Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Cl)(Cl)Cl.[Cl:5][C:6]1[C:15]2[C:10](=[C:11]([O:16]C)[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1>ClCCl.C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:5][C:6]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cccc2c(Cl)ncnc12
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Oc1cccc2c(Cl)ncnc12
Temperature: 25 °C

Procedure:
A solution of boron trichloride in dichloromethane (1.0 molar, 46.0 mL) is added via syringe to a solution of 4-chloro-8-methoxyquinazoline (2.24 g, 11.5 mmol) in chloroform, under a nitrogen atmosphere. The reaction mixture is heated at reflux for 1/2 hour, cooled to room temperature and diluted with a mixture of ice and saturated sodium bicarbonate solution. The phases are separated and the aqueous phase is extracted with chloroform. The organic phases are combined, washed with a 10% ethylenediaminetetraacetic acid (EDTA) solution, dried over MgSO4 and concentrated in vacuo to obtain the title product as a white solid, 1.93 g (93%), mp>252° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH:6]([NH2:8])[CH3:7])[CH3:2].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH:6]([NH:8][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)CC(C)N
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CC(C)NCc1ccccc1
Reaction time: 20 h
Yield: 27.7 %

Procedure:
To a solution of 3-amino-butyric acid ethyl ester (5.00 g, 34.3 mmol), benzaldehyde (4.1 mL, 40 mmol) and acetic acid (1.9 mL, 34 mmol) in 1,2-dichloroethane (120 mL) was added sodium triacetoxyborohydride (17 g, 80 mmol) at room temperature and the mixture was stirred for 20 hours. The reaction mixture was poured into sodium bicarbonate saturated aqueous solution and extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by flash column chromatography on silica gel (chloroform/methanol=10/1 as an eluant) to afford 3-benzylamino-butyric acid ethyl ester (2.1 g, 9.5 mmol, 28%) as colorless oil.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:49])[CH:6]([NH:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27](=[O:48])[NH:28][C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[CH:31][C:30]=2[C:39]([N:41]2[CH2:45][CH2:44][CH2:43][CH:42]2[CH2:46][OH:47])=[O:40])=[CH:21][CH:20]=1)=[O:17])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[CH:2]=[CH2:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[CH2:1]([O:4][C:5](=[O:49])[CH:6]([NH:15][C:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][O:26][C:27]([N:28]2[C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[CH:31][C:30]=3[C:39](=[O:40])[N:41]3[CH2:45][CH2:44][CH2:43][C@H:42]3[C@@H:46]2[OH:47])=[O:48])=[CH:23][CH:24]=1)=[O:17])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)CCC(NC(=O)Oc1ccc(COC(=O)Nc2cc(OC)c(OC)cc2C(=O)N2CCCC2CO)cc1)C(=O)OCC=C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)CCC(NC(=O)Oc1ccc(COC(=O)N2c3cc(OC)c(OC)cc3C(=O)N3CCC[C@H]3[C@@H]2O)cc1)C(=O)OCC=C
Yield: 66 %

