Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].O=[C:12]([CH2:18][CH3:19])[CH2:13][C:14]([O:16][CH3:17])=[O:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:18]([C:12]1[O:3][C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:1][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[CH3:19]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1oc(-c2ccccc2)cc1C(=O)OC
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a solution of phenacyl bromide (10 g) and methyl 3-oxopentanoate (6.5 g) in toluene (100 mL) was added dropwise 1,8-azabicyclo[5.4.0]-7-undecene (7.5 mL) over 30 min or more under ice-cooling. After the completion of the dropwise addition, the mixture was stirred for 30 min under ice-cooling and then at room temperature for 2 hr. The resulting precipitate was filtered, and washed with toluene. The obtained toluene solution was passed through silica gel, and the silica gel was washed with ethyl acetate-hexane (1:1). The collected solutions were concentrated under reduced pressure to remove ethyl acetate-hexane to give a toluene solution. To this toluene solution was added 4-toluenesulfonic acid monohydrate (1.9 g), and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was washed with aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layers were collected, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 5% ethyl acetate/hexane) to give the title compound (6.7 g, 58%) as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:5]1(=[O:20])=[O:19].[CH3:21][C@H:22]1[CH2:27][NH:26][CH2:25][C@@H:24]([CH3:28])[NH:23]1>C(O)C>[CH3:21][C@H:22]1[NH:23][C@@H:24]([CH3:28])[CH2:25][N:26]([CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:5]2(=[O:20])=[O:19])[CH2:27]1
Reactant: O=S1(=O)N(CCBr)c2ccccc2N1c1ccccc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CCO
Product: C[C@@H]1CN(CCN2c3ccccc3N(c3ccccc3)S2(=O)=O)C[C@H](C)N1
Temperature: 90 °C
Yield: 69.9 %

Procedure:
A mixture of 1-(2-bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (212 mg, 0.600 mmol), cis-2,6-dimethylpiperazine (411 mg, 3.60 mmol, 6 equiv.) and ethanol (5 mL) in a sealed reaction vessel was heated at 90° C. for 8 h. After cooling, solvent was removed, and the residue was dissolved in ethyl acetate (15 mL). The resulting solution was washed with an aqueous potassium carbonate solution, water, dried (anhydrous sodium sulfate), and concentrated. The crude oil was pre-adsorbed onto Florisil and purified via Isco flash column chromatography (4-g redisep silica gel column, 1-18% methanol/dichloromethane, with 1% triethylamine as eluent additive) to give 162 mg (70%) of 1-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as a viscous, colorless liquid. This free base was dissolved in ethanol (2 mL), and was treated with an ethereal solution of hydrochloric acid (1 M, 3.0 mL, 3.0 mmol in ethyl ether). To the resulting solution was added ethyl ether until it became cloudy, then cooled to −25° C. in a freezer overnight. The white crystals formed was collected, washed with hexane, and dried in vacuo to yield 176 mg of 1-[2-(cis-3,5-dimethylpiperazin-1-yl)ethyl]-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide dihydrochloride. HRMS: calculated for C20H26N4O2S+H+, 387.1849; found (ESI, [M+H]+), 387.1861.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([NH2:24])=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:25][C:26](=O)[C:27](=O)[CH3:28]>O.C(O)C.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[N:23]=[C:27]([CH3:28])[C:26]([CH3:25])=[N:24]4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)C(C)=O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nc(C)c(C)nc4c3O2)cc1
Temperature: 60 °C

Procedure:
To a solution of [(2R)-7,8-diamino-2,3-dihydro-1,4-benzodioxin-2-yl]-methyl 4-methylbenzenesulfonate (2.170 g, 5.126 mmole) in water (50 mL) was added a solution of 2,3-butanedione (0.552 g, 6.408 mmole) in ethyl alcohol (50 mL) and the reaction mixture was heated at 60° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and was diluted with aqueous sodium hydrogen carbonate (250 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 7:3) gave 1.525 g (74%) of the (R)-enantiomer of the title compound as a white crystalline solid. Rf=0.50 (silica, ethyl acetate:hexanes 7:3); mp 153–155° C.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.[H][H]>Cl.[Pd]>[NH2:11][C@@H:12]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[C:13]([O:15][CH3:16])=[O:14]
Reactant: [H][H]
Reactant: COC(=O)[C@H](CNC(C)=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Product: COC(=O)[C@@H](N)CNC(C)=O

