Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH2:32]([O:39][C:40]1[CH:41]=[C:42]([CH:46]([CH:48]2[CH2:50][CH2:49]2)O)[CH:43]=[N:44][CH:45]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[OH:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1.N1(C2OC(N3CCCCC3)=NN=2)CCCCC1>C1(C)C=CC=CC=1>[CH2:32]([O:39][C:40]1[CH:45]=[N:44][CH:43]=[C:42]([C@H:46]2[CH2:48][C@@H:50]2[CH2:49][O:51][C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)[CH:41]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Oc1cccnc1
Reactant: OC(c1cncc(OCc2ccccc2)c1)C1CC1
Agent: C1CCN(c2nnc(N3CCCCC3)o2)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: c1ccc(COc2cncc([C@H]3C[C@@H]3COc3cccnc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.7 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (237 mg, 0.94 mmol, 1.6 equiv.) was dissolved in 2 mL of toluene (dried with molecular sieve 3 Å) in a 10 mL round-bottom flask with a side neck. The flask was equipped with rubber septa and a magnetic stirrer. The atmosphere was exchanged with Ar (3 times), and the flask was cooled with an ice bath. Tri-n-butylphosphine (232 μL, 0.94 mmol, 1.6 equiv.) was added dropwise. The mixture was warmed to room temperature and stirred for 10 min. The resulting colorless solution was then added dropwise (via syringe) with ice cooling to a solution of (1S,2S)-2-[(5-(benzyloxy)-3-pyridyl]cyclopropylmethanol (50 mg, 0.59 mmol) and 3-hydroxypyridine (89 mg, 0.94 mmol, 1.6 equiv.) in a 25 mL round-bottom flask (equipped with a magnetic stirrer and an Ar balloon). The resulting mixture was warmed to room temperature and stirred for 6 h. Air was bubbled through the mixture with stirring for 1 h. Toluene was evaporated, and the residue was purified by CC on SiO2 (15×1.0 cm, EtOAc) to give the crude product, which was contaminated with a by-product, 2,5-di-(1-piperidinyl)-1,3,4-oxadiazole. This material was further purified by preparative HPLC in two portions (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 20% to 100% CH3CN in water within 40 min, then 100% CH3CN for 20 min; tR 22.7-24.0 min) to give a yellowish oil (125 mg, 64%). MS (EI) m/z 332 (M+, 67%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:21])[CH:9]=[C:10]([C:12]3[CH:17]=[C:16]([Cl:18])[C:15]([NH2:19])=[C:14]([Cl:20])[CH:13]=3)[O:11][C:6]=2[C:5]([F:22])=[C:4]([CH2:23][O:24][C:25](=[O:28])[CH2:26]Cl)[C:3]=1[F:29].Cl.[CH3:31][NH:32][CH3:33].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:21])[CH:9]=[C:10]([C:12]3[CH:13]=[C:14]([Cl:20])[C:15]([NH2:19])=[C:16]([Cl:18])[CH:17]=3)[O:11][C:6]=2[C:5]([F:22])=[C:4]([CH2:23][O:24][C:25](=[O:28])[CH2:26][N:32]([CH3:33])[CH3:31])[C:3]=1[F:29]
Reactant: CNC
Reactant: Nc1c(Cl)cc(-c2cc(=O)c3c(N)c(F)c(COC(=O)CCl)c(F)c3o2)cc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3cc(Cl)c(N)c(Cl)c3)oc2c1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
2.00 g (4.31 mmol) of Compound 171 obtained in Example 171 was dissolved in 80 mL of dimethylformamide, 1.76 g (21.6 mmol) of dimethylamine hydrochloride and 3.75 mL (21.6 mmol) of diisopropylethylamine were added, and the mixture was stirred at 50° C., for 3 hours. Water was added to the reaction solution and the precipitated crystals were collected by filtration. The crystals were purified by silica gel column chromatography (chloroform:methanol=9:1), to give 1.68 g of Compound 172 (yield: 83%).
