Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:21])=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])/[C:8]([OH:10])=O)[N:6]=1.[NH2:22][C@@H:23]1[C:41](=[O:42])[N:25]2[C:26]([C:38]([OH:40])=[O:39])=[C:27]([CH2:30][O:31][C:32](=[O:37])[CH2:33][C:34](=[O:36])[CH3:35])[CH2:28][S:29][C@H:24]12>>[NH2:1][C:2]1[S:3][C:4]([Br:21])=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])/[C:8]([NH:22][C@@H:23]2[C:41](=[O:42])[N:25]3[C:26]([C:38]([OH:40])=[O:39])=[C:27]([CH2:30][O:31][C:32](=[O:37])[CH2:33][C:34](=[O:36])[CH3:35])[CH2:28][S:29][C@H:24]23)=[O:10])[N:6]=1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1nc(N)sc1Br
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC(=O)OC(C)(C)C)c3nc(N)sc3Br)[C@H]2SC1
Yield: 99 %

Procedure:
2-(2-Amino-5-bromothiazol-4-yl)-2(Z)-(tert-butoxycarbonylmethoxyimino)acetic acid and 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid are reacted and worked up in the manner Reference Example 40 to give the above-identified compound (99% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([N:23]4[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C1COCC1>[CH3:30][S:31]([O:29][CH2:28][C@H:25]1[CH2:26][CH2:27][N:23]([C:21]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][N:19]=3)[CH:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:8][CH:9]=3)[N:22]=2)[CH2:24]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Solvent: C1CCOC1
Product: CS(=O)(=O)OC[C@H]1CCN(c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (S)-(1-(7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-yl)pyrrolidin-3-yl)methanol (compound 163, 500 mg, 1.27 mmol) in THF (15 mL) were added MsCl (200 mg, 1.6 mmol) and TEA (370 mg, 3.7 mmol). The mixture was stirred for 4 hours at room temperature and concentrated in vacuo. The residue was washed by H2O and EtOAc to give the title compound. MS (m/z): 470 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4](O)=[O:5].[Cl-:14]>>[CH3:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: [Cl-]
Reactant: Cc1c(F)c(F)cc(F)c1C(=O)O
Product: Cc1c(F)c(F)cc(F)c1C(=O)Cl

Procedure:
To 2-methyl-3,4,6-trifluorobenzoic acid (3.2 g) is added thiony chloride (7 ml) and the mixture is refluxed for hour. After concentrating, 2-methyl-3,4,6-trifluorobenzoyl chloride (3.3 g) is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([CH2:8][OH:9])[CH:7]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1>C(O)CCCC>[Cl:28][C:24]1[CH:23]=[C:22]2[C:27]([C:18]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]4)=[C:6]([CH2:8][OH:9])[CH:7]=3)=[CH:19][CH:20]=[N:21]2)=[CH:26][CH:25]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CN1CCN(c2ccc(N)cc2CO)CC1
Solvent: CCCCCO
Product: CN1CCN(c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2CO)CC1
Yield: 83 %

Procedure:
[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol (100 mg, 0.45 mmol) and 4,7-dichloroquinoline (94 mg, 1.1 eq) were refluxed in 1 mL of n-pentanol overnight. The reaction mixture was then evaporated and purified by flash chromatography (DCM/MeOH/NH4OH//8/2/0.1) to yield expected compound as a pale brown solid (143 mg, 83% yield). m/z (ESI) 383.1 [M+H]+;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.CS(O[CH2:31][C:32]#[C:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=O)=O>O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH2:31][C:32]#[C:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[N:13]=2)=[N:4][CH:3]=1
Reactant: O=c1ccc(-c2ncc(Br)cn2)n[nH]1
Reactant: CCCCCCCC#CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCC#CCn1nc(-c2ncc(Br)cn2)ccc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12843.9 %

