Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[C:7]([F:18])[C:3]=1[C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.[N:41]1([C:46]2[C:54]3[C:49](=[N:50][CH:51]=[C:52]([NH2:55])[CH:53]=3)[NH:48][N:47]=2)[CH:45]=[CH:44][N:43]=[CH:42]1>CN(C=O)C>[N:41]1([C:46]2[C:54]3[C:49](=[N:50][CH:51]=[C:52]([NH:55][C:4](=[O:6])[C:3]4[C:7]([F:18])=[CH:8][CH:9]=[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[C:2]=4[F:1])[CH:53]=3)[NH:48][N:47]=2)[CH:45]=[CH:44][N:43]=[CH:42]1
Reactant: Nc1cnc2[nH]nc(-n3ccnc3)c2c1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(-n4ccnc4)c3c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
2,6-Difluoro-3-(propylsulfonamido)benzoic acid (140 mg, 0.495 mmol), HOBt.H2O (89 mg, 0.584 mmol), and EDCI (120 mg, 0.674 mmol) was added to 3-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine (90 mg, 0.450 mmol) in DMF (10 mL). The mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated, and the residue partitioned between ethyl acetate and water. The ethyl acetate was washed with brine, dried over magnesium sulfate, filtered, and concentrated to an oil. The crude product was purified by column chromatography (10:1 DCM:MeOH), which was followed by trituration with DCM to afford N-(3-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (57.7 mg, 28% yield) as a solid. 1H NMR (400 MHz, CD3OD) δ 8.80 (d, 1H), 8.74 (d, 1H), 8.36 (s, 1H), 7.80 (s, 1H), 7.70-7.64 (m, 1H), 7.27 (s, 1H), 7.17-7.12 (m, 1H), 3.14-3.09 (m, 2H), 1.92-1.82 (m, 2H), 1.06 (t, 3H); m/z (ESI-pos) M+1 462.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[CH3:10][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]([OH:9])[CH3:10]
Reactant: C[Mg]Br
Reactant: O=Cc1cnccc1Br
Solvent: C1CCOC1
Product: CC(O)c1cnccc1Br

Procedure:
To a solution of 4-bromo-pyridine-3-carbaldehyde (400 mg, 2.15 mmol) in THF (10 mL) at −78° C. was added dropwise 3.0 M methylmagnesium bromide solution in THF (1.08 mL). After 15 min. the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate, then purified by flash chromatography eluted with 50% ethyl acetate in hexane to yield 1-(4-bromo-pyridin-3-yl)-ethanol as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=1.[N:16]1([S:22](Cl)(=[O:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:22]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:24])=[O:23])=[N:13][CH:14]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2Cl)cn1
Reactant: O=S(=O)(Cl)N1CCCCC1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(-c2ccc(Cl)cc2Cl)cn1)N1CCCCC1
Yield: 67.3 %

Procedure:
A solution of 0.23 g (1 mmol) of 5-(2,4-dichloro-phenyl)-pyridin-2-ylamine and 0.2 g (1.1 mmol) of piperidine-1-sulfonyl chloride (preparation: Bull. Soc. Chim. Fr.; 1936, p 2143) in pyridine (10 ml) was heated to reflux until completion of reaction according to HPLC analysis (20 h). After concentration in vacuo the residue was taken up in EtOAc, which was then washed with 1N aqueous HCl, saturated brine, dried over sodium sulphate and concentrated in vacuo. The residue was applied to a silica gel column with EtOAc/toluene (9/1 to 1/1) as eluent. Combination of the purified fractions and concentration in vacuo gave 0.26 g (67%) of the desired piperidine-1-sulfonic acid [5-(2,4-dichloro-phenyl)-pyridin-2-yl]-amide as a brown crystalline solid. ISN mass spectrum, m/e: 384 (M−1 calculated for C16H17Cl2N2O2S: 384).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([C:9]1[N:13]=[C:12]([NH:14][C:15]3[N:20]=[CH:19][C:18]([S:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][C:16]=3[O:27][C:28]3[C:29]([CH3:34])=[N:30][CH:31]=[CH:32][CH:33]=3)[S:11][N:10]=1)[CH2:2]2.C(N(CC)CC)C.[C:42](OC(=O)C)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([N:8]1[CH:5]2[CH2:6][CH2:7][CH:1]1[CH2:2][CH:3]([C:9]1[N:13]=[C:12]([NH:14][C:15]3[N:20]=[CH:19][C:18]([S:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][C:16]=3[O:27][C:28]3[C:29]([CH3:34])=[N:30][CH:31]=[CH:32][CH:33]=3)[S:11][N:10]=1)[CH2:4]2)(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CSc1cnc(Nc2nc(C3CC4CCC(C3)N4)ns2)c(Oc2cccnc2C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CSc1cnc(Nc2nc(C3CC4CCC(C3)N4C(C)=O)ns2)c(Oc2cccnc2C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.3 %

