Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]2[O:7][C@H:8]([C@H:10]([OH:13])[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:34]([C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)([O-:36])=[O:35].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[N+:34]([C:37]1[CH:38]=[CH:39][C:40]([C:41]([O:13][C@H:10]([C@H:8]2[O:7][C@@H:5]3[O:6][C:2]([CH3:1])([CH3:14])[O:3][C@@H:4]3[CH2:9]2)[CH2:11][CH3:12])=[O:42])=[CH:44][CH:45]=1)([O-:36])=[O:35]
Reactant: CC[C@@H](O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Temperature: 18 °C
Reaction time: 10 h
Yield: 70.9 %

Procedure:
To a stirred solution of (1R)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propan-1-ol (compound 6c, 50 g, 245 mmol), triphenylphosphine (195 g, 743 mmol), 4-nitrobenzoic acid (124 g, 743 mmol) in THF (1200 mL) was added diethyl azodicarboxylate (130 g, 743 mmol) dropwise at 0° C. under N2. After being stirred at 18° C. for 10 hours, the mixture was quenched by addition of saturated NaHCO3 solution and extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:3 EtOAc in petroleum ether) to afford 61 g of [(1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propyl] 4-nitrobenzoate (compound 6d) as a slight yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH:11]1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:4].Br[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].F[B-](F)(F)F.C(O)(=O)C(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].CC(N(C)C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:8][C:9]=1[N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH:11]1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:4]
Reactant: COC(=O)c1sccc1N1C(=O)CCCC1C1CCCCC1
Reactant: Fc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1sc(-c2ccc(F)cc2)cc1N1C(=O)CCCC1C1CCCCC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
A 5 mL vial was charged with 3-(2-cyclohexyl-6-oxo-piperidin-1-yl)-thiophene-2-carboxylic acid methyl ester (32 mg, 0.10 mmol, 1.0 equiv), 1-bromo-4-fluoro benzene (17 mg, 0.10 mmol, 1.0 equiv), potassium carbonate (20.6 mg, 0.15 mmol, 1.5 equiv), tricyclophenylphosphine tetrafluoroborate (8.7 mg, 0.024 mmol, 0.24 equiv), Pd(OAc)2 (2.7 mg, 0.012 mmol, 0.12 equiv), pivalic acid (6.1 mg, 0.060 mmol, 0.6 equiv) and DMA (0.3 mL). The resulted mixture was flushed with nitrogen and stirred at 100° C. for 18 hours. The mixture was loaded to silica gel column and flushed with EtOAc/heptane 67% to give product 27 mg (yield 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=O.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:9][C:8]1[N:7]=[C:5]([C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]=2[O:2][CH3:1])[N:15]2[C:10]=1[CH:11]=[N:12][C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[N:14]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccccc3OC)nn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccccc4OC)n3n2)cc1
Yield: 15.3 %

Procedure:
Applying the Cyclization Procedure 1, 2-(methyloxy)-N[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]benzamide (Intermediate 51) (145 mg, 0.38 mmol), 1,2-dichloroethane (4.5 mL) and phosphorus oxychloride (0.285+0.178 mL, 4.97 mmol), to afford 5-methyl-7-[2-(methyloxy)phenyl]-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (21 mg) as a yellow solid. MS m/z 362 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:33]1C=CC(CCCC(O)=O)=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:33][CH:3]=1
Reactant: O=C(O)CCCc1ccc(Cl)cc1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCCc2ccc(Cl)cc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(4-chloro-phenyl)-butyric acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]([Cu])#[N:13]>N1C=CC=CC=1>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([C:12]#[N:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#C[Cu]
Reactant: Brc1ccc2ncccc2c1
Solvent: c1ccncc1
Product: N#Cc1ccc2ncccc2c1
Temperature: 200 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6-bromoquinoline (2.0 g, 9.61 mmol) in pyridine (30 mL) was added CuCN (3.0 g, 33.6 mmol) at RT under inert atmosphere. The reaction mixture was gradually heated to 200° C. and stirred for 8 h. After complete consumption of the starting material (by TLC), the reaction mixture was cooled to RT, diluted with ice-cold H2O (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with H2O (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 30% EtOAc/hexane) afforded compound I-C (1.25 g, 8.0 mmol, 83%) as white solid. 1H NMR (200 MHz, CDCl3): δ 9.08-9.05 (m, 1H), 8.25-8.19 (m, 3H), 7.86 (dd, J=8.6, 1.8 Hz, 1H), 7.55 (dd, J=8.6, 1.8 Hz, 1H). MS (ESI): 155 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17][CH2:18]O>>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:17][CH3:18])=[O:5]
Reactant: CCO
Reactant: Cc1cccc(C(=O)O)c1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc(C)c1F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
2-Fluoro-3-methylbenzoic acid (8.0 g) was mixed with EtOH (100 ml), and concentrated sulfuric acid was added thereto, followed by stirring at 90° C. overnight. The reaction mixture was concentrated under reduced pressure, and EtOAc and water were then added thereto. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, then dried over Na2SO4, and concentrated under reduced pressure to obtain ethyl 2-fluoro-3-methylbenzoate (7.84 g).
