Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][O:7]1.[CH3:20][NH:21][C:22]([NH2:24])=[O:23].C[O-].[Mg+2].C[O-].CO>>[Cl:18][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][O:7]2)[C:3]([NH:24][C:22]([NH:21][CH3:20])=[O:23])=[O:19])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCO1)c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCO1)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-propionic acid methyl ester (617 mg, 2.04 mmol), methylurea (302 mg, 4.07 mmol), and a solution of magnesium methoxide in methanol (7.4 wt. %, 4.63 mL, 3.06 mmol) was heated at 100° C. for 8 h. After this time, the reaction mixture was concentrated in vacuo, dissolved in ethyl acetate (50 mL), and then filtered through a pad of silica gel. The organics were then concentrated in vacuo to give the crude product. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80/20 hexanes/ethyl acetate) afforded 1-[2-(3,4-dichloro-phenyl)-3-(tetrahydro-furan-2-yl)-propionyl]-3-methyl-urea as a white solid: EI-HRMS m/e calcd for C15H18Cl2N2O3 (M+) 344.0694, found 344.0699.
Reaction SMILES: [O:1]([C:8]1[CH:18]=[CH:17][C:11]2[CH:12]=[C:13]([CH2:15]O)[O:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O.O1CCCC1>[O:1]([C:8]1[CH:18]=[CH:17][C:11]2[CH:12]=[C:13]([CH2:15][N:23]3[C:19](=[O:29])[C:20]4[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:22]3=[O:24])[O:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cc2ccc(Oc3ccccc3)cc2o1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cc2ccc(Oc3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a tetrahydrofuran (4 mL) solution of (6-phenoxy-benzofuran-2-yl)-methanol (177 mg, 737 μmol) described in Production Example 49-1-2 were added phthalimide (119 mg, 811 μmol), triphenylphosphine (232 mg, 884 μmol) and diethylazodicarboxylate (403 μL, 884 mmol) at 0° C., which was stirred at room temperature for 4 hours and 30 minutes. Water was added to the reaction solution followed by extraction with ethyl acetate. The organic layer was washed with sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (209 mg, 77%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>C1COCC1>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)=[CH:3][C:2]([NH:1][C:29](=[O:32])[CH:30]=[CH2:31])=[CH:11][CH:10]=2)#[N:13]
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(F)c1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.00 g (3.60 mmol) of 6-amino-4-(3-fluorophenylamino)quinoline-3-carbonitrile in 12 mL of THF under N2 was chilled in ice. Triethylamine (0.436 g, 4.32 mmol) was added followed by 0.393 g (4.32 mmol) of acryloyl chloride and the reaction was stirred at 25° C. overnight. The solvent was removed and the residue was slurried with water and filtered. The crude product was washed with water, dried, washed with hot ethyl acetate and dried in vacuo (50° C.). This yielded 0.862 g of N-[3-cyano-4-(3-fluorophenylamino)quinolin-6-yl]acrylamide as a brown solid: mass spectrum (electrospray, m/e): M+H 333.1.
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[K+].[Br-].[CH2:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[I:22])[CH3:13]>C1COCC1>[CH:18]([C:17]1[CH:20]=[CH:21][C:14]([CH2:12][CH3:13])=[C:15]([I:22])[CH:16]=1)=[CH2:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCc1ccc(C=O)cc1I
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc(CC)c(I)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Potassium hexamethyldisilazide (0.5 M in THF) (46.1 mL, 23.07 mmol) was added dropwise to a stirred suspension of methyltriphenylphosphohonium bromide (8.24 g, 23.1 mmol) in dry THF (62 mL) at 0° C. and the mixture was stirred for 20 min. A solution of 4-ethyl-3-iodobenzaldehyde (2.40 g, 9.23 mmol) in dry THF (31 mL) was added via cannula. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with satd NH4Cl (50 mL) and the resulting mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 2448 mL) to afford 4-ethenyl-1-ethyl-2-iodobenzene, as a colorless oil. Rf=0.79 (hexanes). 1H NMR (500 MHz, CDCl3): δ 7.37 (d, J=1.8 Hz, 1H); 6.83 (dd, J=7.9, 1.8 Hz, 1H); 6.68 (d, J=7.9 Hz, 1H); 6.11 (dd, J=17.6, 10.9 Hz, 1H); 5.21 (d, J=17.6 Hz, 1H); 4.72 (d, J=9.7 Hz, 1H); 2.23 (q, J=7.5 Hz, 2H); 0.72 (t, J=7.5 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl.[NH4+].[Cl-]>ClCCl>[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25][O:1][C:2]1([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: OC1(c2nccs2)CCC1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCOC1(c2nccs2)CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
To a solution of the alcohol 2-[(1-Hydroxy)cyclobutyl]thiazole from Step 1 (5 g, 32 mmol) and Hunig's base (10.4 mL, 60 mmol) in dichloromethane (100 mL) at 0° C. was added 2-(trimethylsilyl)ethoxymethyl chloride (6.5 mL, 36.7 mmol). The resulting solution was stirred at 0° C. for 1 h, was heated at reflux temperature for 3.5 h and finally was stirred at room temperature for 15 h. Sat. aq. NH4Cl was added and the resulting mixture was extracted with dichloromethane (3×). The combined organics were washed with water, brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel; dichloromethane to dichloromethane/ethyl acetate 95:5) provided 2-{1-[(2-Trimethylsilylethoxy)methoxy]cyclobutyl}thiazole (2 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[C:3]=1[C:4]#[N:5].CN(C)C(=O)C.[CH3:27][NH:28][NH2:29]>O>[CH3:27][N:28]1[C:2]2[C:3](=[C:6]([O:10][C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[C:4]([NH2:5])=[N:29]1
Reactant: N#Cc1c(F)cccc1Oc1ccc2ccccc2c1
Reactant: CNN
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1nc(N)c2c(Oc3ccc4ccccc4c3)cccc21
Temperature: 130 °C
Yield: 97 %

