Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][NH:14][C:13](=S)[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1.[NH2:25][CH2:26][CH:27]([C:29]1([C:32]([F:35])([F:34])[F:33])[CH2:31][CH2:30]1)[OH:28]>C(O)C.[Hg](Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][NH:14]/[C:13](=[N:25]\[CH2:26][CH:27]([OH:28])[C:29]2([C:32]([F:34])([F:35])[F:33])[CH2:31][CH2:30]2)/[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Reactant: NCC(O)C1(C(F)(F)F)CC1
Agent: Cl[Hg]Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN/C1=N\CC(O)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Mercury(II) chloride (149 mg, 0.547 mmol) was added to a solution of tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-yl]carbamate (150 mg, 0.421 mmol, described in Intermediate 7), and 2-amino-1-[1-(trifluoromethyl)cyclopropyl]ethanol (569 mg, 3.367 mmol) in ethanol (5 mL) at 60° C. After 10 min, the reaction was allowed to cool to ambient temperature. The mixture was filtered and concentrated under reduced pressure. Saturated aqueous NaHCO3 was added and the mixture was extracted with CH2Cl2 (3×). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=492 (M+1).
Reaction SMILES: CC([C:5]1[CH:6]=[C:7]([CH:10]=[C:11](C(C)(C)C)[C:12]=1OCOCCOC)[C:8]#[N:9])(C)C.C(N(CC)CC)C.N1C=CC=CC=1.[SH2:37]>>[C:7]1([C:8](=[S:37])[NH2:9])[CH:10]=[CH:11][CH:12]=[CH:5][CH:6]=1
Reactant: S
Reactant: COCCOCOc1c(C(C)(C)C)cc(C#N)cc1C(C)(C)C
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1ccccc1
Reaction time: 15 h

Procedure:
Into a solution containing 10.0 g (0.03 mole) of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzonitrile, 5.7 ml (0.04 mole) of triethylamine and 14.2 ml (0.18 mole) of pyridine, hydrogen sulfide gas is bubbled over 15 hours. The mixture is poured into ice water (110 ml), and an oily precipitate solidifies upon standing at 0° C. for 15 hours. The solid is thoroughly washed with water and filtered. Recrystallization from ethyl acetate and hexane gives 7.9 g (71%) of analytically pure 3,5-bis(1,1-dimethylethyl)-4-[2-methoxyethoxy)methoxy]benzenecarbothioamide, mp 113°-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[N:14]=[C:15]([CH3:18])[S:16][CH:17]=2)=[CH:7][C:4]=1[CH:5]=O.[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[N:14]=[C:15]([CH3:18])[S:16][CH:17]=2)=[CH:7][C:4]=1/[CH:5]=[CH:20]/[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)=[O:21]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2csc(C)n2)cc1C=O
Product: COc1cc(OC)c(-c2csc(C)n2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-5-(2-methyl-thiazol-4-yl)-benzaldehyde (Ex-69A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 201–202° C. (dec.). 1H-NMR (DMSO-d6) δ 8.47 (s, 1H), 8.14–7.97 (m, 5H), 7.76 (s, 1H), 7.65 (d, J=15.8 Hz, 1H), 6.81 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 2.69 (s, 3H). MS m/z=409 (M+, 70%), 378 ([M−OCH3]+, 100%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16](=[O:25])[C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[CH2:26][CH3:27])([OH:3])=[O:2].[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:17]=1[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][C:6]([CH2:26][CH3:27])=[C:5]2[CH2:4][C:1]([O:3][CH3:28])=[O:2])=[O:25]
Reactant: O=C([O-])[O-]
Reactant: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CC(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CC(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of 4-carboxymethyl-8-(2,6-dichlorobenzoylamino)-3-ethylquinoline (405 mg) in dimethylformamide were added potassium carbonate (305 mg) and methyl iodide (314 mg) and the mixture was stirred for 2 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate: n-hexane, 1:3, v/v) and crystallized from ethanol-water to give 8-(2,6-dichlorobenzoylamino)-3-ethyl-4-(methoxycarbonylmethyl)quinoline (282 mg).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:9][C:10]([NH:13][CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:26]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:26][N:13]([CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]1[S:9][C:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:12][CH:11]=1
Reactant: CCOC(=O)C(=CNc1cnc(CN2CCOCC2)s1)C(=O)OCC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(C)c1cnc(CN2CCOCC2)s1)C(=O)OCC
