Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:38])(=[O:37])([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([C@H:15]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([Cl:35])[C:28]=3[CH3:36])[C@@H:16]([O:18][Si](C(C)(C)C)(C)C)[CH3:17])=[N:13][N:14]=2)=[CH:6][CH:5]=1)[NH2:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[S:1](=[O:38])(=[O:37])([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]([C@H:15]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([Cl:35])[C:28]=3[CH3:36])[C@@H:16]([OH:18])[CH3:17])=[N:13][N:14]=2)=[CH:8][CH:9]=1)[NH2:2]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(OS(N)(=O)=O)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(OS(N)(=O)=O)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a pre-cooled (0° C.) solution of 4-(5-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-cyano-2-methylphenylamino)propyl)-1,3,4-oxadiazol-2-yl)phenyl sulfamate (190 mg, 0.422 mmol) in THF (20 mL) was added TBAF (0.63 mL, 0.63 mmol, 1 M solution in THF) dropwise. The mixture was allowed to warm to room temperature and stirred for two hours, whereupon, concentration under reduced pressure furnished a yellow oil (195 mg). The resulting residue was taken up in EtOAc (60 mL) and washed with H2O (20 mL). The biphasic mixture was separated and the aqueous layer extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel [Dichloromethane-Methanol (7:1) as eluent] to provide the title compound as a white solid (0.032 g, 16%). The resulting solid was diluted with CH2Cl2 (30 mL) and hexanes (70 mL) was added. Upon concentration of the suspension a white solid was provided (1.02 g, 35%). 1H NMR (400 MHz, Acetone d6, δ in ppm) 8.2 (d, J=8.8 Hz, 2 H), 7.99 (d, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 1H), 6.86 (d, J=9 Hz, 1 H), 5.64 (d, J=8 Hz, 1 H), 5.18-5.15 (m, 1 H), 4.81 (br s, 1 H), 4.63 (br s, 1 H), 2.40 (s, 3 H), 1.40 (d, J=7 Hz, 3 H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:5]=1[OH:18])[CH:2]=[CH2:3]>C(Cl)Cl.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:6]1[C:5]([OH:18])=[C:4]([CH:1]=[CH:2][CH3:3])[CH:9]=[CH:8][C:7]=1[F:10]
Reactant: C=CCc1ccc(F)c(-c2ccccc2Cl)c1O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Product: CC=Cc1ccc(F)c(-c2ccccc2Cl)c1O
Yield: 39.4 %

Procedure:
Treatment of 3-allyl-2′-chloro-6-fluoro-biphenyl-2-ol (3.8 g, 14.5 mmol) in methylene chloride (150 mL) with dichlorobis(acetonitrile)palladium (II) (0.56 g, 2.2 mmol) according to the procedure described for Example 69, Step 5 provided 1.5 g (39%) of 2′-chloro-6-fluoro-3-(prop-1-enyl)biphenyl-2-ol as a light yellow oil.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH:8]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])[O:9][C:10]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[CH:22]=[CH:21][C:11]=1[C:12]([NH:14][C:15](=[CH2:20])[C:16]([O:18]C)=[O:17])=[O:13])=[O:5])C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:4]([CH2:6][CH2:7][CH:8]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])[O:9][C:10]1[CH:24]=[C:23]([O:25][CH2:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[CH:22]=[CH:21][C:11]=1[C:12]([NH:14][C:15](=[CH2:20])[C:16]([OH:18])=[O:17])=[O:13])([OH:5])=[O:3]
Reactant: C=C(NC(=O)c1ccc(OCc2ccsc2)cc1OC(CCC(=O)OCC)c1ccccc1C)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=C(NC(=O)c1ccc(OCc2ccsc2)cc1OC(CCC(=O)O)c1ccccc1C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of methyl (RS)-2-[2-(3-ethoxycarbonyl-1-(2-methylphenyl)propoxy)-4-(3-thienylmethoxy)benzoylamino]acrylate (200 mg) in methanol (20 mL) containing 10% w/v potassium carbonate (2 mL) is stirred at ambient temperature for 16 hours and at reflux for 3 hours. The reaction mixture is partitioned between 1N HCl (50 mL) and ethyl acetate (50 mL) then the organic phase is washed with water (2×50 mL), dried over magnesium sulphate, filtered and concentrated under reduced pressure. Recrystallisation from cyclohexane/ethyl acetate gives (RS)-2-[2-(3-carboxy-1-(2-methylphenyl)propoxy)-4-(3-thienylmethoxy)benzoylamino]acrylic acid as a white, fluffy solid (20 mg), m.p. 140-143° C. [Elemental analysis:- C,61.9, H, 5.32, N, 2.53%. Calculated:- C,61.9, H, 5.16, N, 2.78%]
Reaction SMILES: [C:1]([CH2:3][CH:4](OS(C)(=O)=O)[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)#[N:2].[NH:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([CH2:3][CH:4]([N:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1)[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCCN(CC(CC#N)OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(CC(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)CC1
Temperature: 25 °C
Reaction time: 66 h
Yield: 100.8 %

