Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[S:24][C:25]([Cl:30])=[CH:26][C:27]=1[CH2:28]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCOC(C)=O.C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:28][C:27]5[CH:26]=[C:25]([Cl:30])[S:24][C:23]=5[Cl:22])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1cc(Cl)sc1Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cc(Cl)sc4Cl)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To a mixture of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (2,5-dichloro-3-thienyl)methanol (130 mg), tributylphosphine (0.264 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO4, and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc), followed by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound (39.9 mg) as an off-white solid.
Reaction SMILES: C(O[CH:5]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]([O:8][CH3:9])=[O:7])(=O)C.[CH2:18](Br)[CH:19]=[CH2:20].[Br-]>CN(C=O)C.[Zn]>[CH3:9][O:8][C:6](=[O:7])[CH:5]([NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:20][CH:19]=[CH2:18]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Reactant: C=CCBr
Agent: [Br-]
Agent: [Zn]
Solvent: CN(C)C=O
Product: C=CCC(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To an ice cooled suspension of the product of Example 2 (0.525 mg, 2.12 mmol) and zinc dust (278 mg, 4.25 mmol) in DMF (4 mL) under nitrogen was added slowly via syringe neat allyl bromide (514 mg, 4.25 mmol). The bromide was added at such a rate as to maintain the internal temperature between 20° and 25° C., then stirred at that temperature for an additional 1 hour. Extractive workup and silica gel chromatography as described in Example 3 afforded 486 mg (100%) of product as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=2)=[O:15])=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:36][C:33]1[CH:32]=[CH:31][C:30]([O:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]([O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:41][CH:40]=2)=[O:39])=[CH:35][CH:34]=1
Reactant: O=C(CCCCCOc1ccc([N+](=O)[O-])cc1)OCCOCCOC(=O)CCCCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(OCCCCCC(=O)OCCOCCOC(=O)CCCCCOc2ccc(N)cc2)cc1
Reaction time: 1.5 h
Yield: 55.8 %

Procedure:
6-(4-Nitrophenoxy)-hexanoic acid 2-{2-[6-(4-nitrophenoxy)-hexanoyloxy]-ethoxy}-ethyl ester (12 g) was dissolved in ethyl acetate (200 ml) in a pressure vessel. 5% Palladium on carbon (50% wet, 3 g) was added and the mixture was stirred under an atmosphere of hydrogen (5 Kg) for 1.5 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure to obtain the crude product which self crystallized over a period of time in the cold. The final product was slurried in diethyl ether, filtered and dried to give pure 6-(4-aminophenoxy)-hexanoic acid 2-{2-[6-(4-aminophenoxy)-hexanoyloxy]-ethoxy}-ethyl ester (6 g) as off-white powder. The final product was characterized by 1H NMR (CDCl3) δ 1.52 (m, 2H, CH2), 1.65 (m, 4H, 2×CH2), 2.37 (t, 2H, CH2), 3.20 (bs, 2H, NH2), 3.70 (t, 2H, CH2), 3.88 (t, 2H, CH2), 4.24 (t, 2H, CH2), 6.64 (d, 2H, Ar), 6.74 (d, 2H, Ar). The product has a melting point of 56-58° C.
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5](=O)[CH:6]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH:20]([CH3:34])[C:19]1=[O:35])[CH2:7][CH2:8][N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C@H:11]([OH:17])[CH2:10]1>CCO>[OH:17][C@@H:11]1[CH2:10][N:9]([CH2:8][CH2:7][CH:6]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)[CH:20]([CH3:34])[C:19]2=[O:35])[CH2:5][OH:4])[CH2:16][CH2:15][C:12]21[CH2:13][CH2:14]2
Reactant: COC(=O)C(CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2cccc(C(F)(F)F)c2)C(C)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1C(=O)N(C(CO)CCN2CCC3(CC3)[C@H](O)C2)CCN1c1cccc(C(F)(F)F)c1
Yield: 54.2 %

