Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH:10]([C:25]#[N:26])[CH2:11][CH2:12][C@H:13]([O:23][CH3:24])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[NH2:28][OH:29]>CCO>[C:1]([O:5][C:6](=[O:27])[N:7]([CH:10]([C:25]([NH:28][OH:29])=[NH:26])[CH2:11][CH2:12][C@H:13]([O:23][CH3:24])[CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: NO
Reactant: CCN(C(=O)OC(C)(C)C)C(C#N)CC[C@@H](COCc1ccccc1)OC
Solvent: CCO
Product: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](COCc1ccccc1)OC)C(=N)NO
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl[(4S)-5-(benzyloxy)-1-cyano-4-methoxypentyl]ethylcarbamate (74 g, 197 mmol) in EtOH (1000 mL) was added TEA (54.8 mL, 393 mmol) and NH2OH (50% in water, 14.45 mL, 236 mmol). The resulting solution was stirred at 40° C. overnight and then concentrated in vacuo. The residue was dissolved in MeOH and the solvent was removed under reduced pressure (3×) to remove water. The crude residue was used in the next reaction without further purification. LC-MS: 410.5 (M+1).
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:4]2=[N:3][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[CH:1]1[N:5]2[C:6]3[C:11]([N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:4]2=[N:3][C:2]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CCOC(=O)N1Cc2nccn2-c2ccccc21
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(n1)CN(C(=O)OCC)c1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
A solution of 1.0 g of ethyl 4,5-dihydroimidazo[1,2-a]quinoxaline-5-carboxylate in 5 ml of dry dimethylformamide was treated with 0.5 g of ethyl chloroformate and the mixture was stirred at room temperature. After 2 hours, the mixture was set solid, was filtered and the residue was triturated with water and chromatographed over silica gel with ethyl acetate as eluant to obtain 0.98 g (76% yield) of diethyl 4,5-dihydroimidazo[1,2-a]quinoxaline-2,5-dicarboxylate melting at 151°-3° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)=[N:5][N:4]=[N:3]1.OS([O-])(=O)=O.[K+]>>[C:16]1([CH:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cn1nnnc1CC(O)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: Cn1nnnc1CC(c1ccccc1)c1ccccc1
Temperature: 200 °C
Yield: 83.7 %

Procedure:
A mixture of 2(1-methyltetrazol-5-yl)-1,1-diphenylethanol (2.15 g; 7.68 mmole) and KHSO4 (300 mg) was heated at 200° C. for 20 minutes. The cooled mixture (50° C.) was triturated with CHCl3 (50 mL) and the organic solvent was decanted from the inorganic residue. Evaporation afforded the title compound as a cream solid (1.7 g; 85%); m.p.=147°-148° C. (crystallized from EtOAc-hexane). MS (CI): m/e=263 for (M+H)+ ;
Reaction SMILES: [C:1]([C:4]1[C:16]([OH:17])=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([CH2:18][CH:19]=[CH2:20])[CH:5]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[C:1]([C:4]1[C:16]([OH:17])=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([CH2:18][CH:19]2[O:29][CH2:20]2)[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cc(C(C)=O)c(O)cc1OCCCCC#N
Solvent: ClCCl
Product: CC(=O)c1cc(CC2CO2)c(OCCCCC#N)cc1O
Reaction time: 5 h

