Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:28]1([CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([CH:41]=[CH:42][CH:43]=[O:44])[CH2:37][CH2:36]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1.C1CCCCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[CH:12]=[C:11]2[C:42](=[CH:41][CH:38]2[CH2:37][CH2:36][N:35]([CH2:34][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:40][CH2:39]2)[CH2:43][OH:44])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC=CC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc2ccn(S(=O)(=O)c3ccccc3)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1ccc2cc(C(=CC3CCN(Cc4ccccc4)CC3)CO)n(S(=O)(=O)c3ccccc3)c2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
A solution of N-phenylsulfonyl-6-methyl indole (1.18 g, 4.34 mmol) in 30 ml of dry THF was cooled to −78° C. and treated with 3.5 ml (5.2 mmol) of 1.5 M lithium diisopropylamide in cyclohexane at −78° C. After stirring at −78° C. for 1 hour, a solution of 3-[1-(phenylmethyl)-4-piperidinyl]-2-propenal (1.0 g, 4.36 mmol) in 5 ml of dry THF was added at −78° C. and stirred at that temperature for 40 minutes. The mixture was quenched with water and extracted with chloroform. The organic layer was dried and concentrated to give 2.23 g of an orange oil. The oil was purified through silica gel column chromatography using 2% methanol in chloroform as eluent to give 1.0 g of the title compound as a yellow oil.
Reaction SMILES: [NH:1]([C:8](OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:9])[C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH3:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[CH:32]=O.[F:34][C:35]([F:47])([F:46])[S:36]([C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1)(=[O:38])=[O:37]>>[F:34][C:35]([F:47])([F:46])[C:5]([OH:7])=[O:6].[CH3:5][C@H:2]1[N:1]([CH2:32][C:31]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[CH3:25])[C:8](=[O:9])[N:43]([C:42]2[CH:44]=[CH:45][C:39]([S:36]([C:35]([F:46])([F:34])[F:47])(=[O:37])=[O:38])=[CH:40][CH:41]=2)[C:3]1=[O:4]
Reactant: Cc1cnccc1C=O
Reactant: O=C(N[C@H](CO)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Product: Cc1cnccc1CN1C(=O)N(c2ccc(S(=O)(=O)C(F)(F)F)cc2)C(=O)[C@H]1C
Product: O=C(O)C(F)(F)F

Procedure:
The compound is prepared from 0.04 mmol of resin, 0.12 mmol of N-Fmoc-D-Ala(OH), 0.20 mmol of 3-methyl-4-pyridinecarboxaldehyde and 0.10 mmol of 4-(trifluoromethanesulfonyl)aniline, in the same way as in Example 1. After purification by preparative LC-MS, 6.3 mg of expected product are obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13](C=O)[CH2:12][CH:11]([C:17]([O:19][CH3:20])=[O:18])[CH2:10]2)=[CH:5][C:4]=1[F:21])[CH3:2].O.[ClH:23]>CO>[ClH:23].[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:17]([O:19][CH3:20])=[O:18])[CH2:10]2)=[CH:5][C:4]=1[F:21])[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)OC)CN(C=O)C2)cc1F
Agent: Cl
Solvent: O
Solvent: CO
Product: CCc1ccc(C2CNCC(C(=O)OC)C2)cc1F

Procedure:
1.6 g (5.3 mmol) of methyl 5-(4-ethyl-3-fluorophenyl)-1-formylpiperidine-3-carboxylate were taken up in 10 ml of methanol, and heated to reflux with 1 ml of water and 0.5 ml of concentrated hydrochloric acid for three hours. The reaction mixture was concentrated and dried under reduced pressure. Yield: 1.5 g (63% of theory; purity 68%)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:8][CH3:9].F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.O>CN(C)C(=O)C.C(Cl)Cl>[CH2:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[CH2:8][CH3:9]
Reactant: CCCc1ccc(O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCc1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
Anhydrous potassium carbonate (14.9 g, 0.12 mol) was added to a mixture of 4-propylphenol (13.6 g, 0.10 mol) and 4-fluorobenzaldehyde (12.4 g, 0.10 mol) in N,N-dimethylacetamide (100 mL) under argon. The heterogeneous mixture was brought to reflux, maintained at that temperature for 5 h, then cooled to RT. Water (100 mL) and CH2Cl2 (100 mL) were added, resulting in a tri-phase system. The bottom layer was removed; the middle layer was dried over MgSO4 ; and, the top layer was extracted with CH2Cl2 (100 mL) and dried over MgSO4. The dried layers were combined and concentrated in vacuo at 50° C. to give an orange oil. The crude product was purified by distillation to give title compound (16.6 g, 69%) as a colorless oil. bp 138°-150° C. (0.2 mm Hg)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[NH:27]1[CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]2[NH:29][C:28]1=[O:36]>>[CH3:26][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[N:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:4]3[CH:3]=[C:2]([N:27]4[CH:31]5[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]5[NH:29][C:28]4=[O:36])[CH:7]=[CH:6][CH:5]=3)[CH2:11][CH2:12]2)[N:21]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(I)c4)CC3)cccc2n1
Reactant: O=C1NC2CCCCC2N1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5C(=O)NC6CCCCC65)c4)CC3)cccc2n1
Yield: 100 %

Procedure:
The title compound was prepared in 100% yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and octahydro-2H-benzimidazol-2-one.
