Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1.[C:14](N1C=CN=C1)([N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[O:15]>CN(C)C=O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][NH:1][C:14]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[O:15])=[CH:4][C:5]=1[F:13]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(CN)cc1F
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNC(=O)n2ccnc2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.5 %

Procedure:
To a mixture of methyl 4-(aminomethyl)-2-fluorobenzoate (106.9 mg, 0.584 mmol) in N,N-dimethyl formamide (4.0 mL) was added 1,1′-carbonyldiimidazole (Aldrich, 98.9 mg, 0.592 mmol). After it was stirred at rt overnight under an argon atmosphere, the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give 2-Fluoro-4-{[(imidazole-1-carbonyl)-amino]-methyl}-benzoic acid methyl ester (187.0 mg) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:32]1[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=1.CN(C)C=O>O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([NH:20][C:32]2[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:21]=[CH:22][CH:23]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(N)c1)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1cccc(Nc2ncccc2[N+](=O)[O-])c1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 20 h
Yield: 68.7 %

Procedure:
A mixture of 3-(di-(t-butoxycarbonyl)aminomethyl)aniline (1.50 g), triethylamine (2.0 ml), 2-chloro-3-nitropyridine (1.10 g) and anhydrous dimethylformamide (15 ml) was stirred at 60° C. for 20 h and, thereafter, ethyl acetate and water were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 1.42 g of the titled compound (yield, 69%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][C:22]=1[NH:31][C:32]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:33])[CH3:19]>>[CH3:17][N:15]([CH3:16])[CH2:14][C@H:2]([NH:1][S:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:18][CH3:19])=[C:22]([NH:31][C:32]([N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)=[O:33])[CH:23]=1)(=[O:28])=[O:29])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1NC(=O)N1CCOCC1
Product: CCOc1ccc(S(=O)(=O)N[C@H](CC(=O)OCc2ccccc2)CN(C)C)cc1NC(=O)N1CCOCC1
Yield: 68 %

Procedure:
According to the method described in example S72a, (R)-benzyl 3-amino-4-(dimethylamino)butanoate (30 mg, 0.086 mmol) was reacted with 4-ethoxy-3-(morpholine-4-carboxamido)benzene-1-sulfonyl chloride to yield the title compound as a white solid (32 mg, 68%). MS ESI 549.3 [M+H]+, calcd for [C26H36N4O7S+H]+ 549.23
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH:14]([OH:16])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC(O)c2ccccc21

Procedure:
A solution of 3-(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2,5-dione (0.14 g) and sodium borohydride (7 mg) in ethanol (10 ml) was stirred at room temperature for 18 hours. The ethanol was removed under reduced pressure, and the residue dissolved in dichloromethane (25 ml). The solution was extracted with 2N HCl (2×20 ml) and saturated brine (20 ml), and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue triturated with ether to give 3-(S)-t-butyloxycarbonylamino-1-ethoxycarbonylmethyl-5-hydroxy-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, mp 167°-169.5° C., [α]D =-193° (c=0.52 in DMF). The substance was also obtained by hydrogenation of the benzazepin-2,5-dione derivative with H2 /Pt in ethanol.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=2[N+:6]=1[CH3:7].CC1C=CC(S(O)(=O)=O)=CC=1.[Cl:23][C:24]([Cl:45])([Cl:44])[C:25]1[N:30]=[C:29]([C:31]([Cl:34])([Cl:33])[Cl:32])[N:28]=[C:27]([C:35]2[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=2)[N:26]=1.C1(C)C=CC=CC=1>C(N(CC)CC)C>[Cl:34][C:31]([Cl:32])([Cl:33])[C:29]1[N:30]=[C:25]([C:24]([Cl:45])([Cl:23])[Cl:44])[N:26]=[C:27]([C:35]2[CH:36]=[CH:37][C:38]([C:39]([CH:1]=[C:2]3[N:6]([CH3:7])[C:5]4[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=4[S:3]3)=[O:40])=[CH:42][CH:43]=2)[N:28]=1
Reactant: O=C(Cl)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Reactant: Cc1sc2ccccc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1C(=CC(=O)c2ccc(-c3nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n3)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,3-Dimethylbenzothiazolium-p-toluenesulfonate (13.4 pbw) and 4-(4,6-bis-trichloromethyl-s-triazin2-yl)-benzoylchloride (22.7 pbw) are successively suspended or dissolved, respectively, in 150 pbw of toluene. The mixture is cooled to 15° C. and with the exclusion of moisture 13.1 pbw of triethylamine are added dropwise at this temperature. The mixture discolors towards dark brown and is stirred for 3 hours at room temperature. The precipitate formed is removed by filtration with suction and washed with cold toluene. The residue is digested in 200 pbw of methanol and stirred for about 60 minutes, again filtered and dried.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[C:8]2[C:16](OC)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[C:8]2[CH2:16][OH:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(C(F)(F)F)ccn1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1c(C(F)(F)F)ccn1-c1ccccc1
Temperature: 0 °C
Yield: 67.9 %

