Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6]([CH3:8])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH2:4][CH2:3]1.[Li]C(CC)C.C1CCCCC1.N#N.O1C[CH:31]1[CH2:33][CH2:34][O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1.C1C[O:45]CC1>CCOCC>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C:5]23[CH:6]([CH3:8])[CH:7]([N:2]([CH3:1])[CH2:3][CH2:4]2)[O:45][CH:33]([CH2:34][O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH2:31]3)[CH:14]=[CH:13][CH:12]=1
Reactant: C1CCC(OCCC2CO2)OC1
Reactant: COc1cccc(C2=C(C)CN(C)CC2)c1
Reactant: C1CCOC1
Agent: N#N
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CCOCC
Product: COc1cccc(C23CCN(C)C(OC(COC4CCCCO4)C2)C3C)c1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
Into a dry 1 L flask containing a solution of 1,5-dimethyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine 7 (24 g, 0.11 mol) in dry THF (600 mL) cooled in a salted ice bath was added 1.4 M s-BuLi in cyclohexane (85 mL, 119 mmol) drop wise under a N2 atmosphere over a period of 0.5 h. The dark red solution was further stirred at reduced temperature for an additional 15 min whereupon the mixture was cannula transferred into a second dry 2 L flask containing tetrahydro-2-(oxiranylethoxy)-2H-pyran (13) (20 g, 0.11 mol) in anhydrous Et2O (150 mL) cooled to −10° C. Upon complete addition of the metalated enamine to the epoxide, the resulting mixture was stirred for additional 30 min at −5° C. The reaction was quenched with a solution of 13 g of NaOH and 42 g of NaCl in 350 mL H2O at such a rate so as to maintain the solution temperature below 0° C. and the mixture subsequently poured into 500 mL H2O. The layers were separated, and the aqueous layer extracted with Et2O/EtOAc (1:1, 3×200 mL). The combined organic layers were dried over anhydrous K2CO3, concentrated, and purified via flash column chromatography on silica gel (50% EtOAc/hexanes to 100% EtOAc gradient) to afford 5-(3-methoxyphenyl)-8,9-dimethyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]methyl-2-oxa-8-azabicyclo[3.3.1]nonane (14) as a mixture of diastereomers (30 g, 70%): LCMS (ESI): m/z 390.5 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 7.22-7.28 [m, 1H], 6.71-6.97 [m, 3H], 4.59 [br m, 1H], 4.48 [br m, 1H], 4.19 [br m, 1H], 3.81-3.87 [m, 2H], 3.80 [s, 3H], 3.52 [br m, 2H], 2.62-2.64 [m, 3H], 2.37 [s, 3H], 2.45 [m, 1H], 1.51-1.82 [m, 2H], 0.69 [d, J=6 Hz, 3H].
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:25][C:26]1[CH:27]=[C:28]2[C:34]([CH2:35]CO)=[C:33]([Si:38]([CH2:43][CH3:44])([CH2:41][CH3:42])[CH2:39][CH3:40])[NH:32][C:29]2=[N:30][CH:31]=1>C1COCC1>[Br:5][CH2:1][CH2:35][C:34]1[C:28]2[C:29](=[N:30][CH:31]=[C:26]([Cl:25])[CH:27]=2)[NH:32][C:33]=1[Si:38]([CH2:39][CH3:40])([CH2:43][CH3:44])[CH2:41][CH3:42]
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
Carbon tetrabromide (3.27 g, 9.65 mmol) was added to the solution of triphenylphosphine (2.56 g; 9.65 mmol) in THF (30 mL). The mixture was stirred at room temperature for 30 min. To this green suspension was added a solution of 2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol (2.00 g; 6.43 mmol) in THF (20 mL) and the resulting reaction mixture was stirred for 20 hours. The precipitate was eliminated by filtration and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography (eluent: 5 to 40% of ethyl acetate in heptanes) to give 1.08 g (45%) of 3-(2-bromoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine as a white solid.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].O[CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:5][CH:15]1[CH2:16][CH2:11][CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Reaction time: 1 h