Procedure:
To a solution of 5.46 % of 5-[4-acetyl-5-hydroxy-2-allylphenoxy]pentanenitrile in 100 ml of methylene chloride were added 6.1 % of 85% meta-chloroperbenzoic acid. After stirring for 5 hours, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and a cold sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to approximately 35 ml. The solution was placed in a freezer overnight providing 4.08 g of the crystalline title product which were recovered by filtration, m.p. 86°-87° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[C:16]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][C:36]#[N:37])=[CH:28][CH:27]=2)[NH:15][N:14]=1)(=[O:11])=[O:10].C([Sn]([N:51]=[N+:52]=[N-:53])(CCCC)CCCC)CCC.Cl>C(O)COCCO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[C:16]([S:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][CH2:35][C:36]3[NH:53][N:52]=[N:51][N:37]=3)=[CH:30][CH:31]=2)[NH:15][N:14]=1)(=[O:10])=[O:11]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: Cc1ccc(F)cc1S(=O)(=O)Nc1n[nH]c(SCc2ccc(OCCCC#N)cc2)c1-c1ccccn1
Agent: Cl
Solvent: OCCOCCO
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1n[nH]c(SCc2ccc(OCCCc3nnn[nH]3)cc2)c1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
The 3-(2-methyl-5-fluorophenyl)sulfonylamino-4-(2-pyridyl)-5-(4-(3-cyanopropoxy)benzylthio)-(1H)-pyrazole (0.537 g), prepared as described in Example 7, above, in diethylene glycol was treated with 1.5 equivalents of tributyltin azide and heated at reflux temperature overnight. After cooling, 2N hydrochloric acid (2 ml) was added and the mixture was stirred 1 hr at room temperature. After extraction with tetrahydrofuran, the organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum. Flash chromatography over silica with 3:1 chloroform/ethyl acetate (1 1.), followed by the same solvent plus 5% methanol afforded 0.256 g (44% yield) of the pure product which crystallized from chloroform.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:50][C:51]1[C:56]([F:57])=[C:55]([F:58])[CH:54]=[CH:53][C:52]=1B(O)O>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([O:10][C:7]1[CH:6]=[C:3]([CH:4]=[O:5])[C:2]([C:54]2[CH:53]=[CH:52][C:51]([F:50])=[C:56]([F:57])[C:55]=2[F:58])=[CH:9][CH:8]=1)[CH3:12]
Reactant: CCOc1ccc(Br)c(C=O)c1
Reactant: OB(O)c1ccc(F)c(F)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc(F)c(F)c2F)c(C=O)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
To a degassed solution of 2-bromo-5-ethoxybenzaldehye (300 mg, 1.31 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (53.8 mg, 0.131 mmol; S-Phos ligand), palladium (II) acetate (14.7 mg, 0.065 mmol) in THF (8 mL) were added K3PO4 (834 mg, 3.93 mmol) and (2,3,4-trifluorophenyl)boronic acid (276, 1.57 mmol). Reaction mixture was stirred at 70° C. under a N2 atmosphere for 16 hours, cooled to room temperature and then filtered. The filtrate was concentrated by evaporation under reduced pressure. The residue was purified on a silica gel column eluting with 5 to 10% EtOAc in hexanes to provide the title intermediate (255 mg) as white solid.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:26]=[N:27][N:28]([CH3:44])[C:29]=1[N:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[C@H:32]([CH3:43])[CH2:31]1)=[O:23])=O)(C)(C)C.N>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:26]=[N:27][N:28]([CH3:44])[C:29]=1[N:30]1[CH2:35][CH2:34][NH:33][C@H:32]([CH3:43])[CH2:31]1)=[O:23]
Reactant: C[C@@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2C)CCN1C(=O)OC(C)(C)C
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnn2C)CCN1
Yield: 73.2 %

Procedure:
A solution of tert-butyl (R)-4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-2-methylpiperazine-1-carboxylate (80 mg, 0.126 mmol) in TFA (1 mL) and DCM (4 mL) was stirred at ambient temperature for 3 hours. The pH of the mixture was adjusted to about 8˜9 by addition of ammonia and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to afford 102 (40 mg, 73%). 1H NMR (500 MHz, CDCl3) δ (ppm): 8.48 (s, 1H), 8.33 (s, 1H), 7.69 (s, 1H), 7.30-7.36 (m, 1H), 7.03-7.07 (m, 2H), 6.14-6.17 (m, 2H), 3.78 (s, 3H), 3.53-3.48 (m, 1H), 2.90-3.34 (m, 6H), 1.32 (d, J=6.5 Hz, 3H); MS (ESI) m/z=434 (M+1+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[N:17][O:18][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[N:5]=[C:4]([CH3:29])[CH:3]=1.O.[CH3:31][C:32](OC(C)=O)=[O:33]>>[C:32]([NH:1][C:2]1[N:6]([C:7](=[N:17][O:18][S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=2)(=[O:21])=[O:20])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[N:5]=[C:4]([CH3:29])[CH:3]=1)(=[O:33])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)ON=C(c2cccc([N+](=O)[O-])c2)n2nc(C)cc2N)cc1
Solvent: O
Product: CC(=O)Nc1cc(C)nn1C(=NOS(=O)(=O)c1ccc(C)cc1)c1cccc([N+](=O)[O-])c1
Yield: 86 %

Procedure:
2 g (4.8 mmol) of 5-amino-3-methyl-1-(O-tosyl-3-nitrobenzohydroximoyl)-pyrazole are heated for 5 minutes under reflux in 5 ml of acetanhydride. This is then cooled down and hydrolysed with water. The solid mass which forms after a little while is separated off, washed with water, dried in the air and recrystallised from acetonitrile. 1.9 g (86%) of 5-acetamido-3-methyl-1-(O-tosyl-3-nitrobenzohydroximoyl)-pyrazole with a m. pt. of 208°-212° C. (decomp.) are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.[H-].[Na+].O>C1COCC1.CS(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: BrCCCCCBr
Reactant: N#CCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: N#CC1(c2ccc(Cl)nc2)CCCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 2-(6-chloropyridin-3-yl)acetonitrile (26.2 mmol) and 1,5-dibromopentane (26.2 mmol) in THF/DMSO (1:1, 300 mL) was added NaH (60% in mineral oil, 55.1 mmol) portionwise at 0° C. over 45 min. The mixture was allowed to warm to RT and stirred for 1 h 45 min. The reaction mixture was poured into water and extracted with DCM. The comb. org. layers were washed with brine, dried over MgSO4, and conc. in vacuo. The residue was purified by means of CC (10-80% EtOAc/Hept) to provide a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Cl[CH2:12][CH2:13][CH2:14][O:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COCCCCl
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCOc1ccccc1[N+](=O)[O-]

