Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=1>CCO.C(Cl)Cl.[Pt](=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2Br)CC1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2cc(C(F)(F)F)ccc2Br)CC1
Reaction time: 1 h
Yield: 39.7 %

Procedure:
A solution of tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (from Step 1 of Intermediate VV; 2.435 g, 5.99 mmol) in 20 mL EtOH was treated with platinum(iv) oxide (0.136 g, 0.599 mmol) and was placed under 45 psi H2 for one hour. LC/MS showed mostly product and de-brominated product. The reaction mixture was diluted with DCM and was filtered through diatomaceous earth. The filtrate was concentrated then purified directly by column chromatography (0 to 15% EtOAc/heptane) yielding tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.970 g, 2.376 mmol, 39.6% yield). m/z (ESI) 431.0 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:10][C:9]2[C:4](=[C:5]([O:13]C)[CH:6]=[CH:7][C:8]=2[O:11][CH3:12])[C:3]1=[O:15].B(Cl)(Cl)Cl>ClCCl>[CH3:1][C:2]1([CH3:16])[CH2:10][C:9]2[C:4](=[C:5]([OH:13])[CH:6]=[CH:7][C:8]=2[O:11][CH3:12])[C:3]1=[O:15]
Reactant: COc1ccc(OC)c2c1CC(C)(C)C2=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(O)c2c1CC(C)(C)C2=O
Temperature: -78 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
To a cooled (−78° C.), stirred solution of 2,2-dimethyl-4,7-dimethoxy-indan-1-one (1 g) in dichloromethane (20 mL) was added boron trichloride (9 mL of a 1M solution in dichloromethane) over a 5 min period. The reaction was allowed to warm to RT, stirred for 3 h, then recooled to −78° C., quenched with ice, allowed to warm to RT and stirred for 1 h. The reaction was extracted with dichloromethane, the organic layers dried over sodium sulfate, concentrated in vacuo and flash chromatographed to afford 2,2-dimethyl-7-hydroxy-4-methoxyindan-1-one (0.85 g) as a tan oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].[C:9](O)([CH3:12])([CH3:11])[CH3:10].C1CCN2C(=NCCC2)CC1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:9]([O:5][C:4](=[O:6])[C:3]([CH3:8])([CH3:7])[CH2:2][Cl:1])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)O
Reactant: CC(C)(CCl)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)CCl
Temperature: 40 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
The required 3-Chloro-2,2-dimethyl-propionic acid tert-butyl ester was prepared as follows: To a solution of 3-chloro-2,2-dimethylpropionic acid (5.00 g; 36.6 mmol) in DMF (25 mL) was added N,N′-carbonyldiimidazole (5.94 g; 36.6 mmol) and the resulting mixture was stirred for 1 hour at 40° C. Subsequently, tert-butyl alcohol (7.1 mL; 73 mmol) and DBU (5.5 mL; 36.6 mmol) were added and the mixture stirred overnight at 40° C. After cooling to RT, 5% aqueous NaHCO3 solution (50 mL) was added to the mixture and stirred for another 15 minutes. The reaction mixture was extracted with EtOAc. The organic layer was dried (Na2SO4), concentrated in vacuo and purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 3-chloro-2,2-dimethyl-propionic acid tert-butyl ester (3.34 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.N1CCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH:14]=1
Reactant: CN1CCC(=O)CC1
Reactant: Brc1ccc2[nH]ccc2c1
Solvent: C1CCNC1
Solvent: CCO
Product: CN1CC=C(c2c[nH]c3ccc(Br)cc23)CC1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
5-Bromoindole (4.31 g, 22 mmol), 1-methyl4-piperidone (2.46 mL, 20 mmol) and pyrrolidine (17 mL, 200 mmol) were mixed in ethanol (30 mL) and refluxed for 72 hours. The mixture was cooled to room temperature and the resulting solid, collected by filtration, washed with methanol and dried to provide as 5-bromo-3-(1,2,3,6-tetrahydro-1-methyl4-pyridinyl)-1H-indole white solid (4.40 g, 76%). mp>230° C. dec.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH:20]CC4C=CC(OC)=CC=4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH:19]=[C:18]([NH2:20])[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(CNc2cc3c(Nc4ccc(F)c(Br)c4)ncnc3cn2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc2c(Nc3ccc(F)c(Br)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.6 %

