Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(O)[CH:11]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]([CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:11][CH2:12][Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(O)(COCc1ccccc1)COCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCC=C(COCc1ccccc1)COCc1ccccc1
Reaction time: 0.5 h

Procedure:
Crude 1-benzyloxy-2-benzyloxymethylbut-3-en-2-ol (1.42 g, 3.16 mmol) in 10 ml of CH2Cl2 was added to 0.71 g thionyl chloride (6 mmol) and 2 drops of DMF in 10 ml of CH2Cl2, and the solution was stirred for 0.5 h and evaporated in vacuum. Toluene was added and the mixture was evaporated in vacuum to yield crude 1-benzyloxy-2-benzyloxymethyl-4-chlorobut-2-ene.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccc(C(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-4-tert-butylbenzene (0.62 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.86 g, 61%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9](=[O:22])[NH:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCC[C@@H]3C)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCC[C@@H]3C)nc2c1
Temperature: 0 °C

Procedure:
To a solution of (S)-methyl 3-(2-methylpiperidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (165 mg, 0.55 mmol) in dichloromethane (40 mL) was added pyridine (231 mg, 2.92 mmol) followed by the addition of Tf2O (412 mg, 1.46 mmol) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature and then washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford (S)-methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (240 mg, crude).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4](I)[CH:3]=1.C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>COCCOC.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:3]=1
Reactant: COC(=O)Cc1ccc(F)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: COC(=O)Cc1ccc(F)cc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of ester 325 (3.80 g, 12.9 mmol) in dry DME (100 mL) at 0° C. was added triethylamine (4.5 mL, 3.3 g, 33 mmol), copper (I) iodide (0.50 g, 2.6 mmol), and bis(triphenylphosphine) palladium (II) chloride (0.38 g, 0.54 mmol). The mixture was degassed with a stream of N2 for 5 min, then trimethylsilylacetylene (4.0 mL, 2.8 g, 29 mmol) was added and the reaction mixture was warmed to room temperature and stirred for 3 h. It was then concentrated under reduced pressure, re-dissolved in ether, filtered and concentrated. Silica gel chromatography of the residue (eluent 10% ethyl acetate/hexanes) afforded 326 (3.30 g, 97% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.23 (dd, J=8.6, 5.7 Hz, 1H); 7.14 (dd, J=9.0, 2.7 Hz, 1H); 7.00 (dt, J=8.4, 2.7 Hz, 1H); 3.79 (s, 2H); 3.70 (s, 3H); 0.25 (s, 9H). LCMS: (M+H) 265.2.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[O-]S([O-])(=O)=O.[Na+].[Na+].[CH:17](OC)([O:20][CH3:21])[O:18]C.[CH3:24][C:25]1[CH:26]=[CH:27][C:28](S(O)(=O)=O)=[CH:29][CH:30]=1>C1(C)C=CC=CC=1.CO>[C:17]1([C:26]2[C:25](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:21][O:20]1)=[O:18]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(OC)OC
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=c1occc2ccccc12
Temperature: 25 °C