Procedure:
A suspension of 2.00 g of 2-nitrophenol, 1.72 g of 1-chloro-3-methoxypropane and 3.04 g potassium carbonate in 20 ml of N,N-dimethylformamide is stirred at reflux over 23 hours. The reaction mixture is concentrated by evaporation. The residue is partitioned between ethyl acetate and a 9:1 water/brine mixture. The water phase is extracted using ethyl acetate (2×). The organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.33 (1:2 EtOAc-heptane); Rt=4.08.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])=[CH:10][C:3]=1[O:4][CH:5]([CH2:8][CH3:9])[C:6]#[N:7].[CH3:26][N:27](C)C=O>>[C:26]([C:2]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])=[CH:10][C:3]=1[O:4][CH:5]([CH2:8][CH3:9])[C:6]#[N:7])#[N:27]
Reactant: CCC(C#N)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Br
Reactant: CN(C)C=O
Product: CCC(C#N)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C#N
Reaction time: 2 h

Procedure:
A 10 g of α-[2-bromo-5-(2-chloro-4-trifluoromethyl phenoxy) phenoxy]butyronitrile was dissolved in 20 ml of dimethylformamide. A 2.5 g of cuprous cyanide was added to the solution and the reaction was conducted at 145° to 150° C for 2 hours with stirring the mixture. The reaction mixture was cooled and was poured into suitable amount of aqueous solution of ferric chloride. The product was extracted with chloroform and the extract was washed with water and was dried. The chloroform was distilled off and the product was distilled at reduced pressure to obtain 7 g of the object compound having the boiling point of 202° to 207° C/2 mmHg.
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:10]([O:12]CC3C=CC=CC=3)=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.C1(OC)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl.[N+](C)([O-])=O.O>[NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12
Reactant: CC1=C(C(=O)OCc2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 89.6 %

Procedure:
To a solution of benzyl 7β-amino-3-methyl-3-cephem-4-carboxylate (1.2 g) and anisole (5.2 ml) in methylene chloride (100 ml) is dropwise added a solution of aluminum chloride (3.11 g) in nitromethane (40 ml) under ice cooling, and the mixture stirred for 4.5 hours at room temperature, mixed with water (40 ml), and adjusted to pH 0.3 with 1 N-hydrochloric acid. The aqueous layer is separated, washed with ethyl acetate (30 ml), adjusted to pH 2.4 with an aqueous solution of sodium hydroxide and allowed to stand overnight at 0° C. The resulting crystals are collected by filtration to give 7β-amino-3-methyl-3-cephem-4-carboxylic acid (757 mg). Yield: 89.6%. This product was identical with an authentic specimen in NMR and IR spectra.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].[Br:19]Br>CO>[Br:19][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]=[N:11][C:10]=1[NH2:13]
Reactant: Nc1ccc(-c2ccccc2)nn1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1nnc(-c2ccccc2)cc1Br
Reaction time: 16 h
Yield: 33.1 %

Procedure:
In a 150 mL round bottom flask was placed 6-phenylpyridazin-3-amine (2.5 g, 14.5 mmol), NaHCO3 (2.44 g, 29 mmol) and methanol (50 mL) then to this suspension was added Br2 (2.317 g, 14.5 mmol) drop wise over about 30 minutes at room temperature. The mixture was stirred for 16 h, then filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=2:1) to give 4-bromo-6-phenylpyridazin-3-amine (1.2 g, 33%) as a light orange solid. LC-MS: [M+H]+, 250.0, tR=1.487 min.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH:21]=[CH:20]2)([O-])=O>CO.[Pd]>[NH2:14][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][CH:21]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)[CH2:20]2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc2c(c1)C=CC2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2Cc3ccc(N)cc3C2)CC1
Reaction time: 48 h

