Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]([CH3:41])[CH:33]=1)=[O:31]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([C:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]([CH3:41])[CH:33]=3)=[O:31])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: Cn1cc(C(=O)CCCCCCBr)c2ccccc21
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCC(=O)c2cn(C)c3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.98 g) as starting compound and 7-bromo-1-(1-methyl-1 H-indol-3-yl)-1-heptanone were reacted and treated in the same manner as in Example 172 to give 0.83 g of 4-amino-5-chloro-2-methoxy-N-((1-(7-(1-methyl-1 H-indol-3-yl)-7-oxoheptyl)piperidin-4-yl)methyl)-benzamide. This compound was treated with hydrochloric acid-ethanol to obtain its hydrochloride as crystals.
Reaction SMILES: CO[C:3]1[CH:11]=[CH:10][C:6]2[N:7]=[CH:8][S:9][C:5]=2[CH:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16](SC)=[CH:15][N:14]=1.COC1C=C[C:26]2[N:27]=C(C3C=CC(C(F)(F)F)=CN=3)SC=2C=1>>[S:9]1[C:5]2[CH:4]=[CH:3][CH:11]=[CH:10][C:6]=2[N:7]=[C:8]1[C:16]1[CH:17]=[CH:18][C:13]([NH:27][CH3:26])=[N:14][CH:15]=1
Reactant: CSc1ccc(Br)nc1
Reactant: COc1ccc2nc(-c3ccc(C(F)(F)F)cn3)sc2c1
Reactant: COc1ccc2ncsc2c1
Product: CNc1ccc(-c2nc3ccccc3s2)cn1

Procedure:
6-Methoxy-1,3-benzothiazole (35 mg, 0.21 mmol) and 2-bromo-5-(methylthio)pyridine (1.1 equiv) were reacted according to the procedure used for the preparation of 6-methoxy-2-[5-(trifluoromethyl)pyridin-2-yl]-1,3-benzothiazole. This gave the title compound (1 mg) as a pale yellow solid. 1H NMR (CHLOROFORM-d) δ 8.52 (d, 1H) 8.22 (d, 1H) 7.95 (d, 1H) 7.67 (dd, 1H) 7.40 (d, 1H) 7.11 (dd, 1H) 3.92 (s, 3H) 2.58 (s, 3H); MS m/z (M+H) 289.
Reaction SMILES: [CH3:1][N:2]([N:9]=O)C(N[N+]([O-])=O)=N.[OH-].[K+].CO.[CH2:15]([N:18]([CH2:35][CH2:36][CH3:37])[CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([C:29]3[CH:33]=[C:32]([OH:34])[NH:31][N:30]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:20]1)[CH2:16][CH3:17]>CCOCC>[N+:2](=[CH2:1])=[N-:9].[CH2:35]([N:18]([CH2:15][CH2:16][CH3:17])[CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([C:29]3[CH:33]=[C:32]([O:34][CH3:1])[NH:31][N:30]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:20]1)[CH2:36][CH3:37]
Reactant: CCCN(CCC)C1CCc2cccc(-c3cc(O)[nH]n3)c2C1
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: C=[N+]=[N-]
Product: CCCN(CCC)C1CCc2cccc(-c3cc(OC)[nH]n3)c2C1

Procedure:
A solution of 20 mmol diazomethane was prepared by adding 4.29 g (29 mmol) 1-methyl-3-nitro-1-nitrosoguanidine to a 25% solution KOH (10 ml) and Et2O (30 ml) in an ice bath. The ethereal phase was decanted into a solution of 25 ml methanol containing 400 mg (1.28 mmol) of 2-di-n-propylamino-8-(5-hydroxypyrazol-3-yl)-1,2,3,4-tetrahydronaphthalene. The title compound was isolated by concentrating the reaction and purifying the 500 mg of brown oil crude by flash column chromatography eluting with 9:1 mixture of methylene chloride and methanol. 190 mg were collected. The correct mass of 328 was found using FAB spectrum.
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:7]1[C:12]2[O:13][CH2:14][C:15](=[O:17])[NH:16][C:11]=2[C:10]([O:18]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[OH:6])=[N+]=[N-].[H][H].[C:28]([OH:31])(=[O:30])[CH3:29]>C(O)C.[Pd]>[C:28]([OH:31])(=[O:30])[CH3:29].[NH2:1][CH2:4][C@H:5]([C:7]1[C:12]2[O:13][CH2:14][C:15](=[O:17])[NH:16][C:11]=2[C:10]([OH:18])=[CH:9][CH:8]=1)[OH:6]
Reactant: [N-]=[N+]=NCC(O)c1ccc(OCc2ccccc2)c2c1OCC(=O)N2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: NC[C@@H](O)c1ccc(O)c2c1OCC(=O)N2
Reaction time: 18 h