Procedure:
To a solution of methyl 2(S)-benzyloxycarbonylamino-3-acetylaminopropionate (2.2 g ) in ethanolic HCl was added 10% Pd/C (0.3 g) under nitrogen atmosphere. Hydrogen was applied to the mixture at 60 psi for 16 h. The mixture was filtered and concentrated in vacuo. The residue was triturated with diethyl ether to obtain the product. NMR (300 MHz, CD3OD) δ4.20 (1H, m), 3.88 (3H, s), 3.82 (1H, m), 3.60 (1H, m), 1.99 (3H, s).
Reaction SMILES: O[CH2:2][C@@H:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:6][CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:44].C(=O)([O-])O.[Na+]>ClCCl>[Br:44][CH2:2][C@@H:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H](CO)c3ccccc32)cc1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H](CBr)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
A mixture of (5S)-5-hydroxymethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.33 g), triphenylphosphine (2.10 g), carbon tetrabromide (2.65 g) and dichloromethane (50 ml) is stirred at room temperature for 30 minutes. The reaction solution is poured into a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with dichloromethane. The extract is dried over sodium sulfate, and concentrated under reduced pressure to remove the solvent, and the resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:n-hexane=4:1), and recrystallized from diethyl ether--n-hexane to give (5S)-5-bromomethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.26 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:8]1.C([O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32]Br)C>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[C:25]([OH:34])=[O:24])[CH2:18][CH2:17]2)=[CH:8]1
Reactant: c1coc(Cn2cc(C3CCNCC3)c3ccccc32)c1
Reactant: CCOC(=O)c1ccccc1CBr
Product: O=C(O)c1ccccc1CN1CCC(c2cn(Cc3ccco3)c3ccccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.05 g (0.18 mmol) of 1-furan-2-ylmethyl-3-piperidin-4-yl-1H-indole (example 83, part B) and 0.056 g (0.23 mmol) of 2-bromomethyl-benzoic acid ethyl ester. After standard work-up and purification using a C18 chromatography column, 0.014 g (19% of yield) of the expected acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([OH:20])=O)[CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[N:44]1[CH:49]=[CH:48][CH:47]=[N:46][C:45]=1[C:50]1[CH:55]=[CH:54][C:53]([N:56]2[CH2:61][CH:60]3[CH2:62][CH:57]2[CH2:58][NH:59]3)=[CH:52][CH:51]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18](=[O:20])[N:59]3[CH2:58][CH:57]4[CH2:62][CH:60]3[CH2:61][N:56]4[C:53]3[CH:54]=[CH:55][C:50]([C:45]4[N:44]=[CH:49][CH:48]=[CH:47][N:46]=4)=[CH:51][CH:52]=3)[CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: c1cnc(-c2ccc(N3CC4CC3CN4)cc2)nc1
Reactant: O=C(O)CN1CCC(C(=O)Nc2ccc(O)c(Cl)c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(O)c(Cl)c1)C1CCN(CC(=O)N2CC3CC2CN3c2ccc(-c3ncccn3)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
To a mixture of [3-(3-Chloro-4-hydroxy-phenylcarbamoyl)-pyrrolidin-1-yl]-acetic acid (10 mg, 0.034 mmol) and HOBt (6.8 mg, 0.050 mmol) in DMF (0.5 ml) at 0° C. was added EDCl (9.6 mg, 0.050 mmol). The formed reaction mixture was stirred at 0° C. for 0.5 hour and then 2-(4-Pyrimidin-2-yl-phenyl)-2,5-diaza-bicyclo[2.2.1]heptane hydrochloride salt (12.6 mg, 0.05 mmol) was added. After stirred at RT for overnight, the reaction mixture was purified using a Prep-HPLC to give titled compound (3.4 mg, 19% yield). Mass Spec ES (533.1, M+H)
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:34][C:33](=[O:35])[C:20]3([CH2:25][CH2:24][N:23](CC4C=CC=CC=4)[CH2:22][CH2:21]3)[N:19]=[C:18]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[C:17]=2[CH:43]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[NH:34][C:33](=[O:35])[C:20]3([CH2:25][CH2:24][N:23]([C:2]([O:4][CH2:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)=[O:3])[CH2:22][CH2:21]3)[N:19]=[C:18]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[C:17]=2[CH:43]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccc(Cl)cc2)=NC12CCN(Cc1ccccc1)CC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC2(CC1)N=C(c1ccc(Cl)cc1)c1cc(Cl)ccc1NC2=O
Reaction time: 3 h