Temperature: 75 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a mixture of diethyl 2-(((2-(morpholin-4-ylmethyl)-1,3-thiazol-5-yl)amino)-methylene)malonate (Preparation 28, 1.51 g) and K2CO3 (1.19 g) in DMF (15 mL) at ambient temperature is added iodomethane (0.28 mL). The mixture is heated to 75° C. in a sealed pressure tube and stirred overnight. The solution is cooled to ambient temperature and the solvent is removed. The mixture is diluted with water (75 mL) and extracted with EtOAc (3×75 mL). The organic layer is dried (MgSO4) and the solvent removed to afford 0.984 g (63%) of the title compound as a light brown solid. Physical characteristics: 1H NMR (CDCl3) δ1.24-1.33, 2.60, 3.31, 3.74, 4.17-4.24, 7.60; IR (liq.) 1702, 1608, 1535, 1453, 1383, 1365, 1293, 1270, 1232, 1206, 1117, 1096, 1071, 1010, 865 cm−1; HRMS (FAB) m/z 384.1600 (C17H25N3O5S+H). Anal. Found: C, 53.18; H, 6.64; N, 10.41.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](Cl)=[O:30].N1C=CC=CC=1>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[O:30])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1ccccn1
Yield: 64.3 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) obtained from Referential Example 7 was suspended in 1,2-dichloroethane (40 ml), picolinoyl chloride hydrochloride (1.41 g) and pyridine (1.28 ml) were added, and the mixture was refluxed for 1 hour and 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (150 ml), successively washed with water and saturated aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, diethyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 1.75 g of the titled compound.
Reaction SMILES: [CH:1]1([NH:11][C:12]([NH2:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(O)(=[O:17])C>O>[O:17]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]([NH:11][C:12]([NH2:14])=[O:13])[CH2:2][CH2:3]1
Reactant: NC(=O)NC1CCCc2ccccc21
Reactant: CC(=O)O
Solvent: O
Product: NC(=O)NC1CCC(=O)c2ccccc21

Procedure:
A solution of 0.5 g of 1,2,3,4-tetrahydro-1-naphthylurea in 50 ml of 50% aqueous acetic acid is cooled to below 5° C and 6.0 g of ceric ammonium nitrate added. After 5 minutes the mixture is diluted with water and extracted with 3 × 5 ml of ethyl acetate. The extracts are combined and evaporated to dryness to afford the crude title product.
Reaction SMILES: C(C1C=CC=C(C(C)C)C=1N=[C:14]=[O:15])(C)C.[CH2:16]([O:18][C:19](=[O:36])[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2([C:33](=[O:35])[NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)[CH3:17]>C1(C)C=CC=CC=1>[CH2:16]([O:18][C:19](=[O:36])[C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:27]3([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:33](=[O:35])[NH:34][C:14]2=[O:15])=[CH:24][CH:25]=1)[CH3:17]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCOC(=O)c1ccc(NC2(C(N)=O)CCCCC2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N2C(=O)NC(=O)C23CCCCC3)cc1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
380 μl (1.85 mmol, 1.2 eq.) of 2,6-diisopropylphenyl isocyanate are added to a solution of 450 mg (1.55 mmol, 1 eq.) of 4-(1-carbamoyl-cyclohexylamino)benzoic acid ethyl ester in 15 ml of toluene. The reaction medium is stirred at 180° C. for 2 hours with microwave irradiation. The toluene is evaporated off and the residue is purified on silica gel (heptane/ethyl acetate). The product 4-(2,4-dioxo-1,3-diazaspiro[4.5]dec-1-yl)benzoic acid ethyl ester is obtained in the form of a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17](S(C)(=O)=O)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:35]#[N:36].[K+]>CN(C)C=O.O>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:35]#[N:36])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A solution of N-(2,2-diphenylethyl)-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (Preparation 22) (20.1 g, 42.1 mmol) in dry N,N-dimethylformamide (100 ml) was treated with potassium cyanide (5.5 g, 84.6 mmol) and the mixture was heated at 120° C. for 24 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and diluted with water (1000 ml) and stirring was continued for a further 1 hour. The resultant solid was filtered off and washed several times with water. The solid was then dissolved in dichloromethane and the solution was washed with water, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue was azeotroped with diethyl ether (twice) to afford the title compound as an oil (17 g).
