Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6](CN)=[CH:5][CH:4]=1)#[N:2].[C:11](=[O:14])([O-])[O-:12].[Na+].[Na+].Cl[O-].[Na+].NC(N)=O.S(=O)(=O)(O)O>O.O1CCOCC1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([C:11]([OH:12])=[O:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(CN)cc1
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 50 °C
Yield: 161.7 %

Procedure:
A mixture containing p-cyanobenzylamine (13.2 g), dioxane (70 g), sodium carbonate (5.3 g), water (50 g), and ferric nitrate (0.1 g) was stirred, and a 14 wt. % aqueous solution (200 g) of sodium hypochlorite was added dropwise thereto over three hours while inside temperature of a reactor was maintained at 50° C. or lower. The reaction mixture was further stirred for two hours. Subsequently, water (100 g) and urea (4 g) were added to the mixture, and the resultant mixture was further stirred for 20 minutes. The pH of the mixture was adjusted to four through addition of 98 wt. % sulfuric acid. Precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 11.9 g of p-cyanobenzoic acid (yield 90%, based on p-cyanobenzylamine). The p-cyanobenzoic acid obtained had a purity of 96%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][C:17]3[C:16]4[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:22])[C:3]=1[CH2:23][OH:24].C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([O:24][CH2:23][C:3]1[C:4]([N:8]2[CH2:19][CH2:18][C:17]3[C:16]4[CH2:15][C:14]([CH3:20])([CH3:21])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:22])=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:34])[CH3:33]
Reactant: CC1(C)Cc2sc3c(c2C1)CCN(c1nccc(Cl)c1CO)C3=O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OCc1c(Cl)ccnc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 330a (1.0 g, 2.76 mmol), triethylamine (610 mg, 6.0 mmol), and acetic anhydride (5 mL) was stirred at 25° C. for 2 h. Then the reaction mixture was quenched with water (10 mL) and the pH was adjusted to around 8 with NaHCO3 (aq.). The mixture was extracted with dichloromethane (2×15 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 1:1 ethyl acetate/petroleum ether to afford 330b as a pale yellow solid (1.0 g, 90%). MS-ESI: [M+H]+ 405.2
Reaction SMILES: [CH2:1]([S:5]([N:8]1[CH2:18][CH2:17][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3].[F:19][C:20]([F:31])([F:30])[CH:21]([C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1)[OH:22]>>[CH2:1]([S:5]([N:8]1[CH2:18][CH2:17][C:11]2([C:15](=[O:16])[N:14]([C:26]3[CH:27]=[CH:28][C:23]([CH:21]([OH:22])[C:20]([F:30])([F:31])[F:19])=[CH:24][CH:25]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)(=[O:6])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: OC(c1ccc(I)cc1)C(F)(F)F
Reactant: CC(C)CS(=O)(=O)N1CCC2(CCNC2=O)CC1
Product: CC(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(C(O)C(F)(F)F)cc3)C2=O)CC1

Procedure:
This material was prepared In analogy to example 162 B) from 8-(isobutylsulfonyl)-2,8-diazaspiro[4.5]decan-1-one and 2,2,2-trifluoro-1-(4-iodo-phenyl)-ethanol. White solid. MS (ESI): 449.17 MH+).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:16]=2[O:17][CH3:18])[CH:13]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[NH:12][CH:11]=[C:10]3[CH:28]=[O:29])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:16]=2[O:17][CH3:18])[C:13]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[N:12][CH:11]=[C:10]3[CH:28]=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cccc(CC2NC=C(C=O)c3cc(OC4CCCC4)c(OC)cc32)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1cccc(Cc2ncc(C=O)c3cc(OC4CCCC4)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.7 %

