Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Br)C.I[C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1.[CH3:20][C:21]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:24])[CH:22]=[O:23].[NH4+].[Cl-]>C1COCC1.O>[F:17][C:16]([F:19])([F:18])[C:8]1[CH:7]=[C:6]([CH:22]([OH:23])[C:21]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:24])[CH3:20])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: CC(C)(C=O)NC(=O)OCc1ccccc1
Reactant: FC(F)(F)c1cc(I)cc(C(F)(F)F)c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(NC(=O)OCc1ccccc1)C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethylmagnesium bromide (1.63 mL, 1M in THF, 1.63 mmol) was added dropwise to a stirred solution of 1-iodo-3,5-bis(trifluoromethyl)benzene (608 mg, 317 μL, 1.79 mmol) in dry THF (1 mL) at room temperature under N2 and the reaction was stirred for 30 min. The resulting solution was added to a stirred solution of benzyl (1,1-dimethyl-2-oxoethyl)carbamate (163.5 mg, 0.739 mmol) in dry THF (1 mL) at −20° C. and reaction was allowed to warm to room temperature over 3 h. Saturated NH4Cl (10 mL) and water (10 mL) were added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-40% EtOAc in hexanes gradient) to afford benzyl {2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1,1-dimethylethyl}carbamate. Rf=0.40 (20% EtOAc in hexanes). LCMS calc.=436.1; found=436.0 (M+1)+. 1H NMR (600 MHz, CDCl3) δ 7.80 (s, 1H), 7.77 (s, 2H), 7.39-7.33 (m, 5H), 5.12-5.08 (m, 2H), 1.36 (s, 1H), 4.90 (d, J=4.4 Hz, 1H), 4.81 (s, 1H), 1.36 (s, 3H), 1.23 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([C:23](=[O:32])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:21]([Cl:33])[N:20]=[C:19](S(C)(=O)=O)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:38]#[N:39].[Na+]>C(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([C:23](=[O:32])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:21]([Cl:33])[N:20]=[C:19]([C:38]#[N:39])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2nc(S(C)(=O)=O)nc(Cl)c2C(=O)NCc2ccccc2)CC1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(Cl)c2C(=O)NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the above product, 4-[2-(5-benzylcarbamoyl-6-chloro-2-methanesulfonylpyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2/H2O (20 mL/2 mL) is added NaCN (3.3 mmol) and tetra-n-butylammonium bromide (0.14 mmol) at 0° C. After warmed up to room temperature, the reaction mixture is vigorously stirred for 1.5 h at room temperature. The mixture is diluted with CH2Cl2, washed with aq. NaHCO3. The organic layer is dried over Na2SO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to give 4-[2-(5-benzylcarbamoyl-6-chloro-2-cyano-pyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester as a white solid. 1H-NMR (CDCl3), δ 1.09-1.19 (2H, m), 1.46 (9H, s), 1.63-1.74 (5H, m), 2.66 (2H, br t), 4.07 (2H, m), 4.51 (2H, t), 4.66 (2H, d), 6.11 (1H, t), 7.31-7.37 (5H, m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(OCC)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:26]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=3)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(COc2cccnc2N)cc1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 2-amino-3-(4-methoxybenzyloxy)pyridine (1.80 g, 0.0078 mol), 4chlorophenyl isothiocyanate (1.58 g, 0.0094 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 2.2 g (70.5%), m.p. 136°-138 ° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]=[C:6](OC)[CH:5]=1)[CH3:2].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:6]1[CH:5]=[C:4]([NH:3][CH2:1][CH3:2])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][N:7]=1
Reactant: CCNc1cc(OC)ncc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: CCNc1cc(Cl)ncc1[N+](=O)[O-]

Procedure:
A solution of 4-(ethylamino)-2-methoxy-5-nitropyridine (5.0 g, 25.3 mmol) in POCl3 (25 mL) was heated to 100° C. in a sealed tube for 1 week. The reaction mixture was cooled and concentrated and the residue was taken up in EtOAc/H2O and carefully quenched with sat. K2CO3. The aqueous layer was extracted with EtOAc, washed with H2O, dried (MgSO4) and concentrated to give an orange oil which solidified on standing which was used without further purification. MS (ES+) m/e 202 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[C:26](O)=[O:27])[CH:19]=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:26]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:25]=2[N:16]=[CH:17][CH:18]=[CH:19]3)=[O:27])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc2cccnc12
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Product: CC(C)(C)OC(=O)N1[C@H](CNC(=O)c2cccc3cccnc23)C[C@@H]2C[C@@H]21

