Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH:17]=[CH:18][C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH3:31])[CH2:12]1)=O)C1C=CC=CC=1>Cl>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[S:23][C:19]([CH:18]=[CH:17][CH:13]3[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]3)=[C:20]([CH3:31])[N:21]=2)=[CH:25][CH:26]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C=CC1CCCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Product: Cc1nc(-c2ccc(Cl)cc2)sc1C=CC1CCCNC1
Yield: 91.8 %

Procedure:
1-Benzyloxycarbonyl-3-[2-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]ethenyl]piperidine (1.16 g, 2.56 mmol) in 6 mol/L hydrochloric acid (25 mL) was stirred for 1 hour while being refluxed. Subsequently, the reaction mixture washed with ethyl acetate. A 10 mol/L aqueous sodium hydroxide solution was then added to make the mixture basic and the mixture was extracted with ethyl acetate. The extract washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. The residue was air-dried to give 749 mg (92%) of the desired compound as a yellow powder.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18]N[CH2:16][CH2:15]1)(C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:21].[Na+].[Na+]>O1CCCC1>[CH2:15]([N:14]([CH2:19][CH3:18])[C:1](=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The mixture of benzhydrylpiperazine epimers (7.6 g, 14.9 mmol) was dissolved in 50 mL of dry tetrahydrofuran with 1.6 mL (18.6 mmol) of alkyl bromide and 5.1 g (36.9 mmol) of sodium carbonate and stirred at room temperature under nitrogen for 2 days. The reaction solution was poured into ice water/ethyl acetate and separated. The organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in a small amount of dichloromethane and placed on a column of silica gel. The diastereomers were separated by elution with a stepwise gradient of ethanol in dichloromethane. The first isomer was eluted with 1.3% ethanol in dichloromethane, and the second isomer was obtained with 1.6% ethanol in dichloromethane. Fractions containing the second isomer were combined and the solvent removed in vacuo to give 1.44 g of 4-(αR)-α-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-N,N-diethylbenzamide as a brown oil.
Reaction SMILES: C1(O)C=CC=CC=1.C(O)C/C=C/CCCCCC.CCOC(/N=N/C(OCC)=O)=O.[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]CCCCCCCC)=[CH:36][CH:35]=1>CCOCC>[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42]/[CH:43]=[CH:44]/[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:36][CH:35]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: CCCCCC/C=C/CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: CCCCCC/C=C/CCOc1ccc(C(=O)OC)cc1
Yield: 85 %

Procedure:
Ester 34 (500 mg, 3.29 mmol), 3-decenol 26h (514 mg, 3.29 mmol), TPP (992 mg, 3.78 mmol), DEAD (658 mg, 3.78 mmol), and 33 ml ether were reacted according to the procedure for compound 35a. The crude product was purified via flash chromatography over silica gel with gradual elutions from 95/5-90/10 (v/v, Hex/EtOAc). Evaporation of solvent yielded 810 mg (85%) of colorless liquid which was not quite pure. The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[C:11](O)(=[O:13])C.C1N2CN3CN(C2)CN1C3>O>[Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([CH:11]=[O:13])[C:5]2=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2n1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2nc(Br)ccc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
6-Bromo-1H-pyrrolo[2,3-b]pyridine (0.028 g, 0.14 mmol) was successively added with acetic acid (0.1 mL), water (0.2 mL), and hexamethylenetetramine (0.028 g, 0.20 mmol), and then the mixture was stirred overnight at 120° C. in a sealed tube. The reaction mixture was added with water, and the precipitated solid was collected by filtration to obtain 6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.008 g, 25%).
Reaction SMILES: NC(N)=O.[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH:9]([N:15]=[C:16]=[O:17])[CH2:10]2.Cl.[F:19][CH2:20][CH2:21][NH2:22].C(N(C(C)C)CC)(C)C>>[F:19][CH2:20][CH2:21][NH:22][C:16]([NH:15][CH:9]1[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[F:5])[CH2:10]1)=[O:17]
Reactant: NCCF
Reactant: O=C=NC1Cc2cccc(F)c2C1
Agent: Cl
Agent: NC(N)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCF)NC1Cc2cccc(F)c2C1

