Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](C1C=CC=CC=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15][NH2:16].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)C>[O:15]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH:1]=[N:16]1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: NO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: c1ccc2oncc2c1

Procedure:
FIG. 17B shows the synthesis of the simplified benzophenone subunit. Compound 18 in FIG. 17B was conveniently prepared from commercial available 3-fluoro-4-methoxyacetophenone through Baeyer-Villiger oxidation followed by deacetation and subsequent protection with MOM group. MOM-directed ortholithiation followed by aryllithium addition to commercially available aldehyde 19 provided barbinol 20 in moderate yield. Similarly, Oxidation of barbinol 20 with active manganese dioxide gave the crucial intermediate 21. Unmasking the carboxyl group of 21 with NaOH afforded acid 22. To introduce the desired side chain R, 21 was first treated with HCl to remove MOM group and introduction of R followed by the treatment of NaOH gave the desired benzophenone acid 24. Benzisoxazole acid 25 was prepared from benzophenone 23 by a three-step sequence in which oxime formation was accomplished with hydroxyl-amine in ethanol and dehydration with diethylazodicarboxylate and triphenyl phosphine followed by hydrolysis of the methyl ester furnished the final product 25. See FIG. 17B.
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[C:8]2[N:9]([N:13]=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=2)[CH:10]=[CH:11][CH:12]=1.C([O-])(O)=O.[Na+].[CH2:24](O)[CH3:25]>>[CH2:24]([O:17][C:16]([C:14]1[CH:15]=[C:8]2[C:7]([NH2:6])=[CH:12][CH:11]=[CH:10][N:9]2[N:13]=1)=[O:18])[CH3:25]
Reactant: Nc1cccn2nc(C(=O)O)cc12
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc2c(N)cccn2n1
Temperature: 75 °C

Procedure:
50% Aqueous H2SO4 (60 mL) is added to 4-Aminopyrazolo[1,5-a]pyridine-2,3-dicarboxylic acid dimethyl ester (1.47 g, 5.90 mmol) under air. The mixture is warmed to 80° C. After 6.5 h, the solution is cooled to 0° C. and then neutralized with 10 N aq. NaOH. The resulting slurry is acidified to pH 3 with 1 M aq. HCl. The volatiles are removed under reduced pressure. The residue is washed with 30% EtOH in CH2Cl2. The volatiles are removed under reduced pressure to afford 4-aminopyrazolo[1,5-a]pyridine-2-carboxylic acid in Na2SO4. LC-MS m/z (M+H+): 178.01. A solution of conc. H2SO4 (6.0 mL) and ethanol (120 mL) is added to the crude 4-aminopyrazolo[1,5-a]pyridine-2-carboxylic acid. The mixture is warmed to 75° C. for 3.5 h. After cooling to rt, the mixture is made basic with dropwise addition of sat. aq. NaHCO3. The volatiles are removed under reduced pressure. The aqueous mixture is filtered (EtOAc rinse). The aqueous solution is extracted with EtOAc (3×250 mL). The combined organics are dried over Na2SO4, filtered, and concentrated to afford the title compound as dark brown solid. LC-MS m/z (M+Na+): 228.03.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.O=[C:11]([CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:5]=[C:3]1[CH:12]=[CH:11][CH2:13][C:14]([CH3:16])([CH3:15])[CH:2]1[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(=O)C=C(C)C
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=C1C=CCC(C)(C)C1C(=O)OCC
Yield: 29.6 %