Reaction SMILES: [NH2:1][C:2](=[O:36])[CH2:3][C:4]1[CH:35]=[CH:34][CH:33]=[CH:32][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([NH:24]C(=O)OC(C)(C)C)[CH3:23])=[CH:18][CH:17]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH3:1].[NH2:24][CH:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:10]2[N:9]=[C:8]([CH2:7][CH2:6][C:5]3[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=3[CH2:3][C:2]([NH2:1])=[O:36])[C:13]([Cl:14])=[CH:12][N:11]=2)=[CH:21][CH:20]=1)[CH3:23]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(Cl)c(CCc3ccccc3CC(N)=O)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)c1ccc(Nc2ncc(Cl)c(CCc3ccccc3CC(N)=O)n2)cc1
Product: N
Temperature: 25 °C
Reaction time: 2 h
Yield: 174.3 %

Procedure:
To a solution of tert-butyl 1-(4-(4-(2-(2-amino-2-oxoethyl)phenethyl)-5-chloropyrimidin-2-ylamino)phenyl)ethylcarbamate (A140) (0.0070 g, 0.014 mmol) in DCM (1 mL) was added TFA (0.50 mL). The mixture was stirred at ambient temperature for 2 hours before the volatiles were removed in vacuo. The crude residue was purified using an SCX cartridge, (MeOH then 2 N ammonia in EtOH eluent) to give the title compound (37) as a grey solid (0.005 g, 89%). LCMS-C: rt 4.29 min; m/z 410 [M+H]+
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[C:20]1([CH2:26][C:27]([OH:29])=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)(=O)C>O>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7](/[CH:10]=[C:26](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[C:27]([OH:29])=[O:28])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)Cc1ccccc1
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCCCc1ncc(/C=C(/C(=O)O)c2ccccc2)n1Cc1ccccc1Cl
Temperature: 140 °C
Reaction time: 6 h
Yield: 18.1 %

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde (554 mg, 2 mmol), phenylacetic acid (310 mg, 2.3 mmol), potassium carbonate (126 mg, 0.91 mmol), and acetic anhydride (1 mL) was heated gradually to 140° C. and held at this temperature for 6 hours. The cooled reaction was diluted with water and the oily solid was separated, triturated several times with ether, and the solid was crystallized several times from methanol/ethyl acetate to give 143 mg (18%) of the title compound; mp 210°-212° C. The NMR was consistent with the trans olefinic product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[N+:24]([O-])=O)[O:5][CH2:6][C:7]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12]>C(O)(=O)C.[Fe]>[NH2:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][CH2:6][C:7]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:8]=2[O:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc([N+](=O)[O-])c(F)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(N)c(F)c1
Yield: 61.3 %

Procedure:
By the method of Example 2, Step A, 3.35 g (0.0091 mole) of methyl 2-[2-(3-fluoro-4-nitrophenoxymethyl)-5-methylphenoxy]propionate was reacted with 2.80 g (0.050 mole) of powdered iron in 100 mL of acetic acid, yielding 1.86 g of methyl 2-[2-(4-amino-3-fluorophenoxymethyl)-5-methylphenoxy]-propionate as an amber syrup. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: C(OC([N:8]1[CH2:26][C@@H:25]([CH3:27])[N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]([F:23])([F:22])[F:21])=O)(C)(C)C.[ClH:28]>CCOCC.O>[ClH:28].[CH3:27][C@H:25]1[N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9][NH:8][CH2:26]1)=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]([F:23])([F:22])[F:21]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2c3cccc(OC(F)(F)F)c3C(=O)N12
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: C[C@@H]1CNC[C@H]2c3cccc(OC(F)(F)F)c3C(=O)N12
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(4R,10bR)-1,3,4,10b-tetrahydro-4-methyl-7-trifluoromethoxy-pyrazino[2,1-a]isoindol-6(2H)-one(30 mg, 0.08 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 21 mg of a white solid. MS (ESI) 271 (M−Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][N:28]([CH3:40])[C:29]([S:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1)=[O:30]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:37][CH2:36][C:35]1[CH:34]=[CH:33][C:32]([S:31][C:29](=[O:30])[N:28]([CH3:27])[CH3:40])=[CH:39][CH:38]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CN(C)C(=O)Sc1ccc(CN)cc1