Procedure:
Methyl 2-(6-(3-(8-azabicyclo[3.2.1]octan-3-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)acetate (384 mg, 0.770 mmol) was dissolved in CH2Cl2 (7 mL), and triethylamine (16 μL, 1.16 mmol) and acetic anhydride (87.4 μL, 0.924 mmol) were added. The reaction was stirred at ambient temperature for 5 minutes. The reaction was partitioned between CH2Cl2 and saturated aqueous NaHCO3, dried over sodium sulfate, filtered and concentrated to afford methyl 2-(6-(3-(8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)acetate (397 mg, 0.734 mmol, 95.3% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]3[CH:14]=[C:15]([NH:18][C:19]([C:21]4[CH:30]=[CH:29][C:24]([C:25](OC)=[O:26])=[CH:23][CH:22]=4)=[O:20])[CH:16]=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1.[NH2:31][NH2:32]>C(O)C>[NH:31]([C:25]([C:24]1[CH:23]=[CH:22][C:21]([C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:11]3[N:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[NH:13][C:12]=3[CH:14]=2)=[O:20])=[CH:30][CH:29]=1)=[O:26])[NH2:32]
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc3nc(-c4ccc(OC)cc4)[nH]c3c2)cc1
Solvent: CCO
Product: COc1ccc(-c2nc3ccc(NC(=O)c4ccc(C(=O)NN)cc4)cc3[nH]2)cc1
Temperature: 70 °C

Procedure:
In a 15-mL sealed tube, methyl 4-((2-(4-methoxyphenyl)-1H-benzo[d]imidazol-6-yl)carbamoyl)benzoate (28 mg, 0.07 mmole) was dissolved in 2 mL absolute ethanol and hydrazine (1 mL) was added. The reaction mixture was heated in an oil bath at 70° C. for overnight. In the morning the reaction mixture was evaporated to dryness to provide the title compound (28 mg, 99%, >95% pure by 1H-NMR). This compound was used for next step without any further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].[Br:13]N1C(=O)CCC1=O>C(OC)(C)(C)C.C(#N)C>[Br:13][C:11]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccccc1C1CCCO1
Solvent: COC(C)(C)C
Solvent: CC#N
Product: Nc1ccc(Br)cc1C1CCCO1

Procedure:
To a stirring solution of 2-tetrahydrofuran-2-yl-aniline (4) (53.45 g, 327.5 mmol) in methyl tert-butyl ether (MTBE, 641.4 mL) and acetonitrile (213.8 mL) cooled to 2° C. was added N-bromosuccinimide (58.88 g, 99%, 327.5 mmol, Aldrich B81255) in 4 portions maintaining internal temperature below about 8° C. The reaction mixture was stirred while cooling with an ice-water bath for 30 minutes (NMR of a worked-up aliquot showed complete consumption of starting material). Added aqueous 1 N Na2S2O3 (330 mL), removed the cold bath and stirred for 20 minutes. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with saturated aqueous NaHCO3 (2×), water, brine, dried over MgSO4, filtered through a short plug of silica, eluted with EtOAc, and concentrated under reduced pressure to give (5) as a very dark amber oil (82.25 g, 77-94% HPLC purity). Carried forward without further purification. LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 242.10 (2.89 min). 1H NMR (300 MHz, CDCl3) δ 7.22 (d, J=2.3 Hz, 1H), 7.16 (dd, J=8.4, 2.3 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 4.79-4.73 (m, 1H), 4A5 (s, 2H), 4.10-4.01 (m, 1H), 3.93-3.85 (m, 1H), 2.26-2.13 (m, 1H), 2.12-1.97 (m, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)[CH:6]=[CH:7][CH:8]=1.C(OC(=O)C)(=O)C.CS(O)(=O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:12](=[O:14])[C:11]3[C:10]([S:9][C:5]=2[CH:4]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COc1cccc(Sc2ccccc2C(=O)O)c1
Agent: CS(=O)(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(=O)c3ccccc3sc2c1
Temperature: 0 °C