Procedure:
To a stirred homogeneous solution of compound 165 (15.9 g, 34.9 mmol) in trifluoroacetic acid (80 mL) was added anisole (7.58 mL, 69.8 mmol). The mixture was then stirred at room temperature for 20 h. Most of the trifluoroacetic acid was evaporated under reduced pressure at 35° C. (bath temperature). The resultant red-brown oil was stirred with petroleum ether (400 mL) at room temperature for ca. 10 min. The petroleum ether layer was then decanted and the process was repeated with more petroleum ether (2×300 mL). The residue was then stirred with 5M NH3 at 0° C. for 5 min, then at room temperature for another 45 min. The solid thus obtained was collected by filtration and washed with water (3×60 mL) before being dried in vacuo. The solid was then stirred with warm acetone (500 mL) for 30 min. Water (800 mL) was added and the suspension was stirred at room temperature for 1 h. The solid was again collected by filtration and washed successively with water (6×70 mL) and then petroleum ether/ethyl acetate (3:1, 4×100 mL) before being dried under reduced pressure, to give N4-(3-bromo-4-fluorophenyl)pyrido[3,4-d]pyrimidine-4,6-diamine (159) (11.5 g, 99%), mp 269-271° C. (literature mp 268-270° C.). 1H NMR identical with that reported (Smaill et al. J Med Chem, 1999, 42, 1803-1815).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]#[N:7])[CH3:2].[CH:16]([O:19][C:20](=[O:25])[CH2:21][C:22](=[NH:24])[NH2:23])([CH3:18])[CH3:17].CC[O-].[Na+]>C(O)C>[CH:16]([O:19][C:20]([C:21]1[CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])=[C:6]([NH2:7])[NH:24][C:22]=1[NH2:23])=[O:25])([CH3:18])[CH3:17]
Reactant: CC(C)OC(=O)CC(=N)N
Reactant: CCOC(=O)C(C#N)=Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OC(C)C)C1c1ccccc1
Yield: 54 %

Procedure:
Upon heating a solution of 10.1 g benzylidenecyanoacetic acid ethyl ester, 7.2 g amidinoacetic acid isopropyl ester and 0.6 g sodium ethylate in 150 ml ethanol for four hours, 2,6-diamino-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5-isopropyl ester of m.p. 170° is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH2:15][CH3:16])([C:13]#[N:14])[C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1.Cl.Cl.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([NH2:27])[CH:23]=[N:22]1>CC(O)C>[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([NH:27][C:2]2[N:7]=[C:6]([N:8]3[CH2:12][CH2:11][C@:10]([CH2:15][CH3:16])([C:13]#[N:14])[C:9]3=[O:17])[CH:5]=[CH:4][N:3]=2)[CH:23]=[N:22]1
Reactant: Cc1c(N)cnn1C
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Agent: Cl
Solvent: CC(C)O
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3cnn(C)c3C)n2)C1=O
Yield: 69.7 %

Procedure:
A solution of (3R)-1-(2-chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile (100 mg) obtained in Step A of Example 8 and 1,5-dimethyl-1H-pyrazol-4-amine dihydrochloride (73 mg) in propan-2-ol (4.0 mL) was stirred in a microwave reactor at 160° C. for 1 hr, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate), and recrystallized (diisopropyl ether/ethyl acetate) to give the title compound (90 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([NH:20][CH:21]1[CH2:27][S:26][CH:25]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[CH2:24][N:23]([CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])[C:22]1=[O:41])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]([CH:11]([NH:20][CH:21]1[CH2:27][S:26][CH:25]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[CH2:24][N:23]([CH2:33][C:34]([OH:36])=[O:35])[C:22]1=[O:41])[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN1CC(c2cccs2)SCC(NC(CCc2ccccc2)C(=O)OCc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CC(c2cccs2)SCC(NC(CCc2ccccc2)C(=O)OCc2ccccc2)C1=O

