Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[OH:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][OH:38]>>[OH:32][CH2:33][CH2:34][N:35]([CH2:36][CH2:37][OH:38])[C:20]1[S:21][C:17](=[CH:16][C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=2[C:28]([F:31])([F:30])[F:29])[N:8]=[CH:9]3)[C:18](=[O:25])[N:19]=1
Reactant: OCCNCCO
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N(CCO)CCO)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
2-[Bis-(2-hydroxy-ethyl)-amino]-5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and 2-(2-Hydroxy-ethylamino)-ethanol following General Procedure C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]#[C:16][CH2:17][CH2:18][CH3:19]>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[C:15]#[C:16][CH2:17][CH2:18][CH3:19])[C:6]([O:8][CH3:9])=[O:7])([O-:14])=[O:13]
Reactant: C#CCCC
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCC#Cc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 18 h

Procedure:
A solution of methyl 4-chloro-3-nitrobenzoate (0.70 g), bis(triphenylphosphine) palladium chloride (0.12 g), and 1-pentyne (2 mL) in triethylamine (12 mL) was placed in a sealed tube. The mixture was heated to 75° C. and stirred 18 h. The reaction mixture was cooled, filtered, and concentrated in vacuo. The resulting brown residue was chromatographed on silica gel with hexane/ethyl acetate 9/1 to obtain the product. NMR (300 MHz, CDCl3) δ 8.61 (1H, d, J=2 Hz), 8.16 (1H, m), 7.64 (1H, m), 3.96 (3H, s), 2.49 (2H, t, J=7 Hz), 1.66 (2H, m, J=7 Hz), 1.06 (3H, t, J=7 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Cl.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[N:18]1([CH2:17][CH2:16][N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: N#Cc1ccnc(-c2cn(CCN3CCOCC3)cn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-(2-chloroethyl)morpholine hydrogen chloride according to the procedure for the preparation of Example 43, part A. [M+H] Calc'd for C15H17N5O, 284. Found, 284.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([C:12](O)=[O:13])[CH2:9][CH2:8][CH2:7]2.ClCCl>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([CH2:12][OH:13])[CH2:9][CH2:8][CH2:7]2
Reactant: Cc1cccc2c1C(C(=O)O)CCC2
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cccc2c1C(CO)CCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
8-Methyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid (J. Org. Chem. 1982, 47, 2590–2593) (0.066 g, 0.34 mmol) was dissolved in tetrahydrofuran (3 mL). To the solution was then added at 0° C. a 1.0M solution of borane-methyl sulfide complex in dichloromethane (0.7 mL, 0.69 mmol). The reaction mixture was stirred at room temperature for 15 minutes, refluxed for 2 hrs, then cooled down to 0° C. and quenched with methanol. The solvent was then evaporated in vacuo to yield a crude oil. The crude oil was partitioned with water and diethyl ether. The organic layer was dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield crude (8-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-methanol as an oil which was used directly to the next step.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]2[C:8]([O:13][CH3:14])=[CH:9][CH:10]=[C:11]([F:12])[C:5]=2[O:4][CH2:3]1.[CH3:15][C:16]([CH3:18])=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[F:12][C:11]1[C:5]2[O:4][CH2:3][C@H:2]([NH:1][CH:16]([CH3:18])[CH3:15])[CH2:7][C:6]=2[C:8]([O:13][CH3:14])=[CH:9][CH:10]=1
Reactant: COc1ccc(F)c2c1C[C@@H](N)CO2
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(F)c2c1C[C@@H](NC(C)C)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-3-Amino-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (1.62 g, 8.21 mmol) was dissolved in anhydrous methanol (20 mL) and to this was acetone (6.0 mL, 82.1 mmol) added. The reaction was cooled (ice-bath) then sodium cyanoborohydride (0.92 g, 14.8 mmol) was added, the pH was adjusted to 4-5 with acetic acid and the reaction was allowed to stir at room temperature overnight. The solvent was removed in vacuo, the remains were taken into a 2M solution of NH3 and then extracted thrice with diethyl ether. The combined ether portions were dried (MgSO4), filtered, and the solvent removed in vacuo to give the crude residue that was used as is in the next reaction. GC-MS (70 eV) M=239 (81%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[C:34]([O:38][C:39]([NH:41][CH2:42][C:43](O)=[O:44])=[O:40])([CH3:37])([CH3:36])[CH3:35].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:3][CH2:2][NH:1][C:43](=[O:44])[CH2:42][NH:41][C:39](=[O:40])[O:38][C:34]([CH3:35])([CH3:36])[CH3:37])([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNC(=O)CNC(=O)OC(C)(C)C)(c2ccc(F)cc2)OC1=O
Yield: 72.8 %