Procedure:
To a 20 mL 1 neck flask equipped with magnetic stirrer, and nitrogen inlet was charged 30 milligrams (mg) of 6-(5-bromopyrimidin-2-yl)pyridazin-3(2H)-one (0.12 mmol), 33 mg of potassium carbonate (0.24 mmol), and 5 mL of dry DMF. The reaction mixture was stirred for about 30 minutes at ambient temperature followed by the addition of 100 mg of dec-2-ynyl methanesulfonate (0.43 mmol) in one portion. The reaction was stirred overnight at ambient temperature. The reaction was poured into about 10 mL of water, and extracted with 3×10 mL of ethyl acetate. The combined organic extract was washed with 10 mL of water, 10 mL of saturated aqueous sodium chloride solution, dried, and stripped to the crude product which was purified by silica gel column chromatography (20% ethyl acetate/80% hexanes). The pure fractions were combined and concentrated under vacuum on a rotary evaporator to afford 6 g of a white solid consistent with the title compound upon analysis by NMR. The NMR data is as follows: 300 MHz 1H NMR (CDCl3, TMS=0 ppm) 0.85 (m 3H); 1.25 (m, 6H); 1.60-1.65 (m, 4H); 2.15 (m, 2H); 5.05 (s, 2H); 7.05 (d, 1H); 8.35 (d, 1H); 9.00 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.C(N(C(C)C)CC)(C)C.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1.[OH-].[Na+]>C1COCC1>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:38](=[O:39])[C:37]5[CH:41]=[CH:42][C:34]([F:33])=[CH:35][CH:36]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccc(F)cc4)nc3cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol), diisopropylethylamine (0.36 ml, 2.01 mmol) in THF (0.8 ml), 4-fluorobenzoyl chloride (114 μL, 0.97 mmol) was slowly added at rt. The mixture was stirred overnight at rt. Aqueous NaOH (2 mL, 1M) was added and the solvent was evaporated. Water (25 ml) was added and the mixture was extracted three times with ethyl acetate (3×25 ml). The combined organic layers were washed with brine, dried and evaporated to afford a residue which precipitated after addition of methanol. The precipitate was suspended in MeOH/CH3CN (1:1, 6 mL) and refluxed for 2 hours in aqueous KOH (0.50 mL, 5M). After evaporation of the solvent and addition of water, a white solid was isolated and dried under high vacuum. The title compound was obtained (77 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]([C:18](OCC)=[O:19])([CH3:17])[CH3:16])=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C@H:12]12[CH2:14][C@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[CH2:18][OH:19]
Reactant: CCOC(=O)C(C)(C)N1C[C@@H]2C[C@H]1CN2C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
2-Bromo-2-methylpropionic acid ethyl ester (155 μL, 1.06 mmol) was added to a solution of potassium carbonate (145 mg, 1.05 mmol) and (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg, 1.01 mmol) in anhydrous acetonitrile (1 mL) The resulting mixture was heated at 80° C. for 48 h, then cooled to ambient temperature and partitioned between EtOAc and water. The organic layer was separated, washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 98:2) to give (1S,4S)-5-(1-ethoxycarbonyl-1-methylethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a pale brown oil. To a solution of (1S,4S)-5-(1-ethoxycarbonyl-1-methylethyl)-2,5-diazabicyclo[2.2.1]-heptane-2-carboxylic acid tert-butyl ester (1 mmol) in anhydrous THF (5 mL) at 0° C., a solution of LiAlH4 (1 M in THF, 3.2 mL, 3.2 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a brown oil (168 mg, 99%). 1H NMR (CDCl3, 400 MHz) δ 3.37 (bs, 1H); 3.31 (d, J=10.2 Hz, 1H); 3.21 (d, J=10.2 Hz, 1H); 3.15-3.00 (m, 2H); 2.81-2.61 (m, 2H); 2.45 (s, 2H); 1.76 (d, J=10.0 Hz, 1H); 1.56 (d, J=10.0 Hz, 1H); 1.46 (t, J=5.02 Hz, 1H); 1.03 (s, 3H) and 1.00 (s, 2H).
Reaction SMILES: [CH:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:12]1COCC1.CI>>[CH3:12][C:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCCCOS(=O)(=O)C1CC1
Reactant: C1CCOC1
Solvent: CI
Product: CCCCOS(=O)(=O)C1(C)CC1
Temperature: 0 °C
Yield: 55 %