Procedure:
To a 20 mL vial containing 2-fluoro-6-(naphthalen-2-yloxy)-benzonitrile (966 mg, 3.67 mmol) and a magnetic stir bar was added anhydrous N,N-dimethylacetamide and the mixture was stirred until solution was achieved. Methyl hydrazine (390 uL, 7.34 mmol) was added, the vial was capped, the reaction mixture was placed in an oil bath at 120° C. and stirred at that temperature overnight. The reaction mixture was heated at 130° C. for an additional 3 h. The cooled reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organics were washed with water (3×15 mL), dried (Na2SO4), filtered and concentrated to give 1.03 g of a tan solid. This residue was purified via flash chromatography on silica gel (120 g) utilizing CH2Cl2 and then 9:1 CH2Cl2/EtOAc as eluent to give 770 mg of I-190 an off-white solid. This material was deemed of sufficient purity to be utilized in subsequent reactions. 1H NMR, MS.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[CH:43]1[O:55][C@@H:54]([CH2:56][O:57][C:58](=[O:60])[CH3:59])[C@H:49]([O:50][C:51](=[O:53])[CH3:52])[C@@H:44]1[O:45][C:46](=[O:48])[CH3:47])(=O)C>ClCCCl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]([C@H:43]3[O:55][C@@H:54]([CH2:56][O:57][C:58](=[O:60])[CH3:59])[C@H:49]([O:50][C:51](=[O:53])[CH3:52])[C@@H:44]3[O:45][C:46](=[O:48])[CH3:47])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Nc1nc2c(Cl)cccc2[nH]1
Reactant: CC(=O)OC[C@@H]1OC(OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Product: CC(=O)OC[C@@H]1O[C@H](n2c(NC(C)C)nc3c(Cl)cccc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 46.8 %

Procedure:
4-Chloro-2-(isopropylamino)-1H-benzimidazole (2.24 g, 10.68 mmol), N,O-bis(trimethylsilyl)acetamide (3.00 mL, 2.47g, 12.14 mmol), trimethylsilyl trifluoromethanesulfonate (1.2 mL, 1.42 g, 6.00 mmol), 1,2,3,5-tetra-O-acetyl-L-ribofuranose (4.46 g, 14.01 mmol) and 1,2-dichloroethane (35 mL) were used according to general procedure II. The product was purified by silica gel chromatography using 95:5 dichloromethane/acetonitrile to afford 2.34 g (47%) of an off-white foam MS (EI): m/z 468.2 (M+H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([F:31])=[CH:33][CH:34]=3)[CH2:18][CH2:17]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(=O)CC2)c2ccc(Cl)c(Cl)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Nc3ccc(F)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.1 %

