Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][C:3]1=[O:14].I[CH2:22]C>>[CH2:1]([C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][C:3]1=[O:14])[CH3:22]
Reactant: CCI
Reactant: CCOC(=O)CC1(C)C(=O)Nc2cccc([N+](=O)[O-])c21
Product: CCOC(=O)CC1(CC)C(=O)Nc2cccc([N+](=O)[O-])c21

Procedure:
Essentially following the procedures described for Intermediate 16, but using iodoethane in place of iodomethane, the title compound was prepared. MS: m/z=293 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[F:19][C:20]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[F:19][C:20]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:23]
Reactant: O=C(Cl)c1ccc(-c2ccncc2)cc1F
Reactant: COC(=O)c1cccc(N)c1O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)c2ccc(-c3ccncc3)cc2F)c1O
Temperature: 70 °C
Reaction time: 4 h
Yield: 65.9 %

Procedure:
To a solution of 4-bromo-2-fluorobenzoic acid (4.34 g, 20 mmol) and pyridine-4-ylboronic acid (2.45 g, 20 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.52 g, 40 mmol), bis(triphenylphosphine)palladium(II) chloride (1.08 g, 0.05 mmol) was added. The mixture was degassed and purged withed nitrogen. The mixture was stirred at 100° C. for 24 h. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH 3 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 2-fluoro-4-(pyridine-4-yl)benzoic acid as a white solid (3.15 g, yield 72%. LC-MS (ESI) m/z: 218 (M+1)+.) Thionyl chloride (20 mL) was added to 2-fluoro-4-(pyridine-4-yl)benzoic acid (3.15 g, 14.53 mmol) and the mixture was stirred at 70° C. overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum giving 2-fluoro-4-(pyridine-4-yl)benzoyl chloride. To a solution of methyl 3-amino-2-hydroxybenzoate (2.42 g, 14.5 mmol) and pyridine (1.2 mL, 14.5 mmol) in toluene (20 mL) was added 2-fluoro-4-(pyridine-4-yl)benzoyl chloride (3.41 g, 14.5 mmol) portion-wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain methyl 3-(2-fluoro-4-(pyridin-4-yl)benzamido)-2-hydroxybenzoate as a yellow solid (3.5 g, yield 65%). LC-MS (ESI) m/z: 367 (M+1)+.
Reaction SMILES: [C:1]([C:4](C(OCC)=O)([CH2:16][C:17]#[C:18][CH:19]([O:29]C(=O)C)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[CH3:2].C(C(C(OCC)=O)(CCCC(OC(=O)C)COC1C=CC(F)=CC=1)CC#CCCCC(OC)=O)(=O)C>>[C:1]([CH:4]([CH2:16][C:17]#[C:18][CH:19]([OH:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCCC(CC#CC(COc1ccc(F)cc1)OC(C)=O)(C(C)=O)C(=O)OCC
Agent: CCOC(=O)C(CC#CCCCC(=O)OC)(CCCC(COc1ccc(F)cc1)OC(C)=O)C(C)=O
Product: CC(=O)C(CC#CC(O)COc1ccc(F)cc1)CCCCCCC(=O)O

Procedure:
The synthesis of this compound is carried out by the basic hydrolytic procedure described in Example 4, Step D except that an equivalent amount of ethyl 8-acetyl-8-ethoxycarbonyl-12-acetoxy-13-(4-fluorophenoxy)-10-tridecynoate is substituted for the methyl 8-acetyl-8-ethoxycarbonyl-12-acetoxy-13-(4-fluorophenoxy)-5-tridecynoate of Example 4, Step D. The product is purified by column chromatography on silica gel and is a light yellow viscous oil.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[NH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C@@H:5]1[C:10](O)=[O:11].C[Si](Cl)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.ClCCl>[CH2:1]([O:3][C:10]([C@H:5]1[CH2:6][CH2:7][C:8](=[O:9])[NH:4]1)=[O:11])[CH3:2]
Reactant: CCO
Reactant: O=C1CC[C@H](C(=O)O)N1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1CCC(=O)N1
Temperature: 30 °C