Procedure:
Sodium borohydride (63 mg, 1.7 mmol) was added at RT to a solution of 4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-2-[3-methyl-2-oxo-4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid methyl ester (example 54; 80 mg, 0.17 mmol) in EtOH (2 mL). The reaction mixture was heated at reflux for 2 h, then after cooling partitioned between CH2Cl2 and 10% aq. KHSO4 solution. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (IST Isolute® Flash NH2; EtOAc/MeOH 19:1) afforded the title compound (42 mg, 56%). Colorless oil, MS: 456.3 (M+H)+.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([N:85]2[CH2:90][CH2:89][N:88]([CH2:91][C@@H:92]([OH:94])[CH3:93])[CH2:87][CH2:86]2)[CH:50]=[CH:51][C:52]=1[C:53]1[CH:54]=[C:55]2[C:61]([C:62]3[CH:63]=[N:64][N:65]([CH2:67][C:68]4[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[CH:69]=4)[CH:66]=3)=[CH:60][N:59](S(C3C=CC(C)=CC=3)(=O)=O)[C:56]2=[N:57][CH:58]=1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([N:85]2[CH2:90][CH2:89][N:88]([CH2:91][C@@H:92]([OH:94])[CH3:93])[CH2:87][CH2:86]2)[CH:50]=[CH:51][C:52]=1[C:53]1[CH:54]=[C:55]2[C:61]([C:62]3[CH:63]=[N:64][N:65]([CH2:67][C:68]4[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[CH:69]=4)[CH:66]=3)=[CH:60][NH:59][C:56]2=[N:57][CH:58]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4F)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@H](O)CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)c(F)c2)CC1
Yield: 58.3 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(3-fluoro-4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)propan-2-ol (100 mg, 0.146 mmol) was hydrolyzed with lithium hydroxide (30 mg, 0.73 mmol) in THF/methanol/water (3/2/1 mL) to yield 45 mg (58.4% yield) of desired product. 1H NMR (CD3OD, 300 MHz): δ 8.39-8.36 (m, 2H), 8.15 (s, 1H), 7.914-7.912 (d, 1H), 7.67 (s, 1H), 7.59-7.50 (t, 1H), 7.42-4.30 (m, 1H), 7.11-6.92 (m, 5H), 5.42 (s, 2H), 4.30-4.20 (m, 1H), 4.00-3.60 (m, 4H), 3.27-3.13 (m, 4H), 1.27-1.25 (d, 3H). MS: m/z=529.3 (M+1), HPLC: 95.98% in method A.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([NH2:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([NH:19][C:29](=[O:31])[CH3:30])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@@H]1C[C@H](N)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](NC(C)=O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 57.9 %

Procedure:
A solution of 39 (0.06 g, 0.16 mmol), acetic anhydride (0.4 mL, 4.23 mmol) and a catalytic amount of DMAP in CH2Cl2 (30 mL) was stirred at room temperature for 2 h. The mixture was washed with 2N HCl (30 mL), 2N NaOH (30 mL), and H2O (30 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded a crude solid. The crude solid was purified by column chromatography (eluent: 4% MeOH/CH2Cl2) to afford 0.04 g (58%) of 40 as a white solid, mp 222-224° C. (EtOAc/n-hexanes).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])[C:5]([Cl:8])=[N:6][CH:7]=1.OI(C1C=CC=CC=1)OS(C1C=CC([N+]([O-])=O)=CC=1[N+]([O-])=O)(=O)=O.[C:44]([NH2:47])(=[O:46])[CH3:45]>C1COCC1.ClCCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:47]=[C:44]([CH3:45])[O:46][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C(Cc1cccc(Cl)c1Cl)c1cc(Br)cnc1Cl
Reactant: CC(N)=O
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)OI(O)c2ccccc2)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCCl
Product: Cc1nc(-c2cc(Br)cnc2Cl)c(-c2cccc(Cl)c2Cl)o1
Temperature: 25 °C
Yield: 24 %

