Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]([O:12][C:13](=[O:18])[NH:14][CH2:15][CH2:16][NH2:17])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C1COCC1>[C:8]([O:12][C:13]([NH:14][CH2:15][CH2:16][NH:17][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:18])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl bromoacetate (10.35 ml, 94.0 mmol) was added drop wise to a mixture of tert-butyl(2-aminoethyl)carbamate (15.0 g, 94.0 mmol), triethylamine (16.87 ml, 122 mmol) and THF (200 ml) at 0° C. After stirring 18 h at room temperature the reaction mixture was filtered, the filtrate diluted with DCM, washed with water, the organic layer dried over Na2SO4 and evaporated to give the title compound as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 6.62 (s, br, 1H), 4.00 (q, 2H), 3.28 (s, 2H), 3.04-2.90 (m, 2H), 2.58-2.49 (m, 2H), 1.26 (s, 9H), 1.11 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:20])[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[C:21](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(=O)CC>[CH3:21][O:20][C:3]1[C:2](=[O:1])[C:8]([NH:9][S:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc(=O)c2O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCC(C)=O
Product: COc1ccccc(NS(=O)(=O)c2ccc(C)cc2)c1=O

Procedure:
A mixture of 2-hydroxy-3-[N-[(4-methylphenyl)sulfonyl]-amino]-2,4,6-cycloheptatrien-1-one (14.5 g), potassium carbonate (12.5 g), dimethyl sulfate (12.5 g) and 2-butanone (145 ml) is heated at reflux for one hour. The mixture is filtered and the precipitate is washed with water and suspended in ethyl acetate. Hydrochloric acid (10%) is added until the solution is acidic. The organic phase is collected and dried over sodium sulfate. Evaporation of the solvent and crystallization of the residue from ethyl acetate-hexane gives 2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]amino]-2,4,6-cycloheptatrien-1-one, mp 163°-164° C. The above filtrate is evaporated annd the residue is subjected to chromatography on silica gel using ethyl acetate-hexane (3:1). Evaporation of the eluates are crystallization of the residue from ethyl acetate gives 2-methoxy-3-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one, mp 101°-102° C. and 2-methoxy-7-[N-[(4-methylphenyl)sulfonyl]-N-methylamino]-2,4,6-cycloheptatrien-1-one, mp 94.5° C.
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([OH:23])=[O:22])[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:29][CH2:30][CH3:31])=[O:22])[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCI
Reactant: O=C(O)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
A mixture of 2-benzyl-4-(3-carboxyphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (50 mg), 1-iodopropane (48 mg) and potassium carbonate (58 mg) in N,N-dimethylformamide (1 ml) was stirred at room temperature for 2 hours. The mixture was poured into ethyl acetate and washed with water and brine, dried over magnesium sulfate and concentrated. The residue was subjected to preparative thin layer chromatography (hexane-ethyl acetate, 1:1) to afford 2-benzyl-3-oxo-4-(3-propyloxycarbonylphenyl)-3,4-dihydropyrido[2,3-b]pyrazine (18 mg) as powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:23]2[C:32]3[C:31](=[O:33])[CH2:30][CH:29]([CH2:34][CH2:35][CH3:36])[CH2:28][C:27]=3[NH:26][C:25]([CH3:37])=[C:24]2[C:38]#[N:39])[CH:7]=[C:8]([N+:20]([O-])=O)[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[CH3:2].C(O)(=O)C>C1COCC1.[Zn]>[NH2:20][C:8]1[CH:7]=[C:6]([CH:23]2[C:32]3[C:31](=[O:33])[CH2:30][CH:29]([CH2:34][CH2:35][CH3:36])[CH2:28][C:27]=3[NH:26][C:25]([CH3:37])=[C:24]2[C:38]#[N:39])[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(OCC)c(OCc2cccc(OC)c2)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(N)c(OCc2cccc(OC)c2)c(OCC)c1
Reaction time: 1 h

Procedure:
A solution of 4-[3-ethoxy-4-(3-methoxy-benzyloxy)-5-nitro-phenyl]-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile and acetic acid (1.3 ml) in THF (33 ml) was cooled to 0° C. Zinc dust (3.02 g) was added in portions under vigorous stirring. The mixture was allowed to reach room temperature and stirred for 1 h. The mixture was then filtered and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with sat. aq. NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>ClCCl>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Br:23])[C:9]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(O)ccn1Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=c1c(Br)c(O)ccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of N-benzyl-4-hydroxy-2-pyridone ((0.75 g, 3.7 mmol), NBS (0.7 g, 1.05 