Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C(N(CC)CC)C>C(O)C>[C:15]1(=[O:24])[N:14]([CH2:13][CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Sc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00 g, 20 mmoles) and N-[2-(bromo)ethyl]phthalimide (5.59 g, 22 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 3 hours and heated at reflux for 4 hours. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 3.95 g of the desired product (61.1%, yellow crystals).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(Nc1ccc(F)c(Cl)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 62.8 %

Procedure:
3-chloro-4-fluoroaniline (238 mg, 1.63 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (200 mg, 0.41 mmol, as described in Example 3.03) to give 8-(1-(3-chloro-4-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (122 mg, 63.1%) as a white solid. Mass Spectrum: M+H+ 474. NMR Spectrum: (DMSOd6) 1.51 (d, 3H), 2.70 (s, 3H), 2.94 (s, 3H), 3.50-3.64 (m, 4H), 3.69-3.81 (m, 4H), 4.94-5.05 (m, 1H), 5.60 (m, 1H), 6.47 (ddd, 1H), 6.52 (d, 1H), 6.67 (dd, 1H), 7.05 (dd, 1H), 7.55 (d, 1H), 7.79 (d, 1H).
Reaction SMILES: [ClH:1].[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:20]1=[O:26].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[ClH:1].[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:20]3=[O:26])[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCC(=O)N1CCCCBr
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCC(=O)N1CCCCN1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Phenyl-1,2,3,6-tetrahydropyridine, hydrochloride (10g) is converted to its free base and mixed with 11.0g of N-(4-bromobutyl)glutarimide and 18g of sodium carbonate in 200 ml of toluene. The mixture is refluxed for 5 hours, cooled to 25° C, and 50 ml of water is added. After stirring for 15 minutes, the layers are separated and the organic layer is filtered through fritted glass and extracted with 10% hydrochloric acid. The acid layer is made alkaline (pH 10) with sodium hydroxide producing an insoluble gum that crystallizes on standing. The supernatant is decanted and the residue is recrystallized by dissolving in methanol and slowly diluting with an equal volume of water. An oil is produced that crystallizes on standing.
Reaction SMILES: [CH:1]1([C:5](=[O:20])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH:29]=[O:30]>C1COCC1>[CH2:33]([O:32][C:28](=[O:31])[CH:29]([OH:30])[CH:6]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:11][CH:12]=1)[C:5]([CH:1]1[CH2:2][CH2:3][CH2:4]1)=[O:20])[CH3:34]
Reactant: O=C(Cc1ccc(OC2CCCCC2)cc1)C1CCC1
Reactant: CCOC(=O)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(O)C(C(=O)C1CCC1)c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.2 %

Procedure:
To a stirred solution of 1-cyclobutyl-2-(4-cyclohexyloxy-phenyl)-ethanone (3.60 mmol, 0.98 g) and triethylamine (3.60 mmol, 0.51 mL) in THF (2.0 mL) was added a solution of ethyl glyoxylate (50% in toluene, 18.0 mmol, 3.82 mL) and continued stirring for 12 h at room temperature. After removal of volatiles under reduced pressure, the crude product was pre-absorbed onto 10 g SiO2 followed by purification on a 24 g SiO2 cartridge using a 0-30% ethyl acetate/hexanes gradient to give 4-cyclobutyl-3-(4-cyclohexyloxy-phenyl)-2-hydroxy-4-oxo-butyric acid ethyl ester (0.42 g).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>CN(C=O)C>[O:20]([C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=Cc1cc(C(F)(F)F)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a stirred solution of 2-chloro-5-(trifluoromethyl)benzaldehyde (500 mg, 2.40 mmol) in DMF (5 ml) was added phenol (226 mg, 2.40 mmol), K2CO3 (663 mg, 4.79 mmol). The reaction suspension was stirred at room temperature for 1 hr, then at 80° C. for 1.5 hr. The reaction mixture was neutralizing for acetic acid (0.5 ml), the solvent was removed. To the solid residue was added water and the mixture was extracted with CH2Cl2. The combined CH2Cl2 extracts were washed with sat. NaHCO3 aq., dried with MgSO4, and concentrated to give crude Compound 6 as a yellow oil. This was purified with chromatography to give pure Compound 6 as a yellow oil (466 mg, 72.9%)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4]Br.C([O-])([O-])=[O:12].[Ca+2]>O1CCOCC1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4][OH:12]
Reactant: Fc1ccc(Br)c(CBr)c1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: OCc1cc(F)ccc1Br

