Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[CH:11][C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH:24]=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[C:13]([C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH2:24][C:23]3[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:22]=3[CH3:21])=[CH:7][CH:6]=2)[N:9]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=1)#[N:14]
Reactant: Cc1cccc(C)c1C=O
Reactant: N#Cc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccc(C)c1CNc1ccc(-n2nc(-c3cccnc3)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
To a stirred solution of 1-(4-aminophenyl)-3-(3-pyridyl)-5-cyanopyrazole (130 mg, 0.5 mmol) and 2,6-dimethylbenzaldehyde (0.9 g) in acetic acid (2 mL) and MeOH (5 mL) at room temperature was added sodium cyanoborohydride (79 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 18 hr and then concentrated under a stream of nitrogen, diluted with water, extracted into ethyl acetate, washed with sodium bicarbonate solution, water and dried (MgSO4). The residue obtained on concentration was flash chromatographed on silica gel (elution with a gradient of 15-25% EtOAc in CH2Cl2) providing the title compound (142 mg, 75%). NMR (CDCl3, 400 MHz): 9.1 (s, 1H); 8.7 (br, 1H); 8.3 (d, 1H); 7.6 (d, 2H), 7.5 (m, 1H), 7.35 (s, 1H); 7.2 (m, 1H), 7.1 (overlapping m, 2H), 6.8 (d, 2H), 4.3 (s, 2H), 2.4 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:9](=O)[CH2:10][CH:11](O)[C:12](OCC)=[O:13])=[CH:4][CH:3]=1.O.[NH2:27][NH2:28]>C(O)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:9]2[CH:10]=[CH:11][C:12](=[O:13])[NH:27][N:28]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)CC(=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: O=c1ccc(C(c2ccc(F)cc2)c2ccc(F)cc2)n[nH]1
Temperature: 130 °C
Reaction time: 12 h
Yield: 50.5 %

Procedure:
To a solution of ethyl 5,5-bis(4-fluorophenyl)-2-hydroxy-4-oxopentanoate (796 mg) in 1-butanol (4 mL) was added hydrazine hydrate (137 mg) at ambient temperature. The reaction mixture was stirred at 130° C. for 12 hours. After cooling to ambient temperature, the reaction mixture was evaporated in vacuo. The resulting residue was stirred at 160° C. for 3 hours. After cooling, the reaction mixture was purified by silica gel column chromatography (EtOAc:n-hexane=2:1) and crystallized from solvent (EtOAc:n-hexane=1:2) to give 6-[bis(4-fluorophenyl)methyl]pyridazin-3(2H)-one (344 mg) as a pale brown solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N1CCC(C(=O)O)CC1
Temperature: 34 °C
Yield: 99.3 %

Procedure:
Crude ethyl 1-isopropylpiperidine-4-carboxylate (63.39 g, 318.0 mmol) was dissolved in ethanol (500 mL), and NaOH (25.3 g, 632 mmol) was add d. The solution was heated to reflux for 15.75 h at which point it was allowed to cool to 34° C. A solution of ethanolic HCl (220 mL, 2.9 M solution) was added rapidly which caused a mild exotherm and immediate precipitation. The resulting NaCl was filtered using a fritted funnel, and the cloudy filtrate was refiltered through diatomaceous earth. The filtrate was concentrated and dissolved in 50% EtOAc/EtOH (600 mL) and heated on a steam bath. The insoluble material was removed by a filtration through diatomaceous earth, and the resulting filtrate was concentrated to a solid which was dried in a 50° C. vacuum oven to yield 54.09 g of yellow solid (corrected for 0.2 wt % EtOH by 1H-NMR analysis) which is a 99% yield over two steps. No further purification was attempted:
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[C@:9]12([C:15]3[O:19][N:18]=[C:17]([CH3:20])[N:16]=3)[CH2:14][C@H:13]1[CH2:12][NH:11][CH2:10]2>CO>[C:9]12([C:15]3[O:19][N:18]=[C:17]([CH3:20])[N:16]=3)[CH2:14][CH:13]1[CH2:12][NH:11][CH2:10]2
Reactant: Cc1noc([C@@]23CNC[C@@H]2C3)n1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1noc(C23CNCC2C3)n1

