Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([CH:10]2[CH2:13][CH2:12][CH2:11]2)[NH:7][C:8]=1[Br:9].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>C1COCC1>[Br:9][C:8]1[N:7]=[C:6]([CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:5]([CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[C:4]=1[Br:3]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1nc(C2CCC2)[nH]c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(C2CCC2)nc(Br)c1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 16.7 %

Procedure:
A 250 mL round-bottom flask was purged with nitrogen and charged with NaH (95%, 0.2 g, 8.3 mmol). THF (10 mL) added, and the mixture cooled to 0° C. After 5 minutes, a solution of 4,5-dibromo-2-cyclobutyl-1H-imidazole (1.76 g, 6.29 mmol, ˜40% purity) in THF (20 mL) was added dropwise from an addition funnel over 5 minutes. The reaction was stirred at 0° C. for 35 minutes and SEMCl (1.8 mL, 10.2 mmol) was then added dropwise over 2 minutes. After 5 minutes, ice bath was removed, and the reaction stirred at room temperature for 4 hours. LCMS indicated complete reaction. The reaction was then carefully quenched with water (1.5 mL). Heptane (250 mL) was added and organic layer was washed with water (200 mL). The aqueous layer was extracted with heptane (100 mL), and the combined organic layers were washed with water and brine, dried (Na2SO4), and concentrated to give 2.14 g of crude material. The crude material was purified by flash chromatography (SiO2; EtOAc in heptane) to afford 4,5-dibromo-2-cyclobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (0.43 g) as a yellow oil: LCMS (m/z) 408.9 (MH+), tR=1.25 minutes.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[OH:46]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH2:15][OH:46])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: OCCBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CCO)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromoethanol and isolated as white solid (1.9 mg, 14%). MS (m/e): 327.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH2:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][CH:49]([C:57]([NH2:59])=[O:58])[NH:48]1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:48]2[CH:49]([C:57]([NH2:59])=[O:58])[CH2:50][C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:47]2)=[O:15])=[CH:6][CH:7]=1
Reactant: NC(=O)C1Cc2ccccc2CN1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2oncc2C(=O)N2Cc3ccccc3CC2C(N)=O)cc1
Reaction time: 2 h
Yield: 22.1 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (20 mg, 0.1 mmol), TBTU (39 mg, 0.12 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (35 μL, 0.2 mmol, 2 equ) in DMF (1 mL) was added to 1,2,3,4-tetrahydroisoquinoline-3-carboxamide (18 mg, 0.1 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z calcd for C21H19N3O3: 361.1426, found 361.1418.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.[CH3:35][N:36](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:35]([C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:22]=[N:21][C:20]([N:23]3[CH2:24][CH2:25][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:28]3)=[N:19][CH:18]=2)[CH:3]=1)#[N:36]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C#N)c2s1
Temperature: 100 °C
Yield: 100 %

Procedure:
Ethyl 1-[5-[7-bromo-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (600 mg, 0.658 mmol), zinc cyanide (96 mg, 0.822 mmol) and Pd(PPh3)4 (76 mg, 0.066 mmol) were suspended in DMF (10 mL) and degassed/purged (×3) with Ar. The reaction mixture was then heated at 100° C. under microwave irradiation for 40 mins, cooled to rt, diluted with EtOAc (50 mL), washed with water, brine and separated. The organic fraction was dried (Na2SO4) and concentrated under reduced pressure and the resulting solid purified by flash column chromatography (40 g GraceResolv silica cartridge—dry loaded), eluting with 0-10% MeOH/CH2Cl2. The resulting residue was washed with MeOH to afford desired compound (327 mg, ˜100%) as an off-white solid. MS: 494.14 [M+H]+.
Reaction SMILES: C([Li])(CC)C.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][CH3:20])=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:21]([N:28]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:30]=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)C>[C:6]([O:10][C:11]([N:13]1[CH:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH:18]1[CH:30]([OH:31])[C@@H:29]([N:28]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCC1CCCCN1C(=O)OC(C)(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CCC1CCCC(C(O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)N1C(=O)OC(C)(C)C
Temperature: -35 °C
Reaction time: 1 h