Reaction SMILES: C([C:4]1[CH:36]=[CH:35][C:7]2[N:8]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:6]=2[CH:5]=1)(=O)C.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43]([OH:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1.[CH2:48]([OH:50])[CH3:49]>>[C:48]([C:36]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH3:12])[N:8]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]4[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=4)(=[O:26])=[O:27])=[O:23])=[CH:17][CH:18]=3)[C:7]=2[CH:35]=1)(=[O:50])[CH3:49].[CH3:47][C:37]1[CH:42]=[CH:41][C:40]([S:43]([OH:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: CCO
Reactant: CCc1nc2cc(C(C)=O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCc1nc2ccc(C(C)=O)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A mixture of 5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole (Example 78, 43 mg, 0.085 mmol), p-toluenesulfonic acid (16.2 mg, 0.085 mmol) in ethanol (0.1 ml) was stirred at room temperature for 16 h. The precipitated crystalline solids were filtered, washed with ethanol (0.05 ml×5), and dried in vacuo at 40° C. for 2 h to afford 54 mg (91%) of the title compound as white solids.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:16])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2].CC1(C)OB([C:29]2[CH:30]=[N:31][N:32](C(OC(C)(C)C)=O)[CH:33]=2)OC1(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:29]3[CH:30]=[N:31][NH:32][CH:33]=3)=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:16])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC2CCC2)C[C@@H]1C
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1c2ccc(-c3cn[nH]c3)cc2N(C(=O)OC2CCC2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
A 500-mL round-bottom flask was purged with nitrogen and charged with cyclobutyl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (15.0 g, 40.9 mmol), tert-butyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (20 g, 68 mmol), cesium carbonate (40.0 g, 123 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (2.0 g, 2.45 mmol), 1,4-dioxane (150 mL), and water (15 mL). The resulting mixture was stirred overnight at 100° C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1:3, ethyl acetate/petroleum ether) to afford cyclobutyl (S)-4-acetyl-3-methyl-7-(1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (9.0 g, 62%) of as a yellow solid. MS (ESI, pos. ion) m/z 355 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)[CH2:8][CH2:7][N:6]([CH2:9][C@H:10]2[C@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11]2)[CH2:5][CH2:4]1.Cl.FC1(C2C=CC=C([OH:40])C=2)CCNCC1.C(N(CC)CC)C.[C:48]1([C@@H:54]2[CH2:56][C@H:55]2[C:57](Cl)=[O:58])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1COCC1>[C:48]1([C@@H:54]2[CH2:56][C@H:55]2[C:57]([O:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:3]3([F:2])[CH2:4][CH2:5][N:6]([C:9]([C@@H:10]4[CH2:11][C@H:12]4[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:40])[CH2:7][CH2:8]3)[CH:20]=2)=[O:58])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: Oc1cccc(C2(F)CCN(C[C@@H]3C[C@H]3c3ccccc3)CC2)c1
Reactant: Oc1cccc(C2(F)CCNCC2)c1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Oc1cccc(C2(F)CCN(C(=O)[C@@H]3C[C@H]3c3ccccc3)CC2)c1)[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Preparation of 4-Fluoro-4-(3-hydroxyphenyl)-1-(trans-3-phenylcyclopropyl-methyl)piperidine Hydrochloride To a suspension of 4-fluoro-4-(3-hydroxyphenyl)piperidine hydrochloride (100 mg, 0.43 mmol) in THF (3 mL) was added triethylamine (108 mg, 1.07 mmol) and the resulting mixture cooled in an ice bath. A solution of trans-2-phenylcyclopropanecarbonyl chloride (194 mg, 1.07 mmol) in THF (2 mL) was added slowly via syringe over a period of 5 minutes. The reaction was then stirred for additional 3 hours during which time it was allowed to warm to room temperature. The reaction was then quenched by pouring into water (20 mL) and the mixture extracted with ethyl acetate (2×20 mL). The extracts were dried over magnesium sulfate and filtered. The filtrate was then concentrated to afford crude 3-[4-fluoro-1-(trans-2-phenylcyclopropanecarbonyl)piperidin-4-yl]-phenyl trans-2-phenylcyclopropane carboxylate as a viscous clear oil. This oil was dissolved in THF (5 mL) and a 65 wt % solution of vitride in toluene (1.35 mL, 4.50 mmol) added. The resulting mixture was then stirred at room temperature for 2 hours. After this time the reaction was heated to 60° C. for a further 2 hours then cooled back to room temperature. The reaction was then cooled in an ice-bath and ethyl acetate (10 mL) slowly added. The resulting mixture was then slowly added to 10% hydrochloric acid solution (25 mL) and the mixture rapidly stirred for 1 hour. The reaction mixture was then adjusted to pH 8 by the