Procedure:
To a stirred solution of 6-cyclopentyloxy-7-methoxy-1-(3-methoxy-benzyl)-1,2-dihydro-isoquinoline-4-carbaldehyde (280 mg, 0.71 mmol) in chloroform (8 mL) was addend manganese (IV) oxide (728 mg, 7.12 mmol). The reaction mixture was stirred at room temperature for 15 hrs, filtered through a Celite® pad, and washed with chloroform. The filtrate was concentrated in vacuo to afford 6-cyclopentyloxy-7-methoxy-1-(3-methoxy-benzyl)-isoquinoline-4-carbaldehyde (280 mg, 99% yield). The crude product was without further purification.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[C:44]([C:52]([F:55])([F:54])[F:53])[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([O:38]CC)=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:56]=[CH:57][CH:58]=[CH:59][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:43]=[C:44]([C:52]([F:55])([F:53])[F:54])[CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:33][CH2:34]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:56]=[CH:57][CH:58]=[CH:59][C:6]=2[NH:5]1
Reactant: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.5 mg (0.06 mmol) LiOH in 1 mL water was added to a solution of 35 mg (0.04 mmol) of (R)-1-(3,5-bis-trifluoromethyl-benzyl)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 50) in 5 mL THF and the reaction solution was stirred overnight at RT. The mixture was evaporated down in vacuo, the residue was taken up in water, acidified with 1 N HCl, the precipitate was filtered off and dried in the vacuum drying cupboard.
Reaction SMILES: [CH2:1]([O:4][CH:5]([CH2:15][O:16][CH2:17][C:18]#[CH:19])[CH2:6][NH:7]C(=O)OC(C)(C)C)[C:2]#[CH:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:4][CH:5]([CH2:15][O:16][CH2:17][C:18]#[CH:19])[CH2:6][NH2:7])[C:2]#[CH:3]
Reactant: C#CCOCC(CNC(=O)OC(C)(C)C)OCC#C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CCOCC(CN)OCC#C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 2,3-bis(prop-2-ynyloxy)propylcarbamate (I-13a:1.583 g, 5.92 mmol) in CH2Cl2 (23.69 mL) at 0° C. was added TFA (4.56 mL, 59.2 mmol). The mixture was stirred at room temperature for 2 h. Concentrated, and put on pump for 16 h, giving 2,3-bis(prop-2-ynyloxy)propan-1-amine as a yellow oil used as is for next step. LC-MS (M+1) 168.1, t=0.44 minute.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[F:15][C:16]([F:42])([F:41])[S:17]([O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][NH:32]1)(=[O:19])=[O:18]>C(Cl)Cl>[F:42][C:16]([F:15])([F:41])[S:17]([O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][N:32]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Oc1ccc2ccccc2c1C1NCCc2ccccc21)C(F)(F)F
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: O=S(=O)(Oc1ccc2ccccc2c1C1=NCCc2ccccc21)C(F)(F)F
Reaction time: 0.33 h
Yield: 86.3 %

Procedure:
Powdered 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (46 mg, 0.2 mmol) was added to a solution of 2 (82 mg, 0.2 mmol) in CH2Cl2 (2 mL) at rt. After 20 minutes, the mixture was filtered through a short pad of silica gel using CH2Cl2 as the eluant. The solvent was evaporated and the residue was purified by column chromatography on silica gel (5:1 hexanes/EtOAc). The fractions containing the product (Rf=0.4) were collected and concentrated to yield the title product 3 (70 mg, 87% yield) as an oil. 1H NMR (CDCl3, 400 MHz, ppm): δ 8.02 (d, J=8.8 Hz, 1H), 7.95 (d, J=8.4, 1H), 7.71 (d, J=8.0, 1H), 7.58-7.26 (m, 5H), 7.11 (t, J=7.2 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 4.17-4.09 (m, 2H), 3.05-2.98 (m, 2H); 13C NMR (CDCl3, 100 MHz, ppm): δ 162.51, 144.46, 137.08, 132.42, 131.43, 130.95, 129.52, 129.14, 128.21, 127.83, 127.61, 121.14, 127.09, 126.88, 126.09, 119.95, 119.28, 116.77, 47.93, 25.57.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([NH2:13])[C:10]([NH2:14])=[C:9]([I:15])[CH:8]=2)=[C:5]([CH3:16])[O:4][N:3]=1.[C:17](C1NC=CN=1)(C1NC=CN=1)=[O:18]>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([I:15])[C:10]3[NH:14][C:17](=[O:18])[NH:13][C:11]=3[CH:12]=2)=[C:5]([CH3:16])[O:4][N:3]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Cc1noc(C)c1-c1cc(N)c(N)c(I)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(I)c2[nH]c(=O)[nH]c2c1
Yield: 72 %