Procedure:
The title urea was generated from 4-fluoro-2-isocyanato-indan (11.10 mmol), fluoroethyl amine hydrochloride (1.10 g, 90% purity, 9.95 mmol) and diisopropylethyl amine (3.90 mL, 22.39 mmol) according to the protocols as outlined in general procedure G. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ 2.67-2.80 (m, 2H), 3.12-3.28 (m, 3H), 3.31-3.37 (m, 1H), 4.23-4.55 (m, 3H), 6.0 (t, 1H, J=6.7 Hz), 6.4 (d, 1H, J=7.0 Hz), 7.0 (t, 1H, J=9.1 Hz), 7.1 (d, 1H, J=7.3 Hz), 7.15-7.24 (m, 1H).
Reaction SMILES: [C:1]([Mg]Br)([CH3:3])=[CH2:2].[CH:6]([SiH:9]([CH:11]([CH3:13])[CH3:12])Cl)([CH3:8])[CH3:7]>C1COCC1>[C:1]([SiH:9]([CH:11]([CH3:13])[CH3:12])[CH:6]([CH3:8])[CH3:7])([CH3:3])=[CH2:2]
Reactant: C=C(C)[Mg]Br
Reactant: CC(C)[SiH](Cl)C(C)C
Solvent: C1CCOC1
Product: C=C(C)[SiH](C(C)C)C(C)C
Temperature: 40 °C

Procedure:
0.5 M isopropenylmagnesium bromide in THF (Aldrich, 320 mL, 160 mmol, 1.1 eq. to silane) was added dropwise at 0° C. to diisopropylchlorosilane (22 g, 145 mmol) in anhydrous THF (40 mL). The reaction mixture was heated to 40° C. for 8 hours, then cooled and quenched with water (50 mL) and dilute sulfuric acid (50 mL). The crude product was extracted into pentane, washed with water and brine, dried over MgSO4, filtered and concentrated. Careful removal of solvent (product is volatile) yielded 22 g of crude isopropenyldiisopropylsilane as a pale yellow liquid that was not subjected to further purification.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(C=O)=CC=1.[CH2:15]([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18]C=1>>[C:22]1([C:15]2[CH:16]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:25](/[CH:28]=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:27]=1
Reactant: CCOC(=O)/C=C/c1ccc(Cc2ccccc2)cc1
Agent: O=Cc1ccc(-c2ccccc2)cc1
Product: CCOC(=O)/C=C/c1ccc(-c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-biphenylcarboxaldehyde and triethylphosphonoacetate using the procedure described for ethyl (E)-3-(4-benzylphenyl)acrylate (S38). Column chromatography (SiO2, 4×12 cm, 5% EtOAc-hexanes) afforded S45 (2.90 g, 11.5 mmol, 83%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) 166.9, 144.0, 142.8, 140.0, 133.3, 128.8, 128.4, 127.7, 127.4, 126.9, 118.0, 60.4, 14.2.
Reaction SMILES: O1CCCC1.C([O:8][C:9]([CH:11]([C:24]#[C:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1)=O)C.[CH3:32][NH2:33]>CO>[CH3:32][NH:33][C:9]([CH:11]([C:24]#[C:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][N:15]=1)=[O:8]
Reactant: CN
Reactant: CCOC(=O)C(C#Cc1ccccc1)CNc1ncnc2ccccc12
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)C(C#Cc1ccccc1)CNc1ncnc2ccccc12
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To 5 ml of tetrahydrofuran were added 130 mg of 4-[2-ethoxycarbonyl-4-phenyl-3-butynylamino]quinazoline and 3 ml of a 40% solution of methylamine in methanol, and the mixture was stirred at 60° C. for an hour, then at room temperature for 24 hours. The reaction mixture was concentrated and purified by means of flash chromatography (Isolera™ manufactured by Biotage AB) to give 113 mg of 4-[2-methylaminocarbonyl-4-phenyl-3-butynylamino]quinazoline.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:10]([O-])=O)[C:4]([CH3:13])=[N:3]1>CO.[Ni]>[CH3:1][N:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH2:10])[C:4]([CH3:13])=[N:3]1
Reactant: Cc1nn(C)c(C(N)=O)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Cc1nn(C)c(C(N)=O)c1N