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with quinoline-8-carboxylic acid. LC-MS (acidic): tR=0.95 min; [M+H]+=368.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=O)[CH:13]([CH2:16][C:17]([OH:19])=O)[C:12]3=[N:20][N:21]=[C:22]([CH3:23])[N:11]3[C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)=[CH:4][CH:3]=1.[CH2:28]([NH2:30])[CH3:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH:13]([CH2:16][C:17]([NH:30][CH2:28][CH3:29])=[O:19])[C:12]3=[N:20][N:21]=[C:22]([CH3:23])[N:11]3[C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)=[CH:6][CH:7]=1
Reactant: CCN
Reactant: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)CC1CN(c2ccc(Cl)cc2)c2ccccc2-n2c(C)nnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
A mixture of 2-(6-(4-chlorophenyl)-1-methyl-5-oxo-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-4-yl)acetic acid (15 mg, 0.04 mmol), ethanamine (4 mg, 1.12 mmol), HATU (19 mg, 0.05 mmol), DIEA (8 mg, 0.06 mmol) in DCM (5 mL) was stirred overnight at room temperature. The mixture was concentrated and purified by prep-HPLC to give 2-(6-(4-chlorophenyl)-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-4-yl)-N-ethylacetamide as a white solid (4 mg).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([CH:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[OH:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C(O)c2cc(-c3ccccc3)on2)cc(OC)c1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(C(=O)c2cc(-c3ccccc3)on2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To a solution of 40i (0.110 g, 0.73 mmoL) in 8 mL anhydrous CH2Cl2 was added Dess-Martin reagent (0.274 g, 0.645 mmol). The mixture was allowed to stir for 30 min and quenched with sat. Na2S2O3 solution, extracted with ethyl acetate and dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to give pure compound 1i (70.1%). NMR (CDCl3) δ 7.87-7.85 (m, 2H); 7.72 (s, 2H), 7.53-7.49 (m, 3H), 7.05 (s, 1H), 7.82 (d, 1H, J=1.5 Hz), 3.97 (s, 3H), 3.96 (s, 6H); MS (ESI) m/z 362.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[C@@H:14]2[C@@H:9]([C:10]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:11]=3[CH2:12][CH2:13]2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[C@@H:14]2[C@@H:9]([C:10]3[CH:18]=[CH:17][C:16]([O:19][C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)=[CH:15][C:11]=3[CH2:12][CH2:13]2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(N1CCC[C@@H]2c3ccc(O)cc3CC[C@@H]21)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Oc2ccc3c(c2)CC[C@H]2[C@@H]3CCCN2C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of cis-2,2,2-trifluoro-1-(8-hydroxy-2,3,4a,5,6,10b-hexahydro-1H-benzo[f]quinolin-4-yl)-ethanone (0.98 g), 4-methoxyphenylboronic acid (1.00 g), pyridine (1.30 mL), copper(II) acetate (0.60 g), molecular sieves 3 Å (3.60 g), and dichloromethane (15 mL) is stirred in air at room temperature overnight. The mixture is diluted with dichloromethane and filtered over Celite. The filtrate is concentrated and the residue is chromatographed on silica gel (dichloromethane/methanol containing 1% NH3 99:1→95:5) to give the title compound as a colorless resin-like solid. Yield: 1.05 g (79% of theory); LC (method 1): tR=5.00 min; Mass spectrum (ESI+): m/z=406 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].[CH2:25]([O:27][P:28]([CH2:33][C:34](O)=[O:35])([O:30][CH2:31][CH3:32])=[O:29])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:31]([O:30][P:28]([CH2:33][C:34]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:35])([O:27][CH2:25][CH3:26])=[O:29])[CH3:32]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CC(=O)Nc1ccccc1NC(=O)OC(C)(C)C)OCC
Reaction time: 6 h
Yield: 75.6 %