Procedure:
To a flask containing anhydrous ethanol and D-pyroglutamic acid at ambient temperature (˜23° C.) was slowly added trimethylsilyl chloride while maintaining a reaction temperature NMT 30° C. After stirring at ambient temperature for a period of time, the reaction solution was concentrated under reduced pressure to give a yellow oil. The product was dissolved in toluene and concentrated under reduced pressure to give a yellow oil. The crude product was dissolved in dichloromethane and stirred with the slow addition of aqueous saturated sodium bicarbonate solution until a pH of 7-8 was reached. The organic layer was isolated, and the aqueous layer was extracted further with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give product, (R)-5-oxo-pyrrolidine-2-carboxylic acid ethyl ester, as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[CH:12]1([NH:15][CH2:7][C:6]2[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH3:11])[CH2:14][CH2:13]1
Reactant: COc1ccc(F)cc1C=O
Reactant: NC1CC1
Product: COc1ccc(F)cc1CNC1CC1

Procedure:
Synthesized according to typical procedure J from 5-fluoro-2-methoxybenzaldehyde and cyclopropylamine.
Reaction SMILES: [C:1]1([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)#[N:13].NN>C(O)C>[C:1]1([S:7]([NH:10][N:11]=[CH:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NNS(=O)(=O)c1ccccc1
Agent: NN
Solvent: CCO
Product: N#Cc1ccc(C=NNS(=O)(=O)c2ccccc2)cc1

Procedure:
Benzenesulfonyl hydrazine (20.5 g, 0.12 mole) was dissolved by warming in 110 ml absolute ethanol. p-Cyanobenzaldehyde (15.6 g, 0.12 mole) was separately dissolved in 50 ml of hot ethanol and added to the hydrazine solution. The resulting slurry was refluxed 0.5 hour, cooled and filtered to yield 28.1 g; m.p. 209°-213°. Recrystallization from CH3CN gave purified title product: 23.7 g; m.p. 210°-213°.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][CH3:14])[CH:10]([N:15]2[CH:19]=[N:18][N:17]=[C:16]2[C:20]2[C:25]([NH:26][S:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=3)(=[O:29])=[O:28])=[CH:24][C:23]([Cl:41])=[CH:22][N:21]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([S:27]([NH:26][C:25]2[C:20]([C:16]3[N:15]([CH:10]4[CH:11]([O:13][CH3:14])[CH2:12][NH:8][CH2:9]4)[CH:19]=[N:18][N:17]=3)=[N:21][CH:22]=[C:23]([Cl:41])[CH:24]=2)(=[O:29])=[O:28])=[CH:31][C:32]=1[C:37]([F:39])([F:40])[F:38]
Reactant: COC1CN(C(=O)OC(C)(C)C)CC1n1cnnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1CNCC1n1cnnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
To 3-{3-[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-[1,2,4]triazol-4-yl}-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (71 mg, 0.11 mmol) was added 1:1 mixture of TFA-CH2Cl2 (2 mL) at room temperature and stirred for 2 h. Solvents were evaporated, 1:1 mixture of CH3CN—H2O (5 mL) and lyophilized to obtain 4-chloro-N-{5-chloro-2-[4-(4-methoxy-pyrrolidin-3-yl)-4H-[1,2,4]triazol-3-yl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide as a white solid in quantitative yield. MS (ES) [M+H]+ expected 537.0, found 537.0.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](N)[CH:2]=1.[H+].[B-](F)(F)(F)[F:14].N([O-])=O.[Na+]>O>[F:14][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: Nc1cnc2ccccc2c1
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Fc1cnc2ccccc2c1
Temperature: 25 °C

Procedure:
Quinolin-3-amine (4 g, 27.7 mmol) was added to HBF4 (26 mL, 48% aqueous solution) portionwise at room temperature, and the mixture was stirred at room temperature until it became homogeneous. The mixture was then cooled to 0° C., and a solution of NaNO2 (2.4 g, 34.8 mmol) in H2O (8 mL) was added dropwise, when the reaction mixture became heterogeneous. The mixture was stirred at 0° C. for 1 hour, then the mixture was filtered, and the filtered cake was washed with cold EtOH, then Et2O. The resulting solid was dried under vacuum, then suspended in toluene in a round bottom flask and was refluxed for 1.5 hours. The resulting mixture was cooled to room temperature, and then poured into cold water. The organic layer was dried over Na2SO4, and then concentrated in vacuo to obtain the desired product (1.6 g). LC-MS: m/z 148.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[Cl:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.Cl>C1COCC1>[C:23]([O:22][C:20](=[O:19])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[Cl:8])([CH3:26])([CH3:25])[CH3:24]
Reactant: Nc1ccncc1Cl
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccncc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 194.4 %

