Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([O:23]C)=[O:22])=[CH:6][N:5]2[C:25]=1[CH3:26].[OH-].[Na+]>O1CCOCC1>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([OH:23])=[O:22])=[CH:6][N:5]2[C:25]=1[CH3:26]
Reactant: CCc1cccc(C)c1CNc1cc(C(=O)OC)cn2c(C)c(C)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCc1cccc(C)c1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Yield: 94.3 %

Procedure:
Methyl 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylate (0.4 g, 1.1 mmol) was added to a mixture of 1,4-dioxane (6 ml) and 2 M NaOH (6 ml) and was refluxed for 30 min. The dioxane was evaporated under reduced pressure and the aqueous solution was made acidic by addition of 2 M HCl. The acidic aqueous was basified by the addition of a saturated bicarbonate solution and the solid that formed was isolated by filtration to give 0.35 g (91%) of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:7][CH2:8][CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].CCOC(C)=O>CN(C=O)C>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][N:10]([CH2:9][CH2:8][O:7][C:6]1[CH:15]=[C:16]([Cl:18])[CH:17]=[C:4]([Cl:3])[CH:5]=1)[S:11]([CH3:14])(=[O:12])=[O:13])[CH3:30]
Reactant: CS(=O)(=O)NCCOc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN(CCOc1cc(Cl)cc(Cl)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
A solution of NaH (60% in oil, 338 mg, 8.45 mmol) in DMF (23 mL) was cooled to 0° C. followed by addition of N-[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonamide (2.0 g, 7.04 mmol). The reaction was stirred at room temperature for 0.5 h and was cooled to 0° C. followed by addition of ethyl 7-bromoheptanoate (2.0 g, 8.45 mmol). The reaction was heated at 65° C. for 3 h and was cooled to room temperature. EtOAc was added and the organic solution was washed consecutively with 1N HCl, water, and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Purification by flash chromatography (4:1 hexanes:EtOAc) provided the title compound (2.84 g). 1HNMR (400 MHz, CDCl3) δ 6.95 (m, 1H), 6.75 (m, 2H), 4.06 (m, 5H), 3.56 (t, 2H), 3.22 (t, 2H), 2.86 (s, 3H), 2.26 (t, 2H), 1.60 (m, 4H), 1.32 (m, 4H), 1.22 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH:9]([C:12]#[N:13])[C:10]#[N:11])=O)=[CH:5][CH:4]=1.N1C(C)=CC(C)=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.Cl.[C:43]([NH:47][NH2:48])([CH3:46])([CH3:45])[CH3:44].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C1COCC1>[NH2:11][C:10]1[N:47]([C:43]([CH3:46])([CH3:45])[CH3:44])[N:48]=[C:7]([C:6]2[CH:14]=[CH:15][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)[C:9]=1[C:12]#[N:13]
Reactant: CC(C)(C)NN
Reactant: N#CC(C#N)C(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)(C)n1nc(-c2ccc(C(F)(F)F)cc2)c(C#N)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To a solution of 2-(4-trifluoromethylbenzoyl)propanedinitrile (1.70 g, 7.15 mmol) in CH2Cl2 (60 ml), was added collidine (1.89 ml, 14.3 mmol) followed by trifluoromethanesulphonic anhydride (1.45 ml, 8.58 mmol) and the mixture stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure and the residue dissolved in THF (100 ml). This was added to a suspension of tert-butyl hydrazine hydrochloride (0.98 g, 7.86 mmol) and sodium carbonate (1.14 g, 10.73 mmol) in THF and heated at reflux for 2.5h. The reaction was again concentrated under reduced pressure, the residue dissolved in ethyl acetate (100ml), washed with 2M hydrochloric acid (1×100 ml), water (1×100 ml) and brine (1×100 ml), dried (MgSO4) and solvent then removed under reduced pressure. The resulting solid was subjected to column chromatography to give the title compound (700 mg) as a pale pink solid after recrystallisation from ether, m.p. 155-156°. δH (CDCl3) 1.68 (9H, s), 4.46 (2H, br s), 7.66 (2H, d, J 8.0 Hz), and 8.03 (2H, d, J 8.0 Hz).
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:13])=[C:10]([F:25])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.O.NN>CO>[F:1][C:2]1[C:11]([CH:12]([NH2:14])[CH3:13])=[C:10]([F:25])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(c1c(F)cc2ncccc2c1F)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: CC(N)c1c(F)cc2ncccc2c1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of 2-(1-(5,7-difluoroquinolin-6-yl)ethyl)isoindoline-1,3-dione (2.6 g, 7.7 mmol) in CH3OH (50 mL) was added hydrazine monohydrate (0.38 g, 7.7 mmol). The solution was heated at 50° C. and stirred overnight. After cooling and evaporating, the residue was purified by silica gel and eluted with hexane/EtOAc to give the title compound (1.0 g, 60%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.95 (d, 1H), 8.45 (d, 1H), 7.65 (d, 1H), 7.60 (dd, 1H), 4.49 (q, 1H), 2.20 (bs, 2H), 1.48 (d, 3H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:35])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:53])[C@@H:15]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si](C(C)(C)C)(C)C)[CH2:39]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:35])[CH:21]([O:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([CH3:33])([CH3:34])[CH3:32])=[CH:29][CH:30]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:53])[C@@H:15]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([OH:45])[CH2:39]2)=[CH:10]1
Reactant: CCC(Oc1ccc(C(C)(C)C)cc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1ccc(C(C)(C)C)cc1)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 66.2 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.39 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(4-t-butylphenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 139, above] and 36.0 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 647 mg of the title compound as white powder.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[C:15]([O:17]CC)=O)#[N:2].[CH3:20][NH2:21]>>[C:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([Br:14])=[CH:12][CH:13]=2)[N:6]=[CH:5][C:4]=1[C:15]([NH:21][CH3:20])=[O:17])#[N:2]
Reactant: CN
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1C#N
Product: CNC(=O)c1cnn(-c2ccc(Br)cc2)c1C#N