Procedure:
To a solution of 1-Butyl cyclopropanesulfonate (1 g, 5.58 mmol) in THF (15 ml) butyllithium solution (3.84 ml, 6.14 mmol, 1.6M, THF) was slowly added at −78° C. under nitrogen atmosphere. After 15 minutes MeI (0.72 ml, 11.16 mmol) was added and the solution was allowed to warm to 0° C. and quenched with water (1 ml). The volatiles evaporated under reduced pressure and the residue extracted with CH2Cl2 (100 ml). The extract was washed with water, dried (MgSO4) and evaporated. The residue was purified over silica gel chromatography (eluants: hexane/CH2Cl2) to obtain the titled product (0.59 g, 55.0%) as a colorless oil. 1H NMR (300 MHz, CDCl3)) δ 0.84 (m, 2H), 0.95 (t, J=7.2 Hz, 3H), 1.43 (m, 4H), 1.53 (s, 3H), 1.74 (m, 2H), 4.21 ((t, J=6.6 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[S:9][CH:10]=[CH:11][C:4]=2[CH2:3]1.F[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1>>[CH3:1][N:2]1[CH2:7][CH:6]([O:8][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:5]2[S:9][CH:10]=[CH:11][C:4]=2[CH2:3]1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: CN1Cc2ccsc2C(O)C1
Product: CN1Cc2ccsc2C(Oc2cccc([N+](=O)[O-])c2)C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 14) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and 1-fluoro-3-nitro benzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([SH:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[Cl:13][CH2:14][CH2:15]Cl>>[Cl:13][CH2:14][CH2:15][S:10][C:8]1[NH:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:9]=1
Reactant: ClCCCl
Reactant: CC(C)(C)c1n[nH]c(S)n1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)c1n[nH]c(SCCCl)n1

Procedure:
31.4 g. 3-t-Butyl-1,2,4-triazole-5-thiol was dissolved in 180 ml. industrial methylated spirits containing 12.4 g. potassium hydroxide. 99 g. 1,2-Dichloroethane was added and after four days the insoluble matter removed. 5-(2-Chloroethylthio)-3-t-butyl-1,2,4-triazole was obtained from the solution by evaporation.
Reaction SMILES: C([N:4]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1)[C:5]#[C:6][CH3:7])(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH2:5]([NH:4][C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1)[C:6]#[CH:7]
Reactant: CC#CN(C(C)=O)c1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C#CCNc1nc2ccccc2s1
Yield: 101.4 %

Procedure:
A mixture of compound (f) (1.0 g), 80% methanol (20 ml) and potassium carbonate (1.0 g) was refluxed by heating for 1 hour and evaporated to remove the solvent. The residue was extracted with chloroform. The extract was washed with water, dried, and evaporated to remove the solvent. The residue was applied to column chromatography on silica gel (20 g) to give 2-(2-propynylamino)benzothiazole (g) (829 mg, yield 100%) from chloroform eluate: mp. 134°-135° C. (acetone-hexane).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10](=[NH:12])[CH3:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:14](=[CH:18]OC)[C:15](=[O:17])[CH3:16].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:15]([C:14]1[N:9]([C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[C:10]([CH3:11])=[N:12][CH:18]=1)(=[O:17])[CH3:16]
Reactant: CC(=N)N[C@H](C)c1ccccc1
Reactant: COC=C(Br)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(=O)c1cnc(C)n1[C@H](C)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 26.2 g (0.162 mol) of N—((R)-1-phenylethyl)acetamidine (which was prepared in the above-mentioned Reference Example 2), 19.3 g (0.108 mol) of 3-bromo-4-methoxy-3-buten-2-one and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 80° C. under stirring for 8 hours for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluant: ethyl acetate) to give 18.7 g (yield: 76%) of 5-acetyl-2-methyl-1-((R)-1-phenylethyl)imidazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Cl:13]N1C(=O)CCC1=O>O1CCCC1>[Cl:13][C:9]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(-n2cccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-n2cccc2Cl)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of 1-(4-methylphenyl)pyrrole (1 g) in tetrahydrofuran (50 ml) was added N-chlorosuccinimide (850 mg) in one portion at -78° C. under nitrogen atmosphere. The mixture was warmed to 10° C., stirred for one hour, and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to yield 2-chloro-1-(4-methylphenyl)pyrrole (1.2 g) as an oil. (This product was a mixture of the starting material and the desired product and used to the next reaction furthermore without purification.)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[C:16]([O:15][C:13](=[O:14])[CH2:12][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccccc1CC#N
Reaction time: 12 h
Yield: 97.5 %

