3H); 0.97 (bs, 1H); 0.72 (bs, 1H); 0.42 (m, 4H); 0.13 (m, 2H); 0.1 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][N:10](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:9]2)=[CH:4][CH:3]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.ClC(OC(Cl)C)=O.CO>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][NH:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CO
Solvent: ClCCCl
Product: Clc1ccc(C2CNC2)cc1

Procedure:
To a solution of compound 6 (0.36 g, 1.1 mmol) in 1,2-dichloroethane (10 mL) containing proton sponge (0.02 g), cooled in an ice-water bath under an argon atmosphere, was added dropwise 1-chloroethyl chloroformate (0.3 mL, 3.1 mmol). The resultant solution was boiled at reflux for 4 hours, cooled and was concentrated in vacuo. The residue obtained was mixed with methanol (10 mL) and heated under reflux for 2 hours, then cooled and concentrated in vacuo to give the hydrochloride salt of 3-(4-chlorophenyl)azetidine (7) which was used without further purification.
Reaction SMILES: [OH:1][C:2]1(C(OCC)=O)[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[C:7](C)=[C:6]([C:15]#[C:16][C:17]3[CH:31]=[CH:30][C:20]([C:21]([O:23]CC[Si](C)(C)C)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[F-].C([N+](CC[CH2:53][CH3:54])(CCCC)CCCC)CCC>C1COCC1>[OH:1][C:2]1([CH2:20][C:21]([O:23][CH2:53][CH3:54])=[O:22])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:15]#[C:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)C1(O)CCC(C)(C)c2c1ccc(C#Cc1ccc(C(=O)OCC[Si](C)(C)C)cc1)c2C
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 0.25 g (0.49 mmol) of trimethylsilylethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethyl-5-carboethoxy-methylnaphth-2-yl)ethynyl]benzoate (Compound 117) in 5 ml of dry THF (flushed with argon) was added 1.48 ml (1.5 mmol) of tetrabutyl ammonium fluoride (1M solution in THF). The reaction mixture was stirred at room temperature for 12 hours, concentrated in vacuo to an oil and slowly diluted with water. The solution was acidified to pH 4 with 10% HCl and extracted with Et2O. The organic layer was dried over Na2SO4, concentrated in vacuo to an oil and purified by flash chromatography (silica, 90% EtOAc-hexane) to give the title compound as a white solid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]3[CH2:15][CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>COCCO.[Pd]>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]3[CH2:15][CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCC(C=Cc2ccc(-n3ccnc3)cc2)=NN1
Agent: [Pd]
Solvent: COCCO
Product: O=C1CCC(CCc2ccc(-n3ccnc3)cc2)=NN1
Yield: 76.3 %

Procedure:
A solution of 2.6 g of 4,5-dihydro-6-[2-[4-(1H-imidazol-1-yl)phenyl]ethenyl]-3(2H)-pyridazinone in 100 ml of 2-methoxyethanol containing 0.5 g of 10% Pd/C is shaken under hydrogen atmosphere for 13 hours. The catalyst is filtered, the filtrate is evaporated to dryness, and the residue is crystallized from ethanol to give 2 g of the above product, mp 195°-196° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:21])=[C:7]([CH:20]=1)[CH:8]([C:13]1[N+:18]([O-:19])=[CH:17][N:16]=[CH:15][CH:14]=1)[CH:9]=[C:10]([CH3:12])[CH3:11])#[N:2]>C(OCC)(=O)C.CCCCCC>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:21][C:10]([CH3:12])([CH3:11])[CH2:9][CH:8]([C:13]3[N+:18]([O-:19])=[CH:17][N:16]=[CH:15][CH:14]=3)[C:7]=2[CH:20]=1)#[N:2]
Reactant: CC(C)=CC(c1cc(C#N)ccc1O)c1ccnc[n+]1[O-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2ccnc[n+]2[O-])c2cc(C#N)ccc2O1
Yield: 4.5 %