Procedure:
Following the procedure described in Example 43, 180 mg of isomer B of t-butyl α-[6-(1-benzyloxycarbonyl-3-phenylpropylamino)-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate (prepared as described in Example 54) was de-t-butylated using trifluoroacetic acid, to afford 135 mg of the title compound as a powder.
Reaction SMILES: [CH:1]([C@H:3]1[C@@H:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][O:6][C@@H:5]([CH3:19])[O:4]1)=O.[C:20]1([NH:26][C:27](=[O:30])[NH:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)(=O)C.CO.C(Cl)(Cl)Cl>[CH3:18][O:17][C:15]([CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][C@H:8]1[CH2:7][O:6][C@@H:5]([CH3:19])[O:4][C@H:3]1[CH:1]=[N:29][NH:28][C:27]([NH:26][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:30])=[O:16]
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1C=O
Reactant: NNC(=O)Nc1ccccc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1C=NNC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A mixture of (2R,4R,5S)-4-formyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (300 mg), 4-phenylsemicarbazide (227 mg) and a few drops of acetic acid in methanol (5 ml) was stirred at room temperature for 3 hours and the mixture was diluted with chloroform (30 ml). The solution was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column (15 g) with a mixture of n-hexane and ethyl acetate (3:1) as an eluent to give (2R,4R,5S)-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-4-(4-phenylsemicarbazonomethyl)-1,3-dioxane (403 mg) as an pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH:17]([CH2:22][CH2:23][CH2:24][Br:25])[C:18]([O:20][CH3:21])=[O:19]>>[Br:25][CH2:24][CH2:23][CH2:22][CH:17]([O:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:18]([O:20][CH3:21])=[O:19]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: COC(=O)C(Br)CCCBr
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(OC(CCCBr)C(=O)OC)c1

Procedure:
By a process similar to that of Reference Example 5, ethyl 3-hydroxy-4-nitrobenzoate was allowed to react with methyl 2,5-dibromovalerate to give methyl 5-bromo-2-(5-ethoxycarbonyl-2-nitrophenoxy)valerate as an oily product (yield: 80.2%). This product was subjected to catalytic reduction to obtain ethyl 2-(3-bromopropyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-7-carboxylate, m.p. 118°-119° C. The yield was 90.7%.
Reaction SMILES: [N:1]1[N:9]2[C:4]([N:5]=[C:6]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:7]3=[C:8]2O)=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:18])=O.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[Cl:18][C:8]1[N:9]2[C:4]([N:5]=[C:6]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:7]=13)=[CH:3][CH:2]=[N:1]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1c2c(nc3ccnn13)CCCCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1c2c(nc3ccnn13)CCCCC2
Temperature: 25 °C
Yield: 35.3 %

Procedure:
To a suspension of 6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]inden-10-ol (5 g, 29.4 mmol) in toluene (20 mL) was added phosphorus oxychloride (37 g, 246 mmol) and diisopropylethylamine (3.1 g, 24.6 mmol). The mixture was heated to reflux for 40 min then cooled to room temperature. The product crystallized from the reaction mixture on standing over a two-day period at room temperature. The solid was collected and washed with ether to give 10-chloro-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene (2.3 g, 42.5% yield). The product was used without further purification.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].[CH2:12]1[O:14][CH2:13]1>C(O)C>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][OH:14])[CH3:2]
Reactant: C1CO1
Reactant: CCCCCCCCNCC
Solvent: CCO
Product: CCCCCCCCN(CC)CCO
Yield: 80.6 %