Procedure:
Methanesulfonic anhydride (996 mg, 5.72 mmol) was added to a mixture of 3-hydroxy-N-t-butoxycarbonylpiperidine (959 mg, 4.76 mmol) and triethylamine (0.86 ml, 6.19 mmol) in methylene chloride (30 ml) at 0° C. After stirring for 1 h, the reaction mixture was washed with saturated NaHCO3 and dried (Na2SO4). Concentration gave the title compound. 1H NMR (CDCl3) d 1.46 (s, 9 H), 1.77-2.17 (m, 4 H), 3.05 (s, 3 H), 3.14-3.49 (m, 2 H), 3.62 (m, 2 H), 4.72 (br s, 1 H).
Reaction SMILES: [OH-].[K+].C([O:7][C:8](=[O:19])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][N:12]=1)(C)(C)C.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]([C:34](=[O:36])[CH3:35])[CH:31]=[CH:32][CH:33]=2)[CH2:23][CH2:22]1>CCO.O>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]([C:34](=[O:36])/[CH:35]=[CH:17]/[C:14]3[CH:15]=[CH:16][C:11](/[CH:10]=[CH:9]/[C:8]([OH:7])=[O:19])=[N:12][CH:13]=3)[CH:31]=[CH:32][CH:33]=2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C=O)cn1
Reactant: CC(=O)c1cccc(CN2CCN(C)CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCN(Cc2cccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)c2)CC1
Temperature: 0 °C
Reaction time: 7 h
Yield: 47.4 %

Procedure:
1.7 M KOH (0.634 ml) was added dropwise to a stirred mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (see Example 11 STEP A-D, 250 mg, 1.078 mmol) and 1-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-ethanone (obtained as described in Preparation 14, 250 mg, 1.078 mmol) in EtOH (15 ml). The resulting solution was stirred at 0° C. for 7 h and then diluted with water and extracted with AcOEt. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude product was purified by chromatographic column (eluent: DCM/MeOH/NH4OH from 97:3:0.1 to 95:5:0.2) and the desired intermediate was dissolved in DCM (4 ml) and TFA (1 ml). The mixture was stirred at room temperature for 6 h and then the solvent was removed in vacuo to give 200 mg of (E)-3-(5-{(E)-3-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylic acid as its tris-trifluoroacetate salt. The crude mixture was used in the next step without further purifications.
Reaction SMILES: [CH2:1]([N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:17]([NH2:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:10]1[C:11](=[O:16])[CH2:12][CH:13]([NH:25][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:14]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCN
Reactant: CCCCCCCCCN1C(=O)C=CC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCN1C(=O)CC(NCCCCCCCC)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-nonyl maleimide (0.01 M) prepared as described in Example 12 above, octylamine (0.01 M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) was stirred for 24 hours at room temperature. Acetonitrile was removed under vacuum to leave a residual liquid product which was flash chromatographed (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:28](O)=[O:29])=[CH:5][C:6]2[N:10]=[C:9]([NH:11][C:12]3[S:13][C:14]4[CH:20]=[C:19]([O:21][C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:15]=4[N:16]=3)[N:8]([CH3:26])[C:7]=2[CH:27]=1.[CH2:31]([NH2:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:31]([NH:33][C:28]([C:4]1[C:3]([O:2][CH3:1])=[CH:27][C:7]2[N:8]([CH3:26])[C:9]([NH:11][C:12]3[S:13][C:14]4[CH:20]=[C:19]([O:21][C:22]([F:23])([F:25])[F:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[N:10][C:6]=2[CH:5]=1)=[O:29])[CH3:32]
Reactant: CCN
Reactant: COc1cc2c(cc1C(=O)O)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1OC

Procedure:
6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ethylamide (37 mg) was prepared by following General Procedure F starting from 6-methoxy-1-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), ethylamine (2 M in THF, 171 uL), HBTU (78 mg), and DIEA (45 uL). LC/MS: m/z 466.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.25 (s, 1H), 8.22 (t, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.71 (d, 1H), 7.34 (d, 1H), 7.24 (s, 1H), 3.98 (s, 3H), 3.64 (s, 3H), 3.39-3.30 (m, 2H), 1.14 (t, 3H).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:12][C:13]1[CH:14]=[C:15]([Mg]Br)[CH:16]=[CH:17][C:18]=1[F:19]>>[F:12][C:13]1[CH:14]=[C:15]([C:7]2([OH:10])[CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: O=C1CCC2(CC1)OCCO2
Product: OC1(c2ccc(F)c(F)c2)CCC2(CC1)OCCO2
Yield: 42 %