Procedure:
260 g of ethyl acetoacetate were mixed with 200 g of mesityl oxide and 200 g of trifluoroboro-etherate in a vessel cooled externally by water and ice in order to maintain the temperature of the mixture at about 0°-5°. The said mixture is maintained at this temperature for 3 days, poured then onto ice (800 g) and neutralized with about 400 g of Na2CO3. Then it was extracted with ether and, after the usual treatments of separation, washing and drying, the combined organic extracts were concentrated. Distillation of the residue (135 g) gave 115 g of the desired product, b.p. 85°-90°/0.1 Torr, which has a purity of 80% as shown by analysis by means of vapour phase chromatography. The product can subsequently be purified by redistillation.
Reaction SMILES: Br.[CH2:2]([C:4]1[N:5]=[C:6]([C@@H:9]([NH2:20])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[S:7][CH:8]=1)[CH3:3].[C:21]([NH:24][C@H:25]([C:33](O)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:23])[CH3:22].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[C:21]([NH:24][C@@H:25]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]([NH:20][C@H:9]([C:6]1[S:7][CH:8]=[C:4]([CH2:2][CH3:3])[N:5]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:34])(=[O:23])[CH3:22]
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCc1csc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1csc([C@H](Cc2ccc([N+](=O)[O-])cc2)NC(=O)[C@H](Cc2ccccc2)NC(C)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide, 3, (0.343 g, 0.957 mmol), N-acetyl-L-phenylalanine (0.218 g), 1-hydroxybenzotriazole (HOBt) (0.161 g), diisopropyl-ethylamine (0.26 g), in DMF (10 mL) at 0°, is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.201 g). The mixture is stirred at 0° C. for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1 N aqueous HCl, 5% aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.313 g (70% yield) of the desired product which is used without further purification. LC/MS ESI+ 467 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH:10]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)([CH3:12])[CH3:11]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:17][C:16]2[CH:18]=[CH:19][C:13]([CH:10]([CH3:12])[CH3:11])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=Cc1ccc(Br)cc1
Product: CC(C)c1ccc(NCc2ccc(Br)cc2)cc1
Yield: 57.6 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-bromobenzaldehyde (1.9 g) and 4-isopropylaniline (1.4 g) as starting materials, [(4-bromophenyl)methyl](4-isopropylphenyl)amine (1.8 g) was obtained. melting point: 30° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH:5]=[CH:4][C:3]=1B(O)O.[CH2:32]([O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40](C2C=CC(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)=C(F)C=2F)=[CH:39][CH:38]=1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:3]2[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[C:7]([F:8])[C:2]=2[F:1])=[CH:39][CH:38]=1)=[O:36])[CH3:33]
Reactant: OB(O)c1ccc(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c1F
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)cc1
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)cc1
Yield: 88 %

Procedure:
2′,3′-Difluoro-4′-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-biphenyl-4-carboxylic acid ethyl ester (13B) was prepared from 2,3-difluoro-4-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-phenylboronic acid (11B) as described in the preparation 2′,3′-difluoro-4′-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-biphenyl-4-carboxylic acid ethyl ester (13A) yielding 2′,3′-difluoro-4′-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-biphenyl-4-carboxylic acid ethyl ester (13B) as a white solid (88%).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[O:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[C:11]([OH:15])(=[O:14])[CH:12]=O>O>[CH3:10][C:5]1[O:6][C:7]([CH3:9])=[CH:8][C:4]=1[C:1](=[O:3])/[CH:2]=[CH:12]/[C:11]([OH:15])=[O:14]
Reactant: CC(=O)c1cc(C)oc1C
Reactant: O=CC(=O)O
Solvent: O
Product: Cc1cc(C(=O)/C=C/C(=O)O)c(C)o1
Yield: 14.2 %

Procedure:
As in Example 1, one starts out with 9 g of 3-acetyl 2.5-dimethylfuran (J. Am. Chem. Soc., 70 739 (1948)), 6 g glyoxylic acid and 6 cm3 water. Following chromatography on silica (eluent: petroleum ether-ethyl acetate (2-8), recrystallization in ethyl acetate, 1.8 g of the expected product is obtained. MP=144°-147° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28](CC3C=CC(OC)=CC=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.CO.O>C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)cc1
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccccn3)c3ncc(C(=O)Nc4ccnc(F)c4)n3n2)CC1
Temperature: 70 °C

Procedure:
The solid from 62B was dissolved in TFA and heated to 70° C. for 1 h and then cooled to room temperature and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) to obtain the pure product 6-((trans-4-aminocyclohexyl)amino)-N-(2-fluoro-4-pyridinyl)-8-(2-pyridinylamino)imidazo[1,2-b]pyridazine-3-carboxamide (23 mg, 0.050 mmol, 41.9% yield) HPLC Rt=1.542 minutes (Phenomenex Luna 5 micron C18 4.6×30 mm: 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). [M+H]=462.17.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH:15]=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[N+:23]([O-:28])([N+]([O-])=O)=[O:24]>C(#N)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH:15]=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[N+:23]([O-:28])=[O:24])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)Cc1ccc2occ(-c3ccc(C(=O)O)cc3)c2c1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: CC#N
Product: O=C(O)Cc1ccc2oc([N+](=O)[O-])c(-c3ccc(C(=O)O)cc3)c2c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a suspension of 2 g. of the product of step B in 10 ml. of acetonitrile is added 0.2 g. of cupric nitrate hydrate and 1 g. of dinitrogen tetraoxide in 2 ml. of acetonitrile. The mixture is stirred at 20° C. for two hours, 0.5 g. of additional dinitrogen tetraoxide is added, and the mixture is stirred for an additional 18 hours. It is then concentrated, and the solid is separated by filtration and recrystallized from acetic acid to provide light yellow crystals of 3-(4-carboxyphenyl-2-nitrobenzofuran-5-acetic acid, m.p. 290° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=O)=[CH:13][CH:12]=1>>[Cl:9][C:4]1[N:3]=[C:2]2[N:1]=[C:15]([C:14]3[CH:18]=[CH:19][C:11]([F:10])=[CH:12][CH:13]=3)[NH:8][C:7]2=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: Nc1ccc(Cl)nc1N
Product: Fc1ccc(-c2nc3nc(Cl)ccc3[nH]2)cc1
Yield: 46.6 %