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Si](C)(C)C)=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:22]([CH3:23])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].[I:24]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl>[C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([I:24])=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:22]([CH3:23])[C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc([Si](C)(C)C)cc2)C[C@@H]2CC[C@H]1N2C
Reactant: ClI
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@H]1[C@@H](c2ccc(I)cc2)C[C@@H]2CC[C@H]1N2C
Reaction time: 2 h

Procedure:
50 mg of 2β-carbomethoxy-3β-(4-trimethylsilylphenyl)tropane was dissolved in 5 ml of CCl4 at ambient temperature. To this was added 40 mg of iodine monochloride after which the solution was stirred for 2 h, then poured into 20 mL of 10% sodium thiosulfate (Reaction 7). The two phase solution was shaken until the dark color disappeared, made basic with saturated sodium bicarbonate, and the organic layer separated. The aqueous layer was extracted three times with 10 mL portions of CHCl3 and the combined organic layers were then washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in a small portion of ether and chromatographed using a flash SiO2 column (10"×1/2", ether/hexane 1/2) and the eluents concentrated to yield 53 mg of (91%) CIT. No isomerization of the ester moiety was detected by TLC or NMR.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=C=O.[CH3:14][S:15]([CH3:17])=O>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[S:15]([CH3:17])[CH3:14]
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: CS(C)=O
Product: CS(C)=Nc1ccccc1C(F)(F)F

Procedure:
The process of claim 15 in which 2-trifluoromethylphenyl isocyanate is reacted with dimethylsulfoxide to produce N-(2-trifluoromethylphenyl)-S,S-dimethylsulfilimine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.C([Mg]Cl)(C)C.[Cl:24][CH2:25][C:26](N(OC)C)=[O:27]>CCOCC.C1COCC1>[Cl:24][CH2:25][C:26]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12)=[O:27]
Reactant: CON(C)C(=O)CCl
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)CCOCn1ccc2c(C(=O)CCl)ccnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
To a solution of 4-bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (2.05 g, 0.00626 mol) in THF (10 mL, 0.123 mol) at 0° C. was added dropwise a solution of isopropylmagnesium chloride in ether (2.0 M, 9.4 mL). The mixture was allowed to warm to room temperature and stirred for 4 hours. This mixture was then transferred via cannula to a solution of 2-chloro-N-methoxy-N-methylacetamide (2.84 g, 0.0207 mol) in THF (10 ml). After 30 minutes reaction time, the solution was quenched by the addition of saturated ammonium chloride aqueous solution. The product was extracted with ethyl acetate, the combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography (0-20% ethyl acetate/hexanes) to afford 2-chloro-1-(1-[2-(trimethylsilyl)-ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)ethanone (711 mg, 35%). 