mmol) in dichloromethane was stirred at room temperature for 1.5 h under argon atmosphere. It was diluted with dichloromethane (25 mL), cooled and filtered. The solids were washed with dichloromethane and dried in vacuo. The filtrate and the washings were combined and washed with water, dried (Na2SO4), filtered, and concentrated to dryness. The resulting residue was washed with EtOAc, and dried in vacuo to give a combined mass of 0.65 g of the title compound as a white powder: 1H NMR (CD3OD) δ: 7.54 (d, 1H, J=7.6 Hz), 7.27 (m, 5H), 6.12 (d, 1H, J=7.6 Hz), 5.15 (s, 2H); ES-MS: m/z=280 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([OH:12])[C:5]2[N:6]([CH3:9])[CH:7]=[N:8][C:4]=2[CH:3]=1.CS(O[C@H:18]([C@@H:20]1[CH2:24][C:23](=[O:25])[N:22]([C@@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:27])[CH2:21]1)[CH3:19])(=O)=O.[C:34]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OC(=O)C)C>[Br:1][C:2]1[CH:11]=[C:10]([O:12][C@@H:18]([C@H:20]2[CH2:21][N:22]([C@@H:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH3:27])[C:23](=[O:25])[CH2:24]2)[CH3:19])[C:5]2[N:6]([CH3:9])[C:7]([CH3:34])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@H](OS(C)(=O)=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: Cn1cnc2cc(Br)cc(O)c21
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc2cc(Br)cc(O[C@H](C)[C@@H]3CC(=O)N([C@H](C)c4ccccc4)C3)c2n1C
Temperature: 90 °C

Procedure:
To a solution of 5-bromo-1-methyl-1H-benzo[d]imidazol-7-ol (30 mgs, 0.124 mmol) in DMF (3 mL) was added (S)-1-((R)-5-oxo-1-((R)-1-phenylethyl)pyrrolidin-3-yl)ethyl methanesulfonate 1.17 (60 mgs, 0.193 mmol) and Cs2CO3 (69 mgs, 0.212 mmol) and the reaction mixture was heated at 90° C. for 1 h. The reaction mixture was then diluted with ethylacetate and washed with water (3×), brine and dried over anhydrous magnesium sulfate. Filtration, followed by concentration gave (R)-4-((R)-1-(5-bromo-1,2-dimethyl-1H-benzo[d]imidazol-7-yloxy)ethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one, which was used for next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([Br:18])=[C:13]([CH3:19])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[Br:18][C:14]1[C:13]([CH3:19])=[CH:12][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:16][C:15]=1[CH3:17]
Reactant: Cc1cc(CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc(C)c1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CCNC(=O)OC(C)(C)C)cc(C)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N,N-di-tert.-butoxycarbonyl-2-(4-bromo-3,5-dimethylphenyl)ethanamine (1.19 g) in dichloromethane (25 mL) is added trifluoroacetic acid (320 μL). The mixture is stirred for 12 hours at room temperature. Then the mixture is partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The organic phase is dried (MgSO4), the solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. Yield: 550 mg; LC (method 8): tR=0.68 min; Mass spectrum (ESI+): m/z=328 [M+H]+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:20].[CH2:21]([N:23]([CH2:35][CH3:36])[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)[CH3:22]>O1CCCC1>[CH2:35]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([NH:34][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=4)=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:20])=[CH:32][CH:33]=1)[CH3:36]
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: CCN(CC)CCCOc1ccc(N)cc1
Solvent: C1CCOC1
Product: CCN(CC)CCCOc1ccc(NC=C2C(=O)Nc3cc(-c4cccc(OC)c4)ccc32)cc1
Temperature: 25 °C

Procedure:
The named compound is prepared by refluxing 0.020 gms E & Z 3-Hydroxymethylene-6-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (see example 268) with 0.0327 gms 4-(3-diethylamino-propoxy)-phenylamine (used in the preparation of Example 214) in tetrahydrofuran (0.33 mL) for 36 h. Following cooling to room temperature, solvent evaporation in vacuo, trituration with ethyl acetate/(min) hexanes and filtration the reaction yields the named compound as a solid in the amount of 9.0 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][N:3]=1
Reactant: BrCc1ccc(Br)nc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Brc1ccc(CN2CCCC2)cn1
Yield: 84 %

Procedure:
A solution of 2-bromo-5-(bromomethyl)pyridine (9.06 g, 36.1 mmol), pyrrolidine (3.62 ml, 43.3 mmol) and potassium carbonate (9.98 g, 72.2 mmol) in acetonitrile (45 ml) was stirred at room temperature for 6 hrs. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous potassium carbonate solution and saturated, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (developing solvent; ethyl acetate) to give the title compound (7.31 g).