Procedure:
2,3-Diamino-6-chloropyridine (Davos-Bulk supplier, 2.25 g 15.6 mmol) and 4-fluorobenzoic acid (2.62 g 18.7 mmol) are treated with polyphosphoric acid (56.4 g) at 150° C. for 6 h. The reaction mixture is poured on ice-water/NH3conc. and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crude product, which is purified by recrystallisation from ethyl acetate/tert.butyl methyl ether to yield the title compound (1.8 g 44%) as grey crystals.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[NH2:10][C:11]1[N:16]=[CH:15][C:14]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:13]2[N:12]=1>O>[NH2:10][C:11]1[NH:16][CH:15]([CH:7]2[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][C:8]2=[O:9])[C:14]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:13]2[N:12]=1
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: CCCc1nc(C)c2cnc(N)nn12
Solvent: O
Product: CCCc1nc(C)c2n1N=C(N)NC2C1C(=O)NC(=O)NC1=O

Procedure:
Barbituric acid (1.36 g.) and 2-amino-5-methyl-7-propylimidazo[5,1-f]-as-triazine (Example 4) (2 g.) in water (60 ml.) were stirred for 1.75 hours. The solid was collected and crystallised from water to give a solid m.p. 256°-258°.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.C([O:14][CH:15](OCC)[CH:16]=[CH2:17])C.C([O-])([O-])=O.[K+].[K+].[Cl-].[K+].Cl>CN(C=O)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:9]=[C:6]1[C:5]2[CH:10]=[CH:11][C:2](/[CH:17]=[CH:16]/[CH:15]=[O:14])=[CH:3][C:4]=2[CH2:8][O:7]1
Reactant: C=CC(OCC)OCC
Reactant: O=C1OCc2cc(Br)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C/C=C/c1ccc2c(c1)COC2=O
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 5-Bromo-2-benzofuran-1(3H)-one (20 g, 94 mmol) in DMF (500 mL) was added Acrolein diethyl acetal (37 g, 282 mmol), Bu4NOAc (57 g, 188 mmol), K2CO3 (19.5 g, 141 mmol), KCl (7.0 g, 94 mmol) and Pd(OAc)2 (200 mg). The mixture was stirred for 2.5 hours at 90° C. After the mixture was cooled, 2 N HCl was slowly added and the resulting reaction mixture was stirred at room temperature for 10 min, and diluted with EtOAc, washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified with silica gel chromatography (petrol ether/EtOAc=2:1) to give title product.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([F:12])[CH:6]=1)=[O:4].[N-:13]=[C:14]=[S:15].[K+]>C(O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][S:15][C:14]#[N:13])=[CH:6][C:7]=1[F:12]
Reactant: O=C(CBr)c1ccc(Cl)c(F)c1
Reactant: [N-]=C=S
Agent: [K+]
Solvent: CCO
Product: N#CSCC(=O)c1ccc(Cl)c(F)c1
Yield: 100.5 %

Procedure:
In the same manner as described in step 4 of Example 78, using 2-bromo-1-(4-chloro-3-fluoro-phenyl)-ethanone (2.7 g, 10.7 mmol), prepared in the previous step, and potassium isothiocyanate (1.25 g, 12.8 mmol) in ethanol (150 mL) the crude product was collected by suction filtration to give 1-(4-chloro-3-fluoro-phenyl)-2-thiocyanato-ethanone (2.47 g, 100%), which was used in the next step without further purification. MS (ES) m/z 230[M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[C:19]1([CH2:25][C:26](=[NH:30])OCC)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[ClH:16].[Cl:17][C:11]1[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26](=[NH:30])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: Nc1ncccc1OCc1cc(Cl)ccc1Cl
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1cc(Cl)ccc1Cl
Yield: 6.3 %