Procedure:
The alcohol 44 (0.55 g, 0.8 mmol) was reacted (Method B) with pyridinium dichromate (0.36 g, 0.96 mmol) and 4 Å molecular sieves (0.4 g) in anhydrous CH2Cl2 (4 mL). The product was obtained (flash column chromatography 80% EtOAc/20% n-hexane) as a white foam (0.36 g, 66%). 1H NMR (CDCl3) δ 7.22 (m, 3H), 7.07 (d, J=7.5 Hz, 2H), 6.50 (s, 1H), 5.95 (m, 3H), 5.70 (dd, J=3, 10 Hz, 1H); 5.30 (m, 5H), 4.90 (d, J=13 Hz, 1H), 4.60 (m, 4H), 4.45 (m, 1H), 3.92 (s, 3H), 3.55 (m, 8H), 2.50 (m, 2H), 2.30 (m, 1H), 2.10 (m, 4H).
Reaction SMILES: [C:1](Cl)([C:3](Cl)=O)=[O:2].CN(C=O)C.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([C:22]#[N:23])[CH:21]=1)[NH:18][CH:17]=C2.CCOC(C)=O>C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([C:22]#[N:23])[CH:21]=1)[NH:18][CH:17]=[C:3]2[CH:1]=[O:2]
Reactant: N#Cc1cc(F)cc2cc[nH]c12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(F)cc2c(C=O)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (COCl)2 (4 mL) in DCM (100 mL) at 0° C. was added a solution of DMF (4 mL) in DCM (50 mL) dropwise. Half an hour later, a solution of 5-fluoro-1H-indole-7-carbonitrile (D132) (7 g) in DCM (100 mL) was added. The reaction was allowed to warm to RT to form a yellow precipitate. After 5 hours the solvent was removed by evaporation, and then THF (100 mL) and 2 M aqueous NaOH (100 mL) solution were added to the residue obtained above. After being stirred for about 1 h, EtOAc (3×200 mL) was added, the organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to afford 5-fluoro-3-formyl-1H-indole-7-carbonitrile (D133) (8 g) as a yellow solid. δH (DMSO-d6, 400 MHz): 7.20 (1H, dd), 7.82 (1H, dd), 8.08 (1H, s), 9.64 (1H, s).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[CH:16][C:15]([C:28](=[O:33])[NH:29][CH:30]3[CH2:32][CH2:31]3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)C.O1CCCC1.CO.[OH-].[Li+]>O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:34])=[O:3])[CH2:7][CH2:8]2)=[N:13][CH:14]=[C:15]([C:28](=[O:33])[NH:29][CH:30]2[CH2:31][CH2:32]2)[CH:16]=1)=[O:27]
Reactant: CCOC(=O)CC1CCN(c2ncc(C(=O)NC3CC3)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CC1CCN(c2ncc(C(=O)NC3CC3)cc2NC(=O)c2cccc(Cl)c2)CC1
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a solution of 0.23 g (0.47 mmol) of [3′-(3-chloro-benzoylamino)-5′-cyclopropylcarbamoyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester in a 5:2 mixture of tetrahydrofuran:methanol is added a solution of 0.056 g (2.3 mmol) of lithium hydroxide in water (1 mL). The reaction mixture is stirred overnight and then concentrated under reduced pressure to remove volatile organics. The pH of the mixture is adjusted to approximately pH 2 by the addition of concentrated hydrochloric acid causing a solid to precipitate. The formed colorless solid is collected by filtration and dried under vacuum to provide 0.14 g (66%) of [3′-(3-chloro-benzoylamino)-5′-cyclopropylcarbamoyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1[N:9]=[CH:10][S:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:24][C:25]1[C:26]([F:36])=[CH:27][C:28]([F:35])=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:30]=1.C(=O)=O.[Cl-].[NH4+]>O1CCCC1>[Cl:24][C:25]1[C:26]([F:36])=[CH:27][C:28]([F:35])=[C:29]([S:31]([N:7]([C:8]2[N:9]=[CH:10][S:11][CH:12]=2)[C:6](=[O:13])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:33])=[O:32])[CH:30]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: CC(C)(C)OC(=O)Nc1cscn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of thiazol-4-yl-carbamic acid tert-butyl ester (Preparation 72, 503 mg, 0.00251 mol) in tetrahydrofuran (5.0 mL) cooled to −78° C. was added lithium hexamethyldisilazide (1.0 M in tetrahydrofuran, 2.76 mL, 0.00276 mol). The reaction was stirred for 30 minutes at room temperature and then cooled to −78° C. A solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (620.5 mg, 0.002512 mol) in tetrahydrofuran (5.0 mL) was added slowly via syringe. After addition was complete, the reaction mixture remained immersed in the cooling bath; the temperature of the dry ice bath was not maintained, allowing the reaction mixture to slowly warm to room temperature. After 24 hours, the reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo onto Celite™. The residue was purified by automated flash chromatography (40 g SiO2) eluting with ethyl acetate:dichloromethane (gradient 0:1 to 5:95, by volume) to afford the title compound as a white solid, 733 mg, 71% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:16]=1)(=[O:12])=[O:11]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1cccc(-c2nnn[nH]2)c1
Yield: 79.6 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting with 2,4-dichloro-6-methylbenzene sulfonyl chloride (14.3 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) yielding 15.3 mg (80%) of the title compound. MS (ESI+) calcd for C14H11Cl2N5O2S 383.001051, found 383.001071.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:20]#[N:21])=[C:11](I)[S:12][C:13]=1[C:14]1[NH:18][CH:17]=[N:16][N:15]=1.C[Sn](C)(C)[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:25]=1.[Cl-].[Li+]>O1CCOCC1.[Cu]I.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>[C:20]([C:10]1[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[C:13]([C:14]2[NH:18][CH:17]=[N:16][N:15]=2)[S:12][C:11]=1[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH:25]=1)#[N:21]
Reactant: N#Cc1c(I)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)Nc1cc([Sn](C)(C)C)ccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(-c2sc(-c3nnc[nH]3)c(-c3ccc(Cl)cc3Cl)c2C#N)ccn1
Yield: 131.5 %