Procedure:
This compound was prepared from 1,4-cyclohexanedione monoethylene ketal (15.6 g, 100 mmole) and 3,4-difluorophenyl magnesium bromide (100 mmole) in the usual manner. The crude product was crystallized from isopropyl ether to give the product (42%, mp: 118°-120° C.).
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][N:4]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.O.C(OCC)(=O)C>C(=O)(O)[O-].[Na+]>[CH3:14][C:12]1([CH3:15])[CH2:11][O:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([N:20]3[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]3)=[N:4][CH:5]=2)=[N:13]1
Reactant: CN1CCNCC1
Reactant: CC1(C)COC(c2ccc(Cl)nc2)=N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCN(c2ccc(C3=NC(C)(C)CO3)cn2)CC1
Yield: 67 %

Procedure:
2-Chloro-5-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-pyridine hydrochloride was transformed into its free base by dissolving 8.0 g (32 mmol) in saturated sodium bicarbonate solution and extracting the base into dichloromethane. The solvent was evaporated and the residue was dissolved in toluene. After addition of 11.35 g (113 mmol) N-methylpiperazine, the mixture was refluxed for 36 h. After cooling to room temperature water (50 ml) and ethyl acetate (150 ml) were added and the aqueous layer was extracted with ethyl acetate (150 ml). The combined organic layers were extracted two times with 1 N hydrochloric acid, the acidic aqueous layer was made alkaline with 28% sodium hydroxide solution and extracted two times with dichloromethane. The organic layer was dried (magnesium sulfate) and evaporated. The residue was crystallized from ethyl acetate/hexane to yield 6.0 g (67%) of a white crystalline compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.S(Cl)(Cl)=O.[NH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22]>C(Cl)Cl.CCOCC>[OH:22][CH2:21][C:20]([NH:19][C:8](=[O:10])[C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:14])[F:13])=[CH:12][CH:11]=1)([CH3:24])[CH3:23]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
To a 100 ml round bottom flask was loaded 4-(trifluoromethoxy)benzoic acid (4.85 g, 23.5 mmol). Thionyl chloride (5.15 ml, 70.6 mmol) was added at 0° C. The reaction mixture was allowed to warm up to room temperature and then heated at 80° C. for 1 hour. After cooling down to room temperature, the volatiles were removed. The residue was diluted with 50 ml methylene chloride, and 2-amino-2-methylpropan-1-ol (7.34 g, 82 mmol) was added at 0° C. The reaction mixture was allowed to warm up to room temperature. It was diluted with 150 ml ether, washed sequentially with 100 ml 1N HCl, 100 ml 5% KOH and 50 ml brine. The organics were dried over sodium sulfate, filtered and concentrated to give 4.2 g desired product. It was used for the next step directly without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[NH:9][C:8]2=O)(=[O:3])[CH3:2].CN(C=O)C.O=S(Cl)[Cl:32]>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1)[N:9]=[C:8]2[Cl:32])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c2c1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2nc(-c3cccc([N+](=O)[O-])c3)nc(Cl)c2c1

Procedure:
A suspension of 2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl acetate (3.30 g, 10.1 mmol) in SOCl2 (65 mL) was added DMF (2 mL). The mixture was refluxed for 2.5 h, upon which the volatiles were removed in vacuo. The residue was taken up in CHCl3 (450 mL) and washed with sat NaHCO3 (200 ml) and water (200 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give the product 4-chloro-2-(3-nitrophenyl)quinazolin-6-yl acetate (3.53 g, 10.3 mmol). HPLC retention time 9.748 min.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C=O.[OH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([CH3:24])[CH:20]=[CH:19]2.[CH2:25](NCCCC)CCC>>[CH3:24][C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[C:14]([OH:13])[C:15]([CH2:25][N:6]3[C:5]4[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=4[S:3][C:2]3=[S:1])=[CH:16][CH:17]=2)[N:22]=1
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: Sc1nc2ccccc2s1
Reactant: CCCCNCCCC
Agent: C=O
Product: Cc1ccc2ccc(Cn3c(=S)sc4ccccc43)c(O)c2n1