Procedure:
To a solution of 4-amino-3-chloropyridine (15 g, 116.7 mmol) in THF (60 mL) is added NaHMDS in THF (1 M, 233. mL, 233 mmol). After stirring at rt for 30 min, BOC20 (23.2 g, 106 mmol) in THF (45 mL) is added in one portion and the mixture is stirred for 3 h at rt. Additional BOC2O (2 g, 9.0 mmol) in THF (40 mL) is added and the reaction is stirred for 18 h at rt. 0.1% aqueous HCl (1.35 L) is added. The mixture is extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is recrystallized from ether to afford (3-chloro-pyridin-4-yl)-carbamic acid tert-butyl ester (4 g). The mother liquor is purified by silica gel column chromatography eluting with 0-50% EtOAc in heptane. The collected product is crystallized from ether to afford additional 4.5 g of (3-chloro-pyridin-4-yl)-carbamic acid tert-butyl ester (total yield 8.5 g). MS: 229 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.48 (s, 1H), 8.38 (d, 1H), 8.17 (d, 1H), 7.18 (broad s, 1H) 1.57 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][S:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][S:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CSCc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: COC(=O)CSCc1ccccc1N

Procedure:
Methyl (o-nitrobenzylthio)-acetate (24.4 g) was dissolved in ethanol (500 ml). Raney nickel was added and the mixture was hydrogenated at room temperature and 1 atm. of hydrogen pressure. The title compound was obtained as an oil after filtration and evaporation of the reaction mixture.
Reaction SMILES: [C:1]([O-:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].[Ca+2].[C:17]([O-])(=O)[CH2:18][CH2:19]NC(=O)[C@@H](C(CO)(C)C)O.F[C:33](F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.COC(OC)(C)C>[CH3:17][C:18]1([CH3:19])[O:7][CH:6]([C:5]([NH:4][CH2:3][CH2:2][C:1]([O:15][CH3:33])=[O:14])=[O:13])[C:8]([CH3:10])([CH3:9])[CH2:11][O:12]1
Reactant: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)[O-]
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [K+]
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Product: COC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Reaction time: 8 h

Procedure:
A 5.0 g portion of calcium pantothenate was slurred in 100 ml of acetone:2,2-dimethoxypropane (1:1). Trifluoroacetic acid (3.0 ml) was added until solution was complete and stirring was continued overnight. A 10 g portion of potassium carbonate was added, this mixture stirred vigorously for 10 minutes and then concentrated to a gummy solid. A 100 ml portion of acetonitrile and 10 ml of methyl iodide were added to the solid. This mixture was stirred for 1 day, then poured into water and extracted twice with ethyl acetate. The extracts were combined, dried and concentrated, giving 4.8 g of the desired compound as a yellow oil.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CN(C=O)C.[C:14]1([CH2:20][CH:21]=[N:22][OH:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)C>O>[C:14]1([CH2:20][C:21]([Cl:1])=[N:22][OH:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=CCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: ON=C(Cl)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of N-chlorosuccinimide (3.25 g, 24 mmol) in abs. DMF (18 ml) was added to a solution of compound V (2.7 g, 20 mmol) in abs. DMF (12 ml) at a temperature of 30-40° C. within 20 min. Cooling in an ice bath was carried out if necessary. The reaction mixture was stirred for 3 h at RT and then mixed with diethyl ether (175 ml) and water (115 ml). The phases were separated and the aqueous phase was extracted with diethyl ether (2×75 ml). The combined organic extracts were washed successively with water (100 ml) and sat. NaCl solution (100 ml). The organic phase was dried and concentrated. Compound W was obtained as a yellowish-green oil (3.33 g) and immediately reacted further.