Procedure:
To a solution of 5-nitro-indene bocpiperazine (0.740 g, 2.13 mmol) in methanol (20 mL) was added Pd/C (0.280 g, 2.63 mmol). The reaction mixture was stirred under H2 for 48 h. When the hydrogenation was complete, the reaction mixture was passed through a pad of Celite® and washed several times with methanol. The collected organics were then concentrated in vacuo and gave the title product. LC/MS: [(M+1)]+=318;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:13]([CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)=[O:14])[CH:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Yield: 37 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with ethyl 1-(6-chloronaphth-2-ylsulphonyl)piperazine-3-carboxylate to give 4-(6-chloronaphth-2-ylsulphonyl)-2-ethoxycarbonyl-1-[1-(4-pyridyl)-piperidin-4-ylcarbonyl]piperazine in 37% yield;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.[CH3:24][C:25]1[N:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][CH:26]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH:16]=2)[C:11]([NH:32][CH2:31][C:28]2[CH:29]=[N:30][C:25]([CH3:24])=[CH:26][CH:27]=2)=[O:13])=[N:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)nc1
Reactant: Cc1ccc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N3CCCC3)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a round-bottom flask were charged 3-(5-methylpyridin-2-yl)-5-(pyrrolidine-1-carbonyl)benzoic acid (80 mg, 0.26 mmol), (6-methylpyridin-3-yl)methanamine (60 mg, 0.49 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (90 mg, 0.47 mmol), 1-hydroxybenzotriazole hydrate (80 mg, 0.52 mmol), N,N-diisopropylethylamine (80 mg, 0.62 mmol) and methylene chloride (5 mL). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified via preparative HPLC to afford the desired product as a white solid.
Reaction SMILES: [S:1]1[C:5]([C:6]([NH:8][CH:9]([P:18](=[O:25])([O:22]CC)[O:19]CC)[P:10](=[O:17])([O:14]CC)[O:11]CC)=[O:7])=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.I[Si](C)(C)C>C(Cl)Cl>[S:1]1[C:5]([C:6]([NH:8][CH:9]([P:18](=[O:19])([OH:22])[OH:25])[P:10](=[O:11])([OH:17])[OH:14])=[O:7])=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2
Reactant: CCOP(=O)(OCC)C(NC(=O)c1cc2ccccc2s1)P(=O)(OCC)OCC
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: O=C(NC(P(=O)(O)O)P(=O)(O)O)c1cc2ccccc2s1
Temperature: 5 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of tetraethyl [(2-benzo[b]thiophenecarboxamido)methylene]bis(phosphonate) (463 mg) in methylene chloride (2 ml) was added iodotrimethylsilane (1 ml) in one portion at 5° C. The mixture was stirred for one hour at 5° C., allowed to stand for 2 days in a refrigerator and then additionally stirred for one hour at ambient temperature. The mixture was extracted with water. The aqueous layer was washed with methylene chloride and diethyl ether and then evaporated under reduced pressure. The residue was dissolved in water and therein tert-butylamine (183 mg) was added. The mixture was lyophilized to give bis(tert-butylamine)-salt of [(2-benzo[b]thiophenecarboxamido)methylene]bis(phosphonic acid) (277 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[N:33]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[N:36][N:35]=[N:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:41]5[CH2:42][CH2:43][CH:38]([N:33]6[CH:37]=[N:36][N:35]=[N:34]6)[CH2:39][CH2:40]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:31])([F:30])[F:32])[CH:3]=1
Reactant: c1nnnn1C1CCNCC1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC(n3cnnn3)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-tetrazol-1-yl-piperidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-tetrazol-1-yl-piperidine following General Procedure B.
Reaction SMILES: [CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]4[N:19](S(C5C=CC(C)=CC=5)(=O)=O)[CH:18]=[CH:17][C:15]4=3)[CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].CCOC(C)=O.O>O1CCOCC1>[CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]4[NH:19][CH:18]=[CH:17][C:15]4=3)[CH2:10][CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c4c(cnc32)CCCN4C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: c1cc2c3c(cnc2[nH]1)CCCN3C1CCCCC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
To a solution of 1-cyclohexyl-7-tosyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridine (0.132 g, 0.323 mmol) in 1,4-dioxane (2.2 mL) was added aqueous NaOH (2 N, 0.32 mL, 0.65 mmol). The reaction was heated at about 80° C. for about 96 h. Aqueous NaOH (5 N, 0.129 mL, 0.646 mmol) was added and the reaction was continued at about 80° C. for about 18 h. Aqueous NaOH (5 N, 0.065 mL, 0.323 mmol) was added and the reaction mixture was heated at about 100° C. for about 4 h. The reaction was cooled to ambient temperature, EtOAc and water were added (5 mL each) and the layers were separated. The aqueous layer was extracted with EtOAc (2×5 mL) and the combined organics were washed with water and brine (5 mL each), dried over anhydrous Na2SO4, filtered, and concd under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-100% (95/4.5/0.5) DCM/MeOH/DEA in DCM to give 1-cyclohexyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-h][1,6]naphthyridine (0.052 g, 64%) as a tan solid: LC/MS (Table 1, Method b) Rt=1.88 min; MS m/z: 256 (M+H)+.