Procedure:
A solution of 8-(2-azido-1-hydroxyethyl)-5-(benzyloxy)-2H-benzo[b][1,4]oxazin-3(4H)-one, Isomer 2 (example 13, step a) (0.72 g) in a mixture of acetic acid (10 mL) and ethanol (10 mL) was stirred vigorously with 10% palladium on carbon catalyst (0.225 g) under 4 bar pressure of hydrogen for 18 hours. The mixture was filtered and fresh 10% palladium on carbon catalyst (0.225 g) added and stirring under 4 bar pressure of hydrogen was continued for 18 hours. The mixture was filtered and fresh 10% palladium on carbon catalyst (0.225 g) added and stirring under 4 bar pressure of hydrogen was continued for 18 hours. The mixture was filtered and the solvent removed under reduced pressure. The residue was triturated with acetonitrile (30 mL) to afford the subtitled compound. Yield 0.28 g.
Reaction SMILES: COC1C=CC(OC)=CC=1C(=O)CN1C(C(OCC)=O)=CC(C2C=NC=CC=2)=N1.[CH3:30][Si:31]([CH3:43])([CH3:42])[C:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:34][N:33]=1.Br[CH2:45][C:46]([C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1)=[O:47].Br>>[O:47]=[C:46]([C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1)[CH2:45][N:33]1[C:32]([Si:31]([CH3:42])([CH3:43])[CH3:30])=[CH:36][C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N:34]1
Reactant: CCOC(=O)c1cc([Si](C)(C)C)n[nH]1
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Agent: CCOC(=O)c1cc(-c2cccnc2)nn1CC(=O)c1cc(OC)ccc1OC
Product: CCOC(=O)c1cc([Si](C)(C)C)n(CC(=O)c2cccnc2)n1

Procedure:
This compound was made in an analogous fashion to ethyl 1-(2-(2,5-dimethoxyphenyl)-2-oxoethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate using ethyl 3-(trimethylsilyl)-1H-pyrazole-5-carboxylate and 2-bromo-1-(pyridin-3-yl)ethanone.HBr (purchased from Aldrich). 1H-NMR δ 9.17 (d, 1H), 8.88 (dd, 1H), 8.24 (ddd, 1H), 7.50 (td, 1H), 7.03 (s, 1H), 5.73 (s, 2H), 4.40 (q, 2H), 1.39 (t, 3H), 0.28 (s, 9H). Calculated mass for C16H21N3O3Si, 331.14, observed, 332.0 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12]C=C[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:18]1[CH2:22][O:21]C[CH2:19]1.C[Li]>C(OCC)C.O>[CH2:1]([N:8]1[CH2:12][CH:18]([CH3:19])[CH:22]([OH:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C1=CCN(Cc2ccccc2)C1
Agent: O=S(=O)(O)O
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Product: CC1CN(Cc2ccccc2)CC1O
Yield: 75.8 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, and 60.0 g of THF in a quartz round flask reactor, 45.6 g (0.20 mol) of (NH4)2S2O8 (ammonium peroxydisulfate produced by Mitsubishi Gas Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 5 days at room temperature with irradiation by 500W Xe lamps (UXL-500D xenon lamp produced by Ushio). 300 mL (0.30 mol) of 1 mol/L methyllithium (MeLi) in diethyl ether solution (produced by Kanto Chemical Co., Inc.) was continuously added to the reaction mixture and stirred for 5 hours at about 5° C. using an ice-bath. After completion, water was added to destroy excess MeLi at about 5° C. using an ice-bath. Acetone and diethyl ether were evaporated under reduced pressure, and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 14.5 g of 1-benzyl-4-methyl-3-pyrrolidinol (yield 76.0%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[NH:13][C@@H:12]([C@H:14]([OH:16])[CH3:15])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)([O-:38])=[O:37].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.C(OCC)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[NH:13][C@@H:12]([C@@H:14]([O:16][C:43](=[O:44])[C:42]3[CH:41]=[CH:40][C:39]([N+:36]([O-:38])=[O:37])=[CH:47][CH:46]=3)[CH3:15])[CH2:11][O:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Reaction time: 2 h
Yield: 100 %