Reaction SMILES: Cl.[O:2]=[S:3]1(=[O:25])[C:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH2:20][NH2:21])[CH:17]=[CH:18][CH:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]2[CH2:22][CH2:23][CH2:24][CH:5]2[NH:4]1.CO[CH:28]1[CH2:32][CH2:31][CH:30](OC)O1.O.CC(O)=O>C(Cl)CCl>[N:21]1([CH2:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[O:13][C:10]2[CH:11]=[CH:12][C:7]3[N:6]4[CH2:22][CH2:23][CH2:24][CH:5]4[NH:4][S:3](=[O:2])(=[O:25])[C:8]=3[CH:9]=2)[CH:28]=[CH:32][CH:31]=[CH:30]1
Reactant: COC1CCC(OC)O1
Reactant: NCc1cccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=S1(=O)NC2CCCN2c2ccc(Oc3cccc(Cn4cccc4)c3)cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
200 mg (0.58 mmol) of the product obtained in Example 1, in the form of the free amine, and 105 μl (0.81 mmol) of 2,5-dimethoxytetrahydrofuran are added to a two-phase mixture of 2.5 ml of water, 0.95 ml of AcOH and 2.85 ml of dichloro-1,2-ethane. The mixture is stirred at 80° C. for 2 hours, allowed to return to ambient temperature and extracted with CH2Cl2. The organic phase is washed with saturated aqueous NaCl solution and dried over MgSO4. The expected product is purified by chromatography on a silica column (CH2Cl2/heptane 75/25).
Reaction SMILES: C=O.[CH2:3](N(CC)CC)C.Cl.Cl.[CH2:12]([N:19]1[CH2:22][C:21]2([CH2:26][CH2:25][CH2:24][NH:23]2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:12]([N:19]1[CH2:22][C:21]2([CH2:26][CH2:25][CH2:24][N:23]2[CH3:3])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCN(CC)CC
Reactant: c1ccc(CN2CC3(CCCN3)C2)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: ClCCCl
Product: CN1CCCC12CN(Cc1ccccc1)C2
Temperature: 10 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Paraformaldehyde (70.91 g, 787 mmol) and triethylamine (119.5 g, 1.18 mol) were added to a mixture of 2-benzyl-2,5-diazaspiro[3.4]octane dihydrochloride (Intermediate 49, 65 g, 236.2 mmol) in 1,2-dichloroethane (700 mL) and the mixture was stirred for 1 h at 10° C. Sodium triacetoxyborohydride (110.8 g, 1.18 mol) was then added and the mixture was stirred for 12 h at 15° C. The mixture was then filtered and the filter cake was washed with CH2Cl2 (3×500 mL). The combined organic solutions were washed with brine (500 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (51.1 g, 94%) as yellow oil; 1H NMR: (300 MHz, CDCl3) 1.75 (2H, m), 2.16 (2H, m), 2.49 (3H, s), 2.64 (2H, d), 3.10 (2H, d), 3.28 (2H, d), 3.66 (2H, s), 7.22-7.62 (5H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][N:7]=[C:8]3[C:13]=2[C:12]=1[C:11](=[O:14])[C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]3=1.[N-:19]=[N+]=[N-].[Na+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][N:7]=[C:8]3[C:9]4[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=4[C:11](=[O:14])[NH:19][C:12]=1[C:13]=23
Reactant: Cc1ccc2[nH]nc3c2c1C(=O)c1ccccc1-3
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ccc2[nH]nc3c2c1NC(=O)c1ccccc1-3
Temperature: 25 °C
Reaction time: 30 h
Yield: 41.3 %