Procedure:
2-Bromo-5-fluorobenzylbromide (2.0 g, 7.46 mmol) was dissolved in dioxane (25 mL) and H2O (25 mL), and CaCO3 (3.84 g, 38.39 mmol) was added. The mixture was heated to reflux overnight. The solution was concentrated, and the residue was partitioned between H2O and CH2Cl2. The organic phase was washed with 1N HCl and brine, dried (MgSO4), filtered, and concentrated to afford the title compound. 1H NMR (CDCl3): δ 2.00 (t, 1H), 4.72 (d, 2H), 6.85-6.92 (m, 1H), 7.26 (dd, 1H), 7.48 (dd, 1H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].C(N(CC)CC)C.Br[CH2:17][CH2:18][CH2:19]Br>O1CCOCC1>[N:5]1[N:6]2[CH2:17][CH2:18][CH2:19][NH:1][C:2]2=[C:3]([C:7]#[N:8])[CH:4]=1
Reactant: N#Cc1cn[nH]c1N
Reactant: BrCCCBr
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#Cc1cnn2c1NCCC2
Temperature: 95 °C
Reaction time: 120 h

Procedure:
To a solution of 5-aminopyrazole-4-carbonitrile (102 g) and triethylamine (316 ml) in 1,4-dioxane (2000 ml) was added 1,3-dibromopropane (115 ml), and the mixture was stirred at 95° C. for 5 days. The insoluble materials were removed by filtration, and the filtrate was concentrated in vacuo. To the residue was added 10% aqueous citric acid solution, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with 2-propanol and dried in vacuo to give 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (8.0 g) as a solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C>C1COCC1>[Cl:11][C:9]1[C:10]2[C:2]([CH:20]=[O:21])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CN(C)C=O
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (G-1) (2.33 g, 10.0 mmol, 1.0 eq) in anhydrous THF (100 mL) at −78° C. under argon, n-BuLi solution (2.5 M in THF, 8.8 mL, 22.0 mmol, 2.2 eq) is added dropwise (over 10 min). The resulting mixture is stirred at −78° C. for 1 h and then DMF (2.0 g, 11.0 mmol, 1.1 eq) is added dropwise (over 10 min). The mixture is stirred at −78° C. for an additional 30 min and then stirred at RT overnight. The reaction mixture is quenched with H2O (50 mL) and then concentrated in vacuo. The residue is triturated with saturated aqueous NH4Cl solution. The solid is collected by filtration, rinsed with ethyl acetate, and dried in vacuo to afford the product, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (G-2).
Reaction SMILES: [CH:1]1([C:7]2([C:12]3[CH:17]=[C:16]([O:18]C)[CH:15]=[C:14]([O:20]C)[CH:13]=3)[S:11][CH2:10][CH2:9][S:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(O)C=C(O)C=2)SCCS1)CCC>CCCCCC.C(OCC)(=O)C>[CH:1]1([C:7]2([C:12]3[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([OH:20])[CH:13]=3)[S:8][CH2:9][CH2:10][S:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(OC)cc(C2(C3CCCCC3)SCCS2)c1
Agent: CCCCC1(c2cc(O)cc(O)c2)SCCS1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Oc1cc(O)cc(C2(C3CCCCC3)SCCS2)c1