Procedure:
To a stirred solution of the isocaumarin from step 3 above (9.4 mg, 0.4 mmol) in 8 ml of toluene was added dropwise a solution of DIBAL-H (1M, 0.50 ml, 0.50 mmol) at -78° C. under argon. The resulting mixture was stirred at -78° C. for 1.5 hour before Na2SO4 10 H2O (100 mg, 0.31 mmol). After the reaction was warmed to room temperature, it was filtered to remove the solids, and washed with acetone. The filtrate was evaporated to give an oily residue which contained the corresponding lactol. Without further purification, the residue was treated with 5 ml of CH3OH, 1 ml of CH(OMe)3, and PTSA (30 mg, 0.16 mmol) at room temperature for 10 minutes. The solvents were removed by rotavapor and the residue was purified by flash chromatography with hexane and ethyl acetate (7:3) to give pure title isocoumarin (65 mg, 0.26 mmol) in 65% overall yield. 1H NMR (CDCl3) δ:2.47 (1H, dd, J=17.2, 12.0 Hz), 2.85 (1H, dd, J=17.2, 3.6 Hz), 3.56 (3H, s), 3.78 (3H, s), 3.82 (3H, s), 4.63 (1H, m), 5.24 (1H, dt, J=10.6, 1.4 Hz), 5.43 (1H, dt, J=17.3, 1.4 Hz), 5.63 (1H, s), 6.05 (1H, m), 6.70 (1H, d, J=8.9 Hz), 6.76 (1H, d, J=8.9 Hz).
Reaction SMILES: [CH2:1]([N:4](P(OCC)(OCC)=O)[CH2:5][CH2:6][CH2:7][N:8](P(OCC)(OCC)=O)[CH2:9]/[CH:10]=[CH:11]/[CH2:12][N:13](P(OCC)(OCC)=O)[CH2:14][CH2:15][CH2:16][N:17]([CH2:26][CH:27]=[CH2:28])P(OCC)(OCC)=O)[CH:2]=[CH2:3].[ClH:53]>>[ClH:53].[ClH:53].[ClH:53].[ClH:53].[CH2:26]([NH:17][CH2:16][CH2:15][CH2:14][NH:13][CH2:12]/[CH:11]=[CH:10]/[CH2:9][NH:8][CH2:7][CH2:6][CH2:5][NH:4][CH2:1][CH:2]=[CH2:3])[CH:27]=[CH2:28]
Reactant: C=CCN(CCCN(C/C=C/CN(CCCN(CC=C)P(=O)(OCC)OCC)P(=O)(OCC)OCC)P(=O)(OCC)OCC)P(=O)(OCC)OCC
Agent: Cl
Product: C=CCNCCCNC/C=C/CNCCCNCC=C

Procedure:
For conversion into the title compound, 37.45 g of crude (E)-1,14-di-allyl-1,5,10,14-tetra(diethoxyphosphoryl)-1,5,10,14-tetraazatetradec-7-ene are dissolved in 170 ml of 7THF, and hydrogen chloride is passed into the solution at 5° C. until saturated. The reaction mixture is stirred for 15 h at room temperature, 250 ml of diethyl ether are added to the resulting suspension, the mixture is filtered and the filtration residue is washed with a small amount of ethanol and diethyl ether. Recrystallisation from ethanol/water (with treatment with activated carbon) and drying the crystallisate under a high vacuum at 120° C. yield the title compound, m.p. >260° C. 1H-NMR (D2O): δ2.06-2.17(m,4H); 3.13-3.19(m,8H); 3.69(d,4H); 3.78(d,4H); 5.49-5.55(m,4H); 5.84-5.98(m,2H); 6.05-6.07(m,2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[O:6][C:17]1[CH:18]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=1[Cl:19]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: OC(CCCCl)c1cccs1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClCCCC(Oc1cc(Cl)ccc1Cl)c1cccs1
Temperature: 0 °C
Reaction time: 5 h
Yield: 57.3 %