Procedure:
A solution of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (100 mg, 0.22 mmol), 2-(tert-butoxy-carbonyl-amino)acetic acid (58 mg, 0.33 mmol), HOBt (60 mg, 0.44 mmol), EDC (87 mg, 0.44 mmol) and i-Pr2NEt (142 mg, 1.1 mmol) in CH2Cl2 (5 mL) was stirred at rt overnight. After the solvents were evaporated, the crude product was purified by preparative TLC to give tert-butyl 2-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethylamino)-2-oxoethylcarbamate (98 mg, 74%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[CH:3]([OH:10])[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:28]1([CH2:34][C:35]([NH:37][C@@H:38]([C:60]([CH3:63])([CH3:62])[CH3:61])[C:39]([N:41]2[C@H:56]([C:57](O)=[O:58])[CH2:55][C@:43]3([O:47][C:46](=[O:48])[N:45]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[CH2:44]3)[CH2:42]2)=[O:40])=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.NCCC1N=CNC=1>CN(C=O)C.C(OCC)(=O)C>[CH:28]1([CH2:34][C:35]([NH:37][C@@H:38]([C:60]([CH3:63])([CH3:62])[CH3:61])[C:39]([N:41]2[C@H:56]([C:57]([NH:1][C@@H:2]([CH2:11][CH2:12][CH3:13])[CH:3]([OH:10])[C:4]([NH:6][CH:7]3[CH2:8][CH2:9]3)=[O:5])=[O:58])[CH2:55][C@:43]3([O:47][C:46](=[O:48])[N:45]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[CH2:44]3)[CH2:42]2)=[O:40])=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Reactant: CC(C)(C)[C@H](NC(=O)CC1CCCCC1)C(=O)N1C[C@@]2(C[C@H]1C(=O)O)CN(c1ccccc1)C(=O)O2
Agent: NCCc1c[nH]cn1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@]2(CN(c3ccccc3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)CC1CCCCC1)C(C)(C)C)C(O)C(=O)NC1CC1
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
(3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (20 mg, 87 μmol, 1.4 eq.), EDC (17 mg, 87 μmol, 1.4 eq.) and HOBt (13 mg, 87 μmol, 1.4 eq.) were combined in DMF (0.3 mL) and stirred at room temp. for 0.5 hrs. (5S,8S)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylic acid (H1) (31 mg 62 μmol, 1 eq.) and DIEA (33 μL, 186 mol, 3 eq.) were added to the mixture and stirred at room temp. overnight. 1.0 M histamine (aq., 31 μL, 0.5 eq.) was added and the resulting mixture was stirred for 0.5 hrs. Ethyl acetate was added and the mixture was washed first with 1N HCl then with 1M K2CO3; and then extracted with ethyl acetate. The combined organic layers concentrated and chromatography using DCM and 20% MeOH in DCM gave 20 mg (30 μmol) of (5S,8S)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxamide (I1). LC MS+/−: 668.56/666.64 at 3.24 min (10-90%, 3-5 min, Formic Acid).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH3:6][N:7]([CH2:9][C:10]1([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH3:8].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:5][CH2:4][CH2:3][CH2:2][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2([CH2:9][N:7]([CH3:8])[CH3:6])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:17][CH:18]=1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CC1(c2ccc(OCCCCl)cc2)CCOCC1
Temperature: 45 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
1-Bromo-3-chloropropane (0.42 ml, 4.25 mmol) was added to a solution of 4-(4-dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (1.0 g, 4.25 mmol) and potassium carbonate (1.5 g, 10.8 mmol) in N,N-dimethylformamide (10 ml). The reaction mixture was stirred at 45° C. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic layer was separated, dried over sodium sulphate, filtered and concentrated in vacuo to provide the title compound (800 mg, 60%). LRMS APCI+ m/z 412 [MH]+.
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[CH2:3][O:4][C:5]([NH:7][CH2:8][C:9](Cl)=[O:10])=[O:6].[Pb](SC#N)[S:15][C:16]#[N:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:13])([Cl:12])[CH2:3][O:4][C:5]([NH:7][CH2:8][C:9]([N:17]=[C:16]=[S:15])=[O:10])=[O:6]
Reactant: O=C(Cl)CNC(=O)OCC(Cl)(Cl)Cl
Reactant: N#CS[Pb]SC#N
Solvent: Cc1ccccc1
Product: O=C(CNC(=O)OCC(Cl)(Cl)Cl)N=C=S
Temperature: 25 °C