Procedure:
20 ml (0.06 mole) of a 50 percent strength solution of benzyl chloroformate in toluene are added to a mixture of 9.5 g (0.02 nole) of 7-chloro-5-(4-chlorophenyl)-1'-benzyl-spiro[1H-1,4-benzodiazepine-3,4'-piperidin]-2(3H)-one and 5 g (0.06 mole) of NaHCO3 in 150 ml of methylene chloride. The reaction mixture is boiled for 3 hours, with reflux cooling. It is then poured onto ice and the organic phase is separated off and washed twice with 10 percent strength NaHCO3 solution. After drying over Na2SO4, the organic phase is filtered and the solvent is evaporated off. The oily residue is made to crystallise with petroleum ether. The compound is filtered off with suction, boiled up with n-hexane and dried at 60° C. in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]3[CH2:15][CH2:14][NH:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.C=O.[CH3:18]C(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]3[CH2:15][CH2:14][N:13]([CH3:18])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: Fc1ccc2nnc([C@@H]3CCNC3)n2c1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CC[C@@H](c2nnc3ccc(F)cn23)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Intermediate 90c (225 mg, 1.09 mmol), formaldehyde (37% in water, 0.885 mL, 10.9 mmol) and AcOH (0.0625 mL, 1.09 mmol) in DCM (20 mL) and MeOH (1 mL) was added NaBH(OAc)3 (462 mg, 2.18 mmol) (CARE: gas evolution) and the pale yellow solution stirred at RT for 16 h. The solution was concentrated to 2 mL volume, then was applied to an SCX-2 cartridge and was washed with MeOH (25 mL). The product was eluted with 2M NH3 in MeOH (25 mL); concentration in vacuo left the title compound as a pale brown viscous oil (228 mg, 95%). LCMS (Method 3): Rt 0.44 min, m/z 221 [MH+].
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][C:6]=1[N+:17]([O-])=O.[H][H]>[Ni].C(O)C>[F:1][C:2]([F:20])([F:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][C:6]=1[NH2:17]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reaction time: 5 h

Procedure:
A mixture of 59 g. (0.185 mole) of 2,5-bis-(2,2,2-trifluoroethoxy)nitrobenzene, about 15 g. of Raney nickel and 1200 ml. of ethanol is hydrogenated by shaking on a Parr hydrogenation apparatus with a hydrogen pressure of 40 to 50 p.s.i. for about five hours. The mixture is filtered, and the filtrate is evaporated to a liquid residue. The residue is distilled to provide 2,5-bis(2,2,2-trifluoroethoxy)aniline as a clear, colorless liquid, b.p. 95°-98° C/0.35 mm Hg.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl.O>CO.O>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Yield: 67.2 %

Procedure:
To a solution of 74 gm potassium hydroxide in 673 mL methanol were added 10.0 gm (74 mMol) 5-fluoroindole and 23.3 gm (151 mMol) 4-piperidone.HCl.H2O. The reaction mixture was stirred at reflux for 18 hours. The reaction mixture was diluted with 1.3 L of water and the resulting precipitate recovered by filtration and dried under reduced pressure to give 10.75 gm (67.2%) of 5-fluoro-3-[1,2,5,6-tetrahydro-4-pyridyl]-1H-indole as a yellow solid.
Reaction SMILES: [Si]([O:8][C@H:9]1[C@@H:13]([O:14][Si](C(C)(C)C)(C)C)[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:70])[C@@H:40]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:62])[C@H:47]([C@@H:59]([OH:61])[CH3:60])[NH:48][C:49](=[O:58])[O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][C@H:9]1[C@@H:13]([OH:14])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:70])[C@@H:40]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:62])[C@H:47]([C@@H:59]([OH:61])[CH3:60])[NH:48][C:49](=[O:58])[O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@H](C)O)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@H](C)O)C(=O)OC(C)(C)C)[C@@H](O)[C@H]3O)c2=O)cc1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 24.6 %

Procedure:
A solution of tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (63 mg, 0.062 mmol, obtained from Example 10) in anhydrous tetrahydrofuran (1 ml) was cooled at 0° C. under nitrogen. Tetrabutylammonium fluoride (0.186 mL, 0.186 mmol; 1 M solution in tetrahydrofuran, Aldrich) was added and the resulting mixture was warmed to room temperature and stirred for 2.75 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (flash column, silica gel, 5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-12-[(R)-[(3S,4R,5R)-3,4-dihydroxy-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-(hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (12 mg, 25%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:40])([F:39])[C:13]([CH2:34][NH:35][CH2:36][CH2:37][CH3:38])([OH:33])[CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:34][C:13]([CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)([OH:33])[C:12]([F:11])([F:40])[F:39])=[O:6]
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1F
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1F

