Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:55])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:52])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:51])[CH2:21][CH2:22][C@@:23]3([NH:39][CH2:40][CH2:41][N:42]4[CH2:47][C@@H:46]5[CH2:48][C@H:43]4[CH2:44][S:45]5(=[O:50])=[O:49])[CH2:35][CH2:34][C@@H:33]([C:36]([CH3:38])=[CH2:37])[C@@H:24]32)[C:15]1([CH3:54])[CH3:53])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O.CO>C(Cl)Cl.ClCCCl>[O:50]=[S:45]1(=[O:49])[CH2:44][C@@H:43]2[CH2:48][C@H:46]1[CH2:47][N:42]2[CH2:41][CH2:40][NH:39][C@:23]12[CH2:35][CH2:34][C@@H:33]([C:36]([CH3:38])=[CH2:37])[C@@H:24]1[C@@H:25]1[C@@:20]([CH3:51])([CH2:21][CH2:22]2)[C@@:19]2([CH3:52])[C@@H:28]([C@:29]3([CH3:32])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:54])([CH3:53])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:55])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]3)[CH2:27][CH2:26]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
To a solution of 1-tert-butyl 4-((1R,3 aS,5aR,5bR,7aR,9S,11aR,11bR,13 aR,13bR)-3a-((2-((1S,4S)-2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (55.2 mg, 0.070 mmol) in DCM (1 mL) was added TFA (0.3 ml, 3.89 mmol). The reaction mixture was stirred rt and turned purple/red. After 1 h, TLC (95:5 DCM:MeOH) showed the reaction was completed. The reaction mixture was diluted with DCE (2 mL) and concentrated to a red solid. The crude material was redissolved in DCM (0.5 mL). Et2O was added to produce ad precipitate which was filtered and washed with Et2O to give 4-(((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((2-((1S,4S)-2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid as off-white solid (9.5 mg, 18.8% yield). LC/MS: m/e 729.5 (M+H)+, 3.49 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.79 (br. s., 1H), 4.68 (s, 1H), 4.54-4.43 (m, 1H), 4.23 (br. s., 1H), 3.58 (br. s., 1H), 3.49-3.31 (m, 2H), 3.29-3.13 (m, 3H), 3.11-2.91 (m, 4H), 2.79 (br. s., 1H), 2.72-2.64 (m, 1H), 2.59 (s, 1H), 2.56 (d, J=6.4 Hz, 1H), 2.39 (d, J=11.5 Hz, 1H), 2.28 (br. s., 1H), 1.93 (br. s., 4H), 1.70 (s, 3H), 1.69-1.49 (m, 9H), 1.48-1.40 (m, 3H), 1.35 (br. s., 2H), 1.31 (br. s., 3H), 1.30 (br. s., 3H), 1.09 (br. s., 3H), 1.03 (s, 3H), 1.00-0.89 (m, 2H), 0.86 (br. s., 3H), 0.85 (s, 3H), 0.83 (s, 3H), 0.79-0.73 (m, 1H)
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:6]([O:15][CH3:16])=[CH:7][C:8]([OH:14])=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)([CH3:4])[CH3:3].[Br:17]Br.O>C(Cl)Cl>[Br:17][C:7]1[C:8]([OH:14])=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[O:15][CH3:16]
Reactant: COc1cc(O)c(C(C)=O)cc1C(C)(C)C
Reactant: BrBr
Solvent: O
Solvent: ClCCl
Product: COc1c(C(C)(C)C)cc(C(C)=O)c(O)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a solution of 10.7 g (48.1 mmol) of 1-[5-(1,1-dimethylethyl)-2-hydroxy-4-methoxyphenyl]ethanone in 250 ml of methylene chloride was added 8.11 g (50.7 mmol) of bromine. The reaction mixture was stirred at ambient temperature for 2 hours. Water (500 ml) was added. The organic phase was separated, washed with saturated aqueous sodium bicarbonate, dried and evaporated. The residue was filtered through 150 g of silica gel using 10:90 (v/v) ether:hexane as eluent. There was obtained 8.70 g (28.8 mmol, 60%) of 1-[3-bromo-5-(1,1-dimethylethyl)-2-hydroxy-4-methoxyphenyl]ethanone as white crystals after crystallization from hexane; mp 69°-71° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]([N:13]([CH2:20][CH2:21][N:22]([CH2:30][CH2:31][C:32]1[C:37]2[O:38][CH2:39][C:40](=[O:42])[NH:41][C:36]=2[C:35]([OH:43])=[CH:34][CH:33]=1)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12])#N.O.