Product: CN(C)C(=O)Sc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 43.7 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (348 mg, 0.8 mmol) with 4-dimethylcarbamoylthio-benzylamine (345 mg, 1.6 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate (170 mg, 43%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[OH:14][CH2:15][CH2:16][C:17]1[S:21][C:20]([CH2:22][C:23](O)=[O:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1COCC1>[Si:1]([O:24][CH2:23][CH2:22][C:20]1[S:21][C:17]([CH2:16][CH2:15][OH:14])=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)Cc1ccc(CCO)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(CCO)s1
Reaction time: 1 h

Procedure:
tert-Butyldimethylsilyl chloride (6.63 g) was added portionwise to a solution of imidazole (2.99 g) and 2-(5-(2-hydroxyethyl)thiophen-2-yl)acetic acid [WO 2008096129] (3.9 g) in DMF (50 mL) over 20 minutes. The resulting solution was stirred for 1 h. THF (50 mL) was then added and the reaction cooled in an ice bath. A solution of potassium carbonate (4.05 g) in water (50 mL) was then added and the mixture stirred for 20 min. The reaction was partitioned between ethyl acetate and brine. The organic layer was separated and washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated in vacuo. The residue was dissolved in THF (80 mL) and borane tetrahydrofuran complex (1M solution in THF, 62.8 mL) was added dropwise. The resulting solution was stirred for 2 h and quenched by dropwise addition of methanol (30 mL). The solvents were then evaporated in vacuo. Purification was by silica gel chromatography, eluting with 83:17 isohexane:ethyl acetate to give the subtitled compound as a yellow liquid. Yield 4.6 g.
Reaction SMILES: FC1C=CC=CC=1NN[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C.C(Cl)(Cl)(Cl)[Cl:42]>>[Cl:42][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]
Reactant: O=C(NNc1ccccc1F)c1ccccc1F
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C(Cl)c1ccccc1F
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a stirred mixture, under nitrogen, of 3.0 g of 2-fluorobenzoic acid, 2-(2-fluorophenyl)hydrazide, 3.0 g of triphenylphosphine, and 25 ml of acetonitrile was added, dropwise, 1.6 g of carbon tetrachloride. The reaction mixture was stirred for 22 hours at ambient temperature and concentrated to an oil. Flash chromatography on silica gel, eluting with 25% ethyl acetate/hexane afforded α-chloro-2-fluorobenzaldehyde, (2-fluorophenyl)hydrazone as an oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[CH:7][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[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[CH:7][N:8]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=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[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1ncn(Cc2ccc(F)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A mixture of 4′-[(4-butyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.5 g), sodium hydride (0.07 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-4-fluorobenzene (0.22 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 (0.54 g, 82%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20](O)=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl.[CH3:31][O:32][C:33](=[O:37])[C@@H:34]([CH3:36])[NH2:35]>C(Cl)Cl>[CH3:2][C:1]([CH3:3])([O:5][C:6]([NH:8][CH:9]([C:20]([NH:35][C@@H:34]([C:33]([O:32][CH3:31])=[O:37])[CH3:36])=[O:21])[CH2:10][C:11]1[C:12]([CH3:19])=[CH:13][C:14]([OH:18])=[CH:15][C:16]=1[CH3:17])=[O:7])[CH3:4]
Reactant: COC(=O)[C@@H](C)N
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)NC(=O)C(Cc1c(C)cc(O)cc1C)NC(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
Racemic t-butoxycarbonyl 2,6-dimethyltyrosine (3.9 g, 10 mmol) was dissolved in 30 ml of CH2Cl2 by adding 1.12 ml (10 mmol) of NMM. After bringing this mixture to reflux it was cooled to -30° C. and 1.32 ml (10 mmol) of IBCF were added to this stirred solution. The temperature was allowed to rise to -15° C. and then lowered to -50° C. (D)alanine methyl ester hydrochloride (1.54 g, 11 mmol) was added to the solution followed by 1.3 ml (11 mmol) of NMM. The mixture was allowed to warm to room temperature and stand for 16 h. The majority of the CH2Cl2 was removed under reduced pressure. Ethyl acetate (EtOAc, 200 ml) was added and this solution was washed twice with 100 ml portions of 0.5 molar KHSO4, once with 100 ml of H2O and dried over MgSO4. Removal of all solvent gave 3.9 g of the mixture of diastereomers. Recrystallization of this material from Skelly B(hexanes)/CH2Cl2 produced 1.6 g (4.2 mmol) of diastereomer F. Removal of the solvent from the filtrate gave 1.3 g (3.3 mmol) of diastereomer S contaminated by less than 10% of diastereomer DF. The mixture of diastereomers or either of the separated diastereomers were used in subsequent examples without further purification.