Procedure:
Add N,N,N′,N′-tetrametlhylethylenediamine (1.4 mL, 9.11 mmol), then sec-butyllithium (1.4 M in cyclohexane, 7.2 mL, 10.1 mmol) to 2-ethylpiperidine-1-carboxylic acid tert-butyl ester in diethyl ether (18 mL) at −78° C. under a nitrogen atmosphere. Warm to −35° C. and stir for 1 h. Cool to −78° C. and add (2S)-2-(dibenzylamino)-3-phenylpropanal (3.0 g, 9.11 mmol) in diethyl ether (4 mL) and stir for 30 min. Quench at −78° C. with water, warm to room temperature and extract with diethyl ether. Combine the organic layers, dry (magnesium sulfate) and concentrate. Separate the two major diastereomers of 2-((2S)-2-dibenzylaniino-1-hydroxy-3-phenylpropyl)-6-ethylpiperidine-1-carboxylic acid tert-butyl ester using normal-phase preparative HPLC (Kromasil Si 60, 10 μm, 80×180 mm; 98:2 Hexane:Acetone; 130 mL/min).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7]Br)=[CH:4][CH:3]=1.[C:12]([NH2:15])(=[O:14])[CH3:13]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:15]=[C:12]([CH3:13])[O:14][CH:7]=2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CC(N)=O
Product: Cc1nc(-c2ccc(Br)cc2)co1
Reaction time: 2.5 h
Yield: 22.5 %

Procedure:
4-Bromophenacyl bromide (21.3 g) and acetamide (11.3 g) were heated together at 130° C. under argon. After 2.5 h the reaction mixture was allowed to cool, and partitioned between water (150 ml) and Et2O (150 ml). The organic phase was washed with aqueous NaOH (0.5N), aqueous HCl (0.5M) and saturated aqueous NaCl solution (100 ml) of each), dried (MgSO4) and evaporated to give a brown solid which was recrystallised from hexanes to give the title compound (D14) as an orange solid (4.1 g). LCMS electrospray (+ve) 239 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][NH2:11])=[CH:7][C:6]=2[CH:12]=1.C(N(CC)CC)C.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][NH:11][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:27])=[CH:7][C:6]=2[CH:12]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: NCc1cc2cc(Cl)ccc2o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCc1cc2cc(Cl)ccc2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of (5-chloro-1-benzofuran-2-yl)methanamine (420 mg, crude) in dichloromethane (50 ml) was added triethylamine (315 mg, 3.12 mmol). Then ethyl 2-chloro-2-oxoacetate (378 mg, 2.77 mmol) was added dropwise and the contents were stirred for 30 minutes at 0° C. The resulting solution was quenched with water (100 ml) and extracted with dichloromethane (3×70 ml). The organic fractions were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 20% ethyl acetate in petroleum ether to afford ethyl [[(5-chloro-1-benzofuran-2-yl)methyl]carbamoyl]formate as an off-white solid (600 mg). (ES, m/z): [M+H]+ 282.0; 1H NMR (400 MHz, CDCl3): δ 7.52 (s, 2H), 7.38 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 6.64 (s, 1H), 4.68 (d, J=4.2 Hz, 2H), 4.39 (q, J=7.2 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH:10]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1.CCCCCC>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH:10]=[C:6]([CH2:4][OH:3])[CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)C1=CCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC=C(CO)C1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of 5.43 g (22.5 mmol) 2,5-dihydro-pyrrole-1,3-dicarboxylic acid 1-tert.-butylester 3-ethyl ester in 50 ml THF, cooled to −78° C. was dropwise added 50 ml of a 1N DIBAL-H solution in hexane. The mixture was allowed to warm to room temperature overnight. As TLC analysis indicated complete consumption of starting material, the mixture was cooled in an ice bath and 1.90 g water were cautiously added, followed by 1.90 g 15% aqueous NaOH and 5.70 g water. The white precipitate was filtered off, washed thoroughly with ether and the combined filtrates were evaporated. Bulb-to-bulb distillation of the residual pale yellow oil gave 4.13 g (93%) 3-hydroxymethyl-2,5-dihydro-pyrrole-1-carboxylic acid tert.-butylester as a colorless oil, b.p. 130° C. (0.2 mbar).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:6]=1.[CH2:21]([O:23][C:24]([CH2:26][C:27](Cl)=[O:28])=[O:25])[CH3:22].Cl.[Na]>CN(C)C=O>[CH2:21]([O:23][C:24]([CH2:26][C:27]([NH:1][C:2]1[S:3][C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:6]=1)=[O:28])=[O:25])[CH3:22]
Reactant: COc1ccc(-c2nc(N)sc2-c2cccnc2)cc1
Reactant: CCOC(=O)CC(=O)Cl
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)Nc1nc(-c2ccc(OC)cc2)c(-c2cccnc2)s1
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
In 5 ml of dimethylformamide was dissolved 1 g of 2-amino-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole. To the solution was added under ice-cooling 580 mg of ethoxycarbonylacetylchloride. The mixture was stirred for 30 minutes, to which was then added a saturated aqueous solution of sodium hydrogen chloride. The resultant was subjected to extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated, followed by recrystallization from tetrahydrofuran to give 850 mg (61%) of 2-ethoxycarbonylacetylamino-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole, m.p. 202°-203° C.
Reaction SMILES: [CH2:1]([N:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][Si](C)(C)C)=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].CO>O>[CH2:1]([N:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)c1ccc(C#C[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1ccc(N(CC)CC)cc1
Temperature: 65 °C
Reaction time: 30 h