[PH2]([O-])=[O:49].[Na+]>N1C=CC=CC=1.C(O)(=O)C.O.[Ni]>[CH:14]1([N:13]([CH2:20][CH2:21][N:22]([CH2:30][CH2:31][C:32]2[C:37]3[O:38][CH2:39][C:40](=[O:42])[NH:41][C:36]=3[C:35]([OH:43])=[CH:34][CH:33]=2)[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[C:11](=[O:12])[CH2:10][CH2:9][O:8][CH2:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[C:3]([CH:1]=[O:49])[CH:4]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=[PH2][O-]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)c2c1OCC(=O)N2)CCN(C(=O)CCOCCc1cccc(C#N)c1)C1CCCCC1
Agent: [Ni]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(CCc1ccc(O)c2c1OCC(=O)N2)CCN(C(=O)CCOCCc1cccc(C=O)c1)C1CCCCC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 2-(3-(3-cyanophenethoxy)-N-cyclohexylpropanamido)ethyl(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)carbamate [Examples 81-175, step e] (7.3 g) in pyridine (115 mL), acetic acid (58 mL) and water (58 mL), pre-cooled in ice-water under nitrogen, was added sodium hypophosphite monohydrate (14.6 g) followed by Raney® nickel (50% in water, 3.0 g). The reaction mixture was stirred at 45° C. for 8 hours, then allowed to cool and stand over a weekend. Celite was added and the suspension was filtered through a pad of Celite, washing the residue well with acetic acid and ethyl acetate. The filtrate was washed three times with water, once with brine, then dried (MgSO4), filtered and concentrated in-vacuo. The residue was azeotroped twice with toluene to afford the subtitled compound as a pale yellow foam. Yield 6.6 g.
Reaction SMILES: [CH2:1]1[O:8][C@@H:7]2[O:9][C@H:2]1[CH:3]=[CH:4][C:5]2=[O:6].[K].[BH4-].[Na+].[C:13]([OH:16])(=O)[CH3:14]>C(O)C1C=CC=CC=1.C(O)C>[CH2:13]([O:16][C@@H:3]1[C@H:2]2[CH2:1][O:8][C@H:7]([O:9]2)[C:5](=[O:6])[CH2:4]1)[C:14]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: CC(=O)O
Reactant: O=C1C=C[C@H]2CO[C@@H]1O2
Agent: [BH4-]
Agent: [K]
Agent: [Na+]
Solvent: OCc1ccccc1
Solvent: CCO
Product: O=C1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,6-anhydro-4-O-benzyl-3-deoxy-β-D-erythro-hexopyranos-2-ulose in benzyl alcohol was prepared as described in Example 6, except that 0.088 g of levoglucosenone were used as starting material and, 5 min after the addition of potassium benzoxide, a suspension of sodium borohydride (0.073 g) in ethanol (4 ml) was added to the mixture, which was then stirred for 0.5 h at room temperature, made neutral with acetic acid, evaporated under vacuum, and the resulting white residue transferred to a short column of silica, which was eluted with a gradient of ethyl acetate/hexane (from 1:2 to 2:1). The fractions found by t.l.c. to contain the title compound A were combined and evaporated, to give material that spontaneously crystallized (0.106 g, 64% from levoglucosenone). 1H-Nmr spectroscopy of this material showed it to be an 9:11 mixture of the title compound A and the D-arabino isomer determined from the relative intensities of their H-3 resonances.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[CH:9]=[C:8](F)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[O:14][CH3:15].[NH2:18][C:19]1[S:20][C:21]([C:31]([NH2:33])=[O:32])=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN(C)C=O>[Cl:30][C:26]1[CH:25]=[C:24]([C:22]2[N:23]=[C:19]([NH:18][C:8]3[CH:9]=[C:4]([CH:3]([O:16][CH3:17])[O:2][CH3:1])[C:5]([O:14][CH3:15])=[CH:6][C:7]=3[N+:11]([O-:13])=[O:12])[S:20][C:21]=2[C:31]([NH2:33])=[O:32])[CH:29]=[CH:28][CH:27]=1
Reactant: NC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Reactant: COc1cc([N+](=O)[O-])c(F)cc1C(OC)OC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)cc1C(OC)OC
Yield: 60.9 %