Procedure:
The combined mother liquors were evaporated and the salt was free-based in dichloromethane as described above for 106b prior to adding L-tartaric acid (400 mg, 2.66 mmol) in 20 mL of methanol. The exact recrystallization procedure was repeated as described above; obtained 168 mg of 5-((1R,5R)-3-azabicyclo[3.1.0]hexan-1-yl)-3-methyl-1,2,4-oxadiazole (106a). The optical purity (99.5%) was determined by HPLC analysis (Chiral Technologies Chiral-AGP, 4.0 mm×150 mm, 0.5% methanol, 20 mM sodium phosphate pH=7). (106a) MS (ESI) m/z 165.8 [M+H]+. 1H NMR (DMSO-d6) δ: 1.44 (m, 2H), 2.23 (m, 1H), 2.28 (s, 3H), 3.06 (s, 2H), 3.35 (m, 2.H), 4.13 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH2:9]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH2:10][C:11]#[CH:12]>>[CH3:8][C:4]1[N:3]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(Br)n1
Reactant: C#CCCc1ccc2ccccc2n1
Product: Cc1cccc(C#CCCc2ccc3ccccc3n2)n1
Reaction time: 0.25 h
Yield: 29.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-methyl-pyridine (209 mg, 1.21 mmol) and 2-but-3-ynyl-quinoline (220 mg, 1.21 mmol Example 118(B)). Microwave conditions: 120° C. for 15 minutes. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 1:1) to yield 98 mg (0.36 mmol, 30%) of 2-(4-(6-methylpyridin-2-yl)but-3-ynyl)quinoline as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=O.[NH2:8][C:9]([NH2:11])=[S:10]>>[CH:5]1([C:3]2[N:8]=[C:9]([NH2:11])[S:10][CH:2]=2)[CH2:7][CH2:6]1
Reactant: NC(N)=S
Reactant: O=C(CBr)C1CC1
Product: Nc1nc(C2CC2)cs1

Procedure:
A mixture of 2-bromo-1-cyclopropyl-ethanone (0.50 g, 3.0 mmol, Waterstone Technology) and thiourea (0.23 g, 3.1 mmol) were processed as in Example 71A to afford the title compound. MS (DCI/NH3) m/z 141 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:4]=1[O:5][C:6]1[CH:7]=[CH:8][C:9]([F:26])=[C:10]([NH:12][C:13](=[O:25])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:11]=1)#[N:2].O1CCCC1>C(O)C.[C].[Pd]>[NH2:31][C:29]1[CH:28]=[CH:27][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]([F:26])=[C:10]([NH:12][C:13](=[O:25])[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=3)[CH:11]=2)=[C:3]([C:1]#[N:2])[CH:30]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(F)c(NC(=O)Cc2cccc(C(F)(F)F)c2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cc(N)ccc1Oc1ccc(F)c(NC(=O)Cc2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.1 %

Procedure:
To a solution of N-[5-(2-cyano-4-nitrophenoxy)-2-fluorophenyl]-2-[3-(trifluoromethyl)phenyl]acetamide (1.36 g, 2.96 mmol) in ethanol (25 mL)/tetrahydrofuran (10 mL) was added 10% palladium-carbon (160 mg), and the mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere (1 atm). Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=30/70→100/0), and the fraction containing the object product was concentrated under reduced pressure to give the title compound (1.17 g, 92%) as a beige amorphous form.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]3[CH:36]=[CH:37][CH:38]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:38]1[CH:37]=[CH:36][N:28]2[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[F:1])=[CH:40][CH:39]=3)=[O:24])[CH2:26][C:27]=12
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1F
Reaction time: 0.05 h
Yield: 88.4 %