Procedure:
DIPEA (5.16 g, 6.90 mL, 40 mmol) and tert-butyl 2-aminophenylcarbamate (2.08 g, 10 mmol) were added to a solution of 2-(diethoxyphosphoryl)acetic acid (2.15 g, 11 mmol) in DCM (120 mL). After the mixture was stirred for ten minutes, HATU (4.56 g, 12 mmol) was added to the reaction and stirring was prolonged for 6 h at room temperature under a nitrogen atmosphere. After completion of the reaction as indicated by HPLC, the reaction mixture was washed with saturated NaHCO3 and brine. It was dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo to get the crude product, which was triturated with 30% v/v hexanes in EtOAc for 30 min. The solid was filtered, washed with 30% hexanes in EtOAc and dried to get 2.92 g of tert-butyl (2-(2-(diethoxyphosphoryl)acetamido)phenyl)carbamate as an off-white solid in 76% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][C:20]=3[N:21]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.C[O:39][C:40](=[O:43])[CH2:41][NH2:42]>CN(C1C=CN=CC=1)C>[CH3:32][C:2]([CH3:1])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([C:26]([NH:42][CH2:41][C:40]([OH:39])=[O:43])=[O:27])=[CH:22][C:20]=3[N:21]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:8][C:7]=1[CH3:29]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2cc(C(=O)O)ccc2o1
Reactant: COC(=O)CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2cc(C(=O)NCC(=O)O)ccc2o1
Yield: 76.6 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzooxazole-5-carboxylic acid (150 mg, 0.343 mmol), DMAP (125 mg, 1.03 mmol), EDC (99 mg, 0.514 mmol), and glycine methyl ester hydrochloride (64 mg, 0.514 mmol) are reacted and hydrolyzed analogous to Example 4 to give the title product (130 mg, 76%). MS (ES) m/e: 495.3 (M+1), 493.3 (M−1).
Reaction SMILES: [O:1]=[C:2]1[N:14]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C@@H:24]([C:42]([OH:44])=[O:43])[CH2:25][C:26]3[CH:31]=[C:30]([CH3:32])[C:29]([O:33]CC4C=CC=CC=4)=[C:28]([CH3:41])[CH:27]=3)=[O:22])[CH2:17][CH2:16]2)[C:5]2[CH:6]=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:4]=2[NH:3]1.[H][H]>C1COCC1.CO.[Pd]>[O:1]=[C:2]1[N:14]([CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C@@H:24]([C:42]([OH:44])=[O:43])[CH2:25][C:26]3[CH:27]=[C:28]([CH3:41])[C:29]([OH:33])=[C:30]([CH3:32])[CH:31]=3)=[O:22])[CH2:19][CH2:20]2)[C:5]2[CH:6]=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(n3c(=O)[nH]c4c5ccccc5ncc43)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3c(=O)[nH]c4c5ccccc5ncc43)CC2)C(=O)O)cc(C)c1O

Procedure:
A suspension of 1.80 g (3.03 mmol) (R)-1-carboxy-2-(4-benzyloxy-3,5-dimethyl-phenyl)-ethyl 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carboxylate and 300 mg 10% Pd/C in 30 mL THF and 30 mL MeOH was hydrogenated at 3000 hPa hydrogen pressure and RT for 48 h. The catalyst was suction filtered, the filtrate was evaporated down and the residue was purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][C:18]=3[N:19]2[NH:22][CH3:23])=[CH:11][CH:10]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][C:18]=3[N:19]2[N:22]([C:24](=[O:26])[CH3:25])[CH3:23])=[CH:11][CH:10]=1
Reactant: CNn1c2cnccc2c2ccc(Cl)cc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(C)n1c2cnccc2c2ccc(Cl)cc21
Yield: 28.3 %

Procedure:
A solution of the product of example 43 (19 mg, 0.082 mmol) in pyridine (0.40 ml) was treated with acetic anhydride (0.037 ml, 0.36 mmol) in two portions over 48 h. The reaction was subsequently concentrated to dryness and the residue coevaporated with AcOH under reduced pressure. The crude product was purified as described in example 46. The pure fractions with product were combined and lyophilized to provide 9 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6](Cl)=[O:7].C(N(CC)C(C)C)(C)C.Cl.[N+:22]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29])([O-:24])=[O:23]>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=2)=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1O
Reactant: NCc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cccc([N+](=O)[O-])c1)c1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.1 %