Procedure:
A mixture of 4-(2,4-dichlorophenyl)-2-iodo-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (0.180 g, 0.0004 mol), tert-butyl [4-(trimethylstannyl)pyridin-2-yl]carbamate (0.285 g, 0.0008 mol), lithium chloride (0.051 g, 0.0012 mol), copper(I) iodide (0.023 g, 0.00012 mol), tetrakis(triphenylphosphine)palladium (0.046 g, 0.00004 mol) was dissolved in dioxane (20 mL) and heated to reflux for 3 hours under an atmosphere of argon. The solvent was removed and the residue was purified using ISCO chromatography on silica gel, elution 20% ethyl acetate in hexanes to ethyl acetate to afford the title compound (0.270 g, 40%). LCMS: (FA) ES+, 513, 515. 1H NMR (400 MHz, d4-methanol) δ: 8.39 (s, 1H), 8.38 (d, J=6.31 Hz, 1H), 8.23 (s, 1H), 7.55-7.50 (m, 1H), 7.47 (dd, J=5.28, 1.56 Hz, 1H), 7.39-7.35 (m, 2H), 1.54 (s, 9H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][N:10]=[C:11]2[C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[N:13]=[C:12]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2F)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CS(C)=O>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:14]1[C:15](=[O:16])[C:11]2=[N:10][N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:12]2=[N:13]1
Reactant: O=C1C(=NNCc2ccc(I)cc2)C(c2ccccc2F)=NN1c1ccccc1F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c2nn(Cc3ccc(I)cc3)c3ccccc3c-2nn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,3-Bis(2-fluorophenyl)-1H-pyrazole-4,5-dione 4-{[(4-iodophenyl)methyl]hydrazone} (50 mg, 0.097 mmol) was dissolved in degassed dimethylsulfoxide (3.5 mL), treated with potassium carbonate (120 mg, 0.87 mmol, 9.0 equiv) and placed into an oil bath preheated to 120° C. for 15 minutes. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (50 mL, aqueous saturated) and extracted with ethyl acetate (2×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 20:80; hexanes:ethyl acetate), providing the titled compound as a dark red solid: 1H-NMR (400 MHz, CDCl3) δ 8.32 (1H, d, J=7.7 Hz), 7.70 (2H, d, J=8.3 Hz), 7.66-7.62 (1H, m), 7.59-7.55 (2H, m), 7.49 (1H, d, J=8.9 Hz), 7.42-7.36 (1H, m), 7.31-7.25 (2H, m), 7.07 (2H, d, J=8.0 Hz), 5.77 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 497.0278 [(M+H)+; calculated for C22H15FIN4O: 497.0269].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[C:9](=[O:18])[C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccc(CCBr)cc1
Reactant: Cc1cc(NC(=O)C(=O)c2ccccc2)ccn1
Product: Cc1cc(N(CCc2ccc(C(F)(F)F)cc2)C(=O)C(=O)c2ccccc2)ccn1