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:10]=[C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)[C:8]([O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:7][C:6]=1[O:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[OH:4])#[CH:2].I[C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1.C(N(CC)CC)C>O.C(OCC)C>[OH:4][CH:3]([C:5]1[CH:10]=[C:9]([C:11]23[CH2:20][CH:15]4[CH2:14][CH:13]([CH2:19][CH:17]([CH2:16]4)[CH2:18]2)[CH2:12]3)[C:8]([O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:7][C:6]=1[O:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[C:1]#[C:2][C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1
Reactant: C#CC(O)c1cc(C23CC4CC(CC(C4)C2)C3)c(OCOCCOC)cc1OCOCCOC
Reactant: COC(=O)c1ccc(I)cc1
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COCCOCOc1cc(OCOCCOC)c(C23CC4CC(CC(C4)C2)C3)cc1C(O)C#Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
760 mg (1.6 mmol) of a-ethynyl-5-(1-adamantyl)-2,4-di(methoxyethoxymethoxy)benzenemethanol, 420 mg (1.6 mmol) of methyl 4-iodobenzoate and 20 ml of triethylamine were introduced into a three-necked flask. The reaction medium was degassed with nitrogen for 30 min, then 90 mg of bis(triphenylphosphine)palladium(II) chloride and 37 mg of copper iodide were added successively. The reaction medium was stirred at room temperature for four hours, then evaporated to dryness, and the residue obtained was taken up in water and ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with dichloromethane and 800 mg (82%) of the expected methyl ester were recovered in the form of a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH:30][CH:27]4[CH2:29][CH2:28]4)=[O:17])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NC1CC1)c1ccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.8 %

Procedure:
To a 50 mL round bottom flask, 4-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)benzoic acid (0.2 g, 0.00054 mol), cyclopropyl amine (0.046 g, 0.00081 mol) and DMF (10 mL) were added. To the same flask, HATU (0.3 g, 0.00081 mol) and TEA (0.23 mL, 0.0018 mol) were added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with 10% methanol in chloroform and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to provide the crude product. The crude product was purified by flash column chromatography (0-1% methanol in chloroform) to provide the title compound (0.15 g, 68%). 1H NMR (300 MHz, DMSO-d6): δ 9.21 (d, J=2.4 Hz, 1H), 8.59 (d, J=4.2 Hz, 1H), 8.42 (d, J=2.4 Hz, 1H), 7.94-8.06 (m, 4H), 4.52 (br s, 4H), 3.80 (t, J=4.8 Hz, 4H), 2.88-2.90 (m, 1H), 0.60-0.62 (m, 2H), 0.70-0.73 (m, 2H): LC-MS (ESI): Calculated mass: 409.1; Observed mass [M+H]+: 410.1. (RT=1.34 min).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[C:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([O-:10])=[O:9].ClC(OCC(C)C)=O.[F:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]([NH2:45])[CH3:44])=[CH:39][CH:38]=1>ClCCl>[N+:8]([C:11]1[C:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:45][CH:43]([C:40]1[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=1)[CH3:44])=[O:16])([O-:10])=[O:9]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1OCc1ccccc1
Reactant: CC(N)c1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)c1cccc([N+](=O)[O-])c1OCc1ccccc1)c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 57.6 %

Procedure:
2.4 g (0.011 mol) of triethylamine are added at −10° C. to a solution of 3 g (0.011 mol) of 3-nitro-2-benzyloxybenzoic acid in 40 ml of dichloromethane. After the mixture has been stirred for 5 minutes, 2.8 g (0.011 mol) of isobutyl chloroformate are added dropwise at −10° C., and the mixture is stirred for a further 30 minutes. A solution of 1.53 g (0.011 mol) of 1-(4-fluorophenyl)-ethylamine in 10 ml of dichloromethane is added at −10° C., and stirring is continued for 12 hours without further cooling. The mixture is treated with sodium halogen carbonate solution, and the organic phase is separated off, washed with water and dried over sodium sulphate. After the solvent has been distilled off, 2.5 g (56% of theory) of 3-nitro-2-benzyloxy-N-[1-(4-fluorophenyl)-ethyl)-benzamide are obtained as an oil.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[CH:17]1[C@H:21]([OH:22])[C@H:20]([OH:23])[C@@H:19]([CH2:24]Cl)[O:18]1.C(N(CC)CC)C.[H-].[Ca+2].[H-].[F:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[SH:43]>CN(C)C=O>[OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[CH:17]1[C@H:21]([OH:22])[C@H:20]([OH:23])[C@@H:19]([CH2:24][S:43][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[F:36])[O:18]1
Reactant: Fc1ccccc1S
Reactant: O[C@@H]1[C@@H](CCl)OC(n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@@H]1O
Agent: [Ca+2]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O[C@@H]1[C@@H](CSc2ccccc2F)OC(n2cnc3c(N[C@@H]4CCC[C@H]4O)ncnc32)[C@@H]1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 62.1 %

Procedure:
To a solution of 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]-purin-9-yl}(4S,5S,3R)-5-(chloromethyl)oxolane-3,4-diol (166.5 g, 0.457 mol) and triethylamine distilled from calcium hydride (352 ml, 256 g, 2.53 mol, 4 equivalents) in degassed anhydrous N,N-dimethylformamide (1.8 liters) was added 2-fluorothiophenol (190 ml, 228 g, 1.78 mol, 4 equiv) in 38 5 ml portions every 2-3 hours. The mixture was stirred at room temperature for 4 days with continuous bubbling of nitrogen into the solution (the reaction was monitored by 1H NMR). After the reaction was complete, the reaction mixture was poured into 7 liters of ethyl acetate, which was washed with 3 liters of water. The aqueous layer extracted with ethyl acetate (2×500 ml), and the combined organic layers were washed with water (3×2 liters), then reduced to a volume of about 1.8 liters, providing a suspension of a white solid. The suspension was stirred for 9 hours at room temperature, and the white precipitate filtered off, washed with diethyl ether (3×200 ml), and dried for 24 hours under high vacuum to give 131 g (63% yield) of 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]purin-9-yl}(4S,5S,3R)-5-[(2-fluorophenylthio)methyl]-oxolane-3,4-diol as a white powder (98.9% pure).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]([CH2:9]Cl)=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:11][S:12]([O-:14])=[O:13].[Na+].CCOC(C)=O>CN(C=O)C>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: ClCc1ccccc1CCl
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccccc1CCl
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of α,α′-dichloro-o-xylene (3.5 g, 18 mmol) in DMF (20 mL) is added sodium methanesulfinate (0.612 g, 6.0 mmol) and the mixture is stirred at 65° C. for 4 h. Ice/water and EtOAc are added, the phases are separated and the organic phase is washed with water and brine, dried over Na2SO4/MgSO4, filtered and concentrated. The resulting residue is chromatographed on silica gel, eluting with a gradient of hexane/EtOAc to afford 1-chloromethyl-2-methanesulfonylmethylbenzene as a white solid: MS (M+NH4)+=236.
