Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([O:16]C)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[OH-].[Na+].O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccsc1C(=O)O
Yield: 97.3 %

Procedure:
Methyl 3-t-butoxycarbonylaminothiophene-2-carboxylate (15.0 g, 58.3 mmol) was warmed in a mixture of 1 N sodium hydroxide (116.6 ml) and tetrahydrofuran (60 ml) at 50° C. for 16 hours. The mixture was evaporated to a volume of approximately 60 ml, and acidified (pH=2) with hydrochloric acid under cooling in an ice bath. The precipitate was filtered off, washed with water, and dried to afford 13.8 g (97%) of 3-t-butoxycarbonylaminothiophene-2-carboxylic acid. M.p. 168°-169° C. Litt. m.p. 168-169° C. (i. Chem. Res. (S) , 296, 1985). 1H-NMR (DMSO-D6, δ) : 1.49 (s, 9H), 7.76 (d, 1H), 7.85 (d, 1H), 9.45 (s, 1H), 13.45 (s, 1H) .
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:6]2[O:28][CH:27]=[CH:26][C:7]=2[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[O:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1>>[CH3:4][C:5]1[C:6]2[O:28][CH:27]=[CH:26][C:7]=2[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH:25][C:35]([CH:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)=[O:36])[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)=[N:9][CH:10]=1
Reactant: O=C(O)C1CCOCC1
Reactant: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c2ccoc12
Agent: Cl
Product: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](NC(=O)C4CCOCC4)CC3)CC2)c2ccoc12

Procedure:
The title compound, white solid (121 mg, 89%), MS (ISP) m/z=455.4 [(M+H)+], mp 228° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate F) (136 mg, 0.3 mmol) and tetrahydropyran-4-yl-carboxylic acid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[C:7](=[O:20])[N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[CH2:9][CH:10]=1.[NH2:22][O:23][K].C(O)(=O)C>CO.CO.C(Cl)(Cl)Cl>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][N:8]1[CH2:9][CH:10]=[C:6]([CH2:5][CH2:4][C:3]([NH:22][OH:23])=[O:2])[C:7]1=[O:20]
Reactant: COC(=O)CCC1=CCN(CCc2ccccc2F)C1=O
Reactant: NO[K]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(CCC1=CCN(CCc2ccccc2F)C1=O)NO
Temperature: 0 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
38 mg of 3-{1-[2-(2-fluoro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-propionic acid methyl ester (x) prepared by the above Step 4 was dissolved in methanol solution (0.13 mM) and then 1.7 M methanolic suspension solution containing NH2OK (0.38 ml, 0.65 mM) was added thereto at 0° C. and the resulting mixture was stirred for 8 hrs at room temperature. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with 10% methanol/chloroform solution, filtered and concentrated in vacuo. The resulting compound was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 25 mg of 3-{1-[2-(2-fluoro-phenyl)-ethyl]-2-oxo-2,5-dihydro-1H-pyrrol-3-yl}-N-hydroxy-propionamide (28y) (yield: 65%).