Procedure:
In analogy to the procedure described for the synthesis example 43 (step 2), the title compound N-(2-methyl-pyridin-4-yl)-2-oxo-2-phenyl-N-[2-(4-trifluoromethyl-phenyl)-ethyl]-acetamide (MS m/e: 413.2 [M+H]+) was prepared from N-(2-methyl-pyridin-4-yl)-2-oxo-2-phenyl-acetamide and 1-(2-bromo-ethyl)-4-trifluoromethyl-benzene.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]2)[C:13]([NH:15][C:16]2[S:17][C:18]([S:21]C#N)=[CH:19][N:20]=2)=[O:14])[CH2:8][CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4].SC[C@@H]([C@@H](CS)O)O.Cl[CH2:40][CH2:41][N:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>>[C:1]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]2)[C:13]([NH:15][C:16]2[S:17][C:18]([S:21][CH2:40][CH2:41][N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:19][N:20]=2)=[O:14])[CH2:8][CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)[C@H]2CC[C@H](C)CC2)CC1
Reactant: ClCCN1CCCC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCCC3)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-butyryl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)pyrrolidine.
Reaction SMILES: [H-].[Na+].CS(C)=O.[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:35])[CH2:16][CH2:17][CH2:18][N:19]2[CH2:26][CH:25]3[CH2:27][CH:21]([CH2:22][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]3)[CH2:20]2)=[CH:11][CH:10]=1)#[N:8].[N:36]1[CH:41]=[CH:40][C:39]([CH2:42]Cl)=[CH:38][CH:37]=1>CN(C=O)C.O>[C:7]([C:9]1[CH:10]=[CH:11][C:12]([CH:15]([O:35][CH2:42][C:39]2[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=2)[CH2:16][CH2:17][CH2:18][N:19]2[CH2:20][CH:21]3[CH2:27][CH:25]([CH2:24][N:23]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:22]3)[CH2:26]2)=[CH:13][CH:14]=1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CC2CC(CN(CCCC(O)c3ccc(C#N)cc3)C2)C1
Reactant: ClCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CCCC(OCc3ccncc3)c3ccc(C#N)cc3)C2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
NaH (0.059 g; 55% suspension in oil; 1.35 mmol) was washed with petroleum ether (fraction 40/60). 2 mL of DMSO was added. tert-Butyl 7-[4-(4-cyanophenyl)-4-hydroxybutyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (see Example 1(x) above; 0.54 g; 1.05 mmol) dissolved in 10 mL of DMF was added dropwise at 0° C. After 15 minutes, 4-pyridinylmethyl chloride (0.17 g; 1.05 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 30 minutes, then at rt overnight. The reaction mixture was diluted with water and extracted with ethyl acetate:toluene (1:1). The organic layer was separated and washed with brine and water. Evaporation in vacuo gave 0.56 g of crude product. Purification on silica (DCM:10% MeOH) gave 0.17 g (26%) of the title compound.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:36][C:37]([OH:39])=[O:38])[CH:6]([CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=1)[CH2:7][N:8]([CH2:13][CH2:14][N:15]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][C:17]([OH:19])=[O:18])[CH2:9][C:10]([OH:12])=[O:11])([OH:3])=[O:2]>C(O)C.[Pd]>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][CH2:24][CH:6]([N:5]([CH2:36][C:37]([OH:39])=[O:38])[CH2:4][C:1]([OH:3])=[O:2])[CH2:7][N:8]([CH2:13][CH2:14][N:15]([CH2:16][C:17]([OH:19])=[O:18])[CH2:20][C:21]([OH:23])=[O:22])[CH2:9][C:10]([OH:12])=[O:11])=[CH:28][CH:29]=1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(CCCc1ccc([N+](=O)[O-])cc1)N(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCCC(CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)N(CC(=O)O)CC(=O)O)cc1
Reaction time: 24 h
Yield: 115.8 %

Procedure:
To a solution of 5b (36 mg, 0.0541 mmol) in ethanol (9 mL) at room temperature was added 10% Pd/C (10 mg) under Ar (g). The reaction mixture was placed under hydrogenation apparatus for 24 h. The resulting mixture was filtered via celite bed and washed thoroughly with methanol. The filtrate was concentrated to provide 6b (33 mg, 91%) as a yellowish solid. 1H NMR (D2O, 300 MHz) δ1.03-2.15 (m, 5H), 2.20-4.40 (m, 18H), 7.38 (s, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[N:15]=[C:14](Cl)[N:13]=[C:12]([CH2:17][CH3:18])[N:11]=1>O1CCOCC1>[CH2:17]([C:12]1[N:13]=[C:14]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)[N:15]=[C:10]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)[N:11]=1)[CH3:18]
Reactant: CCc1nc(Cl)nc(Cl)n1
Reactant: Nc1cccc(O)c1
Solvent: C1COCCO1
Product: CCc1nc(Nc2cccc(O)c2)nc(Nc2cccc(O)c2)n1
Reaction time: 3 h