Procedure:
Compound 18 was prepared from Compound 11 using the same procedure as described above for Compound 16. Yield 0.853 g (62.2%) as a waxy solid. Rf=0.27 (hexane:ethyl acetate 8:2); 1H NMR δ 6.78 (d, J=0.9 Hz, 2H), 6.19 (t, J=1.95 Hz, 1H), 4.14 (br s, 2H), 3.32–3.07 (m, 4H), 2.15–2.06 (m, 1H), 1.96–1.58 (m, 4H), 1.19–1.00 (m, 4H); 13C NMR δ 156.95, 147.94, 107.39, 101.12, 80.58, 60.83, 50.56, 38.82, 30.92, 26.77, 26.24, 21.08, 14.17; MS: (ESI, Neg.) m/z 295 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:25]=[CH:26][CH:27]=1)[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=O)=[CH:17][CH:18]=2)[C:13]([CH3:23])=[C:12]1[CH3:24])[CH3:5].[CH:29]([O:32][C:33]1[CH:34]=[C:35]([C@@H:39]([NH2:41])[CH3:40])[CH:36]=[CH:37][CH:38]=1)([CH3:31])[CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:29]([O:32][C:33]1[CH:34]=[C:35]([C@@H:39]([NH:41][C:20]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[N:11]([CH2:10][C:9]2[CH:8]=[C:7]([CH:27]=[CH:26][CH:25]=2)[O:6][C@@H:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:28])[C:12]([CH3:24])=[C:13]3[CH3:23])=[O:22])[CH3:40])[CH:36]=[CH:37][CH:38]=1)([CH3:31])[CH3:30]
Reactant: CC(C)Oc1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(OC(C)C)c4)ccc32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid (50 mg, 0.13 mmol, 1 equiv) in DCM (2 mL) was added (S)-1-(3-isopropoxyphenyl)ethanamine (34 mg, 0.16 mmol, 1.2 equiv), DIEA (70 μL, 0.39 mmol, 3 equiv) and HATU (50 mg, 0.13 mmol, 1 equiv). The reaction mixture was stirred 2 h at room temperature. The solvent was removed in vacuo. The residue was dissolved in AcOEt and washed with a 0.5N HCl aqueous solution, a saturated NaHCO3 solution and brine, dried over MgSO4. The filtrate was concentrated to obtain the crude product which was purified by flash chromatography (AcOEt/Hexane 0->50%) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([OH:14])[C:3]=1[C:15](=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].Cl.[C:25](Cl)(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.O>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]2[C:3]=1[C:15](=[O:17])[CH:16]=[C:25]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[O:14]2
Reactant: CC(=O)c1c(O)cc(N2CCOCC2)cc1O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=c1cc(-c2cccnc2)oc2cc(N3CCOCC3)cc(O)c12
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 12 %