Procedure:
Under a nitrogen atmosphere, to a tetrahydrofuran (20 mL) solution containing (R)-1-[(3R,5R)-5-(4-chlorophenyl)morpholine-3-yl]ethanol (903 mg), triphenylphosphine (1.81 g) and 4-nitrobenzoic acid (1.16 g) was dropwise added diisopropyl azodicarboxylate (1.36 mL) while cooling with ice. The resultant solution was stirred at the same temperature for 30 minutes, and then at room temperature for 2 hours. The reaction solution was diluted with water and ethyl acetate, and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate 9/1→8/2→7/3), to thereby obtain the titled compound (1.46 g). The physical properties of the compound were as follows.
Reaction SMILES: C(N(CC)CC)C.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.Cl.[NH2:23][C@H:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[OH:29].[N:30]1[N:31]([C:35]2[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=2[C:37](O)=[O:38])[N:32]=[CH:33][CH:34]=1>C(Cl)Cl>[OH:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][C@@H:24]1[NH:23][C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=1[N:31]1[N:32]=[CH:33][CH:34]=[N:30]1
Reactant: N[C@H]1CCC[C@H]1O
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCC[C@H]1O)c1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (1.52 ml, 10.90 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.59 g, 4.36 mmol) and EDC (0.84 g, 4.36 mmol) were added to a solution of (1R,2S)-2-aminocyclopentan-1-ol hydrochloride (CAS number 137254-03-6; 0.50 g, 3.63 mmol) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 0.76 g, 4.00 mmol) in DCM (10 ml). The reaction was stirred at room temperature for 18 hours and then diluted with DCM (50 ml) and washed with a saturated solution of sodium bicarbonate (2×20 ml). The crude product was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].[CH3:11][S:12]([O-:14])=[O:13].[Na+]>CS(C)=O.O.C(OCC)(=O)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([S:12]([CH3:11])(=[O:14])=[O:13])=[CH:8][CH:9]=1)=[O:4]
Reactant: CS(=O)[O-]
Reactant: COC(=O)c1ccc(Br)o1
Agent: [Cu]I
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(S(C)(=O)=O)o1
Temperature: 110 °C

Procedure:
To a solution of 5-bromo-furan-2-carboxylic acid methyl ester (4.7 g, 23 mmol) in DMSO (25 mL) was added the sodium methanesulfinate (5.5 g, 46 mmol) followed by copper (I) iodide (4.4 g, 23 mmol). The mixture was then heated to 110° C. for 2 hours. The reaction was diluted with water (100 mL) and ethyl acetate (100 mL) and filtered through diatomaceous earth. The aqueous layer was separated and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (2×50 mL), dried over sodium sulfate, filtered and concentrated to afford 5-methanesulfonyl-furan-2-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:19]=O.S(=O)(=O)(O)O>O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[C:12]([CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)=[CH2:19]
Reactant: COc1ccc(C(=O)CC2CCCC2)c(Cl)c1Cl
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)C1CCCC1
Yield: 61.8 %

Procedure:
2',3'-Dichloro-4'-methoxy-2-cyclopentylacetophenone (51.6 g., 0.18 mole) is dissolved in dioxane (460 ml.) and paraformaldehyde (21.6 g., 0.72 mole) and concentrated sulfuric acid (9.65 g.) are added. The mixture is heated at 80°-85° C. for 20 hours. The dioxane is evaporated at reduced pressure. Water is added to the residual gum which then is extracted into ether. The ether extract is washed with water and dried over magnesium sulfate. The ether is evaporated and upon triturating the residue with hexane (5 ml.) there is obtained a solid that is crystallized from ligroin to obtain 2',3'-dichloro-4'-methoxy-2-cyclopentylacrylophenone (33.3 g.), m.p. 59°-63° C. Crystallization from butyl chloride affords a sample (m.p. 66°-67.5° C.) for analysis.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[C:11]2=[O:16])[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>ClCCl>[F:18][C:2]([F:1])([F:17])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12]([O:15][S:27]([CH3:26])(=[O:29])=[O:28])[C:11]2=[O:16])[CH:7]=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1C(O)CCN1c1cccc(OC(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OC1CCN(c2cccc(OC(F)(F)F)c2)C1=O
Temperature: 25 °C