Procedure:
To a solution of tert-butyl 4-{3-cyano-2-[(methylsulfonyl)oxy]propyl}-1,4-diazepane-1-carboxylate (4.00 g, 11.1 mmol) and 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (3.50 g, 11.1 mmol) in DMF (30 mL) was added potassium carbonate (4.6 g, 33 mmol). The resulting mixture was stirred at room temperature for 66 hours. The reaction solution was diluted with ethyl acetate (˜300 mL) then washed with water twice and brine. The organic solutions were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column (0% to 10% methanol/DCM) to give the desired product as clear oil (6.5 g, 100%). LCMS calculated for C29H45N8O3Si(M+H)+: m/z=581.3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.[CH3:14][NH:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C1(N=C=N)CCCCC1>O1CCCC1>[CH3:14][N:15]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:11](=[O:13])[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCC1
Agent: N=C=NC1CCCCC1
Solvent: C1CCOC1
Product: CN(C(=O)Cc1c[nH]c2ccccc12)[C@@H]1CCCC[C@H]1N1CCCC1

Procedure:
1H-Indole 3-acetic acid (1.05 g, Aldrich) and trans-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine were dissolved in tetrahydrofuran (30 ml) and cyclohexyl carbodiimide (1.24 g) added. The resultant solution was stirred at room temperature overnight, during which time a white precipitate appeared. The solution was filtered and evaporated to an oil, which was chromatographed on silica. Elution with ether gave the product as a white solid (1.3 g), mp 175°-178° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[C:21]([CH:24]=1)[C:22]#[N:23]>>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:10]2[CH:11]=[CH:12][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:9]=2)=[O:15])[CH:18]=[CH:19][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:27][CH2:26]1)#[N:23]
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Reactant: O=C(O)c1ccn(-c2ccc(F)cc2)c1
Product: N#Cc1cc(NC(=O)c2ccn(-c3ccc(F)cc3)c2)ccc1N1CCN(C2CCOCC2)CC1
Yield: 57.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-fluorophenyl)pyrrole-3-carboxylic acid (0.3 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (0.5 g), the title compound (0.4 g) was obtained, melting point: 240° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.S(Cl)(Cl)=O.CN(C=O)C.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH2:36])=[N:20]1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C1COCC1.O.CO>[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:36][C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)=[O:9])=[N:20]1
Reactant: Cn1cccc1C(=O)O
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cn1cccc1C(=O)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 40 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
1-Methyl-2-pyrrolecarboxylic acid (1.49 g, 11.9 mmol) was dissolved in methylene chloride (12 mL) and the solution was added with thionyl chloride (1.3 mL, 17.85 mmol) and DMF (276 μL, 3.57 mmol) at 0° C., stirred at 40° C. for 2 hours and then the mixture was concentrated. The mixture was dissolved in THF, added with a solution of (E)-2-[2-(1H-indazol-3-yl)vinyl]phenylamine (700 mg, 2.98 mmol) and triethylamine (1.25 mL, 8.93 mmol) in THF (10 mL) at room temperature, stirred at 60° C. for 4 hours. Further, potassium carbonate and methanol (10 mL) were added to the mixture and stirred for a while and then added with water. The precipitated solid was collected by filtration and reslurried with ethanol to obtain Compound 29 (703 mg, 69%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([N:17]3[N:18]=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:25][CH:24]=4)[C:20]([C:21]#[N:22])=[C:16]3[NH:15][C:14]2=[O:36])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:37]>OP(O)(O)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([N:17]3[N:18]=[C:19]([C:23]4[CH:24]=[CH:25][C:26]([O:29][C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:27][CH:28]=4)[C:20]([C:21]([NH2:22])=[O:37])=[C:16]3[NH:15][C:14]2=[O:36])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)C21CCN(Cc2ccccc2)CC1
Agent: O=P(O)(O)O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)C21CCN(Cc2ccccc2)CC1
Yield: 58 %