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH:13]=1)[C:10]([OH:12])=O)[C:2]([NH2:4])=[NH:3].Cl.[CH2:15]([O:17][C:18](=[O:37])[CH2:19][C@H:20]([NH:32][C:33](=[O:36])[CH2:34][NH2:35])[C:21]1[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:24]=[C:23]([Br:31])[CH:22]=1)[CH3:16].O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>CN(C=O)C.ClCCl>[Br:31][C:23]1[CH:22]=[C:21]([C@@H:20]([NH:32][C:33](=[O:36])[CH2:34][NH:35][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[CH:13]=2)[CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:37])[CH:26]=[C:25]([C:27]([CH3:30])([CH3:28])[CH3:29])[CH:24]=1
Reactant: N=C(N)Nc1cccc(C(=O)O)c1
Reactant: CCOC(=O)C[C@H](NC(=O)CN)c1cc(Br)cc(C(C)(C)C)c1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cccc(NC(=N)N)c1)c1cc(Br)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-guanidinobenzoic acid (Example C) (179.5 mg, 1.00 mmol), (S)-ethyl 3-(2-aminoacetamido)-3-(3-bromo-5-tert-butyl)phenyl)propanoate hydrochloride (Example H) (439.5 mg, 1.00 mmol) and 1-hydroxybenzotriazole hydrate (31.2 mg, 0.20 mmol) was dissolved in DMF (4 mL) and dichloromethane (4 mL) and stirred at room temperature under nitrogen atmosphere for 10 min to give a colorless suspension. N,N′-diisopropylcarbodiimide (205 uL, 1.33 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The solvent was evaporated in vacuo to give a yellow viscous residue of the intermediate product: (S)-ethyl 3-(3-bromo-5-(tert-butyl)phenyl)-3-(2-(3-guanidinobenzamido)acetamido) propanoate. LC-MS analysis of the crude residue shows the desired product's mass: m/z 546 (79BrM+H), m/z 548 (81BrM+H); m/z 568 (79BrM+Na) and m/z 570 (81BrM+Na); Calcd for C25H32BrN5O4: 546.46. The crude residue will be used as such for the saponification (step #2).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.Cl[C:24]1[C:29]([C:30]#[N:31])=[CH:28][CH:27]=[CH:26][N:25]=1>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][O:22][C:24]2[N:25]=[CH:26][CH:27]=[CH:28][C:29]=2[C:30]#[N:31])=[CH:19][CH:20]=1
Reactant: N#Cc1cccnc1Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(4-[(5-Methyl-2-phenyl-4-oxazolyl)methoxy]phenyl)methanol (400 g) and then 2-chloro-3-cyanopyridine (206.7 g) were added to dimethylformamide (1.6 L). To the obtained mixture was added triturated sodium hydroxide (59.4 g) and the mixture was stirred at 20-30° C. for 48 hrs. Water (1.6 L) was dropwise added at the same temperature and the mixture was stirred for 2 hrs. The precipitated crystals were collected by filtration, washed with water (1.6 L) and then ice-cooled ethyl acetate (800 ml), and dried (40° C.) under reduced pressure to give 2-({4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl}oxy)nicotinonitrile as white crystals.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[C:28]3[C:23](=[C:24]([Br:29])[CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1.[H-].[Na+].Br[CH2:34][CH2:35][O:36][CH2:37][CH3:38]>>[Br:29][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[N:22]([CH2:34][CH2:35][O:36][CH2:37][CH3:38])[CH:21]=[C:20]2[CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][O:11][C:5]2[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[C:3]([OH:30])=[O:2])[CH2:15][CH2:16]1
Reactant: COC(=O)c1cc(C)ccc1OCCN1CCC(c2c[nH]c3c(Br)cccc23)CC1
Reactant: CCOCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOCCn1cc(C2CCN(CCOc3ccc(C)cc3C(=O)O)CC2)c2cccc(Br)c21

