Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([NH:16][NH:17][C:18]([C@H:20]2[CH2:26][CH2:25][C@@H:24]3[CH2:27][N:21]2[C:22](=[O:33])[N:23]3[O:28][S:29]([OH:32])(=[O:31])=[O:30])=[O:19])=[O:15])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([NH:16][NH:17][C:18]([C@H:20]2[CH2:26][CH2:25][C@@H:24]3[CH2:27][N:21]2[C:22](=[O:33])[N:23]3[O:28][S:29](=[O:30])(=[O:31])[OH:32])=[O:19])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)NNC(=O)[C@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NNC(=O)[C@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O)[C@@H]1CCCNC1
Yield: 79 %

Procedure:
By using the procedure described in Step-4 of Example-1 above, and by using tetrabutylammonium salt of trans-3-[N′-(6-sulfooxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)-hydrazinocarbonyl]-(R)-piperidin-1-carboxylic acid tert-butyl ester (24 gm, 0.032 mmol), dichloromethane (60 ml) and trifluoroacetic acid (60 ml) to provide the title compound in 10 gm quantity as a white solid, in 79% yield.
Reaction SMILES: C[O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:24](=[CH:25][CH:26]=1)[O:23][C:11]1([CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12]1)[CH2:10][C:9]2=[O:27].Cl>CC(O)=O>[CH2:16]([N:13]1[CH2:14][CH2:15][C:11]2([CH2:10][C:9](=[O:27])[C:8]3[C:24](=[CH:25][CH:26]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:28])=[O:2])[CH:7]=3)[O:23]2)[CH2:12]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2
Yield: 97.1 %

Procedure:
(−)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (130 mg, 0.34 mmol) was hydrolyzed using aqueous HCl (20%) solution and AcOH following the procedure described in Example 1, Step A, giving (−)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid (120 mg) as a white solid (hydrochloride salt).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].[C:12]([O:16][C:17]([NH:19][C:20]([NH2:22])=[NH:21])=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH:2]=[C:3]([CH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[N:21]=[C:20]1[NH2:22])=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCOC(OCC)C(=O)CBr
Reactant: CC(C)(C)OC(=O)NC(=N)N
Product: CCOC(OCC)c1cn(C(=O)OC(C)(C)C)c(N)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
A mixture of 3-bromo-1,1-diethoxy-propan-2-one (21.3 g, 95 mmol) (Step 179.9) and N-tert-butoxycarbonylguanidine (45.3 g, 284 mmol, 3 equiv) (Step 179.10) was stirred at 50° C. for 8 h. The reaction mixture was concentrated, diluted in EtOAc/H2O and extracted with EtOAc. The organic phase was washed with water and brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (DCM/EtOAc, 3:7) followed by trituration in Et2O to afford 11.3 g of the title compound as a white solid: ES-MS: 286 [M+H]+; Rf=0.34 (DCM/EtOAc, 3:7).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19]Cl)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]1[C:30]([CH:31]2[CH2:33][CH2:32]2)=[N:29][N:28]=[C:27]1[SH:34].[I-].[K+].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41]>CN(C)C=O.C(OCC)(=O)C.O>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][S:34][C:27]3[N:26]([CH3:25])[C:30]([CH:31]4[CH2:33][CH2:32]4)=[N:29][N:28]=3)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCl)CC2)n1
Reactant: Cn1c(S)nnc1C1CC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(SCCCN2CCN(c3cc(C4CCC4)nc(C(C)(C)C)n3)CC2)nnc1C1CC1

Procedure:
0.4 g of 2-tert-Butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidine (1.14 mmol), 0.2 g of 4-methyl-5-cyclopropyl-4H-[1,2,4]triazole-3-thiol (1.29 mmol), 0.07 g lithium-hydroxide (2.92 mmol) and a spatula tip of potassium iodide were stirred in 20 ml of dimethylformamide overnight at room temperature and for an additional 3 h at 40° C. After addition of water and ethyl acetate, the organic layer was separated, dried over magnesium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel using dichloromethane-methanol (0-2%). Fractions containing the product were combined and the solvents were evaporated. The residue was dissolved in isopropanol and 1 equivalent of fumaric acid was added. The solvent was evaporated and the residue was dissolved in diisopropylether to which some drops of isopropanol were added upon warming, thereby forming a precipitate. After cooling the precipitate was collected by filtration and dried. Yield: 0.04 g (6%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH:24]1[C:37]2[C:36](=[O:38])[CH2:35][C:34]([CH3:40])([CH3:39])[CH2:33][C:32]=2[O:31][C:30]2[CH2:29][C:28]([CH3:42])([CH3:41])[CH2:27][C:26](=[O:43])[C:25]1=2.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([C:21]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:22])[N:20]=2)=[CH:11][C:10]=1[CH:24]1[C:25]2[C:26](=[O:43])[CH2:27][C:28]([CH3:41])([CH3:42])[CH2:29][C:30]=2[O:31][C:32]2[CH2:33][C:34]([CH3:40])([CH3:39])[CH2:35][C:36](=[O:38])[C:37]1=2
Reactant: C1COCCN1
Reactant: COc1ccc(-c2cccc(C(=O)O)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(C(=O)N3CCOCC3)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 24.5 h
Yield: 78.4 %