Procedure:
To a mixture of 2.92 g of (2-hydroxyphenyl)acetonitrile, 4.71 g of tert-butyl bromoacetate and 110 mL of DMF was added 6.06 g of potassium carbonate at room temperature, followed by stirring for 12 hours. To the reaction solution was added water, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using hexane/ethyl acetate as an eluent solvent to obtain 5.29 g of tert-butyl[2-(cyanomethyl)phenoxy]acetate as a yellow oily substance.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@@H:7]([OH:14])[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2].[F:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])N>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:21]2[CH:19]=[CH:18][C:17]([F:16])=[C:23]([F:24])[CH:22]=2)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: Nc1ccc(F)c(F)c1
Reactant: CC(=O)N1c2ccccc2[C@@H](O)C[C@@H]1C
Product: CC(=O)N1c2ccccc2[C@H](Oc2ccc(F)c(F)c2)C[C@@H]1C
Yield: 63.6 %

Procedure:
A compound was produced in the same manner as in Example 12, using 60 mg of trans-1-acetyl-4-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline and 112 mg of 3,4-difluoroaniline, and thus 59 mg (64%) of the title compound was obtained as a colorless oily substance.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=O)[NH:11][C@H:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C)C>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(Cc2ccccc2)C(=O)[C@@H](Cc2ccc(Br)cc2)N1
Solvent: CSC
Solvent: C1CCOC1
Product: Brc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To (R)-1-benzyl-3-(4-bromo-benzyl)-piperazine-2,5-dione (0.5 g, 1.34 mmol) in THF (10 mL) was added 2M B3.SMe2 (2.68 mL, 5.36 mmol). The mixture was stirred in RT under argon for 4 days; more 2M B3.SMe2 (2.68 mL, 5.36 mmol) was added and stirred for 3 days. Reaction mixture was quenched with EtOH (3 mL) and removed the solvent in rotavap, added EtOH (5 mL) and stirred at 70° C. for 2 hr and concentrated to give colorless oil as a crude product. MS (ESI) 345 (M+H).
Reaction SMILES: O[C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O.[NH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1>>[CH2:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][CH:17]1[NH:16][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Oc1ncnc2ccsc12
Reactant: NC1Cc2ccccc2C1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2c(c1)CC(Nc1ncnc3ccsc13)C2
Yield: 28.2 %

Procedure:
Using 4-hydroxythieno[3,2-d]pyrimidine (60 mg, 0.39 mmol), and phosphorus oxychloride (0.6 ml), and then 2-aminoindan (210 mg, 1.56 mmol), a similar procedure to Example 5 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=1:2) to obtain the title compound (30 mg, 0.11 mmol) having the following physical properties:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CN(C)CCO
Reactant: Cc1ccc(-c2[nH]c(-c3ccc(O)cc3)nc2C(=O)Nc2nccs2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(-c2[nH]c(-c3ccc(OCCN(C)C)cc3)nc2C(=O)Nc2nccs2)cc1