Procedure:
A solution of 3.2 g of 5-cyano-1-(4-bromophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester in 40 ml of 3A alcohol and 10 ml of 40% aqueous monomethylamine was refluxed for approximately 2 hours. Ten additional milliliters of 40% aqueous monomethylamine was added to the reaction mixture which was then refluxed for an additional 3 hours. The mixture was cooled and the precipitated solid was collected by filtration to provide 1 g of 5-cyano-1-(4-bromophenyl)-N-methyl-1H-pyrazole-4-carboxamide. mp=240°-241° C.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22]4[O:23][C:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=5)=[N:25][N:26]=4)[CH:20]=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:35])[CH:7]=1.[OH-].[Na+].Cl>CO>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[O:23][C:22]([C:19]3[CH:20]=[CH:21][C:15]4[N:14]=[C:13]([C:9]5[C:8]([CH3:35])=[CH:7][C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:11][C:10]=5[CH3:12])[NH:17][C:16]=4[CH:18]=3)=[N:26][N:25]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)CCc1cc(C)c(-c2nc3ccc(-c4nnc(-c5ccc(OC)cc5)o4)cc3[nH]2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2nnc(-c3ccc4nc(-c5c(C)cc(CCC(=O)O)cc5C)[nH]c4c3)o2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4-{6-[5-(4-Methoxyphenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzoimidazol-2-yl}-3,5-dimethylphenyl)-propionic acid methyl ester in MeOH (10 mL) was added 1N NaOH (10 mL). The mixture was stirred at RT for 2 h then the resulting solution was carefully acidified to pH 3-4 with 1N HCl. The resulting precipitate was filtered, washed with water and was dried under reduced pressure to give the title compound. MS: m/z 469.1 (M+1). H1-NMR (MeOD): δ 8.40 (s, broad, 1 H), 8.15-8.08 (m, 3H), 7.81 (s, broad, 1H), 7.16 (d, J=8.97 Hz, 2H), 7.10 (s, 2H), 3.91 (s, 3H), 2.93 (t, 2H), 2.55 (t, 2H), 2.15 (s, 6H).
Reaction SMILES: [CH:1]1([C:4]([N:6]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:26]([CH3:27])=[CH:25][C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=3)[CH:17]=[CH:16][N:15]=2)C(=O)OC(C)(C)C)=[O:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:27][C:26]1[C:21]([O:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH:19]=2)=[N:22][CH:23]=[C:24]([N+:28]([O-:30])=[O:29])[CH:25]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Oc1ccnc(N(C(=O)OC(C)(C)C)C(=O)C2CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc([N+](=O)[O-])cnc1Oc1ccnc(NC(=O)C2CC2)c1
Yield: 98.5 %