Procedure:
To a solution of the compound obtained in Example 208 (1000 mg, 2.2 mmol) and 4-fluoroaniline (269 mg, 2.4 mmol) in THF (3 mL) were added acetic acid (0.126 mL, 2.2 mmol) and sodium triacetoxyborohydride (699 mg, 3.3 mmol) under ice cooling, and the mixture was stirred at room temperature for 20 hours. To the reaction mixture was added saturated aqueous solution of sodium hydrogen carbonate (100 mL). The mixture was stirred at room temperature for 2 hours and extracted with ethyl acetate (100 mL×2). The organic layer was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to flash column chromatography (silica gel 20 g, ethyl acetate/methanol=1/0 to 9/1 to 4/1), and the desired fraction was concentrated under reduced pressure to give the titled compound (695 mg, 1.3 mmol, Yield 58%) as a pale purple amorphous substance.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(O[CH:31](N(C)C)[N:32]([CH3:34])[CH3:33])(C)(C)C>ClCCl>[CH3:31][N:32]([CH3:34])[CH:33]=[CH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])=[CH:22][CH:21]=1)=[O:25]
Reactant: CC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: ClCCl
Product: CN(C)C=CC(=O)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 18 h

Procedure:
A reaction mixture of 1-[4-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-phenyl]-ethanone (1.40 g), t-butoxy-bis-dimethylaminomethane (5.0 ml) and dichloromethane (10 ml) was stirred for 18 hours. The red-orange precipitate was filtered to yield the title compound (1.22 g), m.p. 203-205° C. Additional product (0.18 g) was isolated from the reaction mixture by concentration.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17]C)=O)=[CH:4][N:3]=1.[Li][NH2:20]>C1COCC1>[Cl:1][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([NH2:20])=[O:17])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(Cl)c2c1[nH]c1ccccc12
Reactant: [Li]N
Solvent: C1CCOC1
Product: NC(=O)c1cnc(Cl)c2c1[nH]c1ccccc12
Temperature: 100 °C

Procedure:
A mixture containing methyl 1-chloro-5H-pyrido[4,3-b]indole-4-carboxylate and LiNH2 (prepared in situ from ammonia and n-BuLi; 1.0 M in THF; 3.5 equiv) in THF (0.09 M) was heated in a microwave reactor at 100° C. for 1 min in a sealed tube. The reaction mixture was cooled to room temperature and partitioned between EtOAc and saturated NaHCO3. After separation of the organic phase, the aqueous phase was extracted again with EtOAc, and the combined organic phases were washed with brine, dried over MgSO4 and filtered. After evaporation of the organic solvent, the residue was purified by flash chromatography (10-70% EtOAc in hexanes) to provide the title compound as a white solid.
Reaction SMILES: [CH:1]1([O:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.NN.[N+:20]([C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH:1]1([O:6][NH:7][S:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=2)(=[O:30])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCC1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NOC2CCCC2)c1
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
A mixture of 2-(cyclopentyloxy)-1H-isoindole-1,3(2H)-dione (3.00 g, 12.99 mmol) in anhydrous tetrahydrofuran (25 mL) under an Argon atmosphere was treated with anhydrous hydrazine (0.448 mL, 14.29 mmol). After stirring vigorously for 2.5 hours, the resulting slurry was filtered and washed with approximately 15 mL of anhydrous tetrahydrofuran. The filtrate was combined with 3-nitro-1-benzenesulphonyl chloride (3.17 g, 14.29 mmol) and N,N-diisopropylethylamine (2.72 mL, 15.6 mmol). After stirring at ambient temperature for approximately 18 hours, the reaction mixture was evaporated in vacuo to a residue and partitioned between ethyl acetate and 1N hydrochloric acid. The phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with 5% w/v potassium carbonate and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue. The crude material was purified on flash grade silica gel eluting with 15:85 ethyl acetate:hexane. Fractions containing the product were combined, evaporated in vacuo, and dried under high vacuum to provide N1-(cyclopentyloxy)-3-nitro-1-benzenesulfonamide (3.224 g, 87%) as a solid. H1-NMR (chloroform-D3): 1.71 (m, 8H), 4.71 (m, 1H), 6.93 (bs, 1H), 7.83 (m, 1H), 8.28 (m, 1H), 8.55 (m, 1H), 8.81 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[C:23]([C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C@@H:33]2[CH2:35][O:34]2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:35][C@H:33]([OH:34])[CH2:32][O:31][C:30]5[CH:36]=[CH:37][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCNCC1)O2
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Product: CC(C)(C)c1ccc(OC[C@@H](O)CN2CCC3(CC2)CSC2=C(O3)c3cc(Br)ccc3C(=O)C2=O)cc1