Procedure:
Fifty grams of 1,3-dimethyl-4-nitro-pyrazole-5-carboxamide as prepared in Preparation 2 is dissolved in methanol, 2 g 50% of Raney nickel is added, and the compound is reduced under a hydrogen atmosphere until a 8.15 pound drop in pressure noted. The reaction mixture was filtered, the filtrate concentrated, and the crude material recrystallized in ethyl acetate to yield the product, 1,3-dimethyl-4-amino-pyrazol-5-carboxamide mp 154°-155° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C@@H:3]([CH3:12])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.C([O:17][C:18]([C:20]1([CH2:27][CH2:28]OC)[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)=O)C.[Cl-].C[Al+]C>C1(C)C=CC=CC=1>[OH:26][CH:23]1[CH2:24][CH2:25][C:20]2([C:18](=[O:17])[N:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C@H:3]([CH3:12])[C:2]([F:13])([F:14])[F:1])=[CH:10][CH:9]=3)[CH2:28][CH2:27]2)[CH2:21][CH2:22]1
Reactant: C[C@@H](Oc1ccc(N)cc1)C(F)(F)F
Reactant: CCOC(=O)C1(CCOC)CCC(O)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C[C@@H](Oc1ccc(N2CCC3(CCC(O)CC3)C2=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-((R)-2,2,2-Trifluoro-1-methyl-ethoxy)-phenylamine (7.57 g,) was added to a solution of 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (5.0 g, obtained in example 3, step 3) in toluene (150 ml). The mixture was stirred for 10 minutes at RT. Then, dimethylaluminiumchloride (1M in hexane, 65.1 mL) was added dropwise over a period of 45 minutes. The reaction mixture was heated to reflux for 2 h and was then kept at 95° C. for 16 h. The mixture was cooled, poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The title compound was obtained as an mixture of cis and trans diastereomers as a light brown solid (5.79 g). This mixture was used without further purification. MS (m/e): 358.3 [MH+].
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:48][C@H:49]1[CH2:53][CH2:52][N:51]([C@H:54]2[CH2:59][CH2:58][C@@H:57]([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[CH2:56][C@H:55]2[CH2:68][S:69]([CH3:72])(=[O:71])=[O:70])[C:50]1=[O:73]>CN(C=O)C>[CH3:72][S:69]([CH2:68][C@H:55]1[C@@H:54]([N:51]2[CH2:52][CH2:53][C@H:49]([NH:48][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=3)[C:50]2=[O:73])[CH2:59][CH2:58][C@@H:57]([NH:60][C:61](=[O:67])[O:62][C:63]([CH3:65])([CH3:64])[CH3:66])[CH2:56]1)(=[O:71])=[O:70]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CS(C)(=O)=O)C1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)c3cccc(C(F)(F)F)c3)C2=O)[C@H](CS(C)(=O)=O)C1
Reaction time: 0.17 h
Yield: 129.5 %