Procedure:
Add tert-butyl N-(cyclopropanecarbonyl)-N-[4-[(3-methyl-5-nitro-2-pyridyl)oxy]-2-pyridyl]carbamate (350 mg, 0.84 mmol) in DCM (10 mL), add trifluoroacetic acid (2 mL). Stir the reaction at room temperature for 2 hrs. Concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:3) affords the title compound (260 mg, 98%). MS: (M+1): 315.
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[C:21]3[N:20]=[CH:19][N:18]=[C:16]([OH:17])[C:15]=3[N:14]=[CH:13]2)[C@H:9]([OH:22])[C@@H:8]1[OH:23])([OH:4])([OH:3])=[O:2].[NH2:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:32])[NH2:31].C1(N=C=NC2CCCCC2)CCCCC1>>[NH2:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][CH2:27][CH2:28][NH:29][C:30](=[NH:31])[NH2:32].[CH:19]1[NH:20][C:21]2[N:12]([C@@H:10]3[O:11][C@H:7]([CH2:6][O:5][P:1]([OH:4])([OH:3])=[O:2])[C@@H:8]([OH:23])[C@H:9]3[OH:22])[CH:13]=[N:14][C:15]=2[C:16](=[O:17])[N:18]=1
Reactant: O=P(O)(O)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Product: O=c1nc[nH]c2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
Arginine-5'-inosine monophosphate was prepared by the reaction of inosine-5'-monophosphate with arginine using dicyclohexylcarbodiimide as a condensing agent.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:11]3[N:16]=[C:15]([CH:17]=[O:18])[S:14][C:12]=3[N:13]=2)[C:6]2[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=2[N:4]=1)[CH3:2].CO.[BH4-].[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:11]3[N:16]=[C:15]([CH2:17][OH:18])[S:14][C:12]=3[N:13]=2)[C:6]2[CH:25]=[CH:26][CH:27]=[CH:28][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)sc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CO)sc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
To a solution of 5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carbaldehyde (1.2 g, 3.04 mmol) in DCE (30 mL) was added MeOH (3 mL) and NaBH4 (119 mg, 3.15 mmol) and the resulting mixture stirred at r.t. for 4 h. The reaction mixture was concentrated in vacuo and the resulting residue triturated with H2O. The resulting solid was collected by filtration and dried in vacuo affording the title compound (1.18 g, 98%). LCMS (method H): RT 2.42 min, [M+H]+ 397.4
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]Br.N.CO.C(Cl)(Cl)Cl>CC(O)=O>[CH2:1]([N:8]1[C:12]2[C:13]([Br:18])=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncn(Cc3ccccc3)c2c1
Reactant: BrBr
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc2ncn(Cc3ccccc3)c2c1Br
Yield: 29 %

Procedure:
To a solution of 3-benzyl-5-aminobenzimidazole (0.88 g, 3.9 mmol) in 20 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CHCl3) to provide 0.35 g (1.2 mmol, 29%) of the product.
Reaction SMILES: O[CH:2]([CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[CH:3]1[C:7](=[O:8])[CH:6]=[C:5]([O:9][CH3:10])[CH2:4]1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:10][O:9][C:5]1[CH2:4][C:3](=[CH:2][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:7](=[O:8])[CH:6]=1
Reactant: COC1=CC(=O)C(C(O)C2CCOCC2)C1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=CC(=O)C(=CC2CCOCC2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.1 %