1H NMR (400 MHz, CDCl3): 8.56 (d, 1H), 7.66 (d, 1H), 7.60 (d, 1H), 7.23 (d, 1H), 5.80 (s, 2H), 4.91 (s, 2H), 3.60 (dd, 2H), 0.98 (dd, 2H), 0.01 (s, 9H); MS(ES): 325 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:4]1[C:3](=[O:9])[C:2]([Cl:1])=[C:7]([Cl:8])[CH:6]=[N:5]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a mixture of 4,5-dichloro-2H-pyridazin-3-one (3.3 g, 20.0 mmol) and Cs2CO3 (9.77 mg, 1.5 eq) were added DMF (15 mL) and benzyl bromide (3.10 mL, 1.3 eq), which was then stirred for 3 h at 60° C. under nitrogen atmosphere. The mixture was concentrated under reduced pressure, and the residue was extracted twice with ethyl acetate (200 mL). The extract was washed with saturated aqueous sodium hydrogen carbonate solution (NaHCO3, 100 mL×2) and aqueous sodium chloride solution, dried (anhydrous Na2SO4), and concentrated under reduced pressure. The residue was separated by column chromatography (10% ethyl acetate-hexane) to give 4.48 g (88%) of the title compound.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][CH2:25][CH:26]=O)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3].[N+:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)([O-:30])=[O:29].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][CH2:25][CH2:26][N:40]3[CH2:41][CH2:42][N:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N+:28]([O-:30])=[O:29])[CH2:38][CH2:39]3)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3]
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3ccccc3[N+](=O)[O-])CC2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.9 %

Procedure:
To a stirred solution of 3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde (0.060 g, 0.15 mmol) and 1-(2-nitro-phenyl)-piperazine (0.032 g, 0.157 mmol) in CH2Cl2 (0.5 mL), glacial AcOH (8.5 μL, 0.15 mmol) was added and stirred for 15 min at room temperature. NaBH(OAc)3 (0.041 g, 0.19 mmol) was added and stirred under nitrogen overnight. Saturated NaHCO3 (0.5 mL) was then added and stirred for 15 min. The layers separated and the aqueous layer was extracted with CH2Cl2 (0.5 mL). MPLC purification (silica, 2-15% MeOH/CH2Cl2) afforded the desired product as a white solid (0.063 g, 71%). TLC (silica, 12% MeOH/CH2Cl2): Rf=0.67. MS (electrospray): exact mass calculated for C27H31F3N6O4S, 592.21; m/z found, 593.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.80 (dd, J=1.6, 8.2 Hz, 1H), 7.77 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.3 Hz, 2H), 7.52 (ddd, J=1.6, 7.3, 8.3 Hz, 1H), 7.19 (dd, J=1.2, 8.3 Hz, 1H), 7.09 (m, 1H), 4.59 (s, 2H), 4.17 (t, J=6.9 Hz, 2H), 3.71 (t, J=5.8 Hz, 2H), 3.13 (br t, J=4.8 Hz, 4H), 2.96 (t, J=5.6 Hz, 2H), 2.95 (s, 3H), 2.66 (br t, J=4.4 Hz, 4H), 2.51 (t, J=7.0 Hz, 2H), 2.17 (q, J=6.9 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[Cl:11][C:12]1[CH:13]=[C:14](/[CH:18]=[CH:19]/[C@H:20]2[CH2:24][CH2:23][CH2:22][NH:21]2)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C(O)CCC>[Cl:11][C:12]1[CH:13]=[C:14](/[CH:18]=[CH:19]/[C@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cccc(/C=C/[C@H]2CCCN2)c1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Clc1cccc(/C=C/[C@H]2CCCN2c2ncnc3[nH]cnc23)c1
Yield: 16.5 %

Procedure:
695 mg of 6-chloropurine and 850 mg of (R)-2-[(E)-2-(3-chlorophenyl)vinyl]-pyrrolidine are dissolved in 20 ml of 1-butanol and warmed at 130° C. in the microwave for 6 h with 3.1 ml of triethylamine. For work-up, the batch is partitioned between ethyl acetate and water, the organic phase is dried over sodium sulfate, filtered off and evaporated in vacuo. The residue is purified by chromatography, giving 220 mg of 6-[(R)-2-((E)-2-(3-chlorophenyl)vinyl)pyrrolidin-1-yl]-9H-purine (“A11”); Rt: 1.778 min; [M+H]+326.2; m.p. 194-196°;