Procedure:
A solution of 20 parts of the preceeding acetyl chloride and 30 parts of lead thiocyanate in 150 parts by volume of toluene is refluxed for about 4 hours, then cooled to ambient temperature and filtered. The solvent is removed from the filtrate and the remaining oil distilled using fractionating column under vacuum to give {[(2,2,2-trichloroethoxy)carbonyl]amino}acetyl isothiocyanate. This compound is represented by the following formula
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9]C(=O)OC(C)(C)C)=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.ClC1C=CC=CC=1C(OO)=[O:25].Cl.O1CCOCC1>C(Cl)Cl.CO>[NH2:9][CH2:8][C:5]1[C:4]([C:17]([F:20])([F:19])[F:18])=[CH:3][C:2]([CH3:1])=[N+:7]([O-:25])[CH:6]=1
Reactant: O=C(OO)c1ccccc1Cl
Reactant: Cc1cc(C(F)(F)F)c(CNC(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)c(CN)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a round-bottomed flask was added tert-butyl ((6-methyl-4-(trifluoromethyl)pyridin-3-yl)methyl)carbamate (1.0 equiv.) which was dissolved in DCM (0.7 M). To this solution was added in-chloroperoxybenzoic acid (1.3 equiv.) and the mixture was stirred at room temperature for 12 h. The solvent was removed to afford a crude solid which was dissolved in MeOH and 4 N HCl in dioxane (4.2 equiv.) was added at room temperature. The mixture was stirred for 24 h and some precipitate begun to form. The volatile solvents were removed under reduced pressure to afford a crude residue. The residue was dissolved in methanaol and the resulting mixture was loaded on a Strata ion-exchange column. The column was washed successively with water, acetonitrile, MeOH and 7 N ammonia in MeOH. The product eluted with the 7 N ammonia in MeOH eluent and product containing eluent was concentrated under reduced pressure to afford 5-(aminomethyl)-2-methyl-4-(trifluoromethyl)pyridine 1-oxide (90% yield) as the free base; MS(ESI) m/z 207.0[M+1]+.
Reaction SMILES: [C:1]([NH:6][NH2:7])([CH2:4][CH3:5])([CH3:3])[CH3:2].[C:8]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])[CH2:9][CH2:10][C:11]([CH3:13])=O>>[C:1]([NH:6][N:7]=[C:11]([CH3:13])[CH2:10][CH2:9][C:8]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCOC(=O)CCC(C)=O
Reactant: CCC(C)(C)NN
Product: CCCCOC(=O)CCC(C)=NNC(C)(C)CC
Yield: 90 %

Procedure:
Butyl levulinate t-amylhydrazone was prepared in 90% yield by refluxing an aqueous solution of t-amylhydrazine with an equimolar amount of butyl levulinate.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C@H:7]([NH:8][C@@H](C2C=CC=CC=2)C)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[H][H]>[Pd].C(O)C>[NH2:8][C@@H:7]1[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:2]1([CH3:24])[CH3:1]
Reactant: C[C@@H](N[C@@H]1CCN(C(=O)OC(C)(C)C)CC1(C)C)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)C(C)(C)C1
Reaction time: 5 h
Yield: 97.1 %

Procedure:
A pressure bottle was charged with palladium on carbon (0.192 g, 0.180 mmol) and (R)-tert-butyl 3,3-dimethyl-4-((R)-1-phenylethylamino)piperidine-1-carboxylate (3.00 g, 9.02 mmol) in ethanol (60 mL) and the resulting mixture was shaken under 50 psi of hydrogen on a Parr apparatus. After 5 h, the catalyst was removed by filtration, rinsed with methanol, and the filtrate was concentrated in vacuo to afford the title compound as a clear oil (2.0 g, 8.76 mmol, 97%). Material was not further purified and was used directly in next transformation. 1H NMR (500 MHz, METHANOL-d4) δ 4.07 (d, J=13.0 Hz, 1H), 3.78-3.62 (m, 1H), 3.01-2.62 (m, 2H), 2.56 (dd, J=11.1, 4.2 Hz, 1H), 1.74-1.63 (m, 1H), 1.51 (s, 9H), 1.49-1.43 (m, 1H), 1.00 (s, 3H), 0.88 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[F:14][C:2]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)([F:1])[F:13]
Reactant: Ic1ccccc1
Reactant: FC(F)(F)Oc1ccc2cc[nH]c2c1
Product: FC(F)(F)Oc1ccc2ccn(-c3ccccc3)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 6-(trifluoromethoxy)-1H-indole and iodobenzene: ESMS m/e: 278.0 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([CH:11]([CH3:22])[CH:12]([CH3:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:8]=[C:5]([O:6]C)[CH:4]=1.C(O)(=O)C.Br>O>[CH3:22][CH:11]([C:9]1[CH:10]=[C:3]([OH:2])[CH:4]=[C:5]([CH:8]=1)[OH:6])[CH:12]([CH3:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCC(C)C(C)c1cc(OC)cc(OC)c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCC(C)C(C)c1cc(O)cc(O)c1
Reaction time: 12 h