Procedure:
A mixture of 15.7 g of ethyl-n-octylamine, 5 g of ethyleneoxide and 100 ml of 96% ethanol was held at 100° C. for one hour in a steel autoclave. The reaction mixture was distilled and gave 16.2 g of N-ethyl-N-n-octyl-ethanolamine, b.p. 85°-87° C./0.2 mm Hg, nD22 = 1.4490.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[O:22]=[C:23]1[N:27]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][N:24]1[C:34](Cl)=[O:35].O>C(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:34]([N:24]1[CH2:25][CH2:26][N:27]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:23]1=[O:22])=[O:35]
Reactant: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3)ccn2)cn1
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Solvent: O
Solvent: ClCCl
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)c(F)c3)ccn2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
A mixture of 2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (0.150 g, 0.528 mmol) and TEA (3.2 mL, 22.93 mmol) in DCM (5 mL) was cooled to 0° C., treated with a solution of Example B2 (0.164 g, 0.705 mmol) in DCM (1.5 mL), warmed to RT and stirred for 1 h. The mixture was treated with water, stirred for 10 min, the layers separated and the organic layer dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was treated with Et2O, sonicated and the resulting solid collected via filtration to afford N-(2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (167 mg, 66%). 1H NMR (400 MHz, DMSO-d6): δ 10.74 (d, J=2.5 Hz, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 8.19 (t, J=9.1 Hz, 1 H), 7.95 (d, J=0.7 Hz, 1 H), 7.28 (dd, J=11.7, 2.7 Hz, 1 H), 7.22 (d, J=2.4 Hz, 1 H), 7.03 (dd, J=9.1, 2.5 Hz, 1 H), 6.67 (dd, J=5.7, 2.4 Hz, 1 H), 3.93-3.77 (m, 8 H), 3.46 (t, J=8.2 Hz, 2 H), 3.38 (dd, J=12.5, 10.6 Hz, 2 H), 1.71 (qd, J=12.2, 4.5 Hz, 2 H), 1.60-1.57 (m, 2H); MS (ESI) m/z: 481.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:13]([CH:14]([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH2:8][CH3:9])[C:6]#[N:7].[CH2:17](N)[CH2:18][NH2:19].[S-]SS[S-].[Na+].[Na+]>O>[Cl:1][C:2]1[C:13]([CH:14]([F:15])[F:16])=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([C:6]1[NH:19][CH2:18][CH2:17][N:7]=1)[CH2:8][CH3:9]
Reactant: CCC(C#N)Oc1cccc(C(F)F)c1Cl
Reactant: NCCN
Agent: [Na+]
Agent: [S-]SS[S-]
Solvent: O
Product: CCC(Oc1cccc(C(F)F)c1Cl)C1=NCCN1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-chloro-3-difluoromethyl-phenoxy)-butyronitrile (300 mg, 1.2 mmol), ethylene diamine (0.33 ml, 4.9 mmol) and sodium tetrasulfide (11 mg, 0.1 mmol) was stirred for 2 hrs at 50° C., then cooled to room temperature. Cold water (0° C.) was added to the reaction mixture. The resultant suspension was stirred for ca 15 minutes and then filtered, washed and dried to yield 2-[1-(2-chloro-3-difluoromethyl-phenoxy)-propyl]-4,5-dihydro-1H-imidazole (m.p. 96-97° C.); 1H-NMR (D6-DMSO) 1.0, t, 3H, 1.8-2.0 m, 2H; 3.42 vbr s, 4H, 4.8, dd, 1H, 6.51, br s, 1H, 7.2, t, 1H, 7.25, d, 1H, 7.32, d, 1H, 7.43, t, 1H.
Reaction SMILES: Cl.C(O[C:7]([N:9]1[CH2:20][CH2:19][C@@H:18]([O:21][Si](C(C)(C)C)(C)C)[C@H:10]1[C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:8])(C)(C)C.[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:45]([NH:47][C@@H:48]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C@H:49]([OH:53])C(O)=O)=[O:46])[CH2:41][C:42](=[O:44])[NH2:43])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCOCC1.CO>[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:45]([NH:47][C@@H:48]([CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C@H:49]([OH:53])[C:7]([N:9]1[CH2:20][CH2:19][C@@H:18]([OH:21])[C@H:10]1[C:11]([NH:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[O:8])=[O:46])[CH2:41][C:42](=[O:44])[NH2:43])=[O:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)[C@@H]1[C@H](O)CCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
1.5 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 50 mg (0.13 mmol) of (3R)-1-t-butoxycarbonyl-N-t-butyl-3-t-butyldimethylsilyloxy-L-prolinamide (prepared as described in Preparation 12) in 0.5 ml of methanol, and the mixture was stirred at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with benzene. The excess hydrogen chloride was then removed by distillation as an azeotrope with the benzene. The resulting residue was dried in vacuo for 2 hours and the whole of the resulting (3E)-N-t-butyl-3-t-butyldimethylsilyloxy-L-prolinamide hydrochloride was reacted with 55 mg (0.13 mmol) of (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 1) following a procedure similar to that described in Example 1, to obtain 33 mg of the title compound as a white powder, melting at 109°-112° C.
Reaction SMILES: C(OC(=O)CC(N1C=CC(C2C=CC=CC=2)=C1)C(NC1CC2=CN(C3C2=CC=CC=3)CCOCCNC1=O)=O)C1C=CC=CC=1.[CH2:46]([O:53][C:54](=[O:72])[CH2:55][C@@H:56]([NH2:71])[C:57]([NH:59][C@H:60]([C:65](=[O:70])[N:66]([O:68][CH3:69])[CH3:67])[CH2:61][CH:62]([CH3:64])[CH3:63])=[O:58])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[C:73]1([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[CH:78]=[CH:77][C:76]([CH:79]2[CH2:83][CH:82](OC)O[CH:80]2OC)=[CH:75][CH:74]=1.FC(F)(F)C(O)=O>ClCCCl>[CH2:46]([O:53][C:54](=[O:72])[CH2:55][C@@H:56]([N:71]1[CH:82]=[CH:83][C:79]([C:76]2[CH:77]=[CH:78][C:73]([C:88]3[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=3)=[CH:74][CH:75]=2)=[CH:80]1)[C:57]([NH:59][C@H:60]([C:65](=[O:70])[N:66]([O:68][CH3:69])[CH3:67])[CH2:61][CH:62]([CH3:63])[CH3:64])=[O:58])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CC(=O)OCc1ccccc1
Agent: O=C(CC(C(=O)NC1Cc2cn(c3ccccc23)CCOCCNC1=O)n1ccc(-c2ccccc2)c1)OCc1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Yield: 48 %