Procedure:
4-Chloro-1-thiophen-2-yl-butan-1-ol (2.98 g, 15.6 mmol), 2,5-dichlorophenol (2.55 g, 15.6 mmol) and triphenylphosphine (4.91 g,18.7 mmol) were dissolved in anhydrous tetrahydrofuran (80 ml) and the solution cooled to 0° C. Diethyl azodicarboxylate (3.26 g, 18.7 mmol) was added dropwise and the reaction allowed to warm to room temperature, then stirred for 5 hours. The solvent was removed in vacuo and the residue passed down a flash silica chromatography column, eluting with hexane:ethyl acetate (9:1) to give the title compound as a colourless oil (3.0 g, 57%).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.[CH:21]1([CH2:24][C:25](N(OC)C)=[O:26])[CH2:23][CH2:22]1>C1COCC1>[Si:5]([O:8][C:9]1[C:10]([F:15])=[C:11]([C:25](=[O:26])[CH2:24][CH:21]2[CH2:23][CH2:22]2)[CH:12]=[CH:13][CH:14]=1)([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1F
Reactant: CON(C)C(=O)CC1CC1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)CC2CC2)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
A 1 L round bottom flask was charged with 84.A (17.0 mL, 73.0 mmol) and THF (70 mL) and cooled to −78° C. under N2. To the cold solution was added sec-butyllithium (1.20 M/cyclohexane) (66.3 mL, 79.6 mmol) dropwise. The mixture was stirred for 30 minutes, and to it was added a solution of 84.B (9.31 mL, 66.3 mmol) in THF (70 mL) dropwise. The final mixture was stirred for 30 minutes at −78° C. The cooling bath was removed, and the mixture was stirred for 30 minutes at ambient temperature. The reaction was quenched with saturated aqueous NH4Cl (70 mL) and diluted with EtOAc (100 mL). The organic phase was washed with water (100 mL), 1 N HCl (100 mL) and brine (100 mL). The organic phase was then dried (MgSO4) and concentrated. The residue was purified by silica gel flash chromatography (2% EtOAc/hexane) to afford 84.C (14.9 g, 73% yield) as a yellow oil.
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH2:20][CH3:21])[C:6]1=[O:22])=[O:4].[NH2:23][C:24]1[CH:25]=[C:26]([CH:36]=[CH:37][CH:38]=1)[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:28]>>[CH:30]1([NH:29][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH2:20][CH3:21])[C:6]3=[O:22])=[O:4])[CH:38]=[CH:37][CH:36]=2)=[O:28])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: Nc1cccc(C(=O)NC2CCCCC2)c1
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C3(C)OCCO3)ccc21
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)NC3CCCCC3)c2)c2cc(C(C)=O)ccc21

Procedure:
Prepared as in Example 1 from 1-ethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-cyclohexyl-benzamide. Purified by trituration in ethyl acetate. mp 180° C. dec.
Reaction SMILES: C1COCC1.[C:6]1([S:12][CH:13]=[CH:14][C:15](Cl)=[O:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>C(N(CC)CC)C>[CH3:18][C:19]1[CH:20]=[C:21]([NH:22][C:15](=[O:16])[CH:14]=[CH:13][S:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccc(N)c1
Reactant: O=C(Cl)C=CSc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)C=CSc2ccccc2)c1
Temperature: 25 °C
Yield: 85 %

Procedure:
THF (45 ml) solution of 3-(phenylthio)acryloyl chloride (3.03 g) was added to THF (45 ml) solution of triethylamine (2.09 ml) under ice-cooling. 3-methylaniline (1.62 g) was added to the mixture under ice-cooling and stirred at room temperature for ten hours. The reaction solution was concentrated under reduced pressure. Ice cooled 1N hydrochloric acid (40 ml) and ethyl acetate (200 ml) were added to the residue and separated to two layer. The organic layer was washed with aqueous saturated sodium chloride solution (40 ml) twice, dried over anhydrous magnesium sulfate, filtered off inorganic salt and concentrated under reduced pressure to obtain N-(3-methylphenyl)-3-(phenylthio)acrylamide (3.46 g).
Reaction SMILES: [F:1][C:2]1([F:37])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=5)[C:26]([O:28]C(C)(C)C)=[O:27])[C:20]([CH3:36])=[CH:19][N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.C(O)(C(F)(F)F)=O>>[F:37][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=5)[C:26]([OH:28])=[O:27])[C:20]([CH3:36])=[CH:19][N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 3-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-5-methylpyrimidin-4-yl)benzoate (48 mg, 0.094 mmol) dichloromethane (1 mL) and TFA (726 μL) were added and stirred at room temperature for four hours. The dichloromethane and TFA were evaporated under reduced pressure. The crude product was dissolved in DMSO (1 mL), filtered and purified by reverse phase preparative HPLC to yield 3-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-5-methylpyrimidin-4-yl)benzoic acid. ESI-MS m/z calc. 453.11, found 454.3 (M+1)+. Retention time 1.63 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]([O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[NH2:17])([CH3:12])[CH3:11]>>[NH2:17][C:16]1[CH:15]=[C:14]([O:13][CH:10]([CH3:11])[CH3:12])[C:20]([O:21][CH3:22])=[CH:19][C:18]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: COc1ccc(N)cc1OC(C)C
Reactant: O=Cc1ccccc1Cl
Product: COc1cc(C(=O)c2ccccc2Cl)c(N)cc1OC(C)C