Procedure:
A mixture of 0.240 g (0.98 mmole) of 1-dimethoxymethyl-5-fluoro-2-methoxy-4-nitro-benzene (IV.46d), 0.248 g (0.98 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.2), 0.956 g (2.94 mmole) of cesium carbonate and 5 mL of dimethylformamide was heated at 60 degrees for 3 hours. The mixture was cooled, poured into dilute ammonium chloride solution, and the precipitated orange solid was collected by filtration, washed with water, and air dried to give 0.286 g of 4-(3-chloro-phenyl)-2-(5-dimethoxymethyl-4-methoxy-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.46a).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([O:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:30])[F:31])[CH:24]=3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: [Cu]I
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(Oc2ccc(C3CN(Cc4ccccc4)CCO3)cc2)c1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
A mixture of 4-benzyl-2-(4-bromo-phenyl)-morpholine (1.5 g, 4.6 mmol), 3-(trifluoromethyl)phenol (0.83 mL, 6.8 mmol), copper(I) iodide (438 mg, 2.3 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.48 mL, 2.3 mmol), and cesium carbonate (2.96 g, 9.1 mmol), in toluene (20 mL) was heated under reflux for 3 days. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The layers were separated. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (EtOAc:heptanes 5:95) to afford 4-benzyl-2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-morpholine (0.9 g), which was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[N+:9]([C:12]1[C:17](Cl)=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:9]([C:12]1[C:17]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:11])=[O:10]
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Reactant: Sc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cccc(Sc2ccccc2Cl)c1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
A mixture of 2-chlorobenzenethiol (8.0 g.), ethyl 2-(2-nitro-3-chlorophenyl)acetate (12.2 g.), anhydrous potassium carbonate (7.5 g.) and dry dimethylformamide (50 ml.) was stirred for an hour at 85° C. The reaction mixture was poured into water (300 ml.) and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure. The oily residue was pulverized and recrystallized from methanol (20 ml.) to give the captioned compound (11.6 g.). mp 78° to 80° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13](OC(=O)C)[CH:12]2[N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CC(=O)OCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[N:25]([CH3:30])[S:26]([CH3:29])(=[O:27])=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC1C(N(C)S(C)(=O)=O)c2cc(OCc3ccccc3)ccc2OC1(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C1=CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(C)(=O)=O
Yield: 99 %