Procedure:
A mixture of N,N-diethyl-(4-trimethylsilanylethynyl-phenyl) amine (500 mg 2.03 mmol), K2CO3 (1.5 g 10.8 mmol) and methanol (30 mL) was stirred at 65° C. for 30 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate (50×3). The combined extract was dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the crude material was further purified by filtration through a short silica gel column with hexane/EAC (0-5%) and the product separated as a semi solid. Yield: 250 mg (72.2%) IR (neat) 2971, 2098, 1607, 1551 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J=8.4 Hz, 2H), 6.59 (d, J=8.4 Hz, 2H), 3.36 (q, J=6.8 Hz, 4H), 1.16 (t, 6.8 Hz, 6H); 13CNMR (100 MHz, CDCl3) δ 147.68, 133.31, 110.90, 107.46, 84.96, 74.38, 44.19, 12.41.
Reaction SMILES: [NH2:1][C@H:2]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([CH3:13])[CH2:9][CH:8]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4].O=C1CCC(=O)N1[O:40][C:41](=O)[C:42]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])([CH3:44])[CH3:43].O>C1COCC1>[C:49]([O:48][C:46](=[O:47])[NH:45][C:42]([C:41](=[O:40])[NH:1][C@H:2]([CH2:23][O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([CH3:13])[CH2:9][CH:8]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:6]1)=[O:4])([CH3:44])[CH3:43])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)ON1C(=O)CCC1=O
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@H](N)COCc3ccc(F)cc3)C2)C1=O
Solvent: C1CCOC1
Solvent: O
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccc(F)cc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A solution of 7-[(R)-2-Amino-3-(4-fluoro-benzyloxy)-propionyl]-2-methyl-4-phenyl-2,7-diaza-spiro[4.5]decan-1-one (130 mg, 0.3 mmol) (step 2) and 2-tert-Butoxycarbonylamino-2-methyl-propionic acid 2,5-dioxo-pyrrolidin-1-yl ester (synthesis described in EP1486498A1 page 20) (89 mg, 0.3 mmol) in THF (4 ml)/water (1 ml) was treated with TEA (0.12 ml, 0.89 mmol). The resulting mixture was stirred at 50° C. for 6 h. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc (25 ml) and 5% citric acid aqueous solution (10 ml). The organic phase was separated, washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 50-100% EtOAc in iso-hexane to afford the title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[C:7]([O:15][CH3:16])[CH:8]=[CH:9][C:10]=2[O:13][CH3:14])[CH2:5][C@H:4]1[OH:17].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>O.C1C=CC=CC=1>[C:18]([NH:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[C:7]([O:15][CH3:16])[CH:8]=[CH:9][C:10]=2[O:13][CH3:14])[CH2:5][C@H:4]1[OH:17])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(OC)c2c1C[C@@H](N)[C@H](O)C2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(OC)c2c1C[C@@H](O)[C@H](NC(=O)c1ccccc1)C2
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A solution of 74.8 g of trans-3-amino-1,2,3,4-tetrahydro-5,8-dimethoxy-2- naphthalenol, hydrochloride in 2 liters of water is cooled in an ice bath and a solution of 40 g of benzoyl chloride in 300 ml of benzene is added. While stirring vigorously a solution of 23 g of sodium hydroxide in 100 ml of water is added dropwise at 0°-5° C over a period of 30 minutes. Semi-solid material begins adhering to the sides of the flask almost immediately. The mixture is stirred at 0°-5° C for an additional 2 hours. The solid is removed by filtration, washed with a small amount of water, then washed with chloroform and dried in vacuo over phosphorous pentoxide to give 78.5 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[CH2:13][S:14]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[N:27]1([CH2:32][C@@H:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)O)[CH:31]=[CH:30][N:29]=[CH:28]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[N:27]1([CH2:32][C@@H:33]([O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=3[C:3]=2[CH2:13][S:14]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cc2c(O)ccc3c2CCCC3=O)cc1
Reactant: O[C@@H](Cn1ccnc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 96 %