Procedure:
To a solution of 314 mg of 2-fluorobenzoyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in methylene chloride, washed with water, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried with Na2SO4, filtered and concentrated in vacuo to give 620 mg of the desired product as a crystalline solid, m.p. 257°-260° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH3:30][C:31]1([OH:39])[CH2:34][N:33]([CH:35]2[CH2:38][NH:37][CH2:36]2)[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:37]4[CH2:38][CH:35]([N:33]5[CH2:34][C:31]([CH3:30])([OH:39])[CH2:32]5)[CH2:36]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC1(O)CN(C2CNC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CC(C)(O)C4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.092 g, 0.234 mmol), 3-methyl-[1,3′]biazetidinyl-3-ol (0.040 g, 0.28 mmol) and 4 Å molecular sieves (0.25 g) in DCE (3 mL). The reaction mixture was stirred for 90 min at room temperature. Sodium triacetoxyborohydride (0.099 g, 0.47 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give 587 as a white solid (0.107 g, 89%). LCMS (Method I): RT=2.33 min, [M+H]+ 518.2 1H NMR (300 MHz, DMSO-d6): δ 8.03-7.99 (m, 1 H), 7.65-7.61 (m, 1 H), 7.27-7.22 (m, 2 H), 4.49-3.95 (m, 4 H), 3.84 (s, 2 H), 3.80-3.74 (m, 4 H),3.36-3.31 (s, 3 H), 3.31-3.20 (m, 6 H), 3.11-3.01 (m, 4 H), 2.98-2.93 (m, 2 H), 1.34 (m, 5 H)
Reaction SMILES: C(C[C:4]([CH2:10]C)(Br)[P:5]([O-:8])(=[O:7])[O-:6])C.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21]>O>[OH2:6].[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:10][CH2:4][P:5]([OH:6])(=[O:7])[OH:8]
Reactant: NCCCCCCCCN
Reactant: CCCC(Br)(CC)P(=O)([O-])[O-]
Solvent: O
Product: NCCCCCCCCNCCP(=O)(O)O

Procedure:
Diethylbromoethanephosphonate (15.3 g, 0.062 moles) and 1.8-diaminooctane (54.0 g, 0.375 moles) were heated under reflux in water (250 cm3) for 5 hours. The water and excess diamine were then distilled off. Concentrated hydrochloric acid (280 cm3) was added and the solution heated under reflux for 8 hours. The solution was then evaporated to dryness on a rotary evaporator and the residue was dissolved in methanol (75 cm3) and propylene oxide wad added to pH 6. The phosphonic acid was filtered off and dried. The crude yield was 10.2 g (60.5%). A sample was purified by recrystallization from water/ethanol to give N-(8-aminooctyl)-2-aminoethanephosphonic acid monohydrate as a fine white crystalline solid having a melting point of 210° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:30])[C@H:17]([N:27]=[C:28]=[O:29])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31]([NH2:33])[CH3:32]>ClCCl>[CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:30])[C@H:17]([NH:27][C:28]([NH:33][CH2:31][CH3:32])=[O:29])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN
Reactant: COc1ccc(C[C@@H](N=C=O)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Product: CCNC(=O)N[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 42 %