Procedure:
Prepared similarly to Example 1 from 2-fluorobenzoic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9]O)[CH:6]=[C:5]([O:11][CH3:12])[N:4]=1.P(Br)(Br)[Br:14].CCCCC>C(Cl)Cl>[Br:14][CH2:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH3:12])[CH:6]=1
Reactant: BrP(Br)Br
Reactant: COc1cc(CO)cc(OC)n1
Solvent: CCCCC
Solvent: ClCCl
Product: COc1cc(CBr)cc(OC)n1
Reaction time: 10 h

Procedure:
1 g of (2,6-dimethoxypyridin-4-yl)methanol, prepared according to J. Heterocl. Chem., 1974, 11, 251, is dissolved in 20 ml of CH2Cl2, 0.84 ml of PBr3 is added and then the mixture is left stirring at AT for 10 hours. Pentane is added and the precipitate formed is filtered off, washed with pentane and then dried to produce 850 mg of the expected compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[O:53][N:52]=[C:51]2[CH:54]=[C:55]([C:58]3[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=3)[CH:56]=[CH:57][C:50]=12>CN(C=O)C>[N:49]1[O:53][N:52]=[C:51]2[CH:54]=[C:55]([C:58]3[CH:59]=[C:60]([NH:64][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=3)[CH:56]=[CH:57][C:50]=12
Reactant: Nc1cccc(-c2ccc3nonc3c2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3nonc3c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 19.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-benzo[1,2,5]oxadiazol-5-yl-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.005 g of product in 18% yield: LCMS (ESI) m/z 400 (MH+).
Reaction SMILES: Cl[C:2]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:18][CH:17]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11]2)=[CH:6][C:5]=1[O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])=[O:3].[NH3:54]>C1(C)C=CC=CC=1>[C:2]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:18][CH:17]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11]2)=[CH:6][C:5]=1[O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])(=[O:3])[NH2:54]
Reactant: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)Cl
Reactant: N
Solvent: Cc1ccccc1
Product: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(N)=O
Reaction time: 0.25 h

Procedure:
The solution of 0.290 g of benzyl 3-[4-chlorocarbonyl-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 1.0 ml of toluene is added dropwise slowly to 2.30 ml of ammonia solution (7M in methanol, precooled to 0° C.). After 15 minutes, the reaction solution is poured onto water (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed with brine (1×30 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.06 (2:1 EtOAc-heptane); Rt=5.56.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:22]=[CH:21][C:12]([O:13][CH2:14][C@H:15]2[O:19][C:18]([NH2:20])=[N:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].C([O:25][C:26](=O)[C:27]#[C:28][CH2:29][CH3:30])C>C(Cl)(Cl)Cl>[CH2:29]([C:28]1[N:17]2[CH2:16][C@@H:15]([CH2:14][O:13][C:12]3[CH:21]=[CH:22][C:9]([C:2]([CH3:1])([CH3:8])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[CH:10][CH:11]=3)[O:19][C:18]2=[N:20][C:26](=[O:25])[CH:27]=1)[CH3:30]
Reactant: CC(C)(C)CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Reactant: CCC#CC(=O)OCC
Solvent: ClC(Cl)Cl
Product: CCc1cc(=O)nc2n1C[C@@H](COc1ccc(C(C)(C)CC(C)(C)C)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-(1,1,3,3-tetramethyl-butyl) -phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (see Example 27) and pent-2-ynoic acid ethyl ester employing the procedure described in Example 95. [α]D25 −21.00 (c 0.5, CHCl3).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH2:6].[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15](O)=[O:16].CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH:6][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:12]([CH3:11])[CH:13]=1
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)c1ccc([N+](=O)[O-])c(C)c1)[C@@H](C)O
Yield: 900.1 %

Procedure:
The same operation as in Example (102a) was performed using threonine methyl ester hydrochloride (6.73 g, 39.6 mmol), 3-methyl-4-nitrobenzoic acid (7.18 g, 3.96 mmol), WSC hydrochloride (8.05 g, 42 mmol), DMAP (0.18 g, 1.5 mmol), N,N-diisopropylethylamine (5.42 g, 42 mmol) and dichloromethane (100 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/3, 2/3, 3/2, 3/1) to obtain 10.56 g of the title compound as a light yellow amorphous solid (90%).