Procedure:
To a solution of 15 g of 5-methyl-2,6-dihydrodibenzo[cd,g]indazol-6-one prepared in Example 25-b in 70 ml concentrated sulfuric acid was added 12.5 g of sodium azide [CAS No. 26628-22-8], followed by stirring at room temperature for 30 hours. The reaction mixture was poured onto 700 ml of ice-water, the precipitated powder was collected by filtration and dried in vacuo. The resulting powder was dissolved in a solvent mixture of dimethylformamide-ethyl acetate, sequentially washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was recrystallized from dimethylformamide-ethyl acetate, to give 6.59 g of the title compound as ocher yellow crystals.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[OH:19][C@H:20]1[CH2:24][CH2:23][C@H:22]([NH:25]C2C3N(C=CC=3)N=CC=2C(N)=O)[C:21]1([CH3:39])[CH3:38].C(=O)(O)[O-].[Na+]>ClCCl>[OH:19][C@@H:20]1[CH2:24][CH2:23][C@H:22]([NH:25][C:9](=[O:10])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:21]1([CH3:39])[CH3:38]
Reactant: CC1(C)[C@@H](Nc2c(C(N)=O)cnn3cccc23)CC[C@@H]1O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)[C@H](O)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 10.1 %

Procedure:
Triethylamine (6.69 mL, 48.0 mmol) and benzyl chloroformate (4.22 g, 24.71 mmol) were added to a solution of 3-amino-2,2-dimethylcyclopentanol (3.10 g, 23.99 mmol, from Step 3 of Intermediates 15 and 16) in dichloromethane (100 mL) at 0° C. The resulting mixture was stirred at room temperature for 15 h, treated with saturated sodium bicarbonate (50 mL) and extracted with dichloromethane (3×150 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated. Silica gel chromatography, eluting with 0 to 40% ethyl acetate in hexanes, gave separation of the two major components. The first eluted product was found to be benzyl cis-3-hydroxy-2,2-dimethylcyclopentylcarbamate (cis-isomer B, 640 mg, 10% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 7.13-7.53 (5 H, m), 5.06 (2 H, s), 3.53-3.86 (2 H, m), 1.81-2.05 (2 H, m), 1.36-1.71 (2 H, m), 0.86-1.07 (3 H, m), 0.78 (3 H, s); MS (ES+) m/z: 264.2 (M+H); HPLC retention time: 2.32 min (analytical HPLC Method A). The second eluted product was benzyl trans-3-hydroxy-2,2-dimethylcyclopentylcarbamate (trans-isomer A, 1.77 g, 28% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 7.21-7.51 (5 H, m), 5.06 (2 H, s), 3.91 (1 H, t, J=8.25 Hz), 3.64-3.79 (1 H, m), 1.99-2.20 (2 H, m), 1.33-1.62 (2 H, m), 0.94 (3 H, s), 0.79 (3 H, s); MS (ES+) m/z: 264.3 (M+H); HPLC retention time: 2.29 min (analytical HPLC Method A).
Reaction SMILES: [C:1]([CH:3]([C:13]([C:15]1[C:16]2[CH2:29][S:28][C:27]3[C:30]([CH2:34][OH:35])=[CH:31][CH:32]=[CH:33][C:26]=3[C:17]=2[N:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)=[O:14])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].[C:36]1(=[O:42])[O:41][C:39](=[O:40])[CH2:38][CH2:37]1>N1C=CC=CC=1>[C:39]([CH2:38][CH2:37][C:36]([O:35][CH2:34][C:30]1[C:27]2[S:28][CH2:29][C:16]3[C:15]([C:13](=[O:14])[CH:3]([C:1]#[N:2])[C:4]([NH:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[O:5])=[N:19][N:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:17]=3[C:26]=2[CH:33]=[CH:32][CH:31]=1)=[O:42])([OH:41])=[O:40]
Reactant: O=C1CCC(=O)O1
Reactant: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1CSc1c(CO)cccc1-2
Solvent: c1ccncc1
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1CSc1c(COC(=O)CCC(=O)O)cccc1-2
Temperature: 45 °C
Reaction time: 20 h
Yield: 65.5 %

Procedure:
2-Cyano-3-(1,4-dihydro-6-hydroxymethyl-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide (1.2 g) is reacted with succinic anhydride (0.8 g) in anhydrous pyridine (40 ml) under stirring at 45° C. for 20 hours. After cooling the reaction mixture is diluted in ice water and the precipitate is filtered and washed with water. Crystallization from CH2Cl2 /isopropanol yields 0.95 g of 3-[6-(3-carboxy-propanoyloxymethyl)-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-2-cyano-3-oxo-N-phenyl-propanamide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][CH:31]=[CH:30]3)=[CH:23][C:13]=1[CH2:14][NH:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]([CH2:14][C:13]2[CH:23]=[C:24]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[NH:32][CH:31]=[CH:30]4)[CH:25]=[CH:26][C:12]=2[F:11])[CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2ccc3[nH]ccc3c2)cc1CNCCN1CCCC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)N(CCN1CCCC1)Cc1cc(-c2ccc3[nH]ccc3c2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 145.9 %

Procedure:
4-Fluorobenzoyl chloride (93 mg, 0.59 mmol) was added to a solution of [2-fluoro-5-(1H-indol-5-yl)-benzyl]-(2-pyrrolidin-1-yl-ethyl)-amine (90 mg, 0.27 mmol) and triethyl amine (81 mg, 0.8 mmol) in 10 ml of dichloromethane at room temperature. The resulting mixture was stirred at ambient temperature for 2 h, and then the volatiles were removed in vacuo and the residue was dissolved in ethyl acetate and washed with 1 M HCl solution and water. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with methanol/dichloromethane) provided 181 mg of product. This was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated to afford 92 mg of the title compound. LC/MS: Retention time, 2.55 min; (M+H)=460.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+]([O-])=O)=[C:9]([C:11](=[N:13][OH:14])[CH3:12])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[F:1][C:2]1[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][N:13]=[C:11]([CH3:12])[C:9]=2[CH:10]=1
Reactant: CC(=NO)c1cc(Oc2ccc(Br)cc2F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1noc2ccc(Oc3ccc(Br)cc3F)cc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 2.0 g sample of the oxime prepared as above was combined with 1.2 g of potassium carbonate in 25 ml of dimethyl sulfoxide and the mixture was allowed to stir at room temperature for two days. The resulting mixture was diluted with water and extracted with ether. The ether extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting oil was distilled in a Kugelrohr apparatus to obtain 0.6 g of a thick, amber oil, the nmr spectrum of which was consistent with the assigned structure.