Procedure:
Using the procedure of example 12 33.4 g of mercaptobenzothiazole, 6 g of paraformaldehyde, 31.8 g of 8-hydroxyquinaldine and 2 ml of dibutylamine are reacted to give 64 g of 3-(2-methyl-8-hydroxyquinolin-7-ylmethyl)-benzothiazole-2-thione (compound No. 60) melting at 211°-215°.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1N.[ClH:10].N([O-])=O.[Na+].[S:15](=[O:17])=[O:16]>C(O)(=O)C.O>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[S:15]([Cl:10])(=[O:17])=[O:16]
Reactant: Cl
Reactant: O=S=O
Reactant: Nc1cccc(Cl)c1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 70.0 g of 2,3-dichloroaniline in 51 mL of acetic acid was added 180 mL of concentrated hydrochloric acid portionwise. External cooling was used to maintain the temperature below 50° C. To this thick mixture at -5° C. was added a solution of 37.0 g of sodium nitrite in 80 mL of water dropwise at a rate that maintained the temperature below 50° C. After the addition was complete, the cloudy mixture was stirred at 0° C. for 10 minutes, and was then poured slowly into a suspension of 500 mL of acetic acid, 150 mL of sulfur dioxide and 10 g of cupric chloride dihydrate at 10°-20° C. Moderate gas evolution with excessive foaming occurred, but subsided after approximately ten minutes. This light brown mixture was stirred at ambient temperature for 1-1.5 hours and was then poured into 2 L of ice water with stirring. The resultant light brown precipitate was filtered, washed twice with 200 mL portions of water, and dried to yield 110 g of 2,3-dichlorobenzenesulfonyl chloride as a light brown solid, m.p. 56°-58° C., which was used without further purification; IR (nujol): 1375, 1175 cm-1.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:18][CH2:17]1)([O:8][Si](CC)(CC)CC)[C:4]([F:7])([F:6])[F:5].[Li][CH2:35][CH2:36][CH2:37][CH3:38].BrCC1CC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCCCCC>[CH:37]1([CH2:38][N:22]([C@H:19]2[CH2:20][CH2:21][C@H:16]([C:3]([OH:8])([C:2]([F:33])([F:1])[F:32])[C:4]([F:7])([F:6])[F:5])[CH2:17][CH2:18]2)[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH2:35][CH2:36]1
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NS(=O)(=O)c2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Reactant: [Li]CCCC
Agent: BrCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N(CC1CC1)[C@H]1CC[C@H](C(O)(C(F)(F)F)C(F)(F)F)CC1
Temperature: -40 °C