Procedure:
A mixture of 2-amino-3-(2,5-dichlorobenzyloxy)pyridine (5.08 g, 18.8 mmol) and ethyl phenylacetimidate hydrochloride (3.52 g, 25.5 mmol) in ethanol (150 ml) was heated under reflux for 2 hours, then evaporated. Flash chromatography (dichloromethane/methanol) and trituration with ether gave the product (0.25 g), m.p. 191°-193° C.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[C@H:11]([N:15]2[CH2:18][C:17]4([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[CH2:16]2)[CH2:10][CH2:9]3)[N:3]=[CH:4][CH:5]=1.[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32](O)=[O:33])=[N:29][CH:30]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>CN(C)C=O.CN(C1C=CN=CC=1)C>[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32]([N:21]2[CH2:22][CH2:23][C:17]3([CH2:16][N:15]([CH:11]4[C:12]5[C:8](=[CH:7][C:6]([N:2]6[N:3]=[CH:4][CH:5]=[N:1]6)=[CH:14][CH:13]=5)[CH2:9][CH2:10]4)[CH2:18]3)[CH2:19][CH2:20]2)=[O:33])=[N:29][CH:30]=1
Reactant: c1cnn(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)n1
Reactant: Cc1ccc(CC(=O)O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(CC(=O)N2CCC3(CC2)CN(C2CCc4cc(-n5nccn5)ccc42)C3)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 2-((R)-5-[1,2,3]triazol-2-yl-indan-1-yl)-2,7-diaza-spiro[3.5]nonane (6-1c, 200 mg, 0.65 mmol) in 3 mL of dimethylformamide was added (5-methyl-pyridin-2-yl)-acetic acid (SM-1ab, 98 mg, 0.65 mmol), triethylamine (131 mg, 1.29 mmol), EDCI (130 mg, 0.68 mmol) and a catalytic amount of DMAP. The mixture was stirred at room temperature overnight. The reaction mixture was quenched by the addition of 10 mL of saturated NaHCO3 and diluted with 50 mL of dichloromethane. The organic layer was washed with saturated brine, dried over Na2SO4 and concentrated. The crude product was purified on Analogix (Analogix Inc., Burlington, Wis.) 4 g silica column (0-20% MeOH in ethyl acetate (1% triethyl amine)) to provide the title compound (207 mg, 72.4%) as a brown gum. MS (ES+) 443.4 (M+H)+. 1H NMR (CD3OD) δ 1.58-1.79 (m, 4H), 1.94-2.16 (m, 2H), 2.20-2.31 (m, 2H), 2.31 (s, 3H), 2.78-2.98 (m, 1H), 3.09-3.16 (m, 1H), 3.17-3.32 (m, 2H), 3.38-3.57 (m, 4H), 3.88 (s, 2H), 3.99-4.20 (m, 1H), 7.21 (d, 1H), 7.39-7.51 (m, 2H), 7.80 (d, 2H), 7.89-7.94 (m, 1H), 7.97 (s, 1H), 8.24-8.38 (m, 1H). [α]D20=+47.2 deg (c=9.4 mg/mL, methanol).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[F:9][CH:10]([F:18])[C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.CO>O>[F:9][CH:10]([F:18])[C:11]1[CH:12]=[C:13]([NH:14][C:1]2[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH:2]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCCC(=O)C1
Reactant: Nc1cccc(C(F)F)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CO
Product: O=C1C=C(Nc2cccc(C(F)F)c2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of cyclohexane-1,3-dione (2.00 g, 17.84 mmol), 3-(difluoromethyl)aniline (2.55 g, 17.82 mmol) and Ytterbium(III) trifluormethanesulfonate (111 mg, 178 μmol, 1.0 mol %) is stirred at room temperature for 2 h. Methanol and water are added and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate). Yield: 2.76 g; ESI mass spectrum [M+H]+=237, Retention time HPLC: 0.40 min (X012_S01).
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.O.[C:24]1(C)C=CC=C[CH:25]=1>C(O)C>[CH2:24]([O:2][C:1]([C:4]1[O:8][C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:6][CH:5]=1)=[O:3])[CH3:25]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1ccc(-c2n[nH]c3ccccc23)o1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(-c2n[nH]c3ccccc23)o1
Yield: 60 %