addition of solid sodium bicarbonate and the layers separated. The aqueous was extracted with ethyl acetate (3×10 mL) and the combined organics dried over magnesium sulfate. Subsequent filtration and concentration afforded a brown oil. This material was treated with 10% methanolic hydrogen chloride (5 mL) and re-concentrated. The resulting oil was triturated with 1:1 ethyl acetate/acetone to afford a light brown solid. This solid was isolated by filtration and dried on the pump overnight. This afforded the title compound in 11% overall yield as a tan colored solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[CH2:7][OH:8])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: CC(=O)OCC(CO)c1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(COS(=O)(=O)c1ccc(C)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a solution of (−)-2-(4-bromophenyl)-3-hydroxypropyl acetate (5.88 g, 21.5 mmol) in dichloromethane (100 ml) was added triethylamine (5.45 g, 53.8 mmol), p-toluenesulfonyl chloride (4.93 g, 25.8 mmol) and 4-dimethylaminopyridine (0.263 g, 2.15 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours and partitioned between saturated ammonium chloride solution and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=4/1) to afford (+)-3-acetoxy-2-(4-bromophenyl)propyl 4-methyl-benzenesulfonate as colorless oil (8.32 g, 90%). [α]D=+1.63 (C=0.5, CHCl3).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([OH:14])[CH:10]=[C:11]([Cl:13])[CH:12]=1)[CH3:2].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[C:18]1([NH:24][C:25](=[O:26])[O:14][C:9]2[CH:10]=[C:11]([Cl:13])[CH:12]=[C:7]([O:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:15][CH2:16][CH3:17])[CH:8]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(COc1cc(O)cc(Cl)c1)OCC
Reactant: O=C=Nc1ccccc1
Agent: [N-]=C=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(COc1cc(Cl)cc(OC(=O)Nc2ccccc2)c1)OCC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(2,2-Diethoxyethoxy)-5-chlorophenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. Phenyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added, and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[3-(2,2-diethoxyethoxy)-5-chlorophenyl] N-phenylcarbamate as the residue.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][N:16]=1>C(Cl)Cl.CC(N(C)C)=O>[Br:12][C:5]1[C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]([NH:1][C:21](=[O:22])[C:18]2[CH:19]=[CH:20][C:15]([F:14])=[N:16][CH:17]=2)=[C:3]([Cl:13])[CH:4]=1
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1Cl
Reactant: O=C(Cl)c1ccc(F)nc1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)c(Br)cc1Cl)c1ccc(F)nc1

Procedure:
To a solution of 5-amino-2-bromo-4-chlorobenzotrifluoride (466 mg, 1.70 mmol) dissolved in DCM (1 mL) was slowly added a solution of 2-fluoropyridine-5-carbonyl chloride (270 mg, 1.70 mmol) in DCM (1 mL). A few drops of DMA were added and the reaction mixture was concentrated to form N-(4-bromo-2-chloro-5-trifluoromethyl-phenyl)-6-fluoro-nicotinamide as a purple solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13](F)[N:12]=[CH:11][N:10]=2)[C:5](=[O:16])[N:4]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)([CH3:21])[NH:18][C:19](=[O:20])[C:3]=12.[C:29]([NH-:31])#[N:30].[Na+].O.Cl>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:31][C:29]#[N:30])[CH:14]=2)[C:5](=[O:16])[N:4]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)([CH3:21])[NH:18][C:19](=[O:20])[C:3]=12
Reactant: CC1(c2cccc(Cl)c2)NC(=O)c2c(Cl)cc(Nc3cc(F)ncn3)c(=O)n21
Reactant: N#C[NH-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1(c2cccc(Cl)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC#N)ncn3)c(=O)n21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 8-chloro-3-(3-chlorophenyl)-6-((6-fluoropyrimidin-4-yl)amino)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (3, 100 mg, 0.24 mmol) in N-methyl-2-pyrrolidinone (4 mL) was added sodium hydrogencyanamide (46 mg, 0.72 mmol). The reaction was stirred at 50° C. for 2 h. The resulting mixture was cooled to room temperature, poured into water and acidified to pH=5.5 with concentrated hydrochloric acid. The mixture was filtered. The solid crude was purified via HPLC to afford N-(6-((8-chloro-3-(3-chlorophenyl)-3-methyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyanamide (Cpd. No. 184).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[F:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34]Cl)=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:25]=2[CH:42]=1>CC(N(C)C)=O>[F:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34][O:1][N:2]4[C:3](=[O:12])[C:4]5=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]5[C:6]4=[O:7])=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:25]=2[CH:42]=1