Reaction SMILES: [S:1]([Cl:5])([Cl:4])(=[O:3])=[O:2].[CH3:6][NH:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11]>C(Cl)(Cl)Cl>[Cl-:4].[Cl:5][S:1]([N:7]([CH3:6])[CH2:8][CH2:9][NH+:10]([CH3:12])[CH3:11])(=[O:3])=[O:2]
Reactant: CNCCN(C)C
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CN(CC[NH+](C)C)S(=O)(=O)Cl
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of sulfuryl chloride (1.0 eq.) in CHCl3 at 0° C. was added dropwise trimethylethylenediamine (1.0 eq.) over 15 mins. After the addition, the cooling bath was removed and the mixture was stirred overnight at RT. The solvent was removed under reduced pressure and the residue was left under high vacuum for 4 h. The crude product was obtained as a pale yellow solid and was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ: 3.46-3.29 (4H, m), 2.83 (6H, s), 2.60 (3H, s).
Reaction SMILES: S(Cl)(Cl)(=O)=O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(Cl)(Cl)(Cl)[Cl:20]>[OH-].[Na+]>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:9][C:8]=1[Cl:20]
Reactant: Oc1ccc(C2CCOCC2)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(=O)(Cl)Cl
Product: Oc1ccc(C2CCOCC2)cc1Cl

Procedure:
10 ml of sulfuryl chloride were added with stirring to a mixture of 14.1 g of 4-(p-hydroxyphenyl)-tetrahydropyran and 40 ml of carbon tetrachloride and the mixture was heated to 45°-50° C for 16 hours. The mixture was concentrated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with methylene chloride yielded a crystal product which was dissolved in 200 ml of N sodium hydroxide and the solution was washed with ether and acidified with 2N hydrochloric acid. The mixture was extracted with ether and the organic phase was washed with water, then an aqueous sodium bisulfite solution and then with water. The extracts were dried and evaporated to dryness to obtain 6.4 g of 4-(4-hydroxy-3-chlorophenyl)-tetrahydropyran melting at 123°-125° C.
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:39][C:40]1[CH:41]=[C:42]([CH:47]=[C:48]([F:51])[C:49]=1F)[C:43]([O:45][CH3:46])=[O:44].N[C@H](C(O)=O)[C@@H](C)O>C(OCC)(=O)C.CS(C)=O>[C:16]([O:15][C:14]([N:13]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:25][N:24]([C:49]2[C:48]([F:51])=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][C:40]=2[F:39])[CH2:23]1)[C@@H:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:12])=[O:20])([CH3:18])([CH3:19])[CH3:17]
Reactant: COC(=O)c1cc(F)c(F)c(F)c1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: C[C@@H](O)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)c(N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)c(F)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 10 ml DMSO solution of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate was mixed with 1.3 g of potassium carbonate and 1.0 g of methyl 3,4,5-trifluorobenzoate and stirred overnight at 110° C. Thr reaction solution was mixed with ethyl acetate, washed with water and dried with anhydrous sodium sulfate. This was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (hexane-ethyl acetate) to obtain 2.1 g of methyl 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-3,5-difluorobenzoate as a colorless amorphous substance.