Procedure:
5-(3,5-dimethylisoxazol-4-yl)-3-iodobenzene-1,2-diamine (253 g, 0.77 mol, 1.0 eq) was treated with carbonyl diimidazole (187 g, 1.15 mol, 1.5 eq) and DMAP (47 g, 384 mmol, 0.5 eq) in THF (2.5 L) at 80° C. for 16 h. The precipitate was obtained by filtration. The solid was triturated with EA/PE (1/1) to give 197 g of 6-(3,5-dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one as a white solid.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:5](/[C:18](/[CH3:31])=[CH:19]/[C:20]2[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=2)=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1>C(O)C>[Cl:3][C:4]1[C:5](/[C:18](/[CH3:31])=[CH:19]/[C:20]2[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:14])([CH3:15])[C:12]=2[CH:13]=1
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2cc3c(cc2Cl)C(C)(C)CCC3(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1cc2c(cc1Cl)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of potassium hydroxide in ethanol was added to 20 mg (0.049 mmol) of ethyl 4-[(E)-2-(3-chloro-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)propen-1-yl]benzoate (Compound 12) and the resulting mixture stirred at room temperature for 24 hours. Solvent was removed in-vacuo and the resulting solid taken-up in water, acidified using 1N HCl, and extracted three times with ether. The ether extracts were washed with water, brine and dried (MgSO4). The solvent was removed in-vacuo and recrystallized using acetonitrile to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[O:20][CH3:21])=[CH:11][S:10][C:9]=2/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:7][CH:6]=3)=[C:9](/[CH:22]=[CH:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])[S:10][CH:11]=2)=[C:14]([O:20][CH3:21])[CH:15]=1
Reactant: CCOC(=O)/C=C/c1scc(-c2ccc(Cl)cc2OC)c1-c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1scc(-c2ccc(Cl)cc2OC)c1-c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (E)-ethyl 3-(3-(4-aminophenyl)-4-(4-chloro-2-methoxyphenyl)thiophen-2-yl)acrylate (300 mg, 0.73 mmol) and TEA (75 mg, 0.73 mmol) in DCM (10 mL) was added MsCl (108 mg, 0.95 mmol), and the mixture was stirred at room temperature overnight. The reaction solution was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (E)-ethyl 3-(4-(4-chloro-2-methoxyphenyl)-3-(4-(methylsulfonamido) phenyl)thiophen-2-yl)acrylate, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C([O:12][C:13](=[O:41])[C:14]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[F:40])([CH3:32])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:25]2[CH2:29][NH:28][C:27](=[O:30])[N:26]2[CH3:31])=[CH:18][CH:17]=1)C.[H-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:28]2[CH2:29][CH:25]([CH2:24][CH2:23][O:22][C:19]3[CH:18]=[CH:17][C:16]([CH2:15][C:14]([O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[F:40])([CH3:32])[C:13]([OH:41])=[O:12])=[CH:21][CH:20]=3)[N:26]([CH3:31])[C:27]2=[O:30])=[CH:4][CH:3]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Product: CN1C(=O)N(Cc2ccc(Cl)cc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2F)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chlorobenzyl bromide (0.037 g, 0.179 mmol) and tetrabutyl ammonium iodide (catalytic amount) are added to a 0° C. suspension of 2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.053 g, 0.119 mmol) and sodium hydride (0.012 g, 0.298 mmol, 60% suspension on mineral oil), pre-stirred for 1 h at ambient temperature. The reaction mixture is stirred at ambient temperature for 18 h, diluted with ethyl acetate, and washed. The organic layer is dried, concentrated, and purified by LCMS to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.31-7.21 (m, 4H), 7.16 (d, 2H, J=8.3 Hz), 7.11-7.00 (m, 4H), 6.74 (d, 2H, J=8.3 Hz), 4.33, 4.31 (ABq, 2H, J=15.5 Hz), 3.96 (t, 2H, J=6.0 Hz), 3.71-3.64 (m, 1H), 3.39 (t, 1H, J=8.3 Hz), 3.29, 3.17 (ABq, 2H, J=14.3 Hz), 3.01 (t, 1H, J=8.3 Hz), 2.84 (s, 3H), 2.25-2.20 (m, 1H), 1.93-1.84 (m, 1H), 1.41 (s, 3H). MS [ES+] m/z exact mass calcd for C29H31N2O5 541.1906, found 541.1913.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[O:6]=[S:7]1(=[O:29])[C:12]2[CH:13]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=3)[CH:15]=[CH:16][C:11]=2[N:10]2[CH2:26][CH2:27][CH2:28][CH:9]2[NH:8]1>>[O:29]=[S:7]1(=[O:6])[C:12]2[CH:13]=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:1](=[O:3])[CH3:2])=[CH:20][CH:19]=3)[CH:15]=[CH:16][C:11]=2[N:10]2[CH2:26][CH2:27][CH2:28][CH:9]2[NH:8]1
Reactant: NCc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)NCc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1