Procedure:
To a suspension of 1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone (86 mg, 0.362 mmol) and K2CO3 (250 mg, 1.81 mmol) in acetone (3 mL) was added nicotinoyl chloride hydrochloride (0.71 mL, 0.399). The reaction vessel was sealed and heated to 85° C. for 24 h. After cooling to room temperature, water (about 2 mL) was added, and the mixture was allowed to stir for about 10 min. The contents were transferred to a separatory funnel containing water (5 mL) and extracted with EtOAc (3×15 mL). The organic layer was dried (MgSO4) and concentrated. The concentrate was purified via Biotage chromatography with gradient elution from 100% hexanes to 100% EtOAc to yield 14 mg (12%) of 5-hydroxy-7-morpholin-4-yl-2-pyridin-3-yl-chromen-4-one. Rf=0.22 (100% EtOAc).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20]Br>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccc(Cl)c(Cl)c1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 59.3 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 3,4-dichloro-benzyl bromide (116 mg, 0.48 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(3,4-dichloro-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (104 mg, 59%) as a light yellow solid. APCI-MS (M+H) 365.
Reaction SMILES: FC(F)(F)S(OC)(=O)=O.[CH2:10]([C:14]1[S:23][C:22]2[NH:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[NH:18][C:17](=S)[C:16]=2[N:15]=1)[CH2:11][CH2:12][CH3:13].[CH2:29]([C@H:37]1[CH2:42][NH:41][CH2:40][CH2:39][NH:38]1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1C=CC=CC=1>ClCCl>[CH2:10]([C:14]1[S:23][C:22]2[NH:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[N:18]=[C:17]([N:41]3[CH2:40][CH2:39][NH:38][C@@H:37]([CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:42]3)[C:16]=2[N:15]=1)[CH2:11][CH2:12][CH3:13]
Reactant: c1ccc(CC[C@H]2CNCCN2)cc1
Reactant: CCCCc1nc2c(s1)Nc1ccccc1NC2=S
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
Add methyl trifluoromethanesulfonate (0.850 mL, 7.51 mmol) to a 0° C. solution of 2-Butyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (1.45 g, 5.01 mmol) in anhydrous dichloromethane. Rinse solids into reaction with dichloromethane and stir allowing reaction to slowly reach ambient temperature. After an overnight period, concentrate under reduced pressure to afford crude methylated intermediate. Take 1.06 g of this intermediates (2.0 mmol), and combine the intermediate and 2-(S)-Phenethyl-piperazine (0.38 g, 2.0 mmol), with anhydrous pyridine, heat to 100° C. and stir. After an overnight period, cool to ambient temperature and concentrate under reduced pressure to an oil (2.16 g), followed by two chromatographic purifications, eluting with a gradient of a 8% solution of 2M ammonia in methanol, in dichloromethane (0–100% in dichloromethane), gives the title compound (0.078 g). Mass spectrum (APCI+, m/e): 446 (M+1); 1H NMR (300 MHz, DMSO-d6), δ (ppm): 7.79 (s, 1H), 7.31–7.10 (m, 5H), 6.90–6.74 (m, 3H), 6.71–6.64 (m, 1H), 4.14–3.92 (br. m, 1H), 3.44–3.22 (m, 1H), 2.93–2.52 (m, 10H), 1.65–1.49 (m, 4H), 1.36–1.20 (m, 2H, J=7.1 Hz), 0.82 (t, 3H, J=7.1 Hz).
Reaction SMILES: C([O:8][C:9]([N:11]([CH3:14])[NH:12][CH3:13])=O)C1C=CC=CC=1.ClC(OC(Cl)(Cl)Cl)=O.[CH3:23][NH:24][CH3:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:23][N:24]([CH3:25])[C:9]([N:11]([CH3:14])[NH:12][CH3:13])=[O:8]
Reactant: CNN(C)C(=O)OCc1ccccc1
Reactant: CNC
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CNN(C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of N-benzyloxycarbonyl-N,N'-dimethylhydrazine (1.6 g) in toluene (30 ml) was added trichloromethyl chloroformate (0.553 ml). After the solution was refluxed for 30 minutes, dimethylamine (672 mg) and triethylamine (2.0 g) was added thereto at 0° C. The reaction mixture was stirred at ambient temperature for 2 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate (50 ml). The solution was washed with 5% hydrochloric acid, 1 M sodium bicarbonate solution and water successively, and dried over magnesium sulfate. After evaporation of the solvent, the residue was dissolved in methanol (20 ml) and water (20 ml). The solution was hydrogenated over 10% palladium on carbon (100 mg) at 3 atmospheric pressure of hydrogen for 1 hour. The solution was filtered and concentrated in vacuo to give N-(N,N-dimethylcarbamoyl)-N,N'-dimethylhydrazine (820 mg) as an oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[CH:4]([CH3:9])[O:5][CH:6](O)[CH:7]=1.P(=O)(O)(O)[OH:12]>>[CH3:9][C:4]1[O:5][CH:6]=[CH:7][C:2](=[O:12])[C:3]=1[OH:10]
Reactant: O=P(O)(O)O
Reactant: CC1OC(O)C=C(Br)C1=O
Product: Cc1occc(=O)c1O
Yield: 34 %