Procedure:
A solution of 1′-benzyl-2-oxo-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carbonitrile (200 mg, 0.42 mmol) in H3PO4 (15 mL) was heated to 120° C. for 2 hr. The solution was poured to water (10 mL) and extracted with EA (10 mL×3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product (120 mg, 58.0%) as an off-white solid. MS (ESI, m/e) [M+1]+ 493.9.
Reaction SMILES: [PH2:1](=[O:3])[OH:2].[CH2:4]([C:8](=[CH2:19])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH:5]([CH3:7])[CH3:6].C(N(CC)CC)C.C[Si](Cl)(C)C>ClCCl>[CH2:12]([O:11][C:9]([CH:8]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:19][PH:1](=[O:2])[OH:3])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=C(CC(C)C)C(=O)OCc1ccccc1
Reactant: O=[PH2]O
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CC(C[PH](=O)O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.1 %

Procedure:
A vigorously stirred mixture of 17.6 g (0.27 mol) of crystalline phosphinic acid and 43.6 g (0.2 mol) of benzyl 2-isobutylacrylate in 400 ml of dichloromethane was cooled to 0° C. and treated dropwise with 53.4 g (0.53 mol) of triethylamine while maintaining the temperature at below 5° C. After completion of the addition, a solution of 56.0 g (0.52 mol) of trimethylsilyl chloride in 100 ml of dichloromethane was added while stirring vigorously and maintaining the temperature at 10-12° C. After 30 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 24 hours. The mixture was then treated with 200 ml of water and 30 ml of 10% sulfuric acid. The organic phase was separated and washed with 200 ml of saturated sodium chloride solution. The combined aqueous extracts were re-extracted with 100 ml of dichloromethane and the organic phase was washed with 100 ml of sodium chloride solution and added to the previously obtained dichloromethane extracts. After drying over anhydrous sodium sulfate, the dichloromethane was removed by evaporation to give 59.2 g of [(RS)-2-[(benzyloxy)carbonyl]-4-methylpentyl]phosphinic acid in the form of a colorless oil. (b) The compound prepared in the preceding paragraph was dissolved in 600 ml of ethyl acetate. Thereafter, 25.0 g of S(-)-α-methylbenzylamine were added and the solution was left to crystallize for 24 hours. The crystalline salt was collected by filtration and dried to give 34.0 g of a white solid which was recrystallized overnight from a mixture of 120 ml of ethanol and 48 ml of ethyl acetate. The solid was collected and dried to give 21.3 g of a crystalline salt which was recrystallized overnight from a mixture of 120 ml of ethanol and ethyl acetate. There were obtained 16.8 g of [(R or S)-2-[(benzyloxy)carbonyl]-4-methylpentyl]phosphinic acid S(-)-α-methylbenzylamine salt in the form of white crystals of melting point 137-138° C. and [α]58920 =-8.9° (c=5% in ethanol).
Reaction SMILES: [CH2:1]([N:5]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)[C:6](=[O:17])[CH:7](Cl)[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1)[CH:2]=[CH:3][CH3:4].C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[CH2:3]([CH:2]1[CH2:1][N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[C:6](=[O:17])[CH:7]1[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1)[CH3:4]
Reactant: CC=CCN(C(=O)C(Cl)c1cc(F)cc(F)c1)c1cccc(C(F)(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CCC1CN(c2cccc(C(F)(F)F)c2)C(=O)C1c1cc(F)cc(F)c1
Reaction time: 0.33 h