Reaction SMILES: CB(C)Br.[N:5]([C@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:18]=2)[CH2:9]1)=[N+]=[N-].[CH2:36](O)C>ClCCCl>[CH3:36][NH:5][C@H:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:18]=2)[CH2:9]1
Reactant: CCO
Reactant: Cc1ccc(S(=O)(=O)n2cc([C@@H]3C[C@@H](N=[N+]=[N-])c4ccccc43)c3ccccc32)cc1
Agent: CB(C)Br
Solvent: ClCCCl
Product: CN[C@@H]1C[C@@H](c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Dimethylbromoborane (1.77 mL, 1.05 equiv) (Synthesized according to Nöth, H., Vahrenkamp, H. Journal of Organometallic Chemistry 11(1968), 399-405) was added to 3-((1R,3R)-3-azido-indan-1-yl)-1-(toluene-4-sulfonyl)-1H-indole (17.3 mmol ) in 100 mL 1,2-dichloro-ethane under argon at 0° C. The reaction mixture was warmed to room temperature and stirred 2.5 hours. 1 mL Ethanol was added. The reaction mixture was extracted with ethyl acetate and 0.5N aqueous NaOH. The organic phase was washed with brine, dried over MgSO4, concentrated in vacuo to give methyl-{(1R,3R)-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-indan-1-yl}-amine after flash chromatography (ethyl acetate, methanol, triethylamine, silica gel). Methyl-{(1R,3R)-3-[1-(toluene-4-sulfonyl)-1H-indol-3-yl]-indan-1-yl}-amine was dissolved in 8 mL acetone and 20 mL methanol. 8 mL 28% Aqueous NaOH was added and the reaction mixture was stirred in two portions at 120° C. for 10 minutes under microwave irradiation using the Emry Optimizer™ instrument. The reaction mixture was poured into 250 mL water and a precipitate was formed. Recrystallization gave 2.15 g [(1R,3R)-3-(1H-indol-3-yl)-indan-1-yl]-methyl-amine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[NH2:10][C:11]1[NH:15][N:14]=[N:13][N:12]=1>O1CCCC1.C(N(CC)CC)C.C(Cl)(=O)OCC>[NH:12]1[C:11]([NH:10][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[N:15][N:14]=[N:13]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cnccn1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1nnn[nH]1)c1cnccn1

Procedure:
To a suspension of 1.50 g of pyrazine-2-carboxylic acid in 50 ml of tetrahydrofuran, 1.85 ml of triethylamine and 1.27 ml of ethyl chlorocarbonate were added dropwise successively at 0° C. under stirring. After stirring for 30 minutes at 0° C., 1.35 g of 5-amino-1H-tetrazole was added to the mixture, and the reaction mixture was stirred for 28.5 hours at room temperature. The precipitate was collected by filtration, and washed with dilute hydrochloric acid affording 2.05 g as colorless crystals, which was recrystalized from dimethylsulfoxide giving colorless crystals, m.p. 291°-296 ° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][N:18]=1.CN1CCCC1=O>CO.[C].[Pd]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH:6]=[CH:7][C:2]=2[CH3:1])=[N:18][CH:19]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
To a solution of tert-butyl {4-methyl-3-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate (2.20 g, 6.37 mmol) in methanol (50 mL)/N-methylpyrrolidone (10 mL) was added 10% palladium-carbon powder (440 mg), and the mixture was stirred at room temperature for 4 hr under a hydrogen atmosphere (3.0 atm). 10% Palladium-carbon powder was filtered off by celite filtration, and water (20 mL) was added to the filtrate. The obtained precipitate was collected by filtration, and repeatedly washed with water to give the title compound (1.87 g, 93%) as a pale-gray powder.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:14]1[CH:22]=[C:21]([F:23])[C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)[C:9]([O:11]C)=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:14]1[CH:22]=[C:21]([F:23])[C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)[C:9]([OH:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1cc(F)c2c(c1)OCO2)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H](Cc1cc(F)c2c(c1)OCO2)C(=O)O
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a solution of (S)-methyl 2-(tert-butoxycarbonyl)-3-(7-fluorobenzo[d][1,3]dioxol-5-yl)propanoate (12000 mg, 35 mmol) in 200 mL of THF at 0° C. was added LiOH (0.2 M) (52735 μl, 52735 μmol) dropwise over 10 minutes. After stirring for 1 hour, more LiOH (0.2 M) (17578 μl, 17578 mmol) was added and the mixture was stirred for another 1 hr. The reaction mixture was washed with ether (2×250 mL), the aqueous layer was acidified with 2N HCl to pH of about 4 and extracted with EtOAc (3×300 mL). The combined organics were washed with water, brine, dried over sodium sulfate, filtered and concentrated to provide (S)-2-(tert-butoxycarbonyl)-3-(7-fluorobenzo[d][1,3]dioxol-5-yl)propanoic acid (11.3 g, 98% yield) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1)[CH3:16]>>[CH2:15]([O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:12]([C:9]2[NH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][CH:10]=2)=[O:14])[CH:21]=1)[CH3:16]
Reactant: CCOC(=O)Cc1cccc(N)c1
Reactant: O=C(O)c1cnc(-c2ccccc2)[nH]1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cnc(-c3ccccc3)[nH]2)c1