Procedure:
A stirred solution of 1-(3-trifluoromethoxyphenyl)-3-hydroxy-2-pyrrolidone (19.42 g) in dichloromethane (250 ml) was cooled in an ice bath and treated with triethylamine (11.32 ml). Methanesulfonyl chloride (6.05 ml) was added dropwise via a syringe, and the mixture stirred with cooling for a further 1 hour after which it was allowed to warm to room temperature. After stirring for 2 hours at room temperature methanesulfonyl chloride (0.5 ml) and triethylamine (1.0 ml) were added and the mixture was stirred for a further 2 hours. The reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane extracts were washed with water, dried (MgSO4) and the solvent evaporated under reduced pressure to give the crude sub-title compound (23.0 g), which was used without further purification.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:33][CH2:32][C:18]2([N:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[NH:20][C:19]2=[O:31])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl.C(Cl)Cl.CCCCCC>[ClH:29].[ClH:1].[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:21]1[NH:20][C:19](=[O:31])[C:18]2([CH2:32][CH2:33][NH:15][CH2:16][CH2:17]2)[N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(c1ccc(Cl)cc1Cl)NC2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: C1COCCO1
Product: O=C1NC(c2ccc(Cl)cc2Cl)=NC12CCNCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 219.4 %

Procedure:
4 N HCl-dioxane (20 ml, 80 mmol) was added to a solution of 2-(2,4-dichloro-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (3.11 g, 7.81 mmol) in CH2Cl2 (60 mL), and the mixture was stirred at room temperature for four hours. The reaction mixture was diluted with CH2Cl2-hexane, and the precipitated solid was then filtered. The resulting solid was washed with ethyl acetate and then dried under reduced pressure to give 2-(2,4-dichloro-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one dihydrochloride (3.18 g) as a colorless solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:10]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:8])=[O:7].[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CCOC(C)=O>[Br:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:9]2[S:6]([NH:5][CH2:4][CH2:3][NH:2][CH2:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=1)(=[O:8])=[O:7]
Reactant: COc1ccc(C=O)cc1
Reactant: CCOC(=O)c1c(S(=O)(=O)NCCN)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(S(=O)(=O)NCCNCc2ccc(OC)cc2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product from Example 89, Step A was combined with 1.2 equivalents of 4-methoxybenzaldehyde and 1.5 equivalent of sodium triacetoxyborohydride in dichloroethane. The reaction was stirred for 1.5 hours at room temperature, was diluted with EtOAc and washed with sat. NaHCO3 and brine. The solution was dried with Na2SO4 and concentrated in vacuo to give the titled compound. ESI+ MS: 651 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1>>[CH3:17][N:13]1[CH2:14][CH2:15][CH2:16][C@@H:12]1[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:20]3[CH:21]=[CH:22][S:18][CH:19]=3)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: OB(O)c1ccsc1
Reactant: CN1CCC[C@H]1Cn1ccc2ccc(Br)cc21
Product: CN1CCC[C@@H]1Cn1ccc2ccc(-c3ccsc3)cc21