Procedure:
To a solution of 1-(5-bromo-2-chloropyridin-3-yl)-2-(2,3-dichlorophenyl)ethanone (0.315 g, 0.83 mmol) in THF (3 mL) was added HDNIB (0.585 g, 1.2 mmol, [hydroxy(2,4-dinitrobenzenesulfonyloxy)iodo]benzene, see Lee et al., Synlett, 10: 1563-1564, 2001) in 1,2-dichloroethane (3 mL). The reaction mixture was heated to reflux in a sealed tube for 2 hours, at which point a solution formed. The reaction was cooled to RT and acetamide (2 eq., 0.115 g, 1.9 mmol) was added. The reaction was then heated to reflux for 18 hours. After cooling, the mixture was dissolved in MeOH, adsorbed onto Celite™ and purified by silica gel chromatography (5 to 40% EtOAc/hexanes) to give 5-bromo-2-chloro-3-(5-(2,3-dichlorophenyl)-2-methyloxazol-4-yl)pyridine as a colorless oil [0.084 g, 24% yield; LC-MS m/e=418.8 (M+H)].
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([C@@H:14]([NH:32][C:33]([C@@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][N:36]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:34])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([S:30][CH3:31])[CH:23]=2)=[CH:18][CH:17]=1)#[N:13]>C(Cl)Cl>[C:12]([C@@H:14]([NH:32][C:33]([C@@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][N:36]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:34])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([S:30]([CH3:31])=[O:6])[CH:23]=2)=[CH:18][CH:17]=1)#[N:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(-c2ccc(C[C@@H](C#N)NC(=O)[C@@H]3CCCCN3C(=O)OC(C)(C)C)cc2)ccc1C#N
Solvent: ClCCl
Product: CS(=O)c1cc(-c2ccc(C[C@@H](C#N)NC(=O)[C@@H]3CCCCN3C(=O)OC(C)(C)C)cc2)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
3-Chloroperoxybenzoic acid (0.137 g) was added to a solution of (S)-tert-butyl 2-((S)-1-cyano-2-(4′-cyano-3′-(methylthio)biphenyl-4-yl)ethylcarbamoyl)piperidine-1-carboxylate (0.140 g) in DCM (20 mL) at 0° C. and the mixture was stirred for 2 h then allowed to warm to RT. The mixture was washed with saturated sodium bicarbonate solution, sodium metabisulfite solution, water and brine then dried over sodium sulfate and evaporated. Purification by flash silica chromatography eluting with 30-50% ethyl acetate in isohexane afforded a colourless solid (0.08 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:4]2[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)n2nc(-c3ccco3)cc2n1
Solvent: C1COCCO1
Product: Clc1cc(N2CCOCC2)n2nc(-c3ccco3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
There was dissolved, in 1,4-dioxane (4 mL), 5,7-dichloro-2-furan-2-yl-pyrazolo[1,5-a]pyrimidine (167 mg, 0.657 mM), then morpholine (115 μL, 1.31 mM) was added to the solution and the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture, the resulting residue was diluted with water and then extracted with methylene chloride. The extract thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with methanol to thus give the title compound (186 mg, yield: 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[N:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][N:19]=4)=[C:11]3[C:10]([CH3:27])=[N:9]2)=[CH:5][CH:4]=1>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[N:19]=[CH:20][C:21]([NH2:24])=[CH:22][N:23]=4)=[C:11]3[C:10]([CH3:27])=[N:9]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ncc([N+](=O)[O-])cn4)ccnc32)cc1
Solvent: CCO
Product: COc1ccc(Cn2nc(C)c3c(Oc4ncc(N)cn4)ccnc32)cc1
Temperature: 70 °C