Procedure:
2-Phenyl-1H-imidazole-5-carboxylic acid (105 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[CH2:9]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[C:19]([F:26])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>C1COCC1>[CH2:9]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](=[O:22])[CH2:2][C:1]#[N:3])=[C:19]([F:26])[CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC#N
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
Acetonitrile (1.66 mL, 31.7 mmol) was dissolved in dry THF (40 mL) and the mixture was cooled to −78 C. Butyllithium (2.5 M, 9.5 mL, 23.8 mmol) was added dropwise, and the resulting reaction mixture was stirred for 15 minutes. A solution of 4-(benzyloxy)-2-fluorobenzoyl chloride (2.1 g, 7.93 mmol) in THF was then added dropwise to the reaction mixture, and the resulting reaction mixture was stirred at −78 C for 40 minutes. Saturated ammonium chloride solution was then added carefully to the reaction mixture, and the resulting mixture was allowed to warm to room temperature. Next, the mixture was partitioned between water and EtOAc, and the organic portion was washed further with brine, then dried over sodium sulfate, and concentrated onto silica gel and purified by chromatography (gradient: 9:1 EtOAc:hexanes to 1:1 EtOAc:hexanes to 100% ethyl acetate) to give the title compound in 79% yield.
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([CH2:31][OH:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].CC(C)=[O:35].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:3][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:35])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C:16](=[O:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: CC(C)=O
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of betulin (1, 1.0 g, 2.26 mmol) in acetone (50 mL), cooled to 0° C., freshly prepared Jones' reagent was added dropwise. The resulting mixture was stirred for about 1.5 hours at 0° C., quenched with methanol (25 mL), stirred for an additional 5 minutes, then water (40 mL) was added. The acetone was removed under vacuum and the aqueous residue was extracted two times with 40 mL of ethyl acetate (EtOAc). The ethyl acetate layer was separated from the aqueous layer, then the ethyl acetate layer was washed first with water (20 mL) and then with brine (15 mL). The ethyl acetate layer was dried over magnesium sulfate (MgSO4), then filtered, and finally the ethyl acetate was removed under vacuum. The residue was column chromatographed over silica gel (60-200 mesh) using petroleum ether/EtOAc (4:1 volume ratio) to yield 770 mg of betulonic acid, having a melting point (mp) of 247°-249° C. (literature mp 246°-2470° C.). The reaction provided a 75% yield of betulonic acid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[C:13]([CH2:17][C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=O)[CH:14]=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].B.CSC.Cl.[OH-].[Na+]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CC(=O)N3CCOCC3)c2)n1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)c1cc(N)n(-c2cccc(CCN3CCOCC3)c2)n1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a stirred solution of Example L (1.2 g, 3.5 mmol) in THF (6 ml) was added borane-methylsulfide (9 mmol). The mixture was heated to reflux for 90 min and cooled to RT, and 6 N HCl was added and heated to reflux for 10 min. The mixture was basified by adding sodium hydroxide, followed by extraction with ethyl acetate. The organic layer was dried (Na2SO4) filtered and concentrated in vacuo to yield 3-tert-butyl-1-[3-(2-morpholinoethyl)phenyl]-1H-pyrazol-5-amine (0.78 g), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11](OC)=O)[CH:4]=1.[NH2:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:15][C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[N:22]=2)[CH:4]=1
Reactant: Nc1cccnc1N
Reactant: COC(=O)CCc1cc(OC)ccn1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccnc(CCc2nc3cccnc3[nH]2)c1
Temperature: 160 °C
Yield: 43 %

Procedure:
With stirring, a mixture of 0.643 g of methyl 3-(4-methoxypyridin-2-yl)propionate (starting material A2), 0.359 g of 2,3-diaminopyridine and 10 g of polyphosphoric acid (PPA) is heated at 160° C. for 1 h. After cooling, the mixture is poured into about 50 ml of ice-water and then neutralized (pH 7–8) using 6N aqueous sodium hydroxide solution. The mixture is extracted three times with dichloromethane/methanol 9:1, the combined organic phases are evaporated to dryness and the residue is chromatographed on a silica gel column (dichloromethane/methanol 15:1). Concentration of the chromatographically pure fractions gives 0.36 g of an oil, which crystallizes on standing. The product is recrystallized from ethyl acetate/petroleum ether, giving 0.278 g of the title compound as a light-beige powder of m.p. 116–117° C.; the mass spectrum shows the molecular peaks MH+ and 2MNa+ at 255.3 and 530.9 Da.