Procedure:
A solution of 1.0 g (2.3 mmol) of N-(6-benzyloxy-3-acetoxy-2,2-dimethylchroman-4-yl)-N-methyl-methanesulfonamide (Example 2) and 2.1 g (13.8 mmol) of DBU in 4.2 ml of toluene was heated at 105° C. for 5 h. The reaction mixture was diluted with EA and washed with hydrochloric acid until the aqueous phase gave an acidic reaction. The mixture was washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated i. vac., giving 0.85 g of N-(6-benzyloxy-2,2-dimethyl-2H-chromen-4-yl)-N-methyl-methanesulfonamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][C:24](O)=[O:25])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.C[N:29](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][C:24]([NH2:29])=[O:25])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(=O)O)(c2ccc(F)cc2)OC1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(N)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.8 %

Procedure:
To a solution of 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetic acid (0.0259 g, 0.059 mmol) in DMF (2 mL) was added HATU (0.2298 g, 0.60 mmol), DIPEA (0.5 mL), and 0.8 M NH3 in THF (4 mL). The mixture was stirred at rt for 2 d. After the solvents were removed in vacuo, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.0146 g (57%) of 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetamide. LC-MS Method 1 tR=1.55 min, m/z 435, 437 (MH+), 391, 393; 1H NMR (400 MHz, CD3OD) δ 7.30-7.26 (m, 2H), 7.19-7.16 (m, 2H), 7.04-6.99 (m, 2H), 6.74 (d, J=8.5 Hz, 2H), 5.39 (q, J=7.0 Hz, 1H), 3.06-3.01 (m, 1H), 2.72-2.58 (m, 3H), 2.42-2.34 (m, 1H), 2.26-2.19 (m, 1H), 1.41 (d, J=7.0 Hz, 3H); 19F NMR (376 MHz, CD3OD) δ −116.70 (m).
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:33][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:8]([C:10]2[N:11]([C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([C:35]([F:46])([F:45])[F:34])[CH:41]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCOCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCC(N2CCOCC2)CC1
Yield: 60 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone (example 170), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a brown oil (60%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([CH:21]1[CH:28]2[CH2:29][CH:24]3[CH2:25][C:26]([OH:31])([CH2:30][CH:22]1[CH2:23]3)[CH2:27]2)[C:10]([N:12]1[CH2:17][CH:16]2[CH:14]([CH2:15]2)[CH:13]1[C:18]([NH2:20])=[O:19])=[O:11].[C:32]([O:36][C:37]([NH:39][CH:40]([CH:51]([CH3:53])[CH3:52])[C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH:44]1[C:48](O)=[O:49])=[O:42])=[O:38])([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>C1COCC1>[C:32]([O:36][C:37](=[O:38])[NH:39][CH:40]([C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH:44]1[C:48](=[O:49])[NH:8][CH:9]([CH:21]1[CH:22]2[CH2:23][CH:24]3[CH2:25][C:26]([OH:31])([CH2:27][CH:28]1[CH2:29]3)[CH2:30]2)[C:10]([N:12]1[CH2:17][CH:16]2[CH:14]([CH2:15]2)[CH:13]1[C:18](=[O:19])[NH2:20])=[O:11])=[O:42])[CH:51]([CH3:53])[CH3:52])([CH3:33])([CH3:34])[CH3:35]
Reactant: NC(=O)C1C2CC2CN1C(=O)C(N)C1C2CC3CC1CC(O)(C3)C2
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N1CCCC1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)N1CCCC1C(=O)NC(C(=O)N1CC2CC2C1C(N)=O)C1C2CC3CC1CC(O)(C3)C2
Reaction time: 0.17 h

Procedure:
To the stirred solution 1.7 gm (0.00380 moles) of 3-[2-Amino-2-(5-hydroxy-adamantan-2-yl)-acetyl]-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid amide trifluoro acetic acid of formula 35 and 1.19 gm (0.00380 moles) of 1-(2-tert-Butoxycarbonylamino-3-methyl-butyryl)-pyrrolidine-2-carboxylic acid (Formula 26) in THF was added into HoBT (0.6 gm) and DIPEA (1.3 ml) at room temperature and stirred for 10 minutes. To this stirred solution EDC.HCl (0.94 gm) and DIPEA (1.10 ml) were added at 0° C. and the reaction mixture was stirred over night at room temperature. THF was evaporated and residue was taken into EtOAC. The EtOAC layer was washed with 1N HCl and aq. NaHCO3 solution, dried and concentrated in vacuum to get crude product. The crude product was purified by silica gel column chromatography to get pure (1-{2-[2-(2-Carbamoyl-3-aza-bicyclo[3.1.0]hex-3-yl)-1-(5-hydroxy-adamantan-2-yl)-2-oxo-ethylcarbamoyl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid tert-butyl ester (Formula 36). (Yield: 1.7 gm)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].O>CN(C=O)C>[Si:12]([O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: Oc1cc(F)ccc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc(F)ccc1F
Reaction time: 0.5 h
Yield: 94020.3 %

Procedure:
To a stirred solution of 2,5-difluorophenol (15.1 g, 116 mmol) in DMF (100 ml) was added sodium hydride (60% W/W dispersion in mineral oil; 5.13 g, 139 mmol) with ice-cooling. After stirring for 30 min, tert-butyldimethylsilyl chloride (17.5 g, 0.116 mmol) was added and stirring was continued for an additional 1 hr. The mixture was poured into water (200 ml) and extracted with ether (300 ml). The extract was washed with brine (200 ml), dried (sodium sulfate) and solvent removed by evaporation to give 26.65 g (94%) of the titled compound as a colorless oil.
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]([NH2:8])=[O:7])(=[O:3])[CH3:2].[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCOCC>S(=O)(=O)(O)O.CCCCCC>[C:9]1([CH2:15][C:16]([NH:8][C:6](=[O:7])[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(=O)SCC(N)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(=O)SCC(=O)NC(=O)Cc1ccccc1
Reaction time: 8 h