Procedure:
This compound was prepared following the procedure described in Example 138 (part B) starting with 1.6 g (3.3 mmol) of 2-{2-[4-(7-bromo-1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-5-methyl-benzoic acid methyl ester (prepared as in Example 138, part A), 0.17 g (4.2 mmol) of NaH in 60% of mineral oil and 0.45 mL (4 mmol) of bromoethylethyl ether. The crude mixture was hydrolised following the procedure described in Example 138 (part C) and purified by chromatography over silica gel affording 0.26 g (34% of yield) of the desired product.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1)N>>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:35])=[O:36])=[CH:30][CH:29]=2)[N:2]=[CH:3][CH:4]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)cc1

Procedure:
Reaction of 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 4-hydrazino-benzenesulfonamide according to example 43 gave the desired product. MS: M=478.0 (M+H)+
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:21][C:20]2=[O:31])=[CH:6][C:5]([CH2:32][C:33]([OH:35])=[O:34])=[CH:4][CH:3]=1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:34][C:33](=[O:35])[CH2:32][C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=2[CH2:18][N:19]2[C@@H:23]([CH3:24])[C@@H:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:21][C:20]2=[O:31])[C:2]([O:1][CH2:32][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[CH:3][CH:4]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1O
Reactant: BrCc1ccccc1
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCc2ccccc2)ccc1OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 14, Step 3, using the following starting materials: [6-hydroxy-2′-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid and benzyl bromide.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[CH2:10][C:11]([OH:13])=O.[CH2:14]([C@H:21]1[CH2:25][NH:24][C@H:23]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C@H:21]1[CH2:25][N:24]([C:11](=[O:13])[CH2:10][C:4]2[C:5]([Cl:9])=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])[C@H:23]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cc1c(Cl)cccc1Cl
Yield: 34.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2,6-dichlorophenyl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 119, (2S,4R)-4-benzyl-1-(2-(2,6-dichlorophenyl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (12.1 mg, 34.9%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): a 9.92 (s, 1H), 7.54-7.60 (m, 2H), 7.44 (d, 2H), 7.25-7.34 (m, 5H), 7.15-7.24 (m, 3H), 6.93-7.03 (m, 4H), 4.48-4.51 (m, 1H), 3.95 (m, 2H), 3.50-3.59 (m, 1H), 3.15 (m, 1H), 2.63-2.73 (m, 3H), 1.89-1.93 (m, 2H). MS (EI) for C32H27C12FN2O3. found 578.4 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].C(Cl)(Cl)Cl.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](O)=O>>[C:17]([C:22]1[NH:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=2[N:10]=1)([CH3:21])([CH3:18])[CH3:16]
Reactant: CC(C)(C)C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1nc2ccc([N+](=O)[O-])cc2[nH]1
Yield: 77 %

Procedure:
A solution of 4-nitro-1,2-phenylenediamine (2.0 g, 13 mmol) in 10 ml of trimethylacetic acid was stirred at reflux for 12 h. Reaction mixture was concentrated in vacuo to yield a oil which was subjected to column chromatography (CHCl3, neat) to yield 2.2 g (10 mmol, 77%) of 2-tert-butyl-5-nitrobenzimidazole. The nitrobenzimidazole and 0.5 g of 10% Pd-C were dissolved in 100 ml of MeOH and stirred for 12 h under H2. The reaction mixture was filtered and concentrated in vacuo to provide 1.9 g (10 mmol, >95%) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](I)[CH:21]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(OC(C1CCN(C2C=CC(C(=O)NC3C=CC(C4C=CC=CC=4)=C(C)C=3)=CN=2)CC1)=O)C>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:21]=[C:22]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([F:29])[CH:35]=4)[C:23]([CH3:26])=[CH:24][CH:25]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Reactant: OB(O)c1cccc(F)c1
Agent: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(-c4ccccc4)c(C)c3)cn2)CC1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(-c4cccc(F)c4)c3)cn2)CC1

Procedure:
5′-(3′-Fluoro-6-methyl-biphenyl-3-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from 5′-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester and 3-fluorophenyl boronic acid following a method similar to the one described in the synthesis of 5′-(2-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester, above. The product was isolated after silica gel column purification with 20-40% EtOAc in hexanes gradient. HRMS m/z calcd for C27H28N3O3F [M+H]+: 462.2188. Found: 462.2187.
Reaction SMILES: C1(C2N=CN([C:18]3[N:26]=[CH:25][N:24]=[C:23]4[C:19]=3[NH:20][CH:21]=[N:22]4)C=2C2C=CC=CC=2)C=CC=CC=1.ClC1N=C2C(N=CN2[C@@H]2O[C@H](COC(C3C=CC(C)=CC=3)=O)[C@@H](OC(C3C=CC(C)=CC=3)=O)C2)=C(N2C=CN=C2C(C)C)N=1>>[N:26]1[CH:18]=[C:19]2[C:23]([N:22]=[CH:21][NH:20]2)=[N:24][CH:25]=1
Reactant: c1ccc(-c2ncn(-c3ncnc4nc[nH]c34)c2-c2ccccc2)cc1
Agent: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cnc4c(-n5ccnc5C(C)C)nc(Cl)nc43)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Product: c1ncc2[nH]cnc2n1

Procedure:
Benzylation of sterically hindered 6-(imidazol-1-yl)purines can result in mixtures of benzylated and nonbenzylated products such as when benzylating 2-chloro-9-[2-deoxy-3,5-di-O-p-toluoyl)-β-D-erythro-pentofuranosyl]-6-(4,5-diphenylimidazol-1-yl)purine, 2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-6-(2-isopropylimidazol-1-yl)purine. Partial decomposition can also result with 6-(2-benzylimidazol-1-yl)-2-chloro-9-[2-deoxy-3,5-di-O-p-toluoyl)-β-D-erythro-pentofuranosyl]purine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:15][C:16]1[C:25]2[C:20](=[CH:21][C:22](O)=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1>>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[C:16]([NH2:15])=[N:17][CH:18]=[CH:19]3)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Nc1nccc2cc(O)ccc12
Product: Nc1nccc2cc(OC3CCNCC3)ccc12
Yield: 25.5 %