Procedure:
5-[hydroxy-(tetrahydro-pyran-4-yl)-methyl]-3-methoxy-cyclopent-2-enone (1.1 g, 5 mmol) was dissolved in dichloromethane (25 ml) in a 50 ml round bottom flask fitted with a reflux condenser. Triethylamine (1.4 ml, 10 mmol) and then methane sulfonyl chloride (0.8 ml, 10 mmol) was added dropwise which caused the reaction to warm to reflux. After 10 minutes the reaction was quenched by the addition of 1 M hydrochloric acid (10 ml). The layers were separated and the organics collected, passed through a phase separation cartridge and the solvent removed in vacuo. The crude product was dissolved in methanol (25 ml) and anhydrous potassium carbonate (1.4 g, 10 mmol) added and the mixture was stirred at room temperature for 72 h. The solvent was then removed in vacuo and the residue dissolved in ethyl acetate (25 ml) and filtered to remove any solid. The filtrate was evaporated to dryness and the residue purified on by column chromatography (Hexane/EtOAc (7:3) to 100% EtOAc) to give 3-methoxy-5-[1-(tetrahydro-pyran-4-yl)-methylidene]-cyclopent-2-enone (938 mg).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.C([O-])([O-])=O.[K+].[K+].[CH3:39][NH2:40].O>CS(C)=O>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27]([NH:40][CH3:39])=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CN
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1ncccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1

Procedure:
A mixture of 1 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-chloropyridine-3-carboxamide, 1 g of K2CO3 and 10 ml of a 40% solution of monomethylamine is heated in 25 ml of dimethylsulfoxide for 8 hours at 100° C. The reaction mixture is poured over water and the pale yellow solid separated. The reaction mixture is filtered and the collected solid washed well with water. After drying the solid is purified by column chromatography on silica gel by elution with 9:1 ethyl acetate:methanol to give 850 mg of the desired product as a pale yellow solid: M+ =437.
Reaction SMILES: [C:1]([C:3]1[C:4]2[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:11][N:10]([C:18]3[CH:19]=[C:20]([C:23]([OH:25])=O)[S:21][CH:22]=3)[C:5]=2[C:6](=[O:9])[NH:7][CH:8]=1)#[N:2].CC[N:28]=C=NCCCN(C)C.O>CC(N(C)C)=O>[C:1]([C:3]1[C:4]2[C:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:11][N:10]([C:18]3[CH:19]=[C:20]([C:23]([NH2:28])=[O:25])[S:21][CH:22]=3)[C:5]=2[C:6](=[O:9])[NH:7][CH:8]=1)#[N:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: N#Cc1c[nH]c(=O)c2c1c(C1CCCC1)nn2-c1csc(C(=O)O)c1
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1c[nH]c(=O)c2c1c(C1CCCC1)nn2-c1csc(C(N)=O)c1
Yield: 45.8 %

Procedure:
A solution of 4-(4-cyano-3-cyclopentyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-1-yl)thiophene-2-carboxylic acid (14 mg) obtained in Example 65, EDCI (7.36 mg) and HOBt ammonium salt (18 mg) in DMA (3 mL) was stirred at room temperature for 60 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (6.4 mg).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].B([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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:6]([C:5]1[CH:8]=[CH:9][C:2]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)=[C:3]([CH3:10])[CH:4]=1)#[N:7]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C#N)ccc1-c1ccc(C(=O)O)cc1
Yield: 67.4 %

Procedure:
A stirred solution of 4-bromo-3-methylbenzonitrile (5.0 g, 0.026 mole) and 4-boronobenzoic acid (4.2 g, 0.026 mole) in a mixture of DME (100 ml) and water (100 ml) under argon was treated with sodium carbonate (11.6 g, 0.11 mole) and tetrakis (triphenylphosphine) palladium (O) (0.55 g) and heated under reflux for 20 h. The solution was concentrated in vacuo to approx. 100 ml volume, then washed with ethyl acetate and acidified with 5M HCl acid. The solid which was produced was filtered off, washed with water and dried in vacuo to afford the title compound as a white solid (4.16 g, 69%).
Reaction SMILES: [C:1]([S:9][CH2:10][C@@H:11]([CH3:15])[C:12]([OH:14])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]1[NH:40][C@H:39]([C:41]([OH:43])=[O:42])[CH2:38][S:37]1>O1CCCC1.O>[C:1]([S:9][CH2:10][C@@H:11]([CH3:15])[C:12]([N:40]1[C@H:39]([C:41]([OH:43])=[O:42])[CH2:38][S:37][CH:36]1[C:32]1[S:31][CH:35]=[CH:34][CH:33]=1)=[O:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CSC(c2cccs2)N1
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1C(c2cccs2)SC[C@H]1C(=O)O
Temperature: -5 °C