Procedure:
A 250 mL round-bottomed flask was charged with 1-(4-methoxybenzyl)-3-methyl-4-(5-nitropyrimidin-2-yloxy)-1H-pyrazolo[3,4-b]pyridine (0.420 g, 1.07 mmol), SnCl2 dihydrate (1.45 g, 6.42 mmol), and EtOH (100 mL). The reaction mixture was heated to 70° C. under nitrogen for 2 hours, then concentrated in vacuo. The residue was diluted with EtOAc, water, and brine. Aqueous saturated Na2CO3 was added until the pH was in the 9-10 range. The combined organic phases were dried (Na2SO4). The product was isolated by filtration and flash chromatography (EtOAc/MeOH 95:5) to afford 0.10 g (25%). LRMS M+1 (363.0) observed.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[NH:5][C:6](=[O:8])[CH:7]=1.[Br:13]N1C(=O)CCC1=O.S(=O)(O)[O-].[Na+]>C(#N)C>[Br:13][C:7]1[C:6](=[O:8])[NH:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(F)cc(=O)[nH]1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1cc(F)c(Br)c(=O)[nH]1

Procedure:
To a solution of methyl 4-fluoro-6-oxo-1,6-dihydropyridine-2-carboxylate (4, 1 g, 5.84 mmol) in acetonitrile (25 mL) is added N-bromosuccinimide (1.56 g, 8.76 mmol). The reaction is stirred at reflux for 2 h. The resulting mixture is pour into half saturated aqueous sodium bisulfite and extracted with ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and concentrated. The crude is purified via flash chromatography to afford methyl 5-bromo-4-fluoro-6-oxo-1,6-dihydropyridine-2-carboxylate (5).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH3:21])[CH2:16][CH2:15]2)=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]1([CH:31]=[CH:32][CH2:33][C:34](Cl)=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:15][CH2:16][C@H:17]([N:20]([CH3:21])[C:34](=[O:35])[CH2:33][CH:32]=[CH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:18][CH2:19]2)=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CC=Cc1ccccc1
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NC)CC1
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](N(C)C(=O)CC=Cc2ccccc2)CC1

Procedure:
from trans-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-N-methylcyclohexylamine and 4-phenyl-3-butenoylchloride. Colourless oil. Rf value: 0.5 (silica gel, petroleum ether/ethyl acetate=1:1, v:v).
Reaction SMILES: [H-].[Na+].[CH:3]1([O:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=2[O:31][CH3:32])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>CN(C)C=O>[CH3:33][N:34]([CH3:38])[C:35]([N:17]1[C:18]2[C:14](=[CH:13][C:12]([NH:11][C:9]([O:8][CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7]3)=[O:10])=[CH:20][CH:19]=2)[C:15]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=2[O:31][CH3:32])=[CH:16]1)=[O:36]
Reactant: COc1cc(C(=O)O)ccc1Cc1c[nH]c2ccc(NC(=O)OC3CCCC3)cc12
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)ccc1Cc1cn(C(=O)N(C)C)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.2 %

Procedure:
To a slurry of sodium hydride (60% by wt in mineral oil, 0.037 grams, 0.77 mmol) in dimethylformamide (5 mL), at 0° C., was added a solution of 4-[5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid (0.15 grams, 0.37 mmol) in dimethylformamide (5 mL). The resulting solution was stirred at 0° C. for 20 minutes, then dimethylcarbamoyl chloride (0.071 mL, 0.77 mmol) was added. The solution was warmed to room temperature and stirred for 1 hour. The reaction was quenched by addition of 1 M sodium hydroxide (aq), and the mixture was extracted with ethyl acetate. The combined organics were washed with 1 M hydrochloric acid (aq) and set aside. The aqueous phase was made acidic with 1 M hydrochloric acid (aq) and extracted with ethyl acetate. All the organics were combined and dried over magnesium sulfate and concentrated. Chromatography on silica gel (2% methanol/methylene chloride) gave 4-[1-(dimethylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid (0.16 grams, 89% yield).
Reaction SMILES: [CH:1]12[CH2:7][CH2:6][CH:5]1[CH2:4][C:3](=[O:8])[CH2:2]2.[NH2:9]OS(O)(=O)=O.[OH-].[Na+]>C(O)=O>[O:8]=[C:3]1[CH2:4][CH:5]2[CH:1]([CH2:7][CH2:6]2)[CH2:2][NH:9]1
Reactant: NOS(=O)(=O)O
Reactant: O=C1CC2CCC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: O=C1CC2CCC2CN1
Temperature: 0 °C
Yield: 8.8 %