Procedure:
3-(Trifluoromethyl)benzoic acid (252.4 mg) was dissolved in DMF (5 mL) and 4-methyl morpholine (0.42 mL) was added prior to the addition of BOP (511 mg). After 10 min, tert-butyl (1R,3R,4S)-4-((S)-3-amino-2-oxopyrrolidin-1-yl)-3-(methylsulfonylmethyl)cyclohexylcarbamate (300 mg) was added. The reaction was stirred for 1 h before it was partitioned between EtOAc and 1N HCl solution. The organic phases were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford tert-butyl (1R,3R,4S)-3-(methylsulfonylmethyl)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)cyclohexylcarbamate (560 mg). MS found: (M+H)+=562.2.
Reaction SMILES: F[C:2](F)(F)[C:3]([O-])=[O:4].[CH2:8]([C:10]1[C:15](=[O:16])[NH:14][N:13]=[C:12]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:33])=[C:22]([CH:32]=2)[C:23]([N:25]2[CH2:31][CH2:30][CH2:29][NH2+:28][CH2:27][CH2:26]2)=[O:24])[CH:11]=1)[CH3:9].CCN(C(C)C)C(C)C.C(Cl)(C)=O.[Li+].[OH-]>C(Cl)Cl.CN(C=O)C>[C:3]([N:28]1[CH2:29][CH2:30][CH2:31][N:25]([C:23]([C:22]2[CH:32]=[C:18]([CH:19]=[CH:20][C:21]=2[F:33])[CH2:17][C:12]2[CH:11]=[C:10]([CH2:8][CH3:9])[C:15](=[O:16])[NH:14][N:13]=2)=[O:24])[CH2:26][CH2:27]1)(=[O:4])[CH3:2]
Reactant: O=C([O-])C(F)(F)F
Reactant: CCc1cc(Cc2ccc(F)c(C(=O)N3CCC[NH2+]CC3)c2)n[nH]c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(Cc2ccc(F)c(C(=O)N3CCCN(C(C)=O)CC3)c2)n[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution Example 1, A4 (1 eq) in DCM:DMF (2:1, 0.5 M), it was added DIPEA (3 eq), followed by AcCl (1.2 eq). After stirring 30 min at RT, the solvent was removed under reduced pressure and the crude redissolved in EtOAc, washed with 1M HCl, dried (Na2SO4), and concentrated under reduced pressure. The resulting crude was dissolved in THF:H2O (1:1) and LiOH (2 eq) was added, after stirring for 40 min at RT the reaction mixture was extracted with EtOAc. The combined organic fractions were washed with brine, dried (Na2SO4) and concentrated under reduced pressure, to afford the title compound as yellow powder. 1H NMR (400 MHz, DMSO-d6) δ: 12.6 (1H, s), 7.38 (1H, m), 7.28-7.17 (3H, m), 3.92 (2H, m), 3.82-3.66 (3H, m), 3.60-3.48 (3H, m), 3.43-3.30 (2H, m), 2.46 (2H, q, J=7.3 Hz), 2.05 (1.5H, s), 1.89 (1.5H, s), 1.88-1.49 (2H, m), 1.12 (3H, t, J=7.3 Hz). MS (ES) C21H25FN4O3 required: 400. found: 401 (M+H)+.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].CN(CCN(C)C)C.[Si:13]([O:20][C@H:21]([CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])/[CH:22]=[N:23]\[S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1COCC1>[Si:32]([O:31][CH2:30][C@@H:21]([O:20][Si:13]([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:15])[CH3:14])[C@H:22]([NH:23][S@:24]([C:26]([CH3:27])([CH3:28])[CH3:29])=[O:25])[CH:1]=[CH2:2])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)[S@](=O)/N=C\[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: C=C[C@@H](N[S@@](=O)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 53.3 %