Procedure:
1.75 g (7.7 mmol) of 3-(5-carboxy-2-furyl)indazole together with 2.5 ml of concentrated sulfuric acid in 60 ml of toluene and 20 ml of ethanol were heated on a water separator. Customary work-up gave 1.2 g (60%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S@:27]([CH3:29])=[O:28])[CH2:17][CH2:16]2)[CH2:10][NH:11][CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:30]([C:33]1[C:42]2[CH2:41][CH2:40][CH2:39][CH2:38][C:37]=2[C:36]([C:43](Cl)=[O:44])=[CH:35][CH:34]=1)([O-:32])=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S@:27]([CH3:29])=[O:28])[CH2:19][CH2:20]2)[CH2:10][N:11]([CH3:12])[C:43]([C:36]2[C:37]3[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=3[C:33]([N+:30]([O-:32])=[O:31])=[CH:34][CH:35]=2)=[O:44])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c2c1CCCC2
Product: CN(C[C@@H](CCN1CCC(c2ccccc2[S@](C)=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccc([N+](=O)[O-])c2c1CCCC2

Procedure:
Using a procedure analogous to that described in Example 3, N-[(S)-2-(3,4-dichlorophenyl)4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methylamine was reacted with 4-nitro-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride [prepared from 4-nitro-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (T. Nakayama, T. Okutome, R. Matsui, M. Kurumi, Y. Sakurai, T. Aoyama, S. Fujii, Chem. Pharm. Bull. 32(10) 3968 (1984))] and the product was converted to the citrate salt MS: m/z 656 (M+H). Analysis for C34H39Cl2N3O4S.C6H8O7.1.0H2O: calculated: C, 54.42; H, 5.70; N, 4.85. found: C, 55.03; H, 5.55; N, 4.94.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][C:12]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:8][N:7]=1)=[O:5])C.[CH2:37]([NH2:39])[CH3:38]>CO>[CH2:37]([NH:39][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:14]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:13][C:12]=2[O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:8][N:7]=1)=[O:5])[CH3:38]
Reactant: CCOC(=O)c1cc(-c2cc(C(C)(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Reactant: CCN
Solvent: CO
Product: CCNC(=O)c1cc(-c2cc(C(C)(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Reaction time: 2 h

Procedure:
5-(2,4-Bis-benzyloxy-5-tert-butyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester (10.0 g, 20.6 mmol) was added to a solution of ethylamine in methanol (60 ml, 2.0M) and the suspension heated, oil bath temperature 75° C., for ˜2 hrs. The resulting solution was allowed to cool and concentrated to a pale brown oil, dichloromethane (150 ml) was added and the solution washed with water (100 ml) and saturated aqueous sodium chloride solution (75 ml). The solution was dried over anhydrous sodium sulphate and concentrated to a brown oil, solidified on standing (9.9 g, ˜quant).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:31])[CH:10]2[NH:14][C:15](=[O:30])[CH:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]=[N+:28]=[N-:29])=[CH:22][CH:21]=2)[C:17]([OH:19])=[O:18])[C:7]=1[C:32]([OH:34])=[O:33])(=[O:3])[CH3:2].Cl.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:51]1[C:59]2[C:54](=[CH:55][C:56](O)=[CH:57][CH:58]=2)[CH2:53][CH2:52]1>O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:31])[CH:10]2[NH:14][C:15](=[O:30])[CH:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]=[N+:28]=[N-:29])=[CH:22][CH:21]=2)[C:17]([O:19][C:56]2[CH:55]=[C:54]3[C:59](=[CH:58][CH:57]=2)[CH2:51][CH2:52][CH2:53]3)=[O:18])[C:7]=1[C:32]([OH:34])=[O:33])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)O)c3ccc(CN=[N+]=[N-])cc3)C2SC1
Reactant: Oc1ccc2c(c1)CCC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)Oc3ccc4c(c3)CCC4)c3ccc(CN=[N+]=[N-])cc3)C2SC1
Temperature: 25 °C
Reaction time: 0.29 h

Procedure:
To 25.3 m mole of 3-[(acetyloxy)methyl]-7-[[2-[4-(azidomethyl)phenyl]-2-carboxyacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 35 ml dioxane is added 6N hydrochloric acid to give a pH of 2.5. Then 24.1 m moles N,N'-dicyclohexylcarbodiimide in 35 ml dioxane is added and the mixture is stirred at room temperature for 15 to 20 minutes followed by the addition of 24.1 m moles of 5-indanol. The mixture is stirred for 4 hours. The formed N,N'-dicyclohexylurea is removed by filtration and the filtrate is extracted 3 times with methyl isobutyl ketone. The organic extract is washed with water, dried over magnesium sulfate and concentrated to dryness in vacuo to yield 3-[(acetyloxy)methyl]-7-[[2-[4-(azidomethyl)phenyl]-2-(5-indanyloxycarbonyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.