Procedure:
Compound 189 was synthesized using 9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=150-152° C.; 400 MHz 1H NMR (CDCl3) δ: 7.92-7.89 (m, 1H), 7.87-7.85 (m, 1H), 7.65-7.62 (m, 1H), 7.33-7.29 (m, 2H), 6.89-6.85 (m, 2H), 4.20-4.10 (m, 1H), 4.03-3.98 (m, 2H), 2.96 (s, 2H), 2.83-2.73 (m, 2H), 2.73-2.62 (m, 2H), 2.62-2.50 (m, 1H), 2.20-2.12 (m, 2H), 2.00-1.85 (m, 2H), 1.29 (s, 9H); LCMS: 586 [M+H].
Reaction SMILES: C(O[C:5]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:8]([OH:14])=[C:7](C)[C:6]=1C)(=O)C.[C:17]1(=O)CCC1.N1CCCC1>C1(C)C=CC=CC=1>[CH:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:17][CH2:12][C:11](=[O:13])[C:9]=2[CH:10]=1
Reactant: O=C1CCC1
Reactant: CC(=O)Oc1cc(C(C)=O)c(O)c(C)c1C
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: O=C1CCOc2ccccc21

Procedure:
2,3-Dimethyl-1,4-phenylene diacetate (5.5 g) was heated up with boron trifluoride-acetic acid complex (25 mL) at 120° C. for 5 hours. The mixture was poured into ice, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate water solution to pH about 7. Evaporation gave 5.5 g of 5-acetyl-4-hydroxy-2,3-dimethylphenyl acetate as yellow solid. Refluxing 5-acetyl-4-hydroxy-2,3-dimethylphenyl acetate (5.5 g) with cyclobutanone (1.9 g, 27 mmol) and pyrrolidine (2.1 mL, 24.8 mmol) in toluene failed to give chromanone but gave 3.4 g of 1-(2,5-dihydroxy-3,4-dimethylphenyl)-ethanone as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[N:18]2[CH2:23][CH2:22][CH:21]([NH:24][CH3:25])CC2)=[CH:4][CH:3]=1.[N:26]#[C:27][NH2:28].[C:29]([OH:32])(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([OH:32])(=[O:31])[CH3:30].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[N:18]2[CH2:30][CH2:29][CH:21]([N:24]([CH3:25])[C:27]([NH2:28])=[NH:26])[CH2:22][CH2:23]2)=[CH:6][CH:7]=1
Reactant: CNC1CCN(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: N#CN
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C(=N)N)C1CCN(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 135 °C