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12](=[O:41])[C@@H:13]2[CH2:17][C@@H:16]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=4)[N:22]=[C:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:20]=3)[CH2:15][N:14]2[C:37]([NH:39][NH2:40])=[O:38])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[CH:42](=O)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.Cl>CO.C1COCC1>[CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12](=[O:41])[C@@H:13]2[CH2:17][C@@H:16]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=4)[N:22]=[C:21]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:20]=3)[CH2:15][N:14]2[C:37]([NH:39][NH:40][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:38])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NN)C(=O)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NNCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
To a solution of compound 105 (0.037 mmol) in MeOH:THF (4:1) was added benzaldehyde (0.0448 mmol). The solution was stirred at RT for 18 hrs. Borane-pyridine complex (0.37 mmol) was added followed by HCl (37%, 400 μl). The solution was stirred for 1.5 hrs and then filtrated and concentrated to dryness. The crude material was dissolved in MeOH and purified by Prep LCMS which gave the title compound (0.01 mmol). Purity by HPLC>95%. M+H+650.
Reaction SMILES: ClC1C=CN(C2C=NC=CC=2)N=1.Cl.Cl.[NH:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[NH2:16].[C:23]([NH:26][C:27](=[CH2:32])[C:28](OC)=[O:29])(=[O:25])[CH3:24]>>[O:29]=[C:28]1[CH:27]([NH:26][C:23](=[O:25])[CH3:24])[CH2:32][N:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:16]1
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: NNc1cccnc1
Agent: Cl
Agent: Clc1ccn(-c2cccnc2)n1
Product: CC(=O)NC1CN(c2cccnc2)NC1=O

Procedure:
3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b) in Scheme 1 may alternatively be prepared by reacting 3-hydrazinopyridine dihydrochloride with methyl 2-acetamidoacrylate to yield N-(3-oxo-1-(pyridin-3-yl)pyrazolidin-4-yl)acetamide and subsequent chlorination/elimination as shown in Scheme 2, step a1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[CH2:20][C:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([CH2:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[N:18]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:53]=[O:54]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[CH:20]([CH2:53][OH:54])[C:19]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH2:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[N:18]([C:37](=[O:42])[C:38]([F:40])([F:39])[F:41])[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: O=C(N1N=C(c2cc(F)ccc2OCc2ccccc2)CC1(CCCOC1CCCCO1)c1ccccc1)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N1N=C(c2cc(F)ccc2OCc2ccccc2)C(CO)C1(CCCOC1CCCCO1)c1ccccc1)C(F)(F)F
Temperature: -40 °C
Reaction time: 0.75 h

Procedure:
To a solution of 13.0 g (22.2 mmol) 3-5 in 150 ml of THF at −78° C. was added dropwise a solution of 22.2 ml (44.4 mmol) 2 M NaHMDS in THF. After the addition was complete, the solution was warmed to −40° C. and stirred for 45 min. In a separate flask, 40 g of paraformaldehyde was mixed with 100 ml of mineral oil and heated at 140° C. A stream of argon was passed over the paraformaldehyde/mineral oil mixture and the resulting formaldehyde gas was bubbled into the above solution of C-5 still at −40° C. for 15 minutes. The cold solution was quenched with 100 ml of saturated aqueous NH4Cl and allowed to warm to room temperature. The mixture was dumped into a separatory funnel with EtOAc and the layers were separated. The aqueous was extracted with EtOAc, the combined organics were washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography with EtOAc/hexanes to provide 3-6 as an amber gum. Data for 3-6: LC-MS: rt=3.1 min, m/z=531 (M−THP+1).