Procedure:
2-(4-Hydroxyphenyl)-5-(4-methylphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide, 2-dimethylaminoethanol, triphenylphosphine and diethyl azodicarboxylate are reacted and treated in the same manner as in Example 24 to give 2-(4-(2-dimethylaminoethyloxy)phenyl)-5-(4-methylphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(C(C)C)CC)(C)C.[OH:35][C:36]([CH2:38][CH:39]1[NH:44][CH2:43][CH2:42][NH:41][C:40]1=[O:45])=[O:37].ClCl>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:44]1[CH2:43][CH2:42][NH:41][C:40](=[O:45])[CH:39]1[CH2:38][C:36]([OH:35])=[O:37])=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: O=C(O)CC1NCCNC1=O
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCNC(=O)C2CC(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 32 %

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, PFTU, diisopropylethylamine, and 3-(hydroxycarbonylmethyl)piperazin-2-one in dimethylformamide. Yield: 32%; C23H21Cl2N5O5 (518.355); mass spectrum: (M+H)+=518/520/522 (chlorine isotope).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:3]=1.Cl.[NH2:18][C:19]1[C:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])=[CH:23][CH:22]=[C:21]([NH:31][CH:32]2[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]2)[N:20]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:18][C:19]1[N:20]=[C:21]([NH:31][CH:32]2[CH2:37][CH2:36][CH2:35][N:34]([C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=4)[N:3]=3)[CH2:33]2)[CH:22]=[CH:23][C:24]=1[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27]
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Reactant: N#Cc1ccc(-c2ccc(F)cc2)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccc(F)cc2)nc1N1CCCC(Nc2ccc(C(=O)C(F)(F)F)c(N)n2)C1
Temperature: 120 °C

Procedure:
55 mg (0.24 mmol) of 2-chloro-6-(4-fluorophenyl)pyridine-3-carbonitrile, 83 mg (0.28 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.206 ml (1.18 mmol) of N,N-diisopropylethylamine were initially charged in 2 ml of DMSO. The mixture was heated at 120° C. in a microwave for 30 min. The crude product was purified by means of preparative HPLC (method 13). 72 mg (54% of theory) of the product were obtained in solid form.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH:17]([CH3:19])[O:16][CH:15]([CH3:20])[CH2:14]2)=[C:9]([CH:21]2[O:25]CCO2)[CH:8]=1.CON(C)[C:29](=[O:31])[CH3:30]>C1COCC1>[C:29]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH:15]([CH3:20])[O:16][CH:17]([CH3:19])[CH2:18]2)=[C:9]([CH:8]=1)[CH:21]=[O:25])(=[O:31])[CH3:30]
Reactant: CC1CN(c2ccc(Br)cc2C2OCCO2)CC(C)O1
Reactant: CON(C)C(C)=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(=O)c1ccc(N2CC(C)OC(C)C2)c(C=O)c1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
t-Butyl lithium in hexanes (3.8 ml of a 1.7 M solution, 14.5 mmol) is added to THF at −78° C. in a flame dried round-bottomed flask. 4-[4-Bromo-2-(1,3-dioxolan-2-yl)phenyl]-2,6-dimethylmorpholine (from Step 2) (1.0 g, 2.9 mmol) is dissolved in THF (5 mL) and is slowly added to the t-BuLi solution over 7 minutes keeping the temperature below −70° C. The mixture is stirred for 30 minutes and N-methoxy-N-methyl-acetamide (0.34 mL, 3.2 mmol) is slowly added dropwise. The reaction is stirred at −78° C. for 30 minutes and then stored at 0° C. overnight. The reaction is quenched with 1 M HCl (22.5 mL) and then heated at 65° C. for 1 hour. The mixture is basified with 1 M aqueous Na2CO3 and extracted with EtOAc (2×). The combined organic layers are washed with brine, dried (Na2SO4) and concentrated. The resulting residue is adsorbed onto silica gel and purified by silica gel chromatography using 15-20% EtOAc in heptane as the eluent to afford 0.35 g (45%) a clear oil. 1H NMR (400 MHz, CDCl3) δ 10.1, 8.35, 8.12, 7.08, 3.93, 3.25, 2.76, 2.60, 1.25.