Procedure:
To a 2.0 L round bottom flask containing vinylmagnesium bromide (92 ml, 92 mmol) was added THF (40 mL) and the mixture was allowed to stir at −78° C. for 5 min. At this time, TMEDA (23 ml, 154 mmol) was added via syringe followed by (S,Z)-N—((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide (13.0 g, 31 mmol) in THF. The reaction was allowed to stir at −78° C. for 4 h and then allowed to slowly warm to RT overnight. The reaction was quenched by the addition of ammonium chloride (sat, 100 ml). The aqueous layer was extracted with EtOAc, washed with brine, dried sodium sulfate, filtered and concentrated to give a crude oil that was purified by silica gel column to give (S)—N-((2S,3S)-1,2-his(tert-butyldimethylsilyloxy)pent-4-en-3-yl)-2-methylpropane-2-sulfinamide (5.45 g, 39% yield, higher Rf) and (S)—N-((2S,3R)-1,2-bis(tert-butyldimethylsilyloxy)pent-4-en-3-yl)-2-methylpropane-2-sulfinamide (7.43 g, 54% yield, lower Rf).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:9][CH:8]=1)C.[O:23]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:21][O:20][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:33]2[CH:34]=[CH:35][C:30]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:31][CH:32]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:22]
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCCO)cc1)OC
Reactant: Oc1ccc(Oc2ccccc2)cc1
Product: CO[C@@H](Cc1ccc(C#CCCCCOc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(6-Hydroxy-hex-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester and 4-phenoxyphenol via the standard Mitsunobu coupling-hydrolysis procedure (Standard Procedure A) to produce the title compound. MS(ES) for C28H28O5[M+H]+: 445.2
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([NH:30][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:29])=[CH:24][CH:23]=1
Reactant: COc1ccc([C@@H](C)N)cc1
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Product: COc1ccc(C(N[C@H](C)c2ccc(OC)cc2)c2cccc([N+](=O)[O-])c2)cc1

Procedure:
Following a similar procedure to that described in Example (1a), 6.00 g of 4-methoxyphenyl 3-nitrophenyl ketone and 5.32 g of (R)-1-(4-methoxyphenyl)ethylamine were reacted, to obtain 8.83 of the title compound as a pale yellow oil.
Reaction SMILES: [CH:1]([O:14][C:15]1[C:16](=[O:23])[CH:17]=[C:18]([CH2:21][OH:22])O[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[OH:26][N:25]1[CH:20]=[C:15]([O:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:16](=[O:23])[CH:17]=[C:18]1[CH2:21][OH:22]
Reactant: NO
Reactant: O=c1cc(CO)occ1OC(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1cc(CO)n(O)cc1OC(c1ccccc1)c1ccccc1
Yield: 44 %

Procedure:
17.5 g (0.0568 mol) of the product of Step (1) was added and dissolved in a mixture of ethanol (60 ml) and water (60 ml). Then, 39.5 g (0.568 mol) of hydroxylamine hydrochloride and 77.2 g (0.568 mol) of sodium acetate trihydrate were added thereto, and the mixture was reacted at 60° C. for 18 hours under stirring. Formed precipitates were collected by filtration, washed sequentially with water, ethanol and ethyl ether, and then dried to obtain 8.1 g (yield: 44.0%) of the above identified compound.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20](Cl)=[O:21])=[CH:12][N:11]=2)=[CH:6][CH:5]=1.CC(C[AlH]CC(C)C)C.OS([O-])(=O)=O.[K+]>O1CCCC1>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[C:13]([CH2:20][OH:21])=[CH:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: OCc1cnc(-c2ccc(OC(F)(F)F)cc2)nc1C(F)(F)F
Temperature: 0 °C
Yield: 70.9 %