Procedure:
A solution of 500 mg (0.89 mmol) of trans N-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide (example 1.3) in 10 mL of THF was cooled to −78° C. and treated dropwise with 0.72 mL of a 1.6 M BuLi solution in hexane. The solution was warmed to −40° C. within 30 min, treated with 0.43 mL (4.45 mmol) of bromomethylcyclopropane, allowed to reach RT and then refluxed overnight. An excess of TBAF was added and the mixture was stirred for an additional hour. Distribution of the crude mixture between a saturated aqueous solution of NH4Cl and Et2O, drying of the combined organic phases over Na2SO4, evaporation and chromatography on silica gel with CH2Cl2 gave 200 mg (49%) of trans N-cyclopropylmethyl-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide, as a colorless viscous oil, MS: 460 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:43])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][O:35]C3CCCCO3)=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[C:33]([CH2:34][OH:35])=[CH:32][N:31]=[N:30]4)[CH:24]=3)[CH2:21][C:20](=[O:43])[NH:19][C:9]=2[CH:10]=1
Reactant: CC(C)Nc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Nc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-isopropylamino-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M113) (0.37 g, 0.60 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (209 mg, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29].C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:9])=[CH:4][CH:3]=1)(=[O:30])[CH3:29]
Reactant: Cc1nc(N(C)c2ccc(N)cc2)c2ccccc2n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of (4-amino-phenyl)-(2-methyl-quinazolin-4-yl)-methylamine (28 mg, 0.11 mmol) in 2 mL of dichloromethane with triethylamine (50 uL, 0.36 mmol) cooled at 0° C. was added acetic anhydride (50 uL, 0.53 mmol), followed by a few crystals of 4-dimethylaminopyridine, and the mixture was allowed to warm to room temperature. The reaction mixture was stirred for 0.5 h and 25 mL of ethyl acetate was added. The solution was washed with saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (80% ethyl acetate/hexane) to give the title compound (32.5 mg, 0.11 mmol, 100%). 1H NMR (CDCl3): 7.75 (d, J=8.1, 1H), 7.5-7.57 (m, 3H), 6.94-7.12 (m, 4H), 3.60 (s, 3H), 2.72 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].N1C=CC=CC=1.CO[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1OC)[C:24](Cl)=[O:25].[CH2:32](Cl)[Cl:33]>>[CH2:10]([O:9][C:7]([C:6]1([CH2:32][Cl:33])[C:5]([CH3:12])=[CH:4][S:3][CH:2]1[NH:1][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[CH:21][CH:22]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1c(C)csc1N
Reactant: ClCCl
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: c1ccncc1
Product: CCOC(=O)C1(CCl)C(C)=CSC1NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-amino-4-methylthiophene-3-carboxylate (compound A) (3.0 g) was dissolved in anhydrous methylene chloride (40.0 ml). Subsequently, pyridine (1.5 ml) and 3-(chloromethyl)benzoyl chloride (compound B) (2.8 ml) were added to the solution, and the mixture was stirred at 0° C. for one hr. After the completion of the reaction, distilled water was added, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated to give 2-(3-chloromethyl-benzoylamino-4-methyl-thiophene-3-carboxylic acid ethyl ester as a useful intermediate (3.80 g, yield 70%).
Reaction SMILES: Cl.[N+:2]([O-])([O:4]C1CCNCC1)=[O:3].O[C@H:13]1[C@H:17]2O[CH2:19][C@@H:20]([O:21][C:22](=[O:36])CCC[C@H](O[N+]([O-])=O)CO[N+]([O-])=O)[C@H:16]2O[CH2:14]1.[N+:37]([O-:49])([O:39][C@@H:40]1[CH2:44][O:43][C@@H:42]2[C@H:45]([OH:48])[CH2:46][O:47][C@H:41]12)=[O:38]>>[C:22](=[O:36])([O:21][C:20]1[CH:19]=[CH:14][C:13]([N+:2]([O-:4])=[O:3])=[CH:17][CH:16]=1)[O:48][C@@H:45]1[CH2:46][O:47][C@@H:41]2[C@H:40]([O:39][N+:37]([O-:49])=[O:38])[CH2:44][O:43][C@H:42]12
Reactant: O=[N+]([O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: O=C(CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: O=[N+]([O-])OC1CCNCC1
Agent: Cl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O[N+](=O)[O-]

Procedure:
The title compound was prepared by following the procedure for INTERMEDIATE 13 Step H, except that the reagent (S)-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)5,6bis(nitrooxy)hexanoate was replaced by (3R,3aS,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl nitrate. 1H-NMR (300 MHz, CDCl3); δ 8.37-8.21 (2H, m), 7.46-7.33 (2H, m), 5.41-5.29 (1H, m), 5.20-5.05 (1H, m), 4.97-4.75 (2H, m), 4.25-3.91 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[CH:18]=[CH:17][S:9][C:5]=2[CH:4]=1.[CH2:20]([O:19][CH:18]([O:22][CH2:23][CH3:24])[CH2:17][S:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:21]
Reactant: COc1cccc(S)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(CSc1cccc(OC)c1)OCC
Product: COc1ccc2ccsc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was synthesized by referring to J. Med. Chem., 1989, 32, 2548. To a solution of 3-methoxybenzenethiol (26.9 g) in acetone (100 ml) was added potassium carbonate (27 g), then 2-bromo-1,1-diethoxyethane (29 ml) was added dropwise thereto followed by stirring overnight at room temperature. To the reaction solution was added acetone, the solution was filtered, the solvent was evaporated in vacuo, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide 1-(2,2-diethoxyethylsulfanyl)-3-methoxybenzene (39.1 g). To dichloromethane (2 l) was added boron trifluoride diethyl ether complex (12.7 ml) under a nitrogen atmosphere, then a solution of 1-(2,2-diethoxyethylsulfanyl)-3-methoxybenzene (25.6 g) in dichloromethane (200 ml) was added dropwise over 1.5 hours, the solution was stirred for 40 minutes at room temperature, then a saturated aqueous solution of sodium carbonate (1 l) was added thereto followed by stirring for 1 hour at room temperature. The solution was extracted with dichloromethane, then dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (10.8 g).