Procedure:
A reaction mixture comprising 6.65 g. (0.05 mole) of 2-(acetylthio) acetamide, 10 ml. of 2-phenylacetyl chloride, and 1 drop of sulfuric acid was heated in a steam bath for 0.5 hour, and then allowed to stand overnight at room temperature, after which it solidified. There was then added 50 ml. of ether and 20 ml. of hexane, followed by stirring for 10 minutes and then filtering. A yield of 8.5 g. of a tan solid was obtained, which was then chromatographed on 100 g. of silica gel. eluting with 5% ether in dichloromethane, followed by concentration to dryness. The solid was suspended in 60 ml. of ethanol and stirred in an ice bath for 1 hour. The product of white crystals, m.p. 153°-155° C., was obtained in a 5.6 g. yield.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:5][CH:4]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:2][C:3]2[CH:14]=[CH:13][C:6]([CH2:7][N:8]3[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:5][CH:4]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: ClCc1ccc(Cn2cccc2)cc1
Product: c1ccn(Cc2ccc(CN3CCCC3)cc2)c1

Procedure:
The title compound was prepared starting from 1-(4-chloromethyl-benzyl)-pyrrole (preparation in example 20 step A) and pyrrolidine by the same method reported in Example 19 step B. 1H NMR (400 MHz, MeOD-d4)δ7.26 (m, 2 H), 7.15 (m, 2 H), 7.05 (m, 2 H), 6.85 (m, 2 H), 6.57 (t, J=2.1 Hz, 2 H), 5.96 (t, J=2.1 Hz, 2 H), 4.98 (s, 2 H), 4.92 (s, 2 H), 3.50 (s, 3 H), 2.50 (m, 2 H), 1.70 (m, 2 H).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1.[CH2:18](O)[CH3:19]>>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=1
Reactant: CCO
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1ccc(O)cc1

Procedure:
Sulfuric acid (230 g) was dropped under stirring for 10 minutes to an ethanol solution (1500 mL) of 3-(4-hydroxyphenyl)propionic acid (1150 g), and refluxed successively for 5 hours. The reaction mixture was concentrated and the obtained concentrated solution was poured into water (1,000 mL) and stirred with addition of ethyl acetate. After separation of the solution, an ethyl acetate layer was neutralized with an aqueous solution of a saturated sodium carbonate, washed with a small amount of water and then dried over anhydrous magnesium sulfate. Ethyl acetate and unreacted ingredients were distilled off from the ethyl acetate layer to obtain concentrates (1,400 g). The concentrates were purified by distillation under a reduced pressure to obtain ethyl 3-(4-hydroxyphenyl)propionate (1,144 g). The boiling point was 160° C./4.0 hPa.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([OH:11])=[O:10].[OH-].[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.O>[CH2:14]([O:21][C:22]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([OH:11])=[O:10])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCOCCOCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COCCOCCNC(=O)OCc1ccccc1
Reaction time: 2.5 h

Procedure:
A suspension of 6.7 g (12.5 mmol) of 2-[2-(aminoethoxy)ethoxy]-acetic acid in 30 ml of THF and 10 ml of water is adjusted to pH 10 with 2N NaOH, and reacted dropwise with 1.95 ml of chloroformic acid benzyl ester (Fluka, Buchs, Switzerland). While the mixture is being stirred for 2.5 h, the pH is maintained between 9 and 9.5 by 2N NaOH. After concentration of the reaction mixture under reduced pressure, the resulting aqueous phase is washed twice with ethyl acetate, adjusted to pH 1.8 with 2N sulfuric acid and extracted 3 times with ethyl acetate. The combined organic phases are then washed with water and brine, dried and concentrated under reduced pressure. The title compound so obtained is further used without being further purified. TLC Rf (ethyl acetate/acetic acid: 9/1)=0.39.