Procedure:
Morpholine (0.0625 ml, 0.72 mmol) was added to a solution of the 6-[4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylic acid produced in Example 1-2 (180 mg, 0.36 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (138 mg, 0.72 mmol), and 1-hydroxybenzotriazole monohydrate (55.0 mg, 0.36 mmol) in DMF (4 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 24.5 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was washed with water, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (ethyl acetate). The solid thus obtained was washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (161 mg, yield: 79%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([O:15]C(OCC)=O)=O)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[C:21]([OH:30])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[NH2:24]>CN(C=O)C>[S:3]1[CH:4]=[CH:5][S:1][C:2]1=[C:6]([C:13](=[O:15])[NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=1[C:21]([OH:30])=[O:29])[C:7]([O:9][CH:10]([CH3:11])[CH3:12])=[O:8]
Reactant: Nc1ccccc1C(=O)O
Reactant: CCOC(=O)OC(=O)C(C(=O)OC(C)C)=C1SC=CS1
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C(C(=O)Nc1ccccc1C(=O)O)=C1SC=CS1
Temperature: 60 °C

Procedure:
Isopropyl 2-(1,3-dithiol-2-ylidene)-2-(ethoxycarbonyloxy-carbonyl)acetate (15.9 g) and anthranilic acid (14 dissolved in DMF (100 ml). The mixture was stirred at 60° C. for hrs. The reaction mixture was poured into ice-water. The solid formed was filtered and recrystallized from ethyl acetate to give the titled compound. (5.6 g, 30.7%)
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11](=[S:13])=[S:12].[CH2:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH3:15]>>[F:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:11](=[S:12])[S-:13].[CH2:14]([NH+:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH3:15]
Reactant: S=C=S
Reactant: CCN(CC)CC
Reactant: Nc1ccc(F)c(F)c1F
Product: CC[NH+](CC)CC
Product: Fc1ccc(NC(=S)[S-])c(F)c1F

Procedure:
That is, first 2,3,4-trifluoroaniline (V) is reacted with carbon disulfide in the presence of triethylamine to produce triethylammonium N-(2,3,4-trifluorophenyl)dithiocarbamate (VI). Then the compound (VI) is reacted with ethyl chloroformate in an organic solvent such as chloroform or methylene chloride in the presence of triethylamine to give 2,3,4-trifluorophenylisothiocyanate (VII). The compound (VII) is then reacted with di(lower alkyl) malonate sodium salt, which is prepared from di(lower alkyl) malonate and sodium hydride, in an organic solvent such as tetrahydrofuran or dioxane to give di(lower alkyl) [(2,3,4-trifluoroanilino)(mercapto)methylene]malonate sodium salt (VIII). The compound (VIII) is then reacted with 1-acetoxy-3-halogenoacetone in an organic solvent such as N,N-dimethylformamide, dimethylsulfoxide or acetonitrile to give di(lower alkyl) [(2,3,4-trifluoroanilino)(3-acetoxy-2-oxopropylthio)methylene]malonate (IX). The compound (IX) is then reacted with sulfuric acid to give di(lower alkyl) [3-(2,3,4-trifluorophenyl)-4-hydroxymethyl-2-thiazolidene]malonate (X). The compound (X) is then reacted with sodium hydride in an organic solvent such as dioxane, tetrahydrofuran or N,N-dimethylformamide to give di(lower alkyl) (6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonate (XI).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([O:11][CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[C:18](Cl)=[O:19]>C(Cl)Cl>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:18]([C:8]2[CH:9]=[CH:10][C:5]([O:11][CH3:12])=[CH:6][CH:7]=2)=[O:19])[CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1
Reactant: COc1ccccc1
Reactant: COc1cc(OC)cc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(OC)cc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.1 %