Procedure:
The procedure is as in Example 2, replacing the methanesulphonic anhydride by acetyl chloride and using as starting material the amine obtained in Example 20.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.Br[CH2:21][C:22]1[C:30]2[O:29][C:28]([C:31]#[N:32])=[N:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OC(=O)C)C>[C:31]([C:28]1[O:29][C:30]2[C:22]([CH2:21][O:19][C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)=[CH:18][CH:17]=3)=[CH:23][CH:24]=[CH:25][C:26]=2[N:27]=1)#[N:32]
Reactant: N#Cc1nc2cccc(CBr)c2o1
Reactant: Oc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1nc2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1

Procedure:
1.0 g of 4-(2-quinolinylmethyloxy)phenol, .9 g of 7-bromomethyl-2-cyanobenzoxazole and 0.5 g of potassium carbonate are stirred at room temperature in 5 ml of dimethylformamide for 2 days. The reaction mixture is diluted with ethylacetate, filtered and concentrated. The residue is chromatographed on silica gel to give 2-cyano-7-(4-(quinolin-2-ylmethyloxy)phenoxymethyl)benzoxazole.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23]Cl>CN(C=O)C>[CH3:3][O:4][CH2:5][CH2:6][N:7]([CH2:23][O:22][CH2:21][CH2:20][Si:19]([CH3:26])([CH3:25])[CH3:18])[S:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: COCCNS(=O)(=O)c1ccc(I)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN(COCC[Si](C)(C)C)S(=O)(=O)c1ccc(I)cc1
Reaction time: 1 h
Yield: 103.5 %

Procedure:
Sodium hydride (2.2 g, 55 mmol), was added to a solution of N-(2-methoxyethyl)-4-iodobenzenesulphonamide (Method 4; 15.8 g, 46.3 mmol), in DMF (250 ml), under nitrogen at 0° C. and the mixture stirred for 1 hour. 2-Trimethylsilylethoxymethyl chloride (10 g, 60 mmol), was added and the mixture stirred overnight at ambient temperature. The volatiles were removed by evaporation and the residue dissolved in ether, washed with water and then brine, dried (Na2SO4), and the solvent evaporated to give the title compound (22.6 g, 74%). NMR: 0.2 (s, 9H), 0.89 (t, 2H), 3.30 (s, 3H), 3.40-3.36 (m, 2H), 3.59-3.43 (m, 2H), 4.82 (s, 2H), 7.60 (d, 2H), 7.84 (d, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[F:21][C:22]1[CH:23]=[C:24]([C:28]2[O:29][C:30]([CH3:35])=[C:31]([CH2:33]I)[N:32]=2)[CH:25]=[CH:26][CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([C:28]2[O:29][C:30]([CH3:35])=[C:31]([CH2:33][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:32]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Reactant: Cc1oc(-c2cccc(F)c2)nc1CI
Product: Cc1cccc(COC2CCCC(OCc3nc(-c4cccc(F)c4)oc3C)C2)c1C(=O)O

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3-fluorophenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 52 of molecular weight 453.52 (C26H28FNO5), MS(ESI): 454.35 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([N+:23]([O-])=O)([CH3:22])[CH3:21])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=[CH:6][CH:5]=1)([O-])=O.[N+](C1C=CC=CC=1)([O-])=O.CC(C)([N+]([O-])=O)CC1C=CC=CC=1.CC(C)=O>O1CCOCC1.[Ru]>[NH2:1][CH:4]1[CH2:5][CH2:6][CH:7]([C:10]([CH:13]2[CH2:14][CH2:15][CH:16]([CH2:19][C:20]([NH2:23])([CH3:22])[CH3:21])[CH2:17][CH2:18]2)([CH3:12])[CH3:11])[CH2:8][CH2:9]1
Reactant: CC(C)(c1ccc(CC(C)(C)[N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Ru]
Agent: CC(C)(Cc1ccccc1)[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CC(C)=O
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(C)(N)CC1CCC(C(C)(C)C2CCC(N)CC2)CC1
Yield: 84.3 %