Procedure:
This compound was prepared from 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (455 mg, 2.26 mmol) and 1-amino-6-hydroxyisoquinoline (435 mg, 2.71 mmol) by the Mitsunobu procedure described in 3C. Subsequent Boc deprotection according to procedure described in 3D gave 6-(piperidin-4-yloxy)-isoquinolin-1-ylamine (140 mg), EIMS: m/z=244.6 [M+H]+.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([OH:18])=O)[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[CH2:38]([O:40][C:41](=[O:48])[C@@H:42]1[CH2:46][C@@H:45]([OH:47])[CH2:44][NH:43]1)[CH3:39].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl>[CH2:38]([O:40][C:41](=[O:48])[C@@H:42]1[CH2:46][C@@H:45]([OH:47])[CH2:44][N:43]1[C:16]([C@@H:9]1[NH:8][C:7](=[O:19])[C@@H:6]([CH2:5][S:4][C:1](=[O:3])[CH3:2])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:18])[CH3:39]
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@@H](O)CN1C(=O)[C@H]1CCCCCC[C@H](CSC(C)=O)C(=O)N1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The enantiomer of trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid of Example 16 (0.23 g, 0.80 mmol), 1-hydroxybenzotriazole (0.11 g, 0.80 mmol), 4-methylmorpholine (0.22 mL, 2.0 mmol), and L-hydroxyproline ethyl ester hydrochloride (0.16 g, 0.80 mmol) are dissolved in methylene chloride (5.0 mL), and the reaction is cooled to 0° C. To this solution is added N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (0.31 g, 1.60 mmol), and the reaction is allowed to warm up to room temperature and stirred overnight. The reaction is diluted with more methylene chloride, and the organic layer is washed with 1N hydrochloric acid, saturated sodium bicarbonate, dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (80% ethyl acetate/hexane) to give N-[[trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecan-10-yl]-carbonyl]-trans 4-hydroxy-L-proline ethyl ester as a single enantiomer, [α]D +5.73° (c=4.1 mg/ml,CH2Cl2) which is assigned the 3R, 10S configuration.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][CH:7]=[C:6]2[Cl:13].[Cl-].[Cl-].[Cl-].[Al+3]>C1(C)C=CC=CC=1>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][CH:7]=[C:6]2[Cl:13]
Reactant: COc1ccc2nncc(Cl)c2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Oc1ccc2nncc(Cl)c2c1
Yield: 121.8 %

Procedure:
A solution of 6-methoxy-4-chlorocinnoline (135 mg, 0.7 mmol) in toluene (7 ml) was added to a stirred suspension of aluminium trichloride (231 mg, 1.73 mmol) in toluene (7 ml) and the red brown suspension was refluxed for 1 hr. The solvent was removed under vacuum and the residue was partitioned between water (20 ml) and 10% ethanol/chloroform (2×100 ml). The organic layer was washed with brine and dried (Na2SO4). Removal of the solvent under vacuum gave 6-hydroxy-4-chlorocinnoline (154 mg) as a single component by TLC (1:1 ethylacetate/hexanes). δH (CD3OD)=7.33 (d, 1H); 7.56 (dd, 1H); 8.32 (d, 1H) and 9.15 (br s 1H). MS (ESI) (M+H)+ 181.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16]>CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20])=[C:4]([CH3:9])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(I)ccc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(I)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
4-Iodo-2-methylphenol (15.0 g, 64.1 mmol) was dissolved in N,N-dimethylformamide (250 ml), and imidazole (8.7 g, 128.2 mmol, 2.0 eq.) added to the mixture, tert-Butyldimethyl silyl chloride (10.6 g, 70.5 mmol, 1.1 eq.) was slowly added to the above mixture and stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was extracted with aqueous ammonium chloride solution and ethyl acetate, and dried over magnesium sulfate. The crude product was purified on silica flash column. The solvent was evaporated under reduced pressure to thereby yield 21.8 g of the title compound (yield: 97.5%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10](=[CH:16][NH:17][CH:18]2[CH2:20][CH2:19]2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:6][C:5]([F:21])=[C:4]([Cl:22])[N:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:22][C:4]1[N:3]=[C:2]2[C:7]([C:8](=[O:9])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:17]2[CH:18]2[CH2:20][CH2:19]2)=[CH:6][C:5]=1[F:21]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Yield: 93.9 %