Procedure:
Aluminum chloride (2.20 g, 16.5 mmol) was added to a stirred mixture of anisole (1.63 ml, 15.0 mmol) in anhydrous methylene chloride (20 ml) in an ice bath. Then a solution of 3,5-dimethoxybenzoyl chloride (3.01 g, 15.0 mmol) in anhydrous methylene chloride (10 ml) was added. The mixture was allowed to warm up to rt, then refluxed overnight. After cooling down to rt, the mixture was poured to ice water (50 ml), stirred for 20 min., and extracted with methylene chloride (3×50 ml). The combined organic extracts were washed with sat. NaHCO3 (3×50 ml), H2O (2×50 ml), brine (50 ml), dried over MgSO4, filtered and concentrated in vacuo to an oil, which was purified via flash column chromatography (10% EtOAc in hexane) to give (3,5-dimethoxy-phenyl)-(4-methoxy-phenyl)-methanone as a yellow solid (3.11 g, 76%): mp, 90-92° C.; 1HNMR (CDCl3) δ 7.85 (d, J=8.0 Hz, 2H, Ar), 6.96 (d, J=9.0 Hz, 2H, Ar), 6.88 (d, J=2.3 Hz, 2H, Ar), 6.65 (d, J=2.4 Hz, 1H, Ar), 3.89 (s, 3H, OCH3), 3.83 (s, 6H, 2OCH3). The product was carried over to the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([O:21]CC)=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)[CH:4]=1)#N.[OH-:27].[Na+].C[OH:30].C1COCC1>>[C:19]([CH2:18][CH:17]1[O:16][B:15]([OH:24])[C:14]2[CH:25]=[C:10]([O:9][C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][N:6]=3)[C:1]([OH:30])=[O:27])[CH:11]=[C:12]([CH3:26])[C:13]1=2)([OH:21])=[O:20]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cc(C#N)ccn3)cc(C)c21
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Oc2cc(C(=O)O)ccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-(4-cyanopyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.18 g, 3.31 mmol) in MeOH/THF (12 mL, 1:1) was added aqueous NaOH solution (250 mg in 3 mL water). After stirring at room temperature for two hours, the reaction mixture was evaporated and then acidified to pH 5 using 1 N HCl and then concentrated. HPLC purification gave desired product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (b 1H), 8.26 (d, J=5.2 Hz 1H), 7.47 (dd, J=5.2, 1.2 Hz, 1H), 7.29 (s, 1H), 7.17 (s, 1H), 7.02 (s, 1H), 5.46 (dd, J=9.6, 2.4 Hz, 1H), 3.03 (dd, J=16, 2.8 Hz, 1H), 2.24 (s, 3H), 2.08 (dd, J=15.2, 9.6 Hz, 1H). 2 protons assumed to be exchanged with solvents. MS (ESI) m/z=344 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=1)[C:17]([NH:19][C:20](N)=[O:21])=[O:18].C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:20]([NH:19][C:17](=[O:18])[C:16]1[CH:23]=[CH:24][CH:25]=[C:14]([C:13]([F:12])([F:26])[F:27])[CH:15]=1)=[O:21])[CH2:5]2
Reactant: NC(=O)NC(=O)c1cccc(C(F)(F)F)c1
Reactant: NC1CN2CCC1CC2
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(=O)c1cccc(C(F)(F)F)c1)NC1CN2CCC1CC2

Procedure:
The above compound was prepared from 3-amino quinuclidine dihydrochloride (1.0 g, 5 mmol), 3-trifluoromethylbenzoylurea (1.16 g, 5 mmol) and diisopropylethylamine (1.29 g, 10 mmol) in pyridine (20 ml), by refluxing under nitrogen overnight. The solvent was evaporated and the residue worked-up as in Example 1. The product (1.18 g) was converted to oxalate salt, mp 197°-200° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=O.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20]>>[OH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:1][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)c1ccnc(C=O)c1
Reactant: NCCCCCO
Product: CCOC(=O)c1ccnc(CNCCCCCO)c1