Procedure:
11.2 g of (2S)-S-benzoyl-3-mercapto-2-methylpropanoic acid and 5.1 g of triethylamine are dissolved in 100 ml of dehydrated tetrahydrofuran. To this solution, 6.8 g of isobutyl chloroformate is added dropwise while stirring at the temperature maintained -5° C. After the addition, the mixture is stirred at room temperature for 10 minutes. To this solution, 10.8 g of (4R)-2-(2-thienyl)-4-thiazolidinecarboxylic acid and 5.1 g of triethylamine dissolved in the mixed solution of 5 ml of tetrahydrofuran and 15 ml of water are added. The mixture is stirred at room temperature for 30 minutes. To this reaction mixture, 200 ml of water is added and the mixture is extracted with ethyl acetate. The aqueous layer is acidified with dilute hydrochloric acid and the produced oil is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the titled compound, yield 10.3 g (49%), mp. 136°-137° C. (benzene), [α]D25 +79.6° (c=1.0, methanol).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[S:11])[CH3:8].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[C:14]=1[O:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:27]1[C:28]([CH3:30])=[CH:29][C:25]([O:24][C:14]2[C:15]([F:23])=[CH:16][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:18][C:13]=2[Cl:12])=[N:26]1)=[S:11])[CH3:8]
Reactant: Cc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: CCN=C=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=S)n1nc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
Potassium carbonate (0.22 g, 1.6 mmol) and ethyl isothiocyanate (0.13 g, 1.8 mmol) were added to a solution of 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.44 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-ethyl-3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carbothioamide (0.05 g, yield: 9.4%). mp: 114-115° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.25 (t, J=7.3 Hz, 3H), 2.81 (d, J=0.6 Hz, 3H), 3.67 (dq, J=5.7 and 7.3 Hz, 2H), 5.84 (q, J=0.6 Hz, 1H), 7.41 (dd, JHF=2.1 and 9.4 Hz, 1H), 7.62 (s, 1H), 8.54 (br s, 1H).
Reaction SMILES: [N:1]1[C:6]2[C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[Se:9][C:5]=2[C:4](=[O:14])[NH:3][N:2]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:15][N:3]1[C:4](=[O:14])[C:5]2[Se:9][C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[C:6]=2[N:1]=[N:2]1
Reactant: O=c1[nH]nnc2c3c([se]c12)CCCC3
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1nnc2c3c([se]c2c1=O)CCCC3
Temperature: 25 °C
Yield: 72 %

Procedure:
To a solution of 6,7,8,9-tetrahydro-3H-benzo[1,2-b]1,2,3-triazino[4,5-d]selenophen-4-one (450 mg, 1.76 mmol) in acetone (50 mL) was added sequentially potassium carbonate (480 mg, 3.52 mmol), iodomethane (0.13 mL, 2.11 mmol) and a catalytic amount of PEG-400 was added and stirred at rt and the mixture was stirred at rt for 16 h. The solution was filtered and the solids were washed with acetone. Acetone was evaporated under reduced pressure and the residue was chromatographed over silica gel column using hexane-ethyl acetate (90:10) as eluents to give the product as a pale yellow color solid (340 mg, 72%), which was recrystallized from chloroform-hexane (170 mg), mp 110-112° C. IR (neat) νmax 3438, 1668, 1220, 1018 cm−1; 1H NMR (400 MHz, CDCl3): δ 4.05 (3H, s, —NCH3), 2.94-2.96 (4H, m, H-6,9), 1.91-1.97 (4H, m, H-7,8); 13C NMR (100 MHz, CDCl3): δ 156.1, 155.1, 152.5, 133.9, 128.5, 37.4, 28.4, 24.8, 23.6, 21.4; LC-MS (positive ion mode): m/z 268, 270 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:13]=1[C:14](Cl)=[O:15]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:13]=1[C:14]([NH:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1)=[O:15]
Reactant: Nc1noc2ccccc12
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1noc2ccccc12)c1c(Cl)cccc1Cl

Procedure:
3-Aminobenzisoxazole (2 gram), 2,6-dichlorobenzoylchloride (2 gram), and 50 ml. of toluene are heated at reflux for 16 hours. After evaporation of the solvent at reduced pressure, the resultant oily semi-solid is triturated with ether. The solid so formed is then washed with ether and water and constitutes the desired product.