Procedure:
12.5 g (36 mmol) of ethyl 2-(2,6-dichloro-5-fluoro-pyridine-3-carbonyl)-3-cyclopropylamino-acrylate are heated at 100° C. in 75 ml of dimethylformamide with 6.5 g of potassium carbonate for 1 hour. The reaction mixture is poured onto ice-water and the product which has precipitated is filtered off with suction, washed with water and methanol and dried. 10.5 g (94% of theory) of ethyl 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate of melting point 176°-180° C. are obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].N#N.O>C(OCC)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:3][CH:4]=1)#[N:7]
Reactant: NCCCO
Reactant: N#Cc1ccc(F)cc1
Agent: N#N
Solvent: CCOCC
Solvent: O
Product: N#Cc1ccc(NCCCO)cc1
Yield: 84 %

Procedure:
A mixture of 4-fluorobenzonitrile (1.0 g, 8.26 mmol) and 3-aminopropanol (4.54 g, 58.7 mmol) was refluxed under an inert atmosphere (N2) for 15 h. Water (500 mL) and diethyl ether (500 mL) were then added, and the resulting organic layer separated, dried (Na2SO4) and concentrated. The residue was purified by column chromatography (heptane:EtOAc; 1:3) to give the sub-title compound in 84% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]([CH2:24][CH3:25])[C:14]3[C:19]([C:20]=2[C:21]#[N:22])=[CH:18][CH:17]=[C:16]([OH:23])[CH:15]=3)[CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][CH2:35][CH2:36]Cl.O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:26])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]([CH2:24][CH3:25])[C:14]3[C:19]([C:20]=2[C:21]#[N:22])=[CH:18][CH:17]=[C:16]([O:23][CH2:34][CH2:35][CH2:36][N:13]2[CH2:14][CH2:19][CH2:20][CH2:12]2)[CH:15]=3)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccc(-c2c(C#N)c3ccc(O)cc3n2CC)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Nc1cccc(-c2c(C#N)c3ccc(OCCCN4CCCC4)cc3n2CC)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 164.1 %

Procedure:
To a solution of [3-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester (1.2 g, 2.91 mmol) in DMF (10 mL) is added K2CO3 (538 mg, 3.9 mmol) and 3-bromo-1-chloropropane (383 uL, 3.9 mmol) and the reaction is stirred for overnight at 50° C. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with hexane and dried in vacuo to afford 1.1 g, 89% of the desired product.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[S:14])[NH:12][N:13]=2)=[CH:5][CH:4]=1)[CH3:2].Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][N:12]=[C:11]([S:14][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: BrCc1ccccn1
Reactant: CCc1ccc(-c2n[nH]c(=S)[nH]2)cc1
Agent: Br
Product: CCc1ccc(-c2nc(SCc3ccccn3)n[nH]2)cc1
Yield: 71 %

Procedure:
Prepared in a similar manner to example 1 using 5-(4-ethylphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 4a) and 2-(bromomethyl)pyridine hydrobromide. Yield 71%. 1H NMR (500 MHz, dMSO): δ 1.18-1.22 (t, 3H), 2.64-2.66 (t, 2H), 4.52 (s, 2H), 7.30-7.88 (m, 8H), 14.3 (bs, 1H). MS(M+H, 297).
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]O>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:1]([O:16][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CN(C)CCO
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCC(=O)OCCN(C)C
Yield: 62.6 %

Procedure:
A solution of 91.35 g (0.40 mol) of myristic acid, 35.7 g (0.40 mol) of 2-dimethylaminoethanol, 0.5 g of p-toluenesulfonic acid and a suitable volume of toluene was heated at reflux for approximately 48 hours in a 1-neck 3 liter flask equipped with Dean-Stark trap and condenser. At the end of this time, 7.0 ml of water had collected in the trap. The solution was cooled, stirred with K2CO3, filtered and concentrated. The residue was distilled to give 75.0 g of product; bp=145°-50° C/0.050 mm.