Procedure:
Four grams of 2[ 4-nitrophenyl]-2-[4-(2-nitro-2-methylpropyl)phenyl]propane, prepared from the condensation reaction of nitrobenzene and 1,1-dimethyl-1-nitro-2-phenylethane with acetone, dissolved in 50 ml of dioxane, was hydrogenated at 150° C. and 1400 p.s.i.g. for 5 hours in the presence of 0.55 gram of 10% ruthenium on carbon. The reaction mixture was filtered, and the filtrate was fractionally distilled to produce 2.9 grams of 2[4-aminocyclohexyl]-2-[4-(2-amino-2-methylpropyl)cyclohexyl]propane (boiling point 98° C. at 0.55 mm Hg).
Reaction SMILES: [OH-].[Na+].CS(C)=O.[CH3:7][C:8]1([CH3:23])[O:13][C:12]2[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=2[C:10]2[CH2:19][CH2:20][CH2:21][CH2:22][C:9]1=2.[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>O>[CH3:7][C:8]1([CH3:23])[O:13][C:12]2[CH:14]=[C:15]([O:18][CH2:24][CH:26]3[CH2:27][O:28]3)[CH:16]=[CH:17][C:11]=2[C:10]2[CH2:19][CH2:20][CH2:21][CH2:22][C:9]1=2
Reactant: CC1(C)Oc2cc(O)ccc2C2=C1CCCC2
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)Oc2cc(OCC3CO3)ccc2C2=C1CCCC2

Procedure:
To a stirred solution of NaOH (4.0 g, 0.1 m) DMSO (250 ml) and water (250 ml) was added 7,8,9,10-tetrahydro-6,6-dimethyl-3-hydroxy-6H-dibenzo[b,d]pyran (21.3 g, 0.0926 m) and then epichlorohydrin (60 g, 0.648 m) and the mixture stirred for 5 hours, treated with water (1 L) and extracted with ether (3×500 ml). The combined extracts were dried over MgSO4 and evaporated to give 7,8,9,10-tetrahydro-6,6-dimethyl-3-(oxiranylmethoxy)-6H-dibenzo[b,d]pyran as a pale yellow oil, 23.2 g. This material was of sufficient purity to use as is for further chemical processing.
Reaction SMILES: CC(C(C)(C)C)=O.[C:8]([C:12]([CH:14]=[O:15])=O)([CH3:11])([CH3:10])[CH3:9].CC(=[N:19][OH:20])C>>[C:8]([C:12](=[N:19][OH:20])[CH:14]=[O:15])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)C(=O)C=O
Reactant: CC(C)=NO
Solvent: CC(=O)C(C)(C)C
Product: CC(C)(C)C(C=O)=NO

Procedure:
Yet another oxime intermediate is prepared from t-butyl methyl ketone, which is first transformed into t-butylglyoxal using the procedure of Fuson et al., J. Am. Chem. Soc. 61, 1938 (1939). The t-butylglyoxal, in aqueous solution at pH 4-5, is allowed to react with acetone oxime (commercially available) at about room temperature for about two days. The reaction product mixture is worked up by extracting it with ether, and the t-butylglyoxal oxime is isolated from the ether extract as colorless needles having a melting point of about 50°-52° C.
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[Cl:17].[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[Cl:17]
Reactant: COC(=O)c1cc(-c2c(Cl)cnn2C)c(Cl)o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1cc(C(=O)O)oc1Cl

Procedure:
A solution of methyl 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (224 mg, 0.82 mmol) in 6N sodium hydroxide (1.36 ml, 8.2 mmol) and tetrahydrofuran (5 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording the title compound (201 mg, 0.77 mmol, 94° A yield) as a yellow oil: LCMS (ES) m/e 262 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:25][C:11]1[C:12](=[O:17])[C:13]([CH3:15])([CH3:16])[O:14][C:10]=1[C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C2=CC(=O)C(C)(C)O2)cc1Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1Cl
Reaction time: 1 h
Yield: 37 %

Procedure:
To a stirred solution of afford 5-(3-chloro-4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (0.7 g, 2.77 mmol) in CHCl3 (10 mL), NBS (0.84 g, 4.72 mmol was added portionwise at RT. The reaction mixture was then stirred for 1 h. and diluted with DCM (20 mL). The combined organic layers were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-5-(3-chloro-4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (340 mg, 37%) as a thick syrup.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([O:6][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=1)=[O:5]
Reactant: CN(CC(=O)O)c1ccccc1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CC(=O)OCc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
The product from step 2 (220 mg, 1.3 mmol) was dissolved in DMF (7 mL) and Cs2CO3 (652 mg, 2.0 mmol) added, followed by 4-chlorobenzyl chloride (214 mg, 1.3 mmol). Allow reaction mixture to stir at ambient temperature over 18 hours. The reaction mixture was diluted with EtOAc and washed several times with brine. The organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound as a yellow oil (68%). MS (ES+) m/z 290 (MH+).