Reactant: Fc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1, N-hydroxyphthalimide and triethylamine in dimethylacetamide is treated with 8-fluoro-6-phenyl-1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-fluoro-6-phenyl-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:40])[C@@H:28]([NH2:39])[CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:40])[C@@H:28]([NH:39][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:5]=2)=[O:15])[CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: O=C(O)c1cc(O)n(-c2ccccc2)n1
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCCC(=O)OC(C)(C)C)CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 171 mg of 5-Hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid and 300 mg of 4-((S)-2-Amino-5-tert-butoxycarbonyl-pentanoyl)-piperazine-1-carboxylic acid ethyl ester in 3 ml of DMF, 128 mg of HOBT and 160 mg of EDC was added and the reaction mixture was stirred for 5 h at RT. Then, the reaction mixture was diluted with water and filtered through a Chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure. The solid product was triturated with DCM and the precipitate was dried under reduced pressure. The crude product was used in the subsequent reaction.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34]Cl)=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[C:25]=2[CH:42]=1>CC(N(C)C)=O>[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34][O:1][N:2]4[C:3](=[O:12])[C:4]5=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]5[C:6]4=[O:7])=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[C:25]=2[CH:42]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 1, N-hydroxyphthalimide and triethylamine in dimethylacetamide is treated with 8-bromo-6-(2-pyridyl)-1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-bromo-6-(2-pyridyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([NH:16][C:17](=O)OC(C)(C)C)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[Cl:24][C:25]1[CH:45]=[CH:44][C:28]([CH2:29][C@H:30]2[CH2:34][O:33][S:32](=[O:36])(=[O:35])[N:31]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:27][CH:26]=1.N[C@@H](CC1C=CC(Cl)=CC=1)[C:48]([OH:50])=[O:49]>>[NH2:31][C@@H:30]([CH2:29][C:28]1[CH:27]=[CH:26][C:25]([Cl:24])=[CH:45][CH:44]=1)[CH2:17][NH:16][C:14]1[S:15][C:11]([C:4]2[CH:5]=[CH:6][C:7]3[NH:8][C:48](=[O:49])[O:50][C:2]=3[CH:3]=2)=[N:12][N:13]=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][C@H:30]2[CH2:34][O:33][S:32](=[O:36])(=[O:35])[N:31]2[C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[CH:44][CH:45]=1
Reactant: N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CC(C)(C)OC(=O)Nc1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1
Agent: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(Cl)cc2)COS1(=O)=O
Product: N[C@H](CNc1nnc(-c2ccc3[nH]c(=O)oc3c2)s1)Cc1ccc(Cl)cc1

Procedure:
The title compound was synthesized in a similar manner to that described for Example 11, by alkylating tert-butyl 5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-ylcarbamate, prepared as in Example 1, with tert-butyl (4S)-4-(4-chlorobenzyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide instead of tert-butyl (4S)-4-(4-(trifluoromethyl)benzyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide. tert-Butyl (4S)-4-(4-chlorobenzyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide was prepared as shown in Scheme 1b but using (S)-2-amino-3-(4-chlorophenyl)propanoic acid instead of (S)-2-amino-3-(4-(trifluoromethyl)phenyl)propanoic acid. LCMS (API-ES) m/z: 402 (M+H+); 1H NMR (400 MHz, CD3OD): δ ppm 2.95-3.07 (m, 2H), 3.55-3.60 (m, 1H), 3.70-3.75 (m, 1H), 3.80-3.86 (m, 1H), 7.17 (d, J=8 Hz, 1H), 7.33 (d, J=8 Hz, 2H), 7.40 (d, J=8 Hz, 2H), 7.59 (d, J=8 Hz, 1H), 7.69 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:39][CH2:38][CH2:37][N:36]2[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[C:31]([F:47])[CH:30]=1>C(Cl)(Cl)Cl>[F:47][C:31]1[CH:30]=[C:29]([NH:28][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH:34]=[CH:33][C:32]=1[CH:35]1[CH2:39][CH2:38][CH2:37][N:36]1[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]
Reactant: O=C(O)c1cnccn1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(N)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(NC(=O)c2cnccn2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.5 g of pyrazine-2-carboxylic acid and 3.1 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride were added to a pyridine (50 ml) solution of 3 g of t-butyl 2-(4-amino-2-fluoro-phenyl)-pyrrolidine-1-carboxylate obtained in Example 338 (step 2), and the reaction liquid was stirred at room temperature for 3 hours. The reaction liquid was diluted with chloroform, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=50/1) to obtain the entitled compound as a yellow oily substance.