Procedure:
(39.9 mg, 79%); from (S)-6-bromo-1-((N-methylpyrrolidin-2-yl)methyl)indole (50.0 mg, 0.17 mmol) and thiophene-3-boronic acid (43.6 mg, 0.34 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]2[O:9][C:10](=[O:12])[CH3:11])[CH:5]=[N:4][C:3]=1[C:25]#[N:26].[CH3:27][C:28]([N:30]([CH3:32])[CH3:31])=O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:31][N:30]([CH3:32])[C:28](=[N:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]2[O:9][C:10](=[O:12])[CH3:11])[CH:5]=[N:4][C:3]=1[C:25]#[N:26])[CH3:27]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C#N)c2N)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C#N)c2N=C(C)N(C)C)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 0.73 g of 5-amino-4-cyano-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-imidazole, prepared as described by Suzuki and Kumashiro, Chem. Abstracts 71, 12561n (1969), and dimethylacetamide (0.70 g) in acetonitrile (5 ml) is added dropwise phosphoryl chloride (0.61 g) and the mixture is stirred under nitrogen for 20 hours at room temperature. The mixture is poured into 5% aqueous sodium carbonate and extracted with ethyl acetate and the organic layer washed with saturated sodium chloride solution and dried over sodium sulfate. The organic extract is concentrated to dryness at reduced pressure to afford 5-[1-(dimethylamino)-ethylideneamino]-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-imidazole-4-carbonitrile as an oil.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:69])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH3:68])[N:64]=[C:65]([CH2:66][CH3:67])[C:52]3=[CH:51][CH:50]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:78]>CO.O>[ClH:78].[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:69])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63]([CH3:68])[N:64]=[C:65]([CH2:66][CH3:67])[C:52]3=[CH:51][CH:50]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CCc1nn(C)c2c1ccc1c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCc1nn(C)c2c1ccc1c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 43 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(3-ethyl-1-methyl-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (2 mL), water (3 mL) and 1 M HCl (0.1 mL) and chromatographed on a 2 g C18 cartridge {gradient 40 to 65% MeOH in water+1 M HCl (60 μL in each 5 mL of eluent)} to give the title compound (9 mg, 43%, 3 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.38 (br s, 3H), 7.80 (d, J=8.6 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.55-7.53 (m, 2H), 7.50-7.43 (m, 3H), 7.41-7.37 (m, 2H), 7.32 (d, J=8.3 Hz, 2H), 4.34 (s, 3H), 2.99 (q, J=7.6 Hz, 2H), 2.63-2.52 (m, 4H), 2.22-2.11 (m, 1H), 1.87-1.76 (m, 1H), 1.35 (t, J=7.6 Hz, 3H). LCMS (Method E): RT=3.79 min, [M+H]+=450.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH:12]1([CH2:15][NH2:16])[CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:16][CH2:15][CH:12]2[CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: NCC1CC1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(Br)cnc1NCC1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.8 %

Procedure:
A mixture of 5-bromo-2-chloro-3-nitropyridine (Step B, 5.0 g, 21.1 mmol), cyclopropanemethylamine (2.8 mL, 31.7 mmol) and N,N-diisopropylethylamine (5.5 mL, 31.7 mmol) in ethanol (20 mL) was stirred at room temperature for 24 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate as eluent) to afford the title compound (5.5 g, 96%) as a yellow solid.
Reaction SMILES: [C:1](=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([O-:18])=[O:17])O1.Cl[C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=1>C(COC)OC.C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:33][C:30]1[CH:31]=[CH:32][C:27]([C:22]2[CH:21]=[CH:20][C:19]([CH2:15][C:16]([O:18][CH3:1])=[O:17])=[CH:24][CH:23]=2)=[N:28][CH:29]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)nc1
Reactant: CC1(C)OB(C(C(=O)[O-])c2ccccc2)OC1(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(-c2ccc(O)cn2)cc1
Yield: 24 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (220 mg, 0.193 mmol) and a 2N aqueous sodium carbonate solution (4.63 ml) were added to a solution of methyl [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl(phenyl]acetate (1.07 g, 3.86 mmol) obtained in Example (12-1, and 2-chloro-5-hydroxypyridine (500 mg, 3.86 mmol) in dimethoxyethane (20 ml), and the mixture was stirred under heating with reflux overnight. The reaction mixture was diluted with ethyl acetate and water, and the insolubles were removed by filtration through Celite. After the obtained filtrate was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=2/1-1/1) to give methyl [4-(5-hydroxy-2-pyridinyl)phenyl]acetate (230 mg, yield: 24%).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][C:12]([CH3:26])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])[CH2:13][OH:14]>N1C=CC=CC=1>[C:2]([O:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]([CH3:26])([CH3:11])[CH2:13][O:14][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(CO)CCCCCCC(C)(C)CO
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(CCCCCCC(C)(C)COC(=O)c1cccnc1)COC(=O)c1cccnc1
Yield: 65 %

Procedure:
106.2 Grams (0.6 mole) of nicotinoyl chloride hydrochloride in 300 ml of anhydrous pyridine were reacted with 23.0 grams (0.1 mole) of 2,2,9,9-tetramethyl-1,10-decanediol, according to the procedure described in Example 1. 28.8 Grams of product, recrystallized from ethanol, were obtained, having m.p. 68°-69° C. Yield: 65,5% of theoretical.