Procedure:
After dissolving 3-aminophenol (2.18 g, 20 mmol) in 1,4-dioxane (20.0 mL), 2,4-dichloro-6-ethyl-1,3,5-triazine (1.78 g, 10 mmol) was added and stirring carried out for 3 hours at 100° C. under a nitrogen atmosphere.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)[CH3:3].Cl[C:29]([O:31][CH3:32])=[O:30]>O1CCCC1>[CH2:2]([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:29]([O:31][CH3:32])=[O:30])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1)[CH3:3]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)OCC
Reactant: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NC(=O)OC)cc2)cc1)OCC
Reaction time: 144 h
Yield: 90.3 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid ethyl ester hydro chloride (0.55 g; 1.4 mmole) was dissolved in tetrahydrofuran (5 ml) and methyl chloroformate (0.534 g; 5.68 mmole) was added slowly. The reaction mixture was continuously checked with HPLC and after 6 days was all the starting material consumed. Water was added to the mixture, tetrahydrofuran was evaporated and the residue extracted three times with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated and 0.525 g (90.2%) of (S)-2-ethoxy-3-(4-[2-{4-(methoxycarbonylamino)phenyl}ethoxy]phenyl)propanoic acid ethyl ester was obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH2:10][O:11][CH3:12])[CH:3]=1.O.[NH2:14][NH2:15].C(O)C.[ClH:19]>CO.C(OCC)C>[ClH:19].[NH:14]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH2:10][O:11][CH3:12])[CH:3]=1)[NH2:15]
Reactant: NN
Reactant: COCc1cc(F)ccc1C#N
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: CO
Product: COCc1cc(NN)ccc1C#N
Temperature: 25 °C

Procedure:
A mixture of 4-fluoro-2-(methoxymethyl)benzonitrile (110 mg, 0.67 mmol), hydrazine monohydrate (133 mg, 0.13 mL, 2.6 mmol) and ethanol (5 mL) was heated to reflux overnight. The mixture was cooled to room temp and condensed. The residue was dissolved in methanol and treated with 2.0 N Hydrogen chloride in diethyl ether. The solvent was removed and the solid was dried to give 4-hydrazinyl-2-(methoxymethyl)benzonitrile hydrochloride as an off-white solid.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][C:41]1[CH:42]=[C:43]([CH:47]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=2)[CH2:48][NH2:49])[CH:44]=[CH:45][CH:46]=1>C(O)(C)C>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2[NH:49][CH2:48][CH:47]([C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([CH3:40])[CH:42]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: Cc1cccc(C(CN)c2cccc(C)c2)c1
Solvent: CC(C)O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4cccc(C)c4)c4cccc(C)c4)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Yield: 86.5 %

Procedure:
A solution of ((2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 47) (0.6 g, 0.91 mmol) and 2,2-bis(3-methylphenyl)ethylamine (0.3 g, 1.36 mmol) in isopropanol (20 ml) was stirred at room temperature for 48 hours. Solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1, by volume) to afford the title compound as a beige foam (0.67 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F-:12].[K+].C([O-])(O)=O.[Na+]>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
To a solution of compound 4-Fluorobenzenesulfonyl chloride (50 g, 0.256 mol) in ACN (500 mL) was added KF (74.36 g, 5 eq) and 18-crown-6 (2 g) at r.t., then the mixture was stirred at r.t. overnight. The mixture was detected by LC-MS, then saturated aqueous NaHCO3 was added and the mixture was extracted with EtOAc, the organic layer was washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, concentrated to give the crude compound 4-Fluorobenzenesulfonyl fluoride (46.70 g) as pale yellow oil which was used for the next step without further purification. ESI-MS (M+1): 179 calc. for C6H4F2O2S.