Reaction SMILES: [CH3:1][C@:2]1([NH:17]C(=O)OCC2C=CC=CC=2)[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.I[Si](C)(C)C.Cl>C(Cl)Cl.CO>[CH3:1][C@:2]1([NH2:17])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1
Reactant: C[C@]1(NC(=O)OCc2ccccc2)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: C[C@]1(N)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
To a solution of (S)-benzyl 3-methyl-1-(4-nitrophenyl)piperidin-3-ylcarbamate (525 mg, 1.421 mmol) in CH2Cl2 (5 ml) cooled at 0° C. was added iodotrimethylsilane (0.290 mL, 2.132 mmol) dropwise. After addition, the orange colored solution was stirred at 0° C. for 15 min, then at rt for 1 hr. The reaction was quenched by addition of 4.3 mmol of HCl (1.1 mL of 4N HCl in dioxane) in MeOH (5 mL). The mixture was then concentrated and the dark reddish residue was partitioned between ether and water. The ether layer was extracted with 0.2 N aqueous HCl. The combined acidic aqueous solution was extracted with ether (1×), then basified at 0° C. with 1N aqueous NaOH to pH=10. The aqueous phase was extracted with CH2Cl2 (3×). The combined CH2Cl2 extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to give the desired product, (S)-3-methyl-1-(4-nitrophenyl)piperidin-3-amine (277 mg, 1.177 mmol, 83% yield) as a dark reddish oil. Anal. Calcd. for C12H17N3O2 m/z 235.2, found: 236.0 (M+H)+; 1H NMR (400 MHz, chloroform-d) δ ppm 8.10 (d, J=9.34 Hz, 2H), 6.83 (d, J=9.34 Hz, 2H), 3.62-3.50 (m, 1H), 3.32 (d, J=12.64 Hz, 1H), 3.18 (s, 1H), 3.12 (d, J=13.19 Hz, 1H), 1.82 (d, J=4.95 Hz, 1H), 1.75 (s, 1H), 1.69-1.54 (m, 2H), 1.18 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:17])C=1>C(Cl)Cl.CO>[NH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N+:6]=1[O-:17]
Reactant: Nc1ccc(F)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(F)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a stirred solution of 5-fluoropyridin-2-amine (500 mg, 4.46 mmol) in DCM/MeOH (20 mL) in an ice-bath was added MCPBA (1199 mg, 5.35 mmol). The reaction was slowly warmed to room temperature and stirred overnight. The red-orange color solution was loaded to a SCX resin, which was then washed with methanol, eluted with 2 N ammonia in methanol to collect the product. Evaporation of the solvent gave the title compound as yellow-brownish solid (420 mg) without further purification. LCMS m/z=129.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9](=[O:11])[CH3:10])=[N:4][N:3]=1.[BH4-].[Na+]>CO.O.O.CC(O)=O>[NH2:1][C:2]1[S:6][C:5]([S:7][CH2:8][CH:9]([OH:11])[CH3:10])=[N:4][N:3]=1
Reactant: CC(=O)CSc1nnc(N)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(O)CSc1nnc(N)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a mixture of 1-(5-amino-1,3,4-thiadiazol-2-ylthio)propan-2-one (700 mg, 3.7 mmol) in 8 mL of 1:1 MeOH/H2O at rt was added a solution of NaBH4 (159 mg, 4.2 mmol) in 1.5 mL of H2O dropwise over 10 min. The suspension was stirred at rt for 1 h and diluted with 0.6 mL of HOAc followed by 6 mL of H2O. The precipitate was filtered, washed with H2O and dried under vacuum to afford 0.608 g of the title compound (86%) as an off-white solid. 1H NMR (400 MHz, MeOH-d3) δ 1.25 (d, J=6.6 Hz, 3H), 3.06-3.21 (m, 2H), 3.90-4.04 (m, 1H). HPLC (Method #1) 0.710 min retention time, (90%). MS (ES): m/z 192 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([O:38][C:39]2[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=2)[CH2:34][CH2:33]1>>[CH2:1]([N:3]([CH2:43][C:42]1[CH:45]=[CH:46][C:39]([O:38][CH:35]2[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]2)=[CH:40][CH:41]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CN1CCC(Oc2ccc(C=O)cc2)CC1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OC2CCN(C)CC2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 82 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (35 mg) and 4-(1-methylpiperidin-4-yloxy)benzaldehyde (94 mg) according to an analogous synthetic method to Example 264 and purified by LC-MS, the title compound (37 mg) was obtained.