Procedure:
A solution of 30.6 g. of 5-(1,2-dimethyldecyl)-resorcinol dimethyl ether in 350 ml. of glacial acetic acid and 150 ml. of 48% hydrogen bromide is refluxed eight hours, then stirred at 25° for 12 hours. The reaction mixture is diluted with water and extracted three times with ether. The combined extracts are washed with saturated aqueous sodium bisulfite and saturated aqueous sodium bicarbonate, dried (MgSO4), concentrated and distilled to give 5-(1,2-dimethyldecyl)resorcinol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:40]1[CH2:45][CH2:44][S:43](=[O:47])(=[O:46])[CH2:42][CH2:41]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:26])[F:27])=[N:20][C:21]([C:22]([N:40]3[CH2:45][CH2:44][S:43](=[O:47])(=[O:46])[CH2:42][CH2:41]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: O=S1(=O)CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCS(=O)(=O)CC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 94.3 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), thiomorpholine-1,1-dioxide hydrochloride (73 mg, 0.54 mmol), bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 8 mL of dichloromethane under stirring, and 4 mL of N,N-dimethylformamide was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(1,1-dioxo-thiomorpholine-4-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 6a (170 mg, yield 94%) as a white solid.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[O:30][CH3:31])([C:21]#[N:22])[CH:10]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[NH:9]1)=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[O:30][CH3:31])([C:21]#[N:22])[CH:10]([CH2:32][C:33]([CH3:34])([CH3:35])[CH3:36])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)OC(C)(C)C)C1c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)O)C1c1cccc(Cl)c1F
Yield: 100 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 58b (1.3 g, 2.4 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2S,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.5 g, 100%).
Reaction SMILES: [Mg].[CH2:2]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH:3]=[CH2:4].[B:12]([O:17]C)([O:15]C)[O:13]C.Cl>O1CCCC1>[CH2:2]([C:5]1[CH:10]=[CH:9][C:8]([O:13][B:12]([OH:17])[OH:15])=[CH:7][CH:6]=1)[CH:3]=[CH2:4]
Reactant: C=CCc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCc1ccc(OB(O)O)cc1
Yield: 65.8 %

Procedure:
To a mixture comprising sufficiently dried metal magnesium (120 mmol) and 30 ml of tetrahydrofuran (hereinafter referred to as THF), was gradually added a solution of 120 mmol of the 4-allyl-bromobenzene in 200 ml of THF to prepare a Grignard reagent. To this reagent was added dropwise a solution of trimethyl borate (120 mmol) in 100 ml of THF at a temperature not exceeding -65° C., stirred for a whole day and night. Subsequently, the mixture was kept at 0° C., 200 ml of 10% hydrochloric acid was gradually added thereto at the same temperature, and then the reaction mixture was stirred for 30 min. The mixture thus obtained was extracted twice with 500 ml of diethyl ether, the organic layer was washed with a saturated brine solution, and then the solvent was removed under a reduced pressure. The residue was sufficiently washed with 500 ml of heptane and then dried to obtain 4-allylphenyl boric acid (79 mmol).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH3:15])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=2)[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1ccc(CCN(C)CCCC(C(N)=O)(c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.56 g--see Preparation 3), methyl 4-(2-brom0ethyl)phenylacetate (0.51 g--see Preparation 22), anhydrous potassium carbonate (0.6 g) and acetonitrile (20 ml) was heated under reflux for 5.5 hours. The mixture was partitioned between dichloromethane (70 ml) and 10% aqueous potassium carbonate (50 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing hexane (50%) then with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield 0.2 g.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.C([OH:29])C>C(OCC)C>[ClH:1].[OH:29][C:2]1[C:11]2[C:6](=[C:7]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3c(Cl)nccc23)CC1
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: Oc1nccc2c(NC3CCNCC3)cccc12
Temperature: 85 °C

Procedure:
Intermediate 84 (76.6 mg) was added with concentrated hydrochloric acid (1.5 ml) and stirred with heating at 85° C. for 7 hours. The reaction mixture was cooled to room temperature, and then the residue was added with ethanol (1 ml) and diethyl ether (2 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (55.5 mg) as white powdery solid.