Procedure:
A mixture of 10.1 g (0.03 mole) of 1-[1-[(4-fluorophenyl)methyl]-2(1H)-benzimidazolyl]-N-methyl-4-piperidinamine with 1.4 g (0.032 mole) of cyanamide and 1.8 g (0.03 mole) of acetic acid is heated to 135° C. for 1.5 hours. The mixture is cooled and it is then taken up with methylene chloride under reflux, and the precipitate is filtered off and then dried. N-[1-[1-[(4-fluorophenyl)methyl]-2(1H)-benzimidazolyl]-4-piperidinyl]-N-methylguanidine acetate is thus obtained.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])[C:6]([CH3:22])=[CH:5][C:4]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)#[CH:2].[N:33]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)=[N+:34]=[N-:35].[Na].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O>CN(C=O)C.O.[Cu]I>[CH3:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][N:33]2[CH:2]=[C:1]([C:3]3[N:8]=[C:7]([C:9]([N:11]4[CH2:16][CH2:15][CH:14]([N:17]5[CH2:21][CH2:20][CH2:19][CH2:18]5)[CH2:13][CH2:12]4)=[O:10])[C:6]([CH3:22])=[CH:5][C:4]=3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=3)[N:35]=[N:34]2)=[CH:42][CH:41]=1
Reactant: COc1ccc(CN=[N+]=[N-])cc1
Reactant: C#Cc1nc(C(=O)N2CCC(N3CCCC3)CC2)c(C)cc1-c1cccc(C(F)(F)F)c1
Agent: [Cu]I
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3nc(C(=O)N4CCC(N5CCCC5)CC4)c(C)cc3-c3cccc(C(F)(F)F)c3)nn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A solution of 0.30 g (0.68 mmol) of [6-ethynyl-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 24) and 0.116 g (0.71 mmol) of 1-azidomethyl-4-methoxy-benzene in 3.0 ml of DMF was treated with 0.013 g (0.066 mmol) of (+)-sodium-L-ascorbate and 0.129 g (0.68 mmol) of copper(I) iodide in 1.0 ml of H2O and the reaction was stirred at RT for 2 hours. Then, the solvents were removed by evaporation in high vacuum, the residue was diluted with H2O/NH4OH (25%) and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 95:5) to give 0.363 g (88%) of the title compound as light brown oil. MS: 605.4 (MH).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[F:14][C:15]1[C:21](F)=[CH:20][C:18]([NH2:19])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1.O>CN(C=O)C>[F:14][C:15]1[C:21]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:20][C:18]([NH2:19])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: OCCCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(OCCCCN2CCCCC2)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 24 h

Procedure:
382 mg of sodium hydride (60% in suspension in oil) are added in small portions, over two hours, to a solution of 4-piperidin-1-ylbutan-1-ol in 10 mL of DMF, cooled to 0° C. with an ice bath. A solution of 4,5-difluoro-2-nitroaniline in 5 mL of N,N-dimethylformamide is then added dropwise. The medium is stirred at ambient temperature for 24 hours. 60 mL of distilled water are added and the reaction medium is extracted with 3×30 mL of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under vacuum in a rotary evaporator. The reaction crude is purified by flash chromatography on an Intelliflash apparatus with an Analogix RS-12 silica cartridge, with a 100% to 85/15 dichloromethane/-methanol elution gradient. 700 mg of 4-fluoro-2-nitro-5-(4-piperidin-1-ylbutoxy)phenylamine are isolated in the form of a red oil. 1H NMR (300 MHz, DMSO-d6, δ in ppm): from 1.29 to 1.62 (m, 8H); 1.75 (m, 2H); 2.28 (m, 6H); 4.07 (t, J=6.5 Hz, 2H); 6.62 (d, J=7.5 Hz, 1H); 7.48 (broad s, 2H); 7.74 (d, J=12.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>>[F:20][C:19]([F:22])([F:21])[C:15]1[CH:14]=[C:13]2[C:18]([C:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:31]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([Cl:23])=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:26]=4)=[S:32])=[CH:3][CH:4]=3)=[CH:10][CH:11]=[N:12]2)=[CH:17][CH:16]=1
Reactant: Nc1ccc(Sc2ccnc3cc(C(F)(F)F)ccc23)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1ccc2c(Sc3ccc(NC(=S)Nc4ccc(Cl)c(C(F)(F)F)c4)cc3)ccnc2c1
Yield: 62.7 %

Procedure:
4-(4-aminophenylthio)-7-trifluoromethylquinoline (0.01 mole, 3.2 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (0.01 mole, 2.4 g) were reacted according to procedure C to yield the title compound 3.5 g, 63%. Mass Spec (FD) 557. Calculated for C24H14ClF6N3 S2 : C, 51.66; H, 2.53; N, 7.53. Found: C, 51.92; H, 2.53; N, 7.46.