Procedure:
As described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo-[9.6.1.012,17]-octadeca-11(18),12,14,16-tetraen-9-yl)-3-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-amino-N-(1(S)-(N-methoxy-N-methylcarbamoyl)-3-methyl-butyl)succinamic acid benzyl ester was deprotected. The crude amine salt and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) were condensed in anhydrous 1,2-dichloroethane with trifluoroacetic acid to provide in 48% yield 3(R)-(3-biphenyl-4-yl-1H-pyrrol-1-yl)-N-[1(S)-(N-methoxy-N-methylcarbamoyl)-3-methyl-butyl]succinamic acid benzyl ester as an amorphous solid.
Reaction SMILES: NCC(O)=O.[OH-].[Na+].[C:8]([CH2:11][CH:12]([CH:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:16][OH:17])[CH2:13][OH:14])([OH:10])=[O:9].COC1C=CC(C=O)=CC=1>O.CC(C)=O.C(O)C.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.C(Cl)Cl>[C:19]([CH2:18][C@@H:15]1[C@H:12]([CH2:11][C:8]([OH:10])=[O:9])[CH2:13][O:14][C:16]1=[O:17])([OH:21])=[O:20]
Reactant: O=C(O)CC(CO)C(CO)CC(=O)O
Agent: COc1ccc(C=O)cc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NCC(=O)O
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: O=C(O)C[C@@H]1COC(=O)[C@@H]1CC(=O)O
Yield: 81.6 %

Procedure:
Glycine (18.8 grams) is dissolved in 2 liters of deionized water, and the pH is adjusted by the addition of 10% sodium hydroxide to 9.0. 2,3-bis-carboxymethyl-1,4-butanediol (10.0 grams) is dissolved in 150 ml of acetone added to the glycine solution with stirring, followed by the addition of β-NAD+ (Sigma, 0.5 grams). To the resulting solution is added horse liver alcohol dehydrogenase (Sigma, 250 mg, approximately 400 units). After the enzyme has dissolved the pH is readjusted to 9.0 with 10% sodium hydroxide, and the reaction mixture is stirred at 30° C. During the reaction, the pH is maintained at 9.0 with a pH-stat by the addition of 10% sodium hydroxide. Progress of the reaction is monitored by thin layer chromatography (Silica gel plates, eluent methylene chloride; visualization by dipping in a solution of 5% anisaldehyde in ethanol and heating). When the reaction is complete as judged by thin layer chromatography, the reaction mixture is adjusted to a pH of 13 with 10 M sodium hydroxide and then extracted 3 times with 250 ml of methylene chloride. The pH of the aqueous mixture is then adjusted to 3 with concentrated HCl, followed by continuous extraction with 1 liter of ethyl acetate for 24 hours. The ethyl acetate extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield (2R, 3S)-2,3-bis-carboxymethylbutyrolactone (8 grams) as a yellowish solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:48])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:38]=[C:37]([CH2:39][O:40]C3CCCCO3)[O:36][N:35]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:40][CH2:39][C:37]1[O:36][N:35]=[C:34]([C:30]2[CH:29]=[C:28]([C:27]3[CH2:26][C:25](=[O:48])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:22])[F:23])[C:12]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:38]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cc(CO)on3)c2)=Nc2cc(N3CCOCC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[5-morpholin-4-yl-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M31) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (386 mg).