Procedure:
Finally, 3-methoxythioxanthen-9-one (S-18) was prepared. To a mixture of 2-(3-methoxyphenylthio)benzoic acid (4.60 g, 18 mmol) and 27 g (265 mmol) of acetic anhydride was added dropwise 1.70 g (18 mmol) of methanesulfonic acid. The mixture was heated at reflux for 2 h, cooled to ambient, and poured very slowly onto 250 g of ice. The crude product was extracted with dichloromethane, and the extract was washed with 10% aqueous NaHCO3 and then with brine. The solution was dried (MgSO4), passed through a short column of silica gel, and concentrated to deposit an orange solid. The product was purified by successive recrystallizations from toluene/heptane and from isopropanol to provide 1.57 g (37% of theory) of a yellow powder. 1H NMR (CDCl3): δ 3.91 (s, 3H), 6.95 (d, 1H), 7.01 (dd, 1H), 7.4-7.6 (m, 3H), 8.55 (d, 1H), 8.59 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10].CCOC(C)=O.[CH3:17][N:18](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]#[N:18])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1cc(F)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1C#N
Temperature: 100 °C

Procedure:
To a solution of 1-bromo-4-fluoro-2-methoxybenzene (25 g, 0.12 mol) in 250 mL of DMF was added Zn(CN)2 (28.6 g, 0.240 mol) and Pd(PPh3)4 (7.05 g, 6.10 mmol) at one portion and the reaction was charged with Ar and heated to 100° C. for 10 hours. Then the reaction was poured into 1 L of EtOAc and filtered through a kieselguhr pad. The filtrate was washed with water, brine, dried and concentrated to solid, which was purified by silica gel column to give 4-fluoro-2-methoxybenzonitrile.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](OS(C)(=O)=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[N:16]([CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC1CCC2(CC1)OCCO2
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of methanesulfonic acid 1,4-dioxa-spiro[4.5]dec-8-yl ester (2.80 g, 11.9 mmol) and sodium azide (3.86 g, 59.3 mmol) in 50 mL of dry DMF is stirred for 20 h at 100° C. under nitrogen. The final mixture is cooled to room temperature diluted with brine and extracted with three portions of ether. The organic portions are combined, dried over Na2SO4 and concentrated to give 8-azido-1,4-dioxa-spiro[4.5]decane.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][C:14]1[CH:19]=[C:18]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][C:24](F)=[CH:25][C:26]=3[O:31][CH3:32])[N:21]=2)[CH:17]=[C:16]([CH3:34])[N:15]=1.O>CS(C)=O>[CH3:13][C:14]1[CH:19]=[C:18]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][C:24]([O:10][CH2:9][CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:25][C:26]=3[O:31][CH3:32])[N:21]=2)[CH:17]=[C:16]([CH3:34])[N:15]=1
Reactant: OCCOc1ccccc1
Reactant: COc1cc(F)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(OCCOc2ccccc2)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-phenoxy-ethanol (0.90 g, 6.50 mmol) in DMSO (5 mL) was added sodium hydride (60% in mineral oil, 0.16 g, 4.00 mmol) in small portions. The reaction mixture was stirred at room temperature under nitrogen for 1 hour. 2-(2,6-Dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one (0.20 g, 0.67 mmol) was added and stirring continued at 90° C. for 17 hours. The reaction was then cooled to room temperature, water (100 mL) was added, and was extracted with ethyl acetate (200 mL). The organic phase was washed with brine and dried over anhydrous Na2SO4. Solvent was removed and the crude compound was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in CH2Cl2 as eluent) to give the title compound as a white solid. Yield: 70 mg (25%). MP 223-224° C. 1H NMR (400 MHz, CDCl3): δ 11.35 (s, 1H), 7.75 (s, 2H), 7.32 (t, J=8.0 Hz, 2H), 7.02-6.97 (m, 3H), 6.91 (d, J=2.0 Hz, 1H), 6.60 (d, J=1.6 Hz, 1H), 4.49-4.47 (m, 2H), 4.41-4.39 (m, 2H), 3.97 (s, 3H), 2.67 (s, 6H). MS (ES+) m/z: 418.08 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([N:8]1[C:16]2[C:11](=[C:12]([CH3:19])[C:13]([OH:18])=[C:14]([CH3:17])[CH:15]=2)[CH:10]([CH3:20])[CH2:9]1)(=[O:7])[CH:4]([CH3:6])[CH3:5].[CH3:21]I>O1CCCC1>[C:3]([N:8]1[C:16]2[C:11](=[C:12]([CH3:19])[C:13]([O:18][CH3:21])=[C:14]([CH3:17])[CH:15]=2)[CH:10]([CH3:20])[CH2:9]1)(=[O:7])[CH:4]([CH3:6])[CH3:5]
Reactant: Cc1cc2c(c(C)c1O)C(C)CN2C(=O)C(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(C)cc2c(c1C)C(C)CN2C(=O)C(C)C
Temperature: 0 °C
Yield: 90 %