Procedure:
A solution of 4-fluoro salicylic acid chloride (12.3 g, 70.3 mmol) in dichloromethane (140 mL) was cooled to 0° C., and treated with N,N-diisopropylethylamine (31.0 mL, 175 mmol) and 3-nitrobenzylamine hydrochloride (16 g, 84.6 mmol). After stirring at room temperature for 24 h, the solution was concentrated in vacuo and diluted with ethyl acetate. The organic layer was washed successively with aq 2 N HCl and saturated aq NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (10–100% ethyl acetate in heptane, 23 mL/min, 75 min) provided 4-fluoro-2-hydroxy-N-(3-nitro-benzyl)-benzamide as a yellow solid (13.7 g, 67%): 1H NMR (DMSO-d6 300 MHz) δ 12.75 (s, 1 H), 9.43 (t, J=6.0 Hz, 1 H), 8.11 (ddd, J, =8.3, J2=2.1 Hz, J3=1.2 Hz, 1 H), 8.18 (t, J=1.5 Hz, 1 H), 7.94 (dd, J1=8.9 Hz, J2=6.5 Hz, 1 H), 7.78 (td, J1=7.8 Hz, J2=1.4 Hz, 1 H), 7.63 (t, J=8.0 Hz, 1 H), 6.81–6.72 (m, 2 H), 4.61 (d, J=5.7 Hz, 2 H).
Reaction SMILES: [CH3:1]I.[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@@H:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C@:14]1([CH2:23][O:24][SiH:25]([CH3:27])[CH3:26])[OH:22])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+].O>CN(C=O)C>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@@H:15]([C:18]([CH3:20])([CH3:21])[CH3:19])[C@:14]1([CH2:23][O:24][SiH:25]([CH3:27])[CH3:26])[O:22][CH3:1])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[SiH](C)OC[C@]1(O)[C@H](C(C)(C)C)CCN1C(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@@]1(CO[SiH](C)C)[C@H](C(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
In DMF (10 ml), methyl iodide (0.53 ml, 8.51 mmol) was added to N-benzyloxycarbonyl-(2R)-tert-butyldimethylsilyloxymethyl-(3S)-hydroxypyrrolidine (2.60 g, 7.11 mmol) and sodium hydride (0.34 g, 14.2 mmol) under stirring at 0° C. The reaction mixture was stirred further at the same temperature for 13 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (6:1, v/v) eluate fractions, N-benzyloxycarbonyl-(2R)-tert-butyldimethylsilyloxymethyl-(3S)-methoxypyrrolidine (2.73 g, 100%) as a colorless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[CH:28].C(Br)(Br)(Br)[Br:30]>ClCCl>[Br:30][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[CH:28]
Reactant: BrC(Br)(Br)Br
Reactant: C#CCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C#CCCCCCCBr
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Dehydrated dichloromethane (20 mL) and triphenylphosphine (5.91 g, 22.5 mmol) were added to 8-hydroxy-1-octyne (1.95 g, 15 mmol). The mixture was cooled to 0° C. and was then dropwise added to dehydrated dichloromethane (10 mL) containing carbon tetrabromide (7.46 g, 22.5 mmol), followed by stirring at room temperature for 2 hours. After separation between dichloromethane (100 mL) and 5% sodium bicarbonate (150 mL), the organic layer was washed with saturated brine (150 mL). The organic layer was dried over sodium sulfate and then concentrated. The concentrated product was purified by silica gel column chromatography (dichloromethane:methanol=from 100:0 to 99:1) to yield 8-bromo-1-octyne (crude).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][CH:21]=[N:22]2)=[C:18](Cl)[N:17]=1>C(O)CCC>[CH:1]1([NH:5][C:18]2[N:17]=[C:16]([Cl:15])[N:24]=[C:23]3[C:19]=2[NH:20][CH:21]=[N:22]3)[CH2:4][CH2:3][CH2:2]1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: NC1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1nc(NC2CCC2)c2[nH]cnc2n1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Cyclobutylamine (20 g, 0.28M) and N,N-diisopropylethylamine (50.4 ml, 0.28M) is added to a suspension of 2,6-dichloropurine (48.4 g, 0.25M) in n-butanol (480 ml). The mixture is stirred at 60° C. for 20 hours. The mnixture is cooled and the precipitate isolated by filtration, washed with n-butanol and dried under vacuum to give 6cyclobutylamino-2-chloropurine;ES+ (M−1) 222.5; mp 237.8° C. dec.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]=[O:20])[CH:14]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13]3)[CH2:5]1.C(N(CC)CC)C.[C:32](SCC)(=[S:34])[CH3:33]>CO>[CH3:22][C:21]([CH:14]1[CH2:13][C:12]2[C:16](=[CH:17][CH:18]=[C:10]([N:6]3[CH2:5][C@H:4]([CH2:3][NH:2][C:32](=[S:34])[CH3:33])[O:8][C:7]3=[O:9])[CH:11]=2)[N:15]1[CH:19]=[O:20])([CH3:24])[CH3:23]
Reactant: CCSC(C)=S
Reactant: CC(C)(C)C1Cc2cc(N3C[C@H](CN)OC3=O)ccc2N1C=O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=S)NC[C@H]1CN(c2ccc3c(c2)CC(C(C)(C)C)N3C=O)C(=O)O1
Yield: 45.6 %