Procedure:
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 1-phenyl-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate (460 mg, 1.71 mmol, 1.00 equiv) and tetrahydrofuran (4 mL). To the resulting mixture was then added a solution of LAH (135 mg, 3.56 mmol, 2.00 equiv) in tetrahydrofuran (1 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 60 min at 0° C. in a water/ice bath. The reaction was then quenched by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (5×10 mL) and the organic layers combined. The resulting residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) to yield [1-phenyl-3-(trifluoromethyl)-1H-pyrrol-2-yl]methanol as light yellow oil (280 mg, 66%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:44])[C:34]2[C:14]([CH:15]=[C:16]3[CH:33]=[C:32]4[C:19]([C:20]5[C:25]([C:26]6[C:31]4=[CH:30][CH:29]=[CH:28][CH:27]=6)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:18][C:17]3=2)=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11]1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:13]=[C:14]3[C:34]([C:10]([CH3:44])([CH3:9])[CH:11]=2)=[C:17]2[C:16]([CH:33]=[C:32]4[C:19](=[CH:18]2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]4=2)=[CH:15]3)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CO
Product: CC1(C)C=C(c2ccc(Br)cc2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 53 %

Procedure:
A mixture of 6.6 g (28 mmol) of 1,4-dibromobenzene, 15.1 (32 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-teramethyl-1,3,2-dioxaborolane, 0.32 g (0.28 mmol) of Tetrakis(triphenylphosphine)palladium, 22 ml of 2M Na2CO3, 60 ml of EtOH and 130 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 12 h. After finishing the reaction, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product 7.4 g (53%) as a white solid.
Reaction SMILES: C(N1CCN([C:14]2[CH:23]=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)CC1)C1C=CC=CC=1.ClC(O[CH:28]=[CH2:29])=O>>[N:15]1([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:21]=2[N:22]=[CH:23][CH:14]=[N:15]3)[CH2:29][CH2:28][NH:22][CH2:23][CH2:14]1
Reactant: C=COC(=O)Cl
Reactant: c1ccc(CN2CCN(c3cnc4ccccc4n3)CC2)cc1
Product: c1cc(N2CCNCC2)c2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 127.3 %