Procedure:
Sodium hydride (7 mg, 0.18 mmol) contained in a round-bottom flask was washed using dry hexanes and tetrahydrofuran (2 mL) was added, and the suspension was stirred at 0° C. under nitrogen atmosphere. A solution of N-isobutyryl-5-hydroxy-3,4,6-trimethylindoline (11 b, 42 mg 0.17 mmol) dissolved in tetrahydrofuran (2 mL) was added dropwise using a syringe. Methyl iodide (0.2 mL) was added to the cold solution in one portion, and the mixture was heated under reflux for 17 h. The reaction mixture was cooled, quenched with saturated aq. ammonium chloride solution and extracted with ether. The combined extracts were washed with brine and dried (MgSO4). Removal of solvents gave a viscous liquid which was purified by flash column chromatography using 1:4 ethyl acetate:hexanes as eluent, to afford N-isobutyryl-5-methoxy-3,4,6-trimethylindoline (13, 40 mg, 90% yield) as a viscous liquid. Spectral data: 1H NMR: δ 1.20-1.35 (m, 9H), 2.22 (s, 3H), 2.27 (s, 3H), 2.74 (quintet, 1H, J=6.5 Hz), 3.30 (t, 1H, J=6.5 Hz), 3.65 (s, 3H), 3.76 (dd, 1H, J=10, 1 Hz), 4.15 (t, 1H, J=9 Hz), 8.0 (s, 1H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C:31](=[O:37])[C:30](=[O:38])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)(C(C)(C)C)(C)C.F>C(#N)C>[CH3:20][C@@H:19]1[C@:21]2([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]2)[O:22][C@H:17]2[CH2:16][C@@H:15]3[C@@:29]([CH3:39])([C@@H:18]12)[C:30](=[O:38])[C:31](=[O:37])[C@H:32]1[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[C@:33]1([CH3:36])[CH2:34][CH2:35][C@H:9]([OH:8])[CH2:10]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4C(=O)C(=O)[C@]3(C)[C@H]1[C@@H]2C
Agent: F
Solvent: CC#N
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)C(=O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
Using the procedure described in J. Am. Chem. Soc., 1972, 94, 6190, (3β,5α,25R)-3-(t-butyldimethylsilyloxy)spirostan-11,12-dione was desilylated with hydrofluoric acid in acetonitrile to give the title compound.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.NCC1CCN([NH:27][C:28](=[O:36])[NH:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)CC1>>[CH:30]1([NH:29][C:28]([N:27]2[CH2:7][CH2:6][CH:18]([CH2:10][NH:11][CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]3[C:18]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH2:17][CH2:16]2)=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: NCC1CCN(NC(=O)NC2CCCCC2)CC1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Product: O=C(NC1CCCCC1)N1CCC(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)CC1
Yield: 0.1 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.175 g, 0.73 mmol) and 3-(4-aminomethyl-1-piperidinyl)-1-cyclohexyl urea (0.360 g, 1.5 mmol) according to the procedure used in example 2 to give 0.095 mg of the title compound as an off white solid.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH:14]=[CH:13][C:11]=2[N:12]=1.[OH-].[Na+]>CO>[C:1]1([CH3:24])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: CCOC(=O)CCc1ccc2nc(Nc3ccccc3C)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1Nc1nc2ccc(CCC(=O)O)cc2o1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of ethyl 3-(2-o-tolylamino-benzoxazol-6-yl)propanoate (Reference Example 15) in methanol (50 ml) was treated with aqueous sodium hydroxide (5 ml, 1M). After stirring at 40° C. for 2 hours the mixture was evaporated to low volume and partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous phase was separated and acidified with aqueous hydrochloric acid (10 ml, 1M). The resulting precipitate was dried at 60° C. to give the title compound (1.1 g).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]3[CH:15]=[C:14]([C:16]4[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=4)[CH:13]=[N:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:25]1([CH2:24][NH:31][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([C:14]3[CH:13]=[N:12][C:11]4[N:10]([N:9]=[CH:8][C:7]=4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:15]=3)=[CH:17][CH:18]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: c1ccc(CNCc2ccc(-c3cnc4c(-c5ccccc5)cnn4c3)cc2)cc1