Procedure:
A solution of 4-bromo-6-hydroxy-2-methyl-2H-pyran-3(6H)-one (0.0025 mole) in 20 ml of 35% phosphoric acid was refluxed for about 5 hours. Maltol (34%) was isolated by the method of Example 1.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH2:13]([C:20]1[CH:38]=[CH:37][C:23]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([NH:35][NH2:36])=[O:34])=[CH:29][CH:28]=2)=[O:25])=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(O)(=O)C>[CH2:13]([C:20]1[CH:38]=[CH:37][C:23]([C:24]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][N:36]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[O:34])=[CH:31][CH:32]=2)=[O:25])=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCc1ccc(C(=O)Nc2ccc(C(=O)NN)cc2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: CCCCCCCc1ccc(C(=O)Nc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Temperature: 100 °C
Yield: 91 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-heptyl-N-[4-(hydrazinocarbonyl)phenyl]-benzamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 111 mg of the title compound (91%) as a yellow powder in 93.1% purity by HPLC (Rt: 6.3, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](Cl)=[O:13])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[NH2:15][CH:16]1[C:23](=[O:24])[N:22]2[CH:17]1[S:18][CH2:19][C:20]([CH3:28])=[C:21]2[C:25]([OH:27])=[O:26]>C(OCC)(=O)C>[N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:15][CH:16]2[C:23](=[O:24])[N:22]3[CH:17]2[S:18][CH2:19][C:20]([CH3:28])=[C:21]3[C:25]([OH:27])=[O:26])=[O:13])=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: [N-]=[N+]=NCc1ccc(CC(=O)Cl)cc1
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CN=[N+]=[N-])cc3)C2SC1

Procedure:
A mixture of p-azidomethylphenylacetyl chloride (0.6 g) and 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (0.6 g) in 250 ml of ethyl acetate was refluxed for 50 minutes after which the solvent was removed under vacuum yielding an oily residue which was purified by chromatography using 60 g of silica gel and benzene-acetone as the eluant to give 7-[[2-[4-(azidomethyl)phenyl]acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. M.P. 154°-155° C.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([CH3:48])[C:45]([NH2:49])=[C:44]([CH3:50])[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([O:38]CC)=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:51]=[CH:52][CH:53]=[CH:54][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([CH3:48])[C:45]([NH2:49])=[C:44]([CH3:50])[CH:43]=3)[C:21]([N:23]3[CH2:24][CH2:25][CH:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:31][CH2:30]4)[CH2:27][CH2:28]3)=[O:22])=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:51]=[CH:52][CH:53]=[CH:54][C:6]=2[NH:5]1
Reactant: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C)c(N)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.1 mg (0.13 mmol) LiOH in 1 mL water was added to a solution of 55 mg (0.08 mmol) of (R)-1-(4-amino-3,5-dimethyl-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 90) in 5 mL THF and the reaction mixture was stirred overnight at RT. The mixture was evaporated down i.vac., the residue was taken up in 1 mL DMF and the crude product was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:26][S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH2:36][NH2:37])=[N:34][CH:35]=1)(=[O:29])=[O:28].[CH3:38][C:39]1[N:44]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[C:43](=[O:55])[C:42]([C:56](O)=[O:57])=[CH:41][C:40]=1[C:59]1[N:60]([CH3:64])[N:61]=[CH:62][CH:63]=1.CC(N(C)C)=O>CN1C(=O)CCC1>[CH3:38][C:39]1[N:44]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:52])[F:53])[CH:46]=2)[C:43](=[O:55])[C:42]([C:56]([NH:37][CH2:36][C:33]2[CH:32]=[CH:31][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:35][N:34]=2)=[O:57])=[CH:41][C:40]=1[C:59]1[N:60]([CH3:64])[N:61]=[CH:62][CH:63]=1
Reactant: Cc1c(-c2ccnn2C)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)c1ccc(CN)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccnn2C)cc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 20.4 %

Procedure:
HBTU (30 mg, 0.079 mmol) was added to {[5-(methylsulfonyl)pyridin-2-yl]methyl}amine hydrochloride (20 mg, 0.090 mmol), 6-methyl-5-(2-methyl-2H-pyrazol-3-yl)-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid (Example 92 (a), 27 mg, 0.072 mmol) and DMA (23 μl, 0.31 mmol) in NMP (0.25 ml) and the mixture was stirred in a sealed vial overnight. The product was purified by preparative HPLC and freeze-dried to give the title compound as a white solid (8 mg, 20%).