Procedure:
In an analogous manner to that described in the first paragraph of Example 8, from 0.22 g of 6-[5-cyano-2-hydroxy-α-(2-methylpropenyl)benzyl]pyrimidine 1-oxide there was obtained 0.01 g of 6-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyrimidine 1-oxide in the form of an off-white solid (from ethyl acetate/n-hexane).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[Na].C(=O)([O-])[O-]>O.C(O)C.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH3:11])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: Cn1ccc2ccc(Br)cc21
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1ccc2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Temperature: 25 °C
Yield: 50.8 %

Procedure:
The mixture of 6-bromo-1-methyl-1H-indole (0.216 g, 1.03 mmol), 4-trifluoromethylbenzeneboronic acid (0.216 g, 1.14 mmol), tetrakis(triphenylphosphine) palladium (0.0541 g, 0.0468 mmol) and sodium, carbonate (0.438 g, 4.13 mmol) in water (2.5 mL), ethanol (1 mL) and toluene (5 mL) was refluxed for 1.6 hours. The mixture was cooled to room temperature then evaporated to dryness. The residue was partitioned in methylene chloride and water. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was purified by flash chromatography using 0-0.2% ethyl acetate in hexane as an eluant to give the title compound (0.144 g, 51%) as a white solid, mp: ˜100° C.; 1HNMR (200 MHz, DMSO-d6): δ8.0 (d, 2H, J=6.6 Hz), 7.8 (d, 3H, J=8.7 Hz), 7.65 (d, 1H, J=8.7 Hz), 7.35-7.5 (m, 2 H), 6.45 (d, 1H, J=2.6 Hz), and 3.8-3.95 ppm (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[CH:2].[C:12]1([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])#[CH:2]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: C#Cc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Product: C#Cc1cccc(C(=O)N(c2ccccc2)c2ccccc2)c1

Procedure:
Air in a 20 ml Schlenk tube was replaced by Ar gas and 1.02 g (7 mmol) of m-ethynylbenzoic acid and 5 g (42 mmol) of thionyl chloride were added to the tube and the mixture was stirred at 50° C. for 2 hours and then excess thionyl chloride was removed by distillation under reduced pressure to obtain m-ethynylbenzoyl chloride. To the m-ethynylbenzoyl chloride obtained was added a solution having 2.44 g (14.4 mmol) of diphenylamine dissolved in 7 ml of dichloromethane under ice-cooling and then the resultant mixture was stirred at room temperature for one hour. After completion of the stirring, dichloromethane was removed by distillation under reduced pressure and 35 ml of water was added to the resultant residue. The mixture was extracted with 35 ml of ethyl acetate, the extract was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure using an evaporator. The resultant crude reaction product was purified by column chromatography (hexane/AcOEt10/1) using silica gel to obtain 0.7 g of 3-ethynyl-N,N-diphenylbenzamide which is a desired product as pale yellow liquid. (Yield: 35%)
Reaction SMILES: Br[C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1.[H-].[Na+].C(C1C=C[C:35](C)=[N:36]C=1)C.[C-]#N.[Na+]>[Cu](Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:35]([C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1)#[N:36]
Reactant: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br
Reactant: CCc1ccc(C)nc1
Agent: Cl[Cu]Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Product: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
1.2 g (2.5 mmol) of 3-(4-bromo-5-ethylsulfonylamino-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)pyrimidinedione and 0.11 g of 55% sodium hydride in oil were added to 20 g of 5-ethyl-2-picoline and the mixture was stirred at room temperature for 30 minutes. Next, 0.07 g of copper(II) chloride and 0.15 g of sodium cyanide were added to the mixture, which was then stirred at 140° C. under an argon atmosphere for 1 hour. Further, 0.3 g of tetrakis(triphenylphosphine)palladium was added to the mixture, which was then heated with stirring for 3 hours. After the reaction was completed, 79% of the title compound was detected as the relative area value in liquid chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([CH2:23][SH:24])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:11]([CH2:13][OH:14])[CH:12]=1)[CH3:2].[NH4+].[Cl-].O.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([CH2:23][S:24][C:29](=[O:31])[CH3:30])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[C:11]([CH2:13][OH:14])[CH:12]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(CS)Cc1cnc(NC(=O)OC(C)(C)C)c(CO)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CCOC(=O)C(CSC(C)=O)Cc1cnc(NC(=O)OC(C)(C)C)c(CO)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
A mixture of crude 3-(6-tert-butoxycarbonylamino-5-hydroxymethyl-pyridin-3-yl)-mercaptomethyl-propionic acid ethyl ester (0.38 g, 1.0 mmol) and KHCO3 (0.11 g, 1.1 mmol) in acetic acid anhydride (1 mL) was stirred at room temperature for 5 h. NH4Cl (sat.) and water was then added. The mixture was extracted with dichloromethane, dried and concentrated under reduced pressure. Flash chromatography (CH2Cl2, 2.5% MeOH in CH2Cl2) gave 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-5-hydroxymethyl-pyridin-3-yl)-propionic acid ethyl ester (0.23 g, 60%).
Reaction SMILES: CC1C(C2C=CC=CC=2)C2C(=C(Cl)C(Cl)=C(OC)C=2)C1=O.CI.CC(C)([O-])C.[K+].Cl.[O:31]=[C:32]1[C:40]2[C:35](=[CH:36][C:37]([O:43][CH2:44]C(O)=O)=[C:38]([Cl:42])[C:39]=2[Cl:41])[C:34]([CH3:54])([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:33]1([CH3:56])[CH3:55]>CN(C)C=O>[CH3:55][C:33]1([CH3:56])[C:34]([CH3:54])([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:35]2[C:40](=[C:39]([Cl:41])[C:38]([Cl:42])=[C:37]([O:43][CH3:44])[CH:36]=2)[C:32]1=[O:31]
Reactant: CC1(C)C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1(C)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C)C2(C)c1ccccc1