Procedure:
Prepared by General Procedure A from ethyl 2-formylpyridine-4-carboxylate (1.0 equiv.) and 5-aminopentan-1-ol (1.2 equiv.). Purification by column chromatography (DCM/MeOH (85:15) gave the title compound as greenish oil. 1H-NMR (300 MHz, CDCl3): δ 8.60 (d, 1H), 7.80 (s, 1H), 7.00 (d, 1H), 4.30 (q, 2H), 3.90 (s, 2H), 3.50 (t 2H), 3.10 (s, 2H), 2.60 (m, 2H), 1.50 (m, 4H), 1.30 (t, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]([NH2:23])[CH3:22])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.ClCC1C=CC(C(F)(F)F)=CC=1.C(N(CC)C(C)C)(C)C.Cl[C:46]1[C:51]([N+:52]([O-:54])=[O:53])=[CH:50][C:49]([I:55])=[CH:48][N:47]=1>C(#N)C.O>[I:55][C:49]1[CH:50]=[C:51]([N+:52]([O-:54])=[O:53])[C:46]([NH:23][CH:21]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:13][CH:12]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:22])=[N:47][CH:48]=1
Reactant: COc1cc(C(C)N)ccc1OCc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Agent: FC(F)(F)c1ccc(CCl)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(C)Nc2ncc(I)cc2[N+](=O)[O-])ccc1OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
To a stirred solution of 1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethanamine [prepared from 1-(chloromethyl)-4-(trifluoromethyl)benzene using the procedures described in Example 3-45-1 through Example 3-45-3] (2.52 g, 7.75 mmol) and N,N-diisopropylethylamine (2.7 mL, 15.18 mmol) in acetonitrile (30 mL) was added 2-chloro-5-iodo-3-nitropyridine (2.39 g, 8.13 mmol), The orange solution was heated to reflux. After 15 h, the brown reaction mixture was allowed to cool to room temperature and was diluted with water (60 mL). As the mixture was stirred, a yellow precipitate formed. The solids were isolated by filtration and washed with water (50 mL), and dried to provide 4.19 g (94%) of 5-iodo-N-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3-nitropyridin-2-amine as a yellow solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:16](=[O:17])[N:15]2[CH:18]=[N:19][C:20]([C:21]([NH2:23])=[O:22])=[C:14]2[N:13]=[N:12]1)(C(C)(C)C)(C)C.CC(O)=O.O>C1COCC1>[OH:8][CH2:9][CH2:10][N:11]1[C:16](=[O:17])[N:15]2[CH:18]=[N:19][C:20]([C:21]([NH2:23])=[O:22])=[C:14]2[N:13]=[N:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCn1nnc2c(C(N)=O)ncn2c1=O
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1ncn2c(=O)n(CCO)nnc12
Reaction time: 3 h

Procedure:
A solution of 3-(2-(tert-butyldimethylsilyloxy)ethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (50 mg, 0.148 mmol) in THF:AcOH:water (5 mL of a 1:3:1 v/v/v mixture) was stirred at room temperature. After 3 hours, the reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography (SiO2, gradient 0-100% acetonitrile in dichloromethane) to furnish the title compound as a white solid. Yield: 15 mg, 0.067 mmol, 45%. LCMS (ES+) m/z 225 (M+H)+ at 0.62 minutes. 1H NMR (400 MHz, d6-DMSO) δ: 8.84 (1H, s), 7.81 (1H, br s), 7.68 (1H, bs), 4.85 (1H, t) 4.34 (2H, t), 3.79 (2H, q).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][C:3]#[C:4][CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][O:14][N:15]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][O:14][N:15]=1)[CH2:2][C:3]#[C:4][CH2:5][CH3:6]
Reactant: Clc1nonc1-c1cccnc1
Reactant: CCC#CCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC#CCCOc1nonc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-hexyn-1-ol (980 mg, 10 mmol) and sodium hydride (240 mg, 10 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-oxadiazol-3-yl)pyridine (450 mg, 2.5 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: O.[C:2]1(C)[C:3]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[OH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2.[CH3:24]COCC>C(#N)C>[OH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[NH+:22]=[CH:21][CH:20]=[CH:19]2.[CH3:24][C:6]1[CH:5]=[CH:4][C:3]([S:8]([OH:11])(=[O:9])=[O:10])=[CH:2][CH:7]=1
Reactant: Oc1cccc2cccnc12
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: CCOCC
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)O)cc1
Product: Oc1cccc2ccc[nH+]c12