Procedure:
(2-amino-5-methoxy-4-(1-methylethoxy)phenyl)-(2-chlorophenyl)-methanone (Xii) was prepared by reacting 2-chlorobenzaldehyde with 0.0252 moles of 3-isopropoxy-4-methoxy aniline in a manner analogous to Example 1. MH+/Z=320.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]([CH3:15])[C:8](=[O:14])[CH:9]3[CH2:13][CH:10]32)=[CH:5][CH:4]=1.Cl[CH:17]([O:19]C)Cl>[Ti](Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]([CH3:15])[C:8](=[O:14])[CH:9]3[CH2:13][CH:10]32)=[CH:5][C:4]=1[CH:17]=[O:19]
Reactant: COc1ccc2c(c1)C1CC1C(=O)N2C
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1C=O)N(C)C(=O)C1CC21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a flame dried round bottom flask equipped with a nitrogen cap was added 935 mg (4.6 mmol) 6-Methoxy-3-methyl-1,1a,3,7b-tetrahydro-3-aza-cyclopropa[a]naphthalen-2-one, and 40 ml of methylene chloride. The solution was cooled to 0° C. and 46.1 ml (46.1 mmol) of 1.0 M titanium tetrachloride was added. Dichloromethylmethylether (2.09 ml (23.05 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched in 100 ml ice/1N HCl. The aqueous phase was extracted with chloroform (3×30 ml). The combined organics were then washed with saturated bicarbonate solution and then brine followed by drying over sodium sulfate and evaporation in vacuo. The crude residue was taken up in ethyl acetate whereupon crystals formed. Four crops totaling 902 mg were obtained. Mass spectrum APCI m/e 232 (p+1).
Reaction SMILES: FC(F)(F)C(O)=O.O[C:9]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:11][C:10]1=2.[C:34]1([CH2:40][O:41][NH2:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1>[C:34]1([CH2:40][O:41][NH:42][C:9]2([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18][CH2:17][CH2:16][C:15]3[N:14]=[C:13]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:12]=[CH:11][C:10]2=3)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NOCc1ccccc1
Reactant: OC1(Cc2ccccc2)CCCc2nc(OCc3ccccc3)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: c1ccc(CONC2(Cc3ccccc3)CCCc3nc(OCc4ccccc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 61.3 %

Procedure:
Trifluoroacetic acid (16.6 g) was added in one portion to a solution of 5,6,7,8-tetrahydro-5-hydroxy-2-(phenylmethoxy)-5-(phenylmethyl)quinoline (50 g), phenylmethoxyamine (44.8 g), and toluene (600 ml) at room temperature. The solution was stirred at room temperature for 19 hrs, and the reaction mixture was quenched with conc ammonium hydroxide solution. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over potassium carbonate, filtered, and the filtrate was concentrated. Purification by high performance liquid chromatography (silica gel, elution with ethyl acetate-hexanes) gave 40.0 g (61%) of 5,6,7,8-tetrahydro-N,2-bis(phenylmethoxy)-5-(phenylmethyl)-5-quinolinamine
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[CH:11]=[CH:12][CH:13]=[N:14]4)[N:7]=[CH:6][C:5]=2[C:19]([OH:21])=O)[CH2:3][CH2:2]1.[NH2:22][C:23]([NH2:25])=[NH:24]>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[CH:11]=[CH:12][CH:13]=[N:14]4)[N:7]=[CH:6][C:5]=2[C:19]([NH:24][C:23]([NH2:25])=[NH:22])=[O:21])[CH2:3][CH2:2]1
Reactant: N=C(N)N
Reactant: O=C(O)c1cnn(-c2cccc3ncccc23)c1C1CC1
Product: N=C(N)NC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1