Procedure:
To a solution of 0.48 g of bicyclo[3.2.0]heptan-3-one in 8 ml of formic acid was added 725 mg of hydroxylamine-O-sulfonic acid, followed by heat-refluxing for 3 hours. The reaction mixture was allowed to cool, poured into ice water, neutralized with a 5N sodium hydroxide aqueous solution, and extracted with chloroform. The organic layer was washed, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 48 mg of the title compound as a brown solid, which had the following physical properties.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([CH2:15]OC)[O:12][C:9]2=[N:10][CH:11]=1)=O)C.O1[C:22]2=[N:23][CH:24]=C(CCCNC)C=[C:21]2C=C1>>[CH3:24][NH:23][CH2:22][CH2:21][CH2:4][C:6]1[CH:7]=[C:8]2[CH:14]=[C:13]([CH3:15])[O:12][C:9]2=[N:10][CH:11]=1
Reactant: CNCCCc1cnc2occc2c1
Reactant: CCOC(=O)c1cnc2oc(COC)cc2c1
Product: CNCCCc1cnc2oc(C)cc2c1

Procedure:
Prepared from 2-methoxymethyl-furo[2,3-b]pyridine-5-carboxylic acid ethyl ester in analogy to the methods described for (3-furo[2,3-b]pyridin-5-yl-propyl)methyl-amine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=O)[NH:13][N:14]=2)=[CH:5][CH:4]=1)#[N:2].P(Cl)(Cl)([Cl:18])=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([Cl:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccc(-c2ccc(=O)[nH]n2)cc1
Product: N#Cc1ccc(-c2ccc(Cl)nn2)cc1

Procedure:
A 3.42 g. portion of 6-(p-cyanophenyl)-3(2H)-pyridazinone in 25 ml. of phosphorus oxychloride is stirred and heated at reflux temperature for 3 hours. Most of the excess phosphorus oxychloride is removed under reduced pressure. Cracked ice-water is added to the concentrate which is stirred until the excess phosphorus oxychloride hydrolyzes. The solid is collected by filtration, dried and recrystallized from dimethylformamide-water, yielding 6-(p-cyanophenyl)-3-chloropyridazine, m.p. 236°-238° C.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](C(Cl)=O)=[CH:3][CH:2]=1.[C:11]([C:15]1[CH:30]=[CH:29][C:18]([C:19]([NH:21][C:22]2[C:23]([NH2:28])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:20])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([NH:28][C:23]2[C:22]([NH:21][C:19](=[O:20])[C:18]3[CH:29]=[CH:30][C:15]([C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:16][CH:17]=3)=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(Nc2ccccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 108 %

Procedure:
Using the procedure described in Example 93, Part A, 4-toluoyl chloride (1.1 mmol) and N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (0.93 mmol) yielded 360 mg (100%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH:14]([C:22]1([CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:23]1=[O:34])[C:15]([O:17]C(C)(C)C)=[O:16].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH:14]([C:22]1([CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:23]1=[O:34])[C:15]([OH:17])=[O:16]
Reactant: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)O)CCN(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cold (0° C.) solution of tert-butyl α-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3-pyrrolidineacetate (500 mg, 0.964 mmol) in CH2Cl2 (2 ml) is treated with TFA (2 mL) and maintained at 0° C. for 1 hour, and then at room temperature for 1 hour. The solvent is removed in vacuo to give a quantitative yield of α-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3-pyrrolidineacetic acid as a gelatinous solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].O.[F:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[C:25]([F:27])[CH:26]=1>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8]([C:23]1[CH:22]=[C:21]([F:20])[CH:26]=[C:25]([F:27])[CH:24]=1)=[O:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (3.0 g) in tetrahydrofuran (70 mL), 3,5-difluorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 25.7 mL) was added dropwise at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 3.0 g of the title compound as a pale yellow oil. The property values of the compound are as follows.