Procedure:
To a room temperature solution of 1-benzyl-4-(quinoxalin-yl)-piperazine (1.0 g, 3.3 mmol) in anhydrous CH2C2 under nitrogen was added vinyl chloroformate (0.34 mL, 3.9 mmol) drop wise. The reaction mixture was heated at reflux 2 hours. The reaction was cooled, concentrated to dryness and concentrated HCl (25 mL) and 1,4-dioxane (25 mL) were added. The resulting solution was stirred at ambient temperature overnight. The solution was basified with 2.5 N NaOH (300 mL) and extracted into EtOAc (3×200 mL). The organic layers were combined, dried over Na2SO4, concentrated and chromatographed (10% MeOH/CH2Cl2/NH4OH) to give 450 mg (64%) of an orange solid: mp 106-108° C.: MS (+) ESI m/e 215 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:17][C:13]3[S:14][CH:15]=[CH:16][C:12]=3[C:11]2=O)=O)=[CH:4][CH:3]=1.O.[NH2:20][NH2:21].C(O)(=O)C>C(O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:10]3[CH2:17][C:13]4[S:14][CH:15]=[CH:16][C:12]=4[C:11]=3[NH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)nc1)C1Cc2sccc2C1=O
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Brc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cn1
Temperature: 25 °C
Yield: 65 %

Procedure:
5-(6-Bromo-pyridine-3-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.29 g, 4 mmol), hydrazine monohydrate (0.6 mL, 12 mmol), glacial acetic acid (1.4 mL) and ethanol (20 mL) were heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(6-Bromo-pyridin-3-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.83 g, 2.6 mmol) as white solid in 65% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:12]=[N:13][C:14]([CH3:20])=[C:15]([N+:17]([O-])=O)[CH:16]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([CH3:20])=[C:15]([NH2:17])[CH:16]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ncc(C#CCNC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ncc(CCCNC(=O)OC(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.7 %

Procedure:
To a solution of tert-butyl[3-(6-methyl-5-nitropyridin-3-yl)prop-2-yn-1-yl]carbamate (2.98 g, 10.2 mmol) in MeOH (100 mL) was added palladium hydroxide on carbon (0.72 g). The reaction vessel was flushed with H2 and then the reaction mixture was allowed to stir at rt under an atmosphere of hydrogen overnight. The reaction mixture was filtered over a pad of Celite® and the filtrate was concentrated to give tert-butyl[3-(5-amino-6-methylpyridin-3-yl)propyl]carbamate (2.97 g, >99%) as a yellow oil. LCMS (FA): Rt=0.85 min, m/z=266.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[N:13][C:12]([CH3:15])=[CH:11][N:10]=2)[C:6](=[S:16])[NH:5][C:4](=[O:17])[CH:3]=1.[N:18]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[NH2:18][C:3]1[C:4](=[O:17])[NH:5][C:6](=[S:16])[N:7]([CH2:8][C:9]2[CH:14]=[N:13][C:12]([CH3:15])=[CH:11][N:10]=2)[C:2]=1[NH2:1]
Reactant: O=N[O-]
Reactant: Cc1cnc(Cn2c(N)cc(=O)[nH]c2=S)cn1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cnc(Cn2c(N)c(N)c(=O)[nH]c2=S)cn1
Reaction time: 2 h
Yield: 56.8 %

Procedure:
To 6-amino-1-[(5-methylpyrazin-2-yl)methyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.50 g, 2.00 mmol, obtained from Example 14(b)) in 90% acetic acid (7 mL) was added, dropwise, a solution of sodium nitrite (0.14 g, 2.1 mmol) in water (1 mL). After 2 h, sodium dithionite (1.0 g, 5.0 mmol) was added and after another 2 h the mixture was concentrated in vacuo providing the title compound (0.30 g, 57% yield) as a yellow solid. This was used without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:1]([NH:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[CH2:11][NH2:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(NCc2ccccc2)cccc1-c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCc1c(NCc2ccccc2)cccc1-c1ccccc1
Temperature: 25 °C

Procedure:
The product of example 7a above, 2-benzylamino-6-phenylbenzonitrile, was dissolved in dry tetrahydrofuran (10 mL) and stirred under argon at room temperature. Lithium aluminum hydride (0.175 g, 4.3 mmol) was added and the mixture heated to reflux under argon for 20 hours. The reaction mixture was cooled to room temperature and anhydrous sodium sulfate was added followed by the addition of a freshly prepared saturated solution of anhydrous sodium sulfate. The solvent was evaporated and the residue triturated with ethyl acetate, filtered and evaporated to give the title compound. ES (+) MS m/e=272(M-NH2+)
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH2:11][C:12]2[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:21])[NH:14][N:13]=2)=[C:6]([Cl:22])[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[Cl:10][C:8]1[CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:11][C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:21])[NH:14][N:13]=1
Reactant: COC(=O)c1cc(Cl)c(Cc2cc(C(C)C)c(=O)[nH]n2)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)c1cc(Cc2c(Cl)cc(CO)cc2Cl)n[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 114.1 %