Procedure:
A solution of 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)benzaldehyde (1-5, 75 mg, 0.25 mmol), benzylamine (0.056 mL, 0.50 mmol), acetic acid (14 TL, 0.25 mmol), and sodium triacetoxyborohydride(106 mg, 0.50 mmol) in 1,2-dichloro-ethane (6 mL) was stirred under ambient conditions overnight. The residue was partitioned between sat. NaHCO3 solution (4 mL) and ethyl acetate (3×4 mL). The organic layer was washed with brine and dried over MgSO4 and concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide 1-phenyl-N-[4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)benzyl]methanamine (1-6) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ9.21 (d, 1H, J=2.4 Hz), 8.96 (d, 1H, J=2.4 Hz), 8.61 (s, 1H), 8.12 (br d, 2H, J=7.8 Hz), 7.91 (d, 2H, J=8.2 Hz), 7.67 (d, 2H, J=7.8 Hz), 7.49 (m, 5H), 7.44 (br t, 2H, J=7.8 Hz), 7.27 (t, 1H, J=7.5 Hz), 4.34 (s, 2H), 4.29 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([C:18]2[N:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2].[H-].[Na+].Br[CH2:33][C:34]([O:36]CC)=[O:35].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([N:15]([C:16]([C:18]2[N:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)=[O:17])[CH2:33][C:34]([OH:36])=[O:35])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)COc1ccc(NC(=O)c2cccn2-c2ccc(F)cc2)cc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc(N(CC(=O)O)C(=O)c2cccn2-c2ccc(F)cc2)cc1C#N
Temperature: 25 °C
Yield: 65.3 %

Procedure:
N-[3-Cyano-4-neopentyloxyphenyl]-1-(4-fluorophenyl) pyrrole-2-carboxamide (4.0 g) and sodium hydride (60% content, 0.6 g) were reacted in dimethylformamide (40 ml) under ice-cooling for 1 h. Dimethylformamide solution (3 ml) containing ethyl bromoacetate (3.4g) was added and the mixture was stirred under ice-cooling for 1 h, and after allowed to warm to room temperature, stirred for another 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. To the residue were added ethanol (40 ml) and then 10% aqueous sodium hydroxide solution (50 ml). The mixture was stirred at a refluxing temperature for 30 min. The solvent was evaporated under reduced pressure. Dilute hydrochloric acid was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A mixed solvent of chloroform-n-hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give the title compound (3.0 g), melting point: 140–143° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=1)=[O:4].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]([F:15])([F:16])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=[O:4]
Reactant: COc1ccc(CNC(=O)C(F)(F)F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NCc1ccc(O)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
Dissolve under nitrogen atmosphere 2,2,2-trifluoro-N-(4-methoxybenzyl)-acetamide (11.6 g, 50 mmol) in DCM (250 mL). Cool to 0° C. in an ice bath. Add dropwise 1M boron tribromide in DCM (100 mL, 100 mmol) and stir for 20 min after addition. Warm to ambient temperature and stir for 16 h. Cool the reaction mixture in an ice bath and quench very carefully with saturated aqueous NaHCO3. Separate the organic layer. Extract the aqueous layer twice with chloroform. Dry the combined organic extracts over Na2SO4 and concentrate in vacuo to obtain the desired intermediate (8.8 g, 40 mmol). MS (ES−) m/z: 218 (M−H)−.