Procedure:
coupling said 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid with guanidine to form N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:10]=1[CH2:11][NH:12][C:13]1[N:18]=[N:17][C:16]([C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:41](Br)[CH:42]=[CH2:43].O>C1COCC1>[CH2:43]([N:12]([C:13]1[N:18]=[N:17][C:16]([C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])=[CH:15][CH:14]=1)[CH2:11][C:10]1[CH:26]=[C:27]([Br:30])[CH:28]=[CH:29][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:42]=[CH2:41]
Reactant: C=CCBr
Reactant: CCCCOC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)nn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)OCCCC)nn1
Reaction time: 2 h

Procedure:
To a mixture of butyl 6-[N-(2-benzyloxy-5-bromobenzyl)amino]pyridazine-3-carboxylate (CF3CO2H salt) (1.2 g) in THF (100 ml) under argon, was added potassium di-(trimethylsilyl)amide [7.0 ml of 0.67M solution in toluene] to give a yellow solution. To the solution was added allyl bromide (0.5 ml). The mixture was stirred for 2 hours, poured into water and extracted with diethyl ether. The organic solution was dried (MgSO4), evaporated and the residue purified by HPLC, eluting with dichloromethane, to give butyl 6-[N-allyl-N-(2-benzyloxy-5-bromobenzyl)amino]pyridazine-3-carboxylate (460 mg) as a gum.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
2-Chloropyridine-3-carbonyl chloride (18.02 g, 0.102 mol) in CH2Cl2 (100 ml) was added dropwise (via an addition funnel) to a stirred solution of 3-(trifluoromethyl)-aniline (15.00 g, 0.093 mol) and DIEA (24.39 ml, 0.14 mol) in CH2Cl2 (500 ml) at 0° C. The mixture gradually was warmed to RT. The reaction continued for 18 h before washing several times with saturated NaHCO3 aqueous solution and brine, respectively. The organic layer was dried over Na2SO4 and evaporated. The resulting oil was purified over silica gel with EtOAc/hexane (2:1) as eluant to leave the amide as a white solid (26.08 g). MS: (ES+) 301 (M+1)+; (ES−): 299 (M−1)−. Calc'd for C13H8ClF3N2O: 300.03.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1.C(O[CH:24](N(C)C)[N:25]([CH3:27])[CH3:26])(C)(C)C>>[CH3:24][N:25]([CH3:27])[CH:26]=[C:11]1[C:10](=[O:15])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH2:12]1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CCCC1(c2cccc(OC)c2)CCCCC1=O
Product: CCCC1(c2cccc(OC)c2)CCCC(=CN(C)C)C1=O

Procedure:
2-(3-Methoxy-phenyl)-2-propyl-cyclohexanone (101 mg, 0.41 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (124 mg) as red oil which was used directly in the next step. MS ISP (m/e): 302.1 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14]([C@@H:16]1[C@H:21]2[CH2:22][C@H:18]([CH2:19][CH2:20]2)[N:17]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O.CC(O)=O.[OH-].[Na+]>C(OCC)(=O)C>[Br:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]1[NH:1][C:14]([C@@H:16]3[C@H:21]4[CH2:22][C@H:18]([CH2:19][CH2:20]4)[N:17]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[N:13][C:3]=1[CH:4]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1[C@H]2CC[C@H](C2)[C@H]1C(=O)Nc1ccc2cc(Br)ccc2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@H]2CC[C@H](C2)[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1
Temperature: 50 °C
Reaction time: 14 h
Yield: 93.3 %

Procedure:
(1S,3S,4R)-tert-butyl 3-(1-amino-6-bromonaphthalen-2-ylcarbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (2.01 g, 4.36 mmol) was suspended in AcOH (8.73 mL, 152.7 mmol) and placed in a preheated 50° C. oil bath. The suspension was let stir at 50° C. for 4 hours and at room temperature for 14 hours. Upon completion, the reaction mixture was diluted with ethyl acetate and aqueous NaOH (6M, 25.4 mL, 152.7 mmol) was added slowly with stirring. The layers were separated and the aqueous layer was back extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting oil was purified by normal phase chromatography (30-55-100% ethyl acetate (5% MeOH) in hexanes) to give (1S,3S,4R)-tert-butyl 3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.8 g, 93%). LCMS-ESI+: calc'd for C22H24BrN3O2: 441.11 (M+); Found: 442.7 (M+H+).