Procedure:
1-[2-(R)-Isocyanato-3-(4-methoxyphenyl)-propionyl]-pyrrolidine-2-(S)-carboxylic acid benzyl ester (0.60 g) was dissolved under nitrogene in 20 mL of dichloromethane and ethyl amine was allowed to pass through at-20° C. for 5 minutes. The mixture was kept stirring for 16 h. The volatiles were pumped off and the remaining residue was purified by silica chromatography (dichloromethane/methanol 80/20) to give 0.29 g (42%) of the title compound as a colorless oil. (+)-APCI-MS: 454(MH−).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C@:7]1([CH2:40][CH:41]=[O:42])[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C@@H:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:9]([C@@H:27]([CH2:37][CH3:38])[CH2:28][N:29]([CH3:36])[S:30]([CH:33]2[CH2:35][CH2:34]2)(=[O:32])=[O:31])[C:8]1=[O:39])(=[O:4])=[O:3].OOS([O-])=O.[K+].[CH3:49][OH:50]>C(Cl)Cl.O>[Cl:19][C:15]1[CH:14]=[C:13]([C@@H:11]2[C@@H:10]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[N:9]([C@@H:27]([CH2:37][CH3:38])[CH2:28][N:29]([CH3:36])[S:30]([CH:33]3[CH2:34][CH2:35]3)(=[O:32])=[O:31])[C:8](=[O:39])[C@:7]([CH2:40][C:41]([O:50][CH3:49])=[O:42])([CH2:6][O:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12]2)[CH:18]=[CH:17][CH:16]=1
Reactant: CO
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@](CC=O)(COS(C)(=O)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](COS(C)(=O)=O)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A solution of ((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxo-3-(2-oxoethyl)piperidin-3-yl)methyl methanesulfonate (Example 414, Step F, 1.0 g, 1.516 mmol) in MeOH was treated with Oxone (0.932 g, 1.516 mmol) over a weekend. The reaction mixture was diluted with DCM and water. The organic extract was washed with satd NaCl and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a white solid. The product was purified by chromatography through a RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to provide the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[C:17](=[O:18])[NH:16][C:15]4[CH:19]=[C:20]([CH2:23][CH2:24][O:25][C:26]5[CH:31]=[CH:30][C:29]([N:32]6[CH2:37][CH2:36][O:35][CH2:34][CH2:33]6)=[CH:28][CH:27]=5)[CH:21]=[CH:22][C:14]=4[NH:13][C:12]=3[CH:38]=2)=[CH:4][C:3]=1[O:39][CH3:40].Br[CH2:42][CH2:43][CH2:44][N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].[OH-].[K+]>C(OCC)(=O)C>[CH3:40][O:39][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[C:17](=[O:18])[NH:16][C:15]4[CH:19]=[C:20]([CH2:23][CH2:24][O:25][C:26]5[CH:31]=[CH:30][C:29]([N:32]6[CH2:33][CH2:34][O:35][CH2:36][CH2:37]6)=[CH:28][CH:27]=5)[CH:21]=[CH:22][C:14]=4[NH:13][C:12]=3[CH:38]=2)[CH:6]=[CH:7][C:2]=1[O:1][CH2:42][CH2:43][CH2:44][N:45]1[C:49](=[O:50])[C:48]2[C:47](=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:46]1=[O:55]
Reactant: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)ccc1O
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)ccc1OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of Example 474 (26.9 mg, 0.05 mmol) and N-(3-bromopropyl)phthalimide (16.1 mg, 0.06 mmol) was treated with KOH (3.4 mg, 0.06 mmol) and stirred at room temperature for 5 hours. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by silica gel column chromatography (0 to 60% ethyl acetate in dichloromethane) to give the title compound. MS (ESI) m/e 725 (M+H)+; 1H NMR (300 MHz, DMSO-d.6 □ 9.76 (s, 1H), 7.70-7.88 (m, 5H), 7.71 (d, J=8.1 Hz, 1H), 7.23 (d, J=1.7 Hz, 1H), 7.10-7.16 (m, 3H), 7.00 (d, J=8.5 Hz, 1H), 6.80-6.95 (m, 7H), 3.99-4.08 (m, 4H), 3.78 (t, J=6.4 Hz, 2H), 3.69-3.73 (m, 4H), 3.62 (s, 3H), 2.95-2.98 (m, 4H), 2.86 (t, J=6.8 Hz, 2H), 2.06-2.12 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)=[C:6]([O:20][CH3:21])[CH:5]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH3:21][O:20][C:6]1[CH:5]=[C:4]([CH2:3][CH:2]=[O:1])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:11]=[CH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ccc(CCO)cc2OC)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(CC=O)cc2OC)cc1
Reaction time: 1.5 h

Procedure:
A solution of Example 491B (2.47 g, 8.63 mmol) in dichloromethane (25 mL) at room temperature was treated with Dess-Martin periodinane (4.03 g, 9.49 mmol), stirred for 90 minutes, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 1:1 ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1.[CH2:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]2[C:9](=[CH:8][CH:7]=1)[CH2:12][C:13](=[O:14])[CH2:16][CH:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: C=Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1Cc2ccc(Cl)cc2C(c2ccccc2)C1
Temperature: 25 °C

Procedure:
8.00 g (0.06 mol) of aluminum chloride are suspended in 600 ml of methylene chloride, treated at 0° with 7.56 g (0.04 mol) of 4-chlorophenylacetyl chloride in 250 ml of methylene chloride and a solution of 4.17 g (0.04 mol) of styrene in 400 ml of methylene chloride is added dropwise thereto at -40° to -50°. After warming to room temperature, the mixture is poured on to ice, extracted with methylene chloride, dried with magnesium sulfate, filtered over Dicalit and the solvent is distilled in a vacuum. Chromatography on silica gel with ethyl acetate-hexane (1:4) and recrystallization from ether/hexane gives 6-chloro-3,4-dihydro-4-phenyl-2(1H)-naphthalenone as beige crystals with melting point 61°-62°.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:25]1[N:30]=[C:29]([CH3:31])[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][CH:26]=1>>[CH3:31][C:29]1[N:30]=[C:25]([N:20]2[CH2:21][CH2:22][CH2:23][C@H:18]([NH:17][C@@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]3[NH:10][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])[CH2:19]2)[CH:26]=[CH:27][C:28]=1[N+:32]([O-:34])=[O:33]
Reactant: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1NC1CCCNC1
Reactant: Cc1nc(F)ccc1[N+](=O)[O-]
Product: Cc1nc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)Nc3ccccc3)C2)ccc1[N+](=O)[O-]