Procedure:
N-(2-Butenyl)-N-(3-trifluoromethylphenyl)-2-chloro-2-(3,5-difluorophenyl)acetamide (1.6 g) was added to 30 ml of benzene, followed by the addition of 1.1 ml of tributyltin hydride and a catalytic amount of α,α-azobisisobutyronitrile (AIBN) under stirring at the refluxing temperature. The reaction mixture was then stirred for 20 minutes at the refluxing temperature. The reaction mixture was then concentrated in an evaporator. The resultant concentrate was purified by chromatography on a silica gel, whereby 0.75 g of the 3,4-trans isomer of 4-ethyl-3-(3,5-difluorophenyl)-1-(3-trifluoromethylphenyl)-2-pyrrolidinone and 0.14 g of its 3,4-cis isomer were obtained.
Reaction SMILES: [H-].[Na+].C([N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=O)=C.[Br:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1C(OCC)=O.Cl>O1CCCC1>[Br:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:6]1[CH2:7][CH2:8][CH2:9][N:5]=1
Reactant: C=CN1CCCC1=O
Reactant: CCOC(=O)c1ccccc1Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccccc1C1=NCCC1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 94.1 %

Procedure:
Sodium hydride (977 mmol, 23.45 g) was suspended in tetrahydrofuran (700 mL) and cooled to 5° C. with an ice-water bath. To this cold suspension was added 1-vinyl-pyrrolidin-2-one (465 mmol, 51.7 g) over approximately 20 minutes, maintaining an internal temperature reaction temp of less than 5° C. then ethyl 2-bromobenzoate (437 mmol, 100 g) was added. After the addition was complete the reaction was stirred at 5° C. for 10 minutes then refluxed for 2 hours and allowed to cool to room temperature. To the suspension was added 5N HCl (600 mL) dropwise, maintaining reaction temperature between 25° C. and 35° C. The bulk of the tetrahydrofuran was then distilled off at a temperature of 60° C. under vacuum. The resulting solution was cooled and further 5N hydrochloric acid (600 mL) was added and the mixture was refluxed overnight. The solution was then cooled with a salt-ice bath to 5° C. and basified by the careful addition of sodium hydroxide pellets (˜250 g) maintaining an internal temperature between 10 and 15° C. When reaction mixture was at pH 13, the cooling bath was removed and temperature allowed to reach room temperature. The reaction was then extracted with methylene chloride (1 L) and the aqueous layer was extracted with further methylene chloride (2×1 L). The combined methylene chloride extracts were dried with sodium sulfate, filtered and evaporated to dryness to give 5-(2-bromophenyl)-3,4-dihydro-2H-pyrrole (92.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[OH:27][CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.[H-].[Na+]>CC#N>[Cl:1][C:2]1[C:3]([O:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: OCCN1CCCC1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c2c1OCCN1CCCC1
Yield: 50 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.010 g, 0.025 mmol), 1-(2-hydroxyethyl)pyrrolidine (0.5 ml) and sodium hydride were heated to 120° C. for 3 h. The reaction mixture was diluted with CH3CN and purified by HPLC-C18, giving the title product (0.006 g, 50%)
Reaction SMILES: C(O)(=O)C.Cl[CH2:6][C:7](=[O:30])[C@@:8]1([OH:29])[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][C:9]1=[CH2:28]>C(OCC)(=O)C.[Zn]>[OH:29][C@@:8]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][C:9]1=[CH2:28])[C:7](=[O:30])[CH3:6]
Reactant: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@]1(O)C(=O)CCl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@]1(O)C(C)=O
Reaction time: 16.5 h

Procedure:
Zinc dust (0.030 mg) and glacial acetic acid (0.13 ml) is added to a solution of 21-chloro-17β-hydroxy-16-methylenepregn-4-ene-3,20-dione (III, EXAMPLE 40B, 0.050 g) in ethyl acetate (1.5 ml). The reaction system is purged with nitrogen and warmed to 45°. After stirring for 16.5 hr, THF (5 ml) is added and the mixture is filtered thru celite to remove the remaining zinc. The filtrate is then partitioned between water (5 ml) and ether (5 ml). The organic extract is washed with sodium bicarbonate (5%) and water, dried over sodium sulfate and concentrated to give the title compound, NMR (CD2Cl2) 0.87, 1.17, 2.20, 3.40, 5.10 and 5.65 δ.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C@H:5]([CH:46]([CH3:48])[CH3:47])[CH2:6][C@H:7]([OH:45])[C@@H:8]([NH:16][C:17]([C@@H:19]([NH:26][C:27]([C@@H:29]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)=[O:18])[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CS[C:51]([NH:53][C:54](=[O:63])[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[NH:52].CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:40]([O:39][C:38]([NH:37][C@H:29]([C:27]([NH:26][C@H:19]([C:17]([NH:16][C@@H:8]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[C@@H:7]([OH:45])[CH2:6][C@@H:5]([CH:46]([CH3:48])[CH3:47])[CH2:4][CH2:3][NH:2][C:51]([NH:53][C:54](=[O:63])[O:55][CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)=[NH:52])=[O:18])[CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)=[O:28])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:44])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)[C@@H](CCN)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CSC(=N)NC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](CCNC(=N)NC(=O)OCc1ccccc1)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 80 %