Procedure:
Using the method in Example 154, this compound was prepared from methyl 4-(2-hydroxy-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methylsulfonylbenzoate (1.98 g, 5.3 mmol), (R)-2-imidazol-1-yl-1-phenylethanol (1.00 g, 5.3 mmol), Ph3P (2.10 g, 8.0 mmol), and diethyl azodicarboxylate (1.39 g, 8.0 mmol) as a solid-foam, 2.78 g, 96% yield; mp 105° C. NMR spectrum was consistent with structure. Calcd. For C30H28N2O6S.H2O:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:36])[CH:10]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:11][N:12]1[CH:29]=[N:28][C:14]([CH2:15][C@@H:16]([C:25]([OH:27])=[O:26])[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl:47]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Cl:47][C:10]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:36])[CH2:11][N:12]1[CH:29]=[N:28][C:14]([CH2:15][C@@H:16]([C:25]([OH:27])=[O:26])[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(CC(C(=O)c2ccc(Cl)cc2Cl)c2ccccc2)cn1)C(=O)O
Reactant: O=C1CCC(=O)N1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cn(CC(Cl)(C(=O)c2ccc(Cl)cc2Cl)c2ccccc2)cn1)C(=O)O
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A portion of the 1-[3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[(1,1-dimethylethoxy)carbonyl]-L-histidine (5.5 g) in dry tetrahydrofuran (50 ml) was added dropwise to a stirred solution of lithium hexamethyldisilazide in tetrahydrofuran (33 ml, 1M solution in tetrahydrofuran) at -78° C. under an atmosphere of nitrogen. After 30 minutes the resulting solution was rapidly transferred, under an atmosphere of nitrogen, into a stirred solution of N-chlorosuccinimide (1.6 g) in dry tetrahydrofuran (50 ml). The resulting mixture was cooled in an ice bath under an atmosphere of nitrogen. The mixture was allowed to warm to room temperature over a period of 20 minutes and was quenched upon an addition of an excess of saturated aqueous potassium dihydrogen orthophosphate. The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield a residue. The residue was dissolved in ethyl acetate, washed with water and then brine, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield a foam which was chromatographed on silica gel using a mixture of methanol:dichloromethane (2:23) as an eluent to yield 1-[2-chloro-3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[ (1,1-dimethylethoxy)carbonyl]-L-histidine (2.85 g) as a mixture of diastereoisomers, (δ (CDCl3) 1.45 (9H, s), 1.48 (9H, s), 3.01 (2H, bd, J=15Hz), 3.23 (2H, bd, J=15Hz), 4.35 (2H, bs), 4.62 (2H, bt, J=17Hz), 4.86 (2H, bt, J=17Hz), 5.48 (2H, m, 4 lines), 6.38 (1H, bs), 6.57 (3H, m), 6.98 (2H, dd, J=9Hz and 2Hz), 7.42 (2H, m), 7.46 (5H, s), 7.49 (5H, s), 7.56 (1H, bs) and 7.60 (1H, bs)), having the formula: ##STR33##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:14][O:15][C:16](=[O:23])[C@H:17]([CH2:19][CH2:20][CH2:21][CH3:22])[NH2:18]>>[CH3:14][O:15][C:16](=[O:23])[CH:17]([NH:18][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCC[C@H](N)C(=O)OC
Reactant: O=C(O)Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Product: CCCCC(NC(=O)Cc1cc(Cl)cc(Cl)c1)C(=O)OC

Procedure:
Following General Procedure F′ above, an using 3,5-dichlorophenylacetic acid (from Example C′ above) and L-norleucine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid having a melting point of 77°-78° C. The reaction was monitored by tlc on silica gel (Rf=0.70 in 40% EtOAC/hexanes) and purification was by flash chromatography on silica gel using 40% EtOAc/hexanes as the eluant.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:3]=1.[NH:19]1[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]1.C(O)C>C1(O)C=CC=CC=1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([N:19]3[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Reactant: NC(=O)C1CCNCC1
Solvent: Oc1ccccc1
Solvent: CCO
Product: NC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccccc23)CC1

Procedure:
In a manner analogous to that of Example 6, 4-chloro-2-(4-chlorophenyl)quinoline was reacted with isonipecotamide in phenol at 170° C., yielding the named compound, mp. 245°-247° dec., from ethanol.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Cs+].[CH:15]1([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:4]([O:6][CH2:27][CH2:26][CH2:25][CH2:24][O:23][C:21]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:22])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: O=C(OCCCCCl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Cs+]
Product: COC(=O)/C=C/C(=O)OCCCCOC(=O)C1CCCCC1
Yield: 50 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (1.00 g, 7.68 mmol) was reacted with CsHCO3 (2.22 g, 11.52 mmol) and chlorobutyl cyclohexanecarboxylate (2.16 g, 9.98 mmol) at ca. 55° C. to afford 1.2 g (50% yield) of the title compound (44) as a clear oil after purification by mass-guided preparatory. HPLC and lyophilization. 1H NMR (CDCl3, 400 MHz): δ 6.90-6.77 (m, 3H), 3.81 (s, 3H), 2.34-2.28 (m, 1H), 1.91-1.88 (m, 2H), 1.82-1.73 (m, 4H), 1.65-1.62 (m, 2H), 1.47-1.39 (m, 4H), 1.29-1.23 (m, 2H), 0.98-0.94 (t, 3H). MS (ESI): m/z 313.09 (M+H)+.