Procedure:
The amine hydrochloride salt (200 mg, 0.566 mmol) prepared in Step 12 is stirred in a mixture of methanol (4 ml) and triethylamine (0.234 ml, 1.683 mmol). To this solution is added ethyl dithioacetate (0.08 ml, 0.70 mmol) and the mixture heated to reflux for 2 hours then allowed to cool. The precipitate is filtered to afford the thioamide as white needles (97 mg, 46%): mp 219-221° C. Anal: Calcd. for C19H25N3O3S: C, 60.78; H, 6.71; N, 11.19. Found: C, 60.63; H, 6.80; N, 11.12.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[NH:13]([CH2:17][CH2:18][OH:19])[CH2:14][CH2:15][OH:16]>C(Cl)(Cl)Cl>[OH:16][CH2:15][CH2:14][N:13]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH2:17][CH2:18][OH:19]
Reactant: OCCNCCO
Reactant: COC(=O)c1ccc(CCl)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CN(CCO)CCO)cc1
Yield: 64.4 %

Procedure:
A solution of 1.7 g (9.2 mmol) of methyl 4-chloromethylbenzoate in 25 ml of chloroform was added with 10 g (95 mmol) of diethanolamine, followed by heating under reflux for 10 hours. The resulting solution was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (chloroform), whereby 1.5 g of a colorless oil were obtained.
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3([C:30]4[C:21](=[CH:22][C:23]5[O:28][CH2:27][CH2:26][O:25][C:24]=5[CH:29]=4)[O:20][CH2:19]3)[C:11]2=[O:31])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl>[O:31]=[C:11]1[C:12]2([C:30]3[C:21](=[CH:22][C:23]4[O:28][CH2:27][CH2:26][O:25][C:24]=4[CH:29]=3)[O:20][CH2:19]2)[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]1[CH2:9][C:4]1[C:3]([NH:2][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Agent: Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.5 %

Procedure:
A 50 mL round-bottom flask was charged with 1′-[(3-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one hydrobromide (0.56 g, 1.0 mmol), methanesulfonyl chloride (0.12 g, 1.1 mmol), pyridine (0.25 g, 3.0 mmol) and dichloromethane (20 mL). The reaction mixture was stirred under nitrogen at ambient temperature for 16 h and diluted with dichloromethane (50 mL). The organic phase was washed with water (2×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 0% to 100% gradient of ethyl acetate in dichloromethane, followed by recrystallization from methanol (10 mL) to afford N-{2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-yl}methanesulfonamide (0.18 g, 38%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.27 (dd, J=4.6, 1.2 Hz, 1H), 7.78 (dd, J=8.0, 1.4 Hz, 1H), 7.34 (dd, J=8.0, 4.7 Hz, 1H), 7.21-7.10 (m, 2H), 6.96 (t, J=7.4 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.48 (s, 1H), 6.46 (s, 1H), 5.17 (ABq, 2H), 4.73 (ABq, 2H), 4.18-4.05 (m, 4H), 3.14 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.6, 154.9, 151.0, 147.1, 144.5, 143.2, 138.1, 134.5, 132.6, 132.2, 132.1, 129.0, 123.8, 123.2, 122.2, 112.3, 109.4, 99.0, 79.6, 64.6, 64.1, 57.8, 41.8, 40.6; MS (ES+) m/z 479.9 (M+1).