Procedure:
0.45 g (1.21 mmol) 2-(4-Trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidine-5-carbonyl chloride in 4 ml tetrahydrofurane were cooled (-30° C.) and treated during 10 min with 2.23 ml (2.20 mmol) of a DIBALH-solution (1.2 M in toluene). The solution was allowed to come to 0° C. (1.5 h). The reaction was then powered to an ice-cooled aqueous 10% KHSO4 solution and extracted with ether. The ether-phase was washed with aqueous 10% NaCl solution, dried (NaSO4) and evaporated. The crude product was purified by flash chromatography over silica gel with heptane/AcOEt 9:1, to give 0.29 g of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:53]([CH3:55])[CH3:54])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH:25]=[CH:26][C:16]=2[N:15]=1)=[CH:23][C:22]([C:27]1[S:31][C:30]2[CH:32]=[C:33]([C:36]4[NH:40][C:39]([C@@H:41]5[CH2:45][CH2:44][CH2:43][N:42]5C(OC(C)(C)C)=O)=[N:38][CH:37]=4)[CH:34]=[CH:35][C:29]=2[CH:28]=1)=[CH:21][CH:20]=3)=[O:8])=[O:4].Cl.[CH3:57][O:58][C:59]([NH:61][C@H:62]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:63]([OH:65])=O)=[O:60].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:53]([CH3:55])[CH3:54])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH:25]=[CH:26][C:16]=2[N:15]=1)=[CH:23][C:22]([C:27]1[S:31][C:30]2[CH:32]=[C:33]([C:36]4[NH:40][C:39]([C@@H:41]5[CH2:45][CH2:44][CH2:43][N:42]5[C:63](=[O:65])[C@H:62]([NH:61][C:59](=[O:60])[O:58][CH3:57])[C:66]5[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=5)=[N:38][CH:37]=4)[CH:34]=[CH:35][C:29]=2[CH:28]=1)=[CH:21][CH:20]=3)=[O:8])=[O:4]
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4cc5ccc(-c6cnc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]6)cc5s4)ccc3c2[nH]1)C(C)C
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4cc5ccc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)cc5s4)ccc3c2[nH]1)C(C)C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
To (S)-tert-butyl 2-(5-(2-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)benzo[b]thiophen-6-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (53 mg, 0.07 mmol) in DCM (3 mL) was added HCl (4M in dioxane, 0.25 mL). The solution stirred for 1 h, and the solvent was removed. The intermediate was dissolved in DMF (2 mL). (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (15 mg, 0.07 mmol), COMU (36 mg, 0.08 mmol), and DIPEA (0.06 mL, 0.35 mmol) were added sequentially. The solution was stirred o/n and the mixture was purified by HPLC to yield product (14.8 mg). LCMS-ESI+: calc'd for C47H48N8O6S: 853.00 (M+); Found: 853.22 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[O:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2.C([O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=O)C.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:18]=[C:17]([N:19]4[CH2:20][CH2:21][N:22]([CH2:33][CH2:32][CH2:31][CH2:30][OH:29])[CH2:23][CH2:24]4)[O:16][N:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3noc(N4CCNCC4)n3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3noc(N4CCN(CCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 20 mg (0.06 mmol) of 1-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,4-oxadiazol-5-yl]piperazine and 13 μl (0.09 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Li]CCCC.[CH3:16][S:17]SC>C1COCC1>[CH3:16][S:17][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: CSSC
Reactant: Brc1cccc2cc[nH]c12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cccc2cc[nH]c12
Temperature: 0 °C
Yield: 56.1 %

Procedure:
To a solution of 7-bromo-1H-indole (3.0 g, 15.3 mmol) in THF (60 mL) at −78° C. was added 'BuLi (1.7 M, 33.8 mL, 57.4 mmol) and the mixture was allowed to warm to 0° C. The reaction was re-cooled to −78° C. and a solution of dimethyl disulfide (2.0 mL, 22.9 mmol) was added and the reaction was allowed to warm to 0° C. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to yield the crude product. This material was purified by chromatography over silica gel eluting with ethyl acetate in hexanes (0→2%) to afford pure 7-(methylthio)-1H-indole (1.4 g, 55%). 1H NMR (400 MHz, CDCl3) δ=2.50 (s, 3 H), 6.58 (dd, J=3.03, 2.02 Hz, 1H), 7.09 (t, J=7.58 Hz, 1H), 7.18-7.31 (m, 2H), 7.83 (d, J=7.83 Hz, 1H), 8.45 (br. s., 1 H); MS (ES+): m/z 164.15 [MH+].