Procedure:
1-((1R,2R)-2-((S)-1-(6-Methyl-5-nitropyridin-2-yl)piperidin-3-ylamino)cyclohexyl)-3-phenylurea was synthesized using 1-phenyl-3-((1R,2R)-2-(piperidin-3-ylamino)cyclohexyl)urea (from intermediate C, Example 1) (100 mg, 0.32 mmol) and 6-fluoro-2-methyl-3-nitropyridine (54.3 mg, 0.35 mmol) according to General Procedure A to give 20 mg (14%) of yellow solid. Anal. Calcd. for C24H32N6O3 m/z 452.2, found: 453.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J=9.4 Hz, 1H), 7.17 (m, 4H), 6.98 (m, 1H), 6.59 (d, J=9.4 Hz, 1H), 6.02 (d, J=4.6 Hz, 1H), 4.74 (m, 1H), 4.16 (m, 1H), 3.68 (m, 1H), 3.54 (m, 2H), 3.26 (m, 2H), 2.57 (s, 3H), 2.39 (m, 1H), 2.12 (m, 3H), 1.92 (m, 4H), 1.47 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[N:6]=1.[C:13]([CH:17]=[C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](=O)[CH3:28])=[CH:22][CH:21]=1)[CH3:19])([O:15][CH3:16])=[O:14]>>[C:13]([CH:17]=[C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([N:9]2[CH2:10][CH2:11][O:12][CH:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)[CH2:8]2)[CH3:28])=[CH:22][CH:21]=1)[CH3:19])([O:15][CH3:16])=[O:14]
Reactant: Cc1nc(C2CNCCO2)cs1
Reactant: COC(=O)C=C(C)c1ccc(CC(C)=O)cc1
Product: COC(=O)C=C(C)c1ccc(CC(C)N2CCOC(c3csc(C)n3)C2)cc1

Procedure:
Prepared analogously to Example 13 by reaction of 2-(2-methyl-thiazol-4-yl)morpholine with 1-[4-(2-carbomethoxy-1-methyl-ethenyl)phenyl]propan-2-one followed by purification of the base on a silica gel column using chloroform/methanol/ammonia =9:1:0.1 as eluant.
Reaction SMILES: [Cl:1][C:2]([Cl:16])([Cl:15])[CH2:3][O:4][C:5](=[O:14])[NH:6][C@H:7]1[C@@H:11]([O:12][NH2:13])[CH2:10][CH:9]=[CH:8]1.[C:17]([O:21][C:22](ON=C(C1C=CC=CC=1)C#N)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCCC1>[Cl:1][C:2]([Cl:15])([Cl:16])[CH2:3][O:4][C:5](=[O:14])[NH:6][C@H:7]1[C@@H:11]([O:12][NH:13][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:10][CH:9]=[CH:8]1
Reactant: NO[C@H]1CC=C[C@H]1NC(=O)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NO[C@H]1CC=C[C@H]1NC(=O)OCC(Cl)(Cl)Cl

Procedure:
An 7.8 g. quantity of crude (1R,5S)-2,2,2-trichloroethyl-5-(aminooxy)-2-cyclopentene-1-carbamate is dissolved in 25 ml. of tetrahydrofuran and 6.15 g (25 mm) of 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile and the mixture stirred for 22 hours at room temperature, 20 hours at 50° C., 72 hours at room temperature and then evaporated in vacuo. The residue is chromatographed over 900 g. of silica gel eluted with (15-85) ethylacetate-toluene. Three hundred ml. fractions are collected. The product is found in fractions 10-12. Evaporation and recrystallization of the residue from Skellysolve B yields (1R,5S)-2,2,2-trichloroethyl-5-[[[(t-butyloxy)carbonyl]amino]oxy]-2-cyclopentene-1-carbamate m.p. 83°-84° C. as a white solid.