Procedure:
2-Methyl-3-phenyl-5-methoxy-6,7-dichloro-1-indanone (9.63 g., 0.03 mole) and methyl iodide (18.7 ml., 0.3 mole) dissolved in dimethylformamide (100 ml.) under nitrogen at 25° C. are treated with potassium tert-butoxide (6.72 g., 0.06 mole) portionwise with intermittent cooling in an ice-water bath over 5 hour period. After exhaustive alkylation, i.e., after the addition of methyl iodide (3 × 20 ml.) followed by potassium tert-butoxide (5 g.), this procedure repeated until the addition of the base gives no green color, acidified with 6N hydrochloric acid to precipitate the product which on trituration with hexane and crystallization from acetic acid:water, 1:1, gives 3.49 g. of (1-oxo-2,2,3-trimethyl-3-phenyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 189°-190° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[C:6]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=2)[S:7][C:8]=1[C:9]1[N:13]=[CH:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:10]=1)[CH3:2].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>N1C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[N:5]=[C:6]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:28](=[O:29])[O:30][CH2:31][CH3:32])[CH:21]=2)[S:7][C:8]=1[C:9]1[N:13]=[CH:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:10]=1)[CH3:2]
Reactant: CCOc1nc(-c2ccnc(N)c2)sc1-c1ncn(C2CCCCO2)n1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Nc1cc(-c2nc(OCC)c(-c3ncn(C4CCCCO4)n3)s2)ccn1
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a solution of 4-{4-ethoxy-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyridin-2-amine (100 mg, 0.268 mmol) obtained by similar manner with Example 47-B(ii) in pyridine (2.7 mL), was added ethyl chloroformate (100 μL, 1.08 mmol) at 0° C., and the mixture was stirred for 3 h. The reaction mixture was diluted with water (20 mL), and the mixture was stirred for 1 h. The resulting precipitate was collected by filtration and was washed with water and diethyl ether to give the title compound (99.1 mg, 83%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11]C(=O)C(F)(F)F)[N:10]=2)[N:7]=1.C1COCC1.CO.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1
Reactant: O=C(Nc1cn2nc(Cl)ccc2n1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2,2,2-trifluoroacetamide (80 mg, 0.30 mmol) in a THF:methanol:water (1 mL each) mixture was added anhydrous potassium carbonate (400 mg, 3 mmol). The reaction mixture was refluxed for 8 hrs. After cooling to rt, the reaction mixture diluted with ethyl acetate and water. The phases were separated and the organic layer was washed with brine (2×5 mL), dried over sodium sulfate and concentrated to afford the title compound (45 mg, 90%). 1H NMR (DMSO-d6, 300 MHz): δ 5.65 (s, 2H), 7.02 (d, 1H), 7.7 (d, 1H).