Procedure:
The toluenesulfonic acid salt of 8-hydroxyquinoline was formed by dissolving toluenesulfonic acid monohydrate (1.9 g, 10 mmol) in acetonitrile and adding 8-hydroxyquinoline (1.45 g, 10 mmol). Removal of solvent in vacuo and addition of ether to the residual oil results in crystallization. Trituration several times with ether followed by drying in vacuo yields 8-hydroxyquinolinium, p-toluenesulfonate as a powder (3.11 g).
Reaction SMILES: C[C:2]1[C:3]([CH3:10])=[C:4]([CH:6]=[CH:7][C:8]=1[OH:9])[OH:5].[C:11](=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1COCC1>[OH:5][C:4]1[C:3]([CH3:10])=[CH:2][C:8]([O:9][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:7][C:6]=1[CH3:11]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C([O-])[O-]
Reactant: Cc1c(O)ccc(O)c1C
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(OCC(=O)OC(C)(C)C)cc(C)c1O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
10 g of dimethylhydroquinone are dissolved in 750 ml of a mixture of 40% DMF and 60% THF and treated with 117 g of caesium carbonate. 14.1 g of tert-butyl bromoacetate are added dropwise at −25° C. and the reaction mixture is stirred for 17 hours at room temperature. After addition of 10 g of potassium carbonate the reaction mixture is stirred for 24 hours at room temperature, poured onto water and extracted twice with ethyl acetate. The combined organic phases are washed with NaCl solution, dried over sodium sulphate and the solvent is removed in vacuo. By chromatographic purification (cyclohexane/ethyl acetate) 1.27 g of tert-butyl (4-hydroxy-3,5-dimethylphenoxy)acetate are obtained.
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])[C:20]5=[N:19][C:18]=4[CH3:37])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41].C(N(C(C)C)CC)(C)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[F:1][C:2]1[CH:39]=[CH:38][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([N:50]6[CH2:51][CH2:52][N:47]([C:45]([O:44][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:46])[CH2:48][CH2:49]6)=[O:35])[C:20]5=[N:19][C:18]=4[CH3:37])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OCCCCCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 4 (200 mg, 0.37 mmol) in dichloromethane (10 mL), under argon, was treated with N-t-butoxycarbonylpiperazine (89.57 mg, 0.48 mmol) and diisopropylethylamine (77.42 μL 0.44 mmol). To the stirring solution, diethyl cyanophosphonate (72.06 μL, 0.43 mmol) was added. After stirring for two hours at room temperature, the reaction mixture was poured into water (20 mL) and the aqueous layer extracted with dichloromethane (three times 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude mixture was used without further purification in the next step. (408 mg, ESI-MS (M+1) 709)
Reaction SMILES: C([O:4][C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:23])[C@H:13]([O:24][C:25](=[O:27])[CH3:26])[CH2:12]4)[CH2:9][C@@H:8]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:7]=2[CH:6]=1)(=O)C.[BH4-].[Na+]>CO>[C:25]([O:24][C@@H:13]1[CH2:12][C@H:11]2[C@H:10]3[C@H:19]([CH2:18][CH2:17][C@:15]2([CH3:16])[C@H:14]1[OH:23])[C:20]1[CH:21]=[CH:22][C:5]([OH:4])=[CH:6][C:7]=1[C@H:8]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:9]3)(=[O:27])[CH3:26].[CH2:32]([O:31][C:29]([CH2:28][C@H:8]1[C:7]2[CH:6]=[C:5]([OH:4])[CH:22]=[CH:21][C:20]=2[C@@H:19]2[C@H:10]([C@H:11]3[C@@:15]([CH2:17][CH2:18]2)([CH3:16])[C@@H:14]([OH:23])[C@H:13]([OH:24])[CH2:12]3)[CH2:9]1)=[O:30])[CH3:33]
Reactant: CCOC(=O)C[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)[C@H](OC(C)=O)C[C@@H]23)c2ccc(OC(C)=O)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)[C@@H](O)[C@H](O)C[C@@H]23)c2ccc(O)cc21
Product: CCOC(=O)C[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)[C@@H](O)[C@H](OC(C)=O)C[C@@H]23)c2ccc(O)cc21
Reaction time: 20 h

Procedure:
300 mg. of 3,16α-diacetoxy-6β-ethoxycarbonylmethyl-1,3,5(10)-estratrien-17-one is dissolved in 11 ml. of methanol and gradually combined at +5°C. with 0.17 g. of NaBH4 in 9 ml. of methanol. After allowing the mixture to stand for 20 hours at room temperature, it is concentrated and stirred into water which contains hydrochloric acid. The reduction product is taken up in ethyl acetate, the solution is washed neutral, dried, and evaporated. By preparative thin-layer chromatography, 330 mg. of crude product yields 16α-acetoxy-6β-ethoxycarbonylmethyl-1,3,5(10)-estratriene-3,17β-diol, m.p. 170.5°-171.5°C. and 6β-ethoxycarbonylmethyl-1,3,5(10)-estratriene-3,16α,17β-triol, m.p. 192.5°-193°C.