Procedure:
0.136 g (0.197 mmol) of t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-6-amino-1-(cyclohexylmethyl)-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate hydrochloride, 0.051 g (0.2 mmol) of benzyl [(methylthio)formimidoyl]carbamate and 0.07 ml (0.34 mmol) of Hunig base in 1 ml of absolute ethanol are stirred at 70° under argon for 3 hours. Thereafter, the reaction mixture is cooled, poured into 2N potassium carbonate solution and extracted with methylene chloride. The methylene chloride extracts are dried over magnesium sulphate and evaporated under reduced pressure. Chromatography of the residue obtained on 2 g of silica gel with a mixture of methylene chloride and isopropanol as the eluting agent yields 0.131 g of benzyl [N-[(3S,5S,6S)-6-[[N-[N-(t-butoxycarbonyl)-3-phenyl-L-alanyl]-L-histidyl]amino]-7-cyclohexyl-5-hydroxy-3-isopropylheptyl]amidino]carbamate as a colourless oil, MS: 831 (M+H)+.
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[NH2:27][C@@H:28]1[CH2:32][C@H:31]([CH2:33][OH:34])[CH:30]=[CH:29]1.[Cl:35][C:36]1[C:41]([NH:42][CH:43]=[O:44])=[C:40](Cl)[N:39]=[C:38]([NH:46][C:47](=[O:49])[CH3:48])[N:37]=1.C(N(CC)CC)C>O.C(O)C>[Cl:35][C:36]1[C:41]([NH:42][CH:43]=[O:44])=[C:40]([NH:27][C@H:28]2[CH2:32][C@@H:31]([CH2:33][OH:34])[CH:30]=[CH:29]2)[N:39]=[C:38]([NH:46][C:47](=[O:49])[CH3:48])[N:37]=1
Reactant: CC(=O)Nc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: N[C@H]1C=C[C@@H](CO)C1
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)Nc1nc(Cl)c(NC=O)c(N[C@@H]2C=C[C@H](CO)C2)n1

Procedure:
(1S,4R)-4-Amino-2-cyclopentene-1-methanol dibenzoyl-D-tartrate prepared as described in Example 13 (2.76 g, 9.02 mmol) was dissolved in water (20 ml) and applied to a column of 65 ml of Amberlite IA-400 (OH- form) anion exchange resin. The column was washed with water. Basic fractions were combined and evaporated to a residual oil which was dried by evaporation of absolute ethanol and then at 0.5 mm to give oil (darkens rapidly in air) which was used immediately. This oil was dissolved in ethanol (5 ml) and added to a solution of N-(4,6-dichloro-5-formamido-2-pyrimidinyl)acetamide (2.07 g, 8.31 mmol), prepared as described in Example 15, and triethylamine (2.50 g, 24.8 mmol). The resulting dark solution was heated (oil bath 75°-80° C.) under nitrogen for 50 minutes. The solution was evaporated to a syrup which was applied to a silica gel column. Title compound was eluted with 3 to 5% methanol-chloroform as a pale yellow solid foam (1.59 g, 54%); 1H-NMR identical with that of crystallized sample. Such a sample was crystallized from ethanol to give white granules, m.p. 194°-195° C.; 1H-NMR (DMSO-d6) identical with that of the title compound of Example 15; [α]20D +2.7°, [α]54620 +2.9°, [α]43620 -2.5°, [α]36520 -41.2° (c=0.238, methanol).