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])[C:9]=1[CH3:26].C([O-])(O)=O.[Na+].S(Cl)(Cl)(=O)=O.[C:37]1([CH3:61])[CH:42]=[CH:41][C:40]([S:43]([CH2:46][CH2:47][O:48][C:49](=[O:60])[C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([S:56](Cl)(=[O:58])=[O:57])[CH:51]=2)(=[O:45])=[O:44])=[CH:39][CH:38]=1>C(Cl)Cl.O.CCN(CC)CC>[C:37]1([CH3:61])[CH:42]=[CH:41][C:40]([S:43]([CH2:46][CH2:47][O:48][C:49](=[O:60])[C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([S:56]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:10]3[C:9]([CH3:26])=[C:8]([O:7][CH2:6][CH2:5][CH2:4][O:3][CH3:2])[CH:13]=[CH:12][N:11]=3)=[O:16])(=[O:58])=[O:57])[CH:51]=2)(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)c2cccc(S(=O)(=O)Cl)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2cccc(C(=O)OCCS(=O)(=O)c3ccc(C)cc3)c2)c1C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
To a solution of 2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-1H-benzimidazole sodium salt (RABEPRAZOLE sodium salt, 1.0 g, 2.62 mmol), 5 mL of Et3N, and about 1 g of NaHCO3 in CH2Cl2 (15 mL) was added the sulfonyl chloride (Intermediate 43, 1.27 g, 3.15 mmol, 1.2 eq) in CH2Cl2 at room temperature, and then the mixture was stirred for 1.5 h. Thereafter water was added, the mixture was extracted with CH2Cl2, and the organic layers were dried, and concentrated. The resulting residual oil was purified by column chromatography (CH2Cl2 to 1% MeOH in CH2Cl2) to yield 1.5 g (76%) of 3-{2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl}benzoic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 48) as an off-white foam.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:23](=[O:25])[NH:22][C:21]4[CH:26]=[C:27]([N:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:28]=[CH:29][C:20]=4[C:19]=3[C:18]3[C:36]([CH3:48])=[N:37][N:38](CC4C=CC(OC)=CC=4)[C:17]=3[N:16]=2)=[CH:11][C:10]=1[C:49]([F:52])([F:51])[F:50])C1C=CC=CC=1.C(OC(C)C)(C)C.[ClH:60].O1CCOCC1>FC(F)(F)C(O)=O>[ClH:60].[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]3[C:23](=[O:25])[NH:22][C:21]4[CH:26]=[C:27]([N:30]5[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]5)[CH:28]=[CH:29][C:20]=4[C:19]=3[C:18]3[C:36]([CH3:48])=[N:37][NH:38][C:17]=3[N:16]=2)=[CH:11][C:10]=1[C:49]([F:52])([F:51])[F:50]
Reactant: COc1ccc(Cn2nc(C)c3c4c(c(-c5ccc(OCc6ccccc6)c(C(F)(F)F)c5)nc32)c(=O)[nH]c2cc(N3CCNCC3)ccc24)cc1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1n[nH]c2nc(-c3ccc(O)c(C(F)(F)F)c3)c3c(=O)[nH]c4cc(N5CCNCC5)ccc4c3c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
A solution of 1.8 g (2.55 mmol) of 5-(4-(benzyloxy)-3-(trifluoromethyl)phenyl)-3-(4-methoxybenzyl)-1-methyl-9-(piperazin-1-yl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one dissolved in 25 ml of trifluoroacetic acid is carried at 70° C. for 3 hours. After returning to room temperature, 50 ml of diisopropyl ether is added until a stable precipitate appears; the latter is filtered and then taken up in water. Acidity is neutralized by the addition of 1 M soda. The solid is filtered again and then triturated several times in hot methanol to yield after a final filtration 950 mg of 5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1-methyl-9-(piperazin-1-yl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one. The product is then taken up in 20 ml of anhydrous dioxane; a 4 M solution of hydrochloric acid in dioxane (932 μl, 3.73 mmol) is added and the reaction medium is stirred at room temperature for 2 hours. The precipitate is filtered, rinsed with dioxane and triturated in methanol to yield 475 mg (36%) of 5-(4-hydroxy-3-(trifluoromethyl)phenyl)-1-methyl-9-(piperazin-1-yl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one hydrochloride in the form of a yellow solid.