Reaction SMILES: C(O)C.[H-].[Na+].[CH:6]1([C:10](=[O:12])[CH3:11])[CH2:9][CH2:8][CH2:7]1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].S(=O)(=O)(O)O.O>>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[O:19])[CH:11]=[C:10]([CH:6]1[CH2:9][CH2:8][CH2:7]1)[OH:12])[CH3:18]
Reactant: CC(=O)C1CCC1
Reactant: CCOC(=O)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=O)C=C(O)C1CCC1
Reaction time: 8 h

Procedure:
Ethanol (4.39 mL, 75.2 mmol) was added dropwise to a suspension of sodium hydride (0.607 g, 15.2 mmol, 60% in mineral oil) in a flask that was held in an ice bath. Ten minutes after complete addition, a mixture of 1-cyclobutylethanone (1.5 mL, 14 mmol, Aldrich) and diethyl oxalate (2.01 g, 13.8 mmol, Aldrich) was added dropwise. After stirring overnight, 4.0M sulfuric acid in water (0.00759 L, 30.4 mmol) was added. The product was extracted into diethyl ether. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The material was used without further purification in Step B.
Reaction SMILES: Cl[C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[NH:18]([CH2:22][CH2:23][OH:24])[CH2:19][CH2:20][OH:21]>O1CCOCC1>[OH:21][CH2:20][CH2:19][N:18]([C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[CH2:22][CH2:23][OH:24]
Reactant: COC(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: OCCNCCO
Solvent: C1COCCO1
Product: COC(=O)c1cc(N(CCO)CCO)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 97 %

Procedure:
Methyl 5-chloro-2,4-dinitrobenzoate (IV) (1.24 g, 4.76 mmol) was treated with diethanolarnine (1.00 g, 9.52 mmol) in dioxane (50 mL) at 50 ° C. for 3 h, and the residue after workup was chromatographed on silica gel. Elution with EtOAc gave methyl 5-[N,N-bis(2-hydroxyethyl)amino]-2,4-dinitrobenzoate (V) (1.52 g. 97%). mp (EtOAc/petroleum ether) 104°-106° C. 1H NMR (CDCl3) δ8.48 (s, 1 H, H-3), 7.45 (s, 1H, H-6), 3.95 (s, 3H, OCH3), 3.81 (t, J=5.0 Hz, 4 H, CH2OH), 3.60 (t,J=5.0 Hz, 4H, CH2N), 2.20 (br, 2H, OH). 13C NMR δ165.89 (COOMe), 147.53 (C-5), 138.67, 136.21 (C-2,4), 133.30 (C-1), 124.22. 121.65 (C-3,6), 59.34 (CH2OH), 54.59 (CH2N), 53.74 (OCH3). Anal. (C12H15N3O8) C,H,N.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Br:7][C:8]1[C:9](=[O:20])[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[CH:12]=2.BrC1C=CC(S(O[C@@H:32]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44]([O:46][CH3:47])=[O:45])[CH2:33]2)(=O)=O)=CC=1.CCOC(C)=O>CN1C(=O)CCC1.O>[Br:7][C:8]1[C:9]([O:20][C@H:32]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44]([O:46][CH3:47])=[O:45])[CH2:33]2)=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[CH:12]=2
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reactant: COc1ccc2cc(Br)c(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](Oc2nc3cc(OC)ccc3cc2Br)CN1C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 40 h

Procedure:
Cs2CO3 (2.11 g, 6.46 mmol) was added to a solution of 3-bromo-7-methoxyquinolin-2(1H)-one (1.31 g, 5.17 mmol) and 1-text-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (2.0 g, 4.31 mmol) in NMP (21.5 mL), and the reaction mixture was stirred for 40 h at 40° C. An additional portion of 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (1.0 g, 2.16 mmol) was added, and the reaction mixture was stirred at 40° C. for 16 h. The reaction mixture was cooled and poured onto a mixture of EtOAc and water, and the layers were separated. The organic layer was washed with water twice, NaHCO3 twice and brine, dried over Mg2SO4, filtered and concentrated. The product was used with no further purification. LRMS (M+H-Boc)+=381.2.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:45]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:44]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:45])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCOC(=O)Cl
Reactant: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCCOCc3ccccc3)c3ccccc3)ccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCCOCc4ccccc4)c4ccccc4)ccc3n2C)cc1
Yield: 73 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide-hydrochloride and n-hexyl chloroformate. Yield: 73% of theory, C40H46N6O4 (674.9) Rf value: 0.46 (silica gel; dichloromethane/ethanol=9:1) ##EQU135##