Procedure:
A mixture of 3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-benzoic acid methyl ester (52) (160 mg, 0.45 mmol) in tetrahydrofuran (5 mL) at 25° C. was treated with a 1M solution of diisobutylaluminum hydride in tetrahydrofuran (2.7 mL, 2.7 mmol). The reaction was stirred at room temperature for 24 h. A TLC of the reaction indicated that starting material was still present. An additional amount of the 1 M solution of diisobutylaluminum hydride in tetrahydrofuran (1.0 mL) was added to the reaction. After stirring 30 min at room temperature, the reaction was cautiously quenched by addition to a 1:1 mixture of a saturated aqueous sodium chloride solution (30 mL) and a 2N aqueous hydrochloric acid solution (30 mL). The mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution (20 mL), dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting solid was dried under high vacuum to afford 6-(2,6-dichloro-4-hydroxymethyl-benzyl)-4-isopropyl-pyridazin-3-one (53) (168 mg) as a brown solid that was used without further purification; LRMS-ES(+) for C15H16Cl2N2O2 (M+H) m/z=327. MW=327.2130, Exact Mass=326.0589
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][N:5]([C:15](=[O:17])[CH3:16])[CH2:6][CH2:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[C:20]=1[CH:21]=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:15]([N:5]1[CH2:6][CH2:7][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:3]([CH2:2][O:18][C:19]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[C:20]=2[CH:21]=[O:22])[CH2:4]1)(=[O:17])[CH3:16]
Reactant: CC(=O)N1CCC(c2ccccc2)=C(CCl)C1
Reactant: O=Cc1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(c2ccccc2)=C(COc2cccc(O)c2C=O)C1
Yield: 18.5 %

Procedure:
To a solution of 1-(3-(chloromethyl)-4-phenyl-5,6-dihydropyridin-1(2H)-yl)ethanone (100 mg, 0.40 mmol) and 2,6-dihydroxybenzaldehyde (110 mg, 0.80 mmol) in DMF (2.5 mL) was added K2CO3 (170 mg, 1.20 mmol), after heated at 50 degree for 2 h, the reaction was diluted with EtOAc, organic layer was separated and aqueous layer was extracted with EtOAc. EtOAc layers were combined, washed with Sat. NaHCO3, brine, dried over Na2SO4, and was concentrated to give crude oil, which was purified by preparative HPLC (eluted with ACN/H2O) to give 2-((1-acetyl-4-phenyl-1,2,5,6-tetrahydropyridin-3-yl)methoxy)-6-hydroxybenzaldehyde (26 mg). 1H NMR (400 MHz, CDCl3, NMR shows rotamers exist, only one set of signal was reported) δ (ppm) 11.97 (s, 1H), 10.34 (s, 1H), 7.34 (m, 4H), 7.17 (m, 2H), 6.49 (d, J=8.0 Hz, 1H), 6.11 (d, J=8.8 Hz, 1H), 4.48 (s, 2H), 4.33 (s, 2H), 3.69 (t, J=6.0 Hz, 2H), 2.55 (m, 2H), 2.18 (s, 3H); MS (ESI) m/z 352.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9]C=[N:11][N:12]=2)=[CH:4][CH:3]=1.FC1C=CC(CCC([O-])=O)=CC=1.O.NN>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:12][NH2:11])=[O:9])=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nnco2)cc1
Agent: NN
Agent: O=C([O-])CCc1ccc(F)cc1
Solvent: O
Product: NNC(=O)c1ccc(F)cc1

Procedure:
In one embodiment, 2-(4-fluorophenyl)-1,3,4-oxadiazole may be prepared as provided in Scheme 11A. In this case, 4-fluoro-phenyl-ethylformate is reacted with hydrazine hydrate to provide 4-fluorobenzohydrazide. This intermediate is then reacted with triethylorthoformate to provide 2-(4-fluorophenyl)-1,3,4-oxadiazole. 2-(4-Fluorophenyl)-1,3,4-oxadiazole may then be converted to a compound of formula (I-A) by the methods described herein.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:17].Cl.[NH2:19][CH2:20][CH2:21][O:22][NH2:23].N1C=CC=CC=1>>[ClH:17].[ClH:17].[NH2:19][CH2:20][CH2:21][O:22][N:23]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCCn1ccnc1)c1ccccc1
Reactant: NCCON
Agent: Cl
Solvent: c1ccncc1
Product: NCCON=C(CCCn1ccnc1)c1ccccc1
Reaction time: 8 h
Yield: 217.5 %

Procedure:
A mixture of 4-(1-(1H)-imidazolyl)-1-phenyl-1-butanone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.50 g), 3 equivalents of pyridine, and absolute ethanoI (75 ml) was heated under reflux, under nitrogen, with stirring, overnight. The reaction mixture was evaporated, toluene was added and evaporated. The residue was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was combined with 5.0 g of crude, previously prepared material and purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized from absolute ethanol to give 6.3 g (58%) of product, mp 196°-198° C. (dec).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)[CH2:13][CH2:12]1)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[BH4-].[Na+].B(F)(F)F.Cl>O1CCCC1>[CH2:1]([NH:8][CH2:9][C:11]1([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)C1(c2ccc(CO)cc2)CC1
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: C1CCOC1
Product: CCCCCCCNCC1(c2ccc(CO)cc2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirred solution of the mixture containing 1-(4-hydroxymethyl-phenyl)-cyclopropanecarboxylic acid heptylamide (Example 28, 1.0 g) in tetrahydrofuran (30 mL) under an nitrogen atmosphere cooled to 0° C. was added sodium borohydride (20.7 mmol, 783 mg) in one portion followed by the dropwise addition of boron trifluoride diethyletherate (27.6 mmol, 3.50 ml). The heterogeneous white mixture was allowed to stir at room temperature for 16 hours. The mixture was cooled to 0° C. and 2 M HCl was added until gas evolution ceased, then was heated to 80° C. for 45 minutes. The mixture was cooled to room temperature and concentrated under reduced pressure to a white solid. The solid was suspended in water (50 mL), then treated with 2 M NaOH in order to bring the pH to 14. The basic solution was extracted with diethyl ether (3×). The organic layers were washed with brine (2×), dried over anhydrous sodium sulfate, and concentrated to give impure [4-(1-heptylaminomethyl-cyclopropyl)-phenyl]-methanol as a clear oil. The crude oil was used in the preparation of heptyl-[1-(4-hydroxymethyl-phenyl)-cyclopropylmethyl]-carbamic acid tert-butyl ester without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([OH:18])[N:13]=[C:12]2[CH3:19])[CH:5]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:21][C:22]3[CH:29]=[CH:28][CH:27]=[C:24]([CH3:25])[CH:23]=3)[N:13]=[C:12]2[CH3:19])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(O)cc2=O)c1
Reactant: Cc1cccc(CBr)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)c3)cc2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
To a solution of Intermediate 2 (460 mg, 1.68 mmol) in N,N-dimethylformamide (2 mL) was added 3-methylbenzyl bromide (0.22 mL, 1.68 mmol), potassium carbonate (350 mg, 2.53 mmol) and 18-crown-6 (40 mg). The slurry was stirred at ambient temperature for one hour. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the alkylated product as a white semi-solid (138 mg, 22% yield). MS (M+H): 379