Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([O:18][CH2:19][CH3:20])[CH3:17])=[CH:11][CH:10]=1)[CH3:8])(=O)CCC.[BH4-].[Na+].[CH2:23](O)C>>[O:18]1[CH2:19][CH2:20][CH2:23][CH2:17][CH:16]1[O:15][C:12]1[CH:11]=[CH:10][C:9]([CH:7]([OH:6])[CH3:8])=[CH:14][CH:13]=1
Reactant: CCCC(=O)OC(C)c1ccc(OC(C)OCC)cc1
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1ccc(OC2CCCCO2)cc1
Yield: 88 %

Procedure:
In 200 ml of ethanol was dissolved 22.0 g (0.1 mole) of 4-(tetrahydro-2-pyranyloxy)acetophenone obtained in Example 4 (i), to which 2.3 g (58 millimoles) of NaBH4 was added, and the mixture was subjected to reaction for 3 hours at 25° C. After ethanol was distilled under reduced pressure, 200 ml of ethanol was added thereto, and it was washed with diluted hydrochloric acid, then water and finally an aqueous solution of sodium hydrogencarbonate. The resulting ether layer was dried with anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure to give 19.5 g of 1-(4-(tetrahydro-2-pyranyloxy)phenyl)ethanol (yield: 88%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1.[Na].[SH:22][C:23]1[NH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>>[N:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[NH:27][C:23]=1[S:22][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1cccc(Nc2ncnc3ccc(CBr)cc23)c1
Agent: [Na]
Product: Cc1cccc(Nc2ncnc3ccc(CSc4nc5ccccc5[nH]4)cc23)c1
Yield: 59 %

Procedure:
Using an analogous procedure to that described in Example 34, 6-bromomethyl-4-(3-methylanilino)quinazoline was reacted with 2-mercaptobenzimidazole sodium salt to give 6-(2-benzimidazolylthiomethyl)-4-(3-methylanilino)quinazoline in 59% yield, m.p. 123°-129° C.;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.3 %

Procedure:
To a solution of 5-bromo-2,3-dihydroinden-1-one (1.1 g, 5.2 mmol) in ethanol (100 mL) was added sodium borohydride (218 mg, 5.7 mmol). The mixture was stirred at room temperature for 24 hours. Then the resultant mixture was filtered. The filtrate was acidified with hydrochloric acid aqueous solution (1N) and the solvent was removed in vacuo. The residue was taken up with water (50 mL) and extracted with dichloromethane (50 mL). The combined organic phase was dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=4:1) to give 5-bromo-2,3-dihydro-1H-inden-1-ol (1 g, 90%) as a yellow oil. LRMS (M+H+) m/z: calcd 211.98. found 211. 1H NMR (300 MHz, CDCl3): δ 7.40 (s, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 5.22-5.18 (m, 1H), 3.09-2.99 (m, 1H), 2.86-2.76 (m, 1H), 2.55-2.46 (m, 1H), 2.01-1.76 (m, 1H), 1.75 (s, 1H).
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:4][CH3:5])#[C-:2].[F:16][C:17]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:4]([C:3]1[N:1]=[CH:2][O:20][C:19]=1[C:18]1[CH:21]=[CH:22][C:23]([C:25]([F:26])([F:27])[F:28])=[CH:24][C:17]=1[F:16])[CH3:5]
Reactant: [C-]#[N+]C(CC)S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1ncoc1-c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Yield: 49.8 %

Procedure:
A mixture of 1-(1-isocyanopropylsulfonyl)-4-methylbenzene (1.55 g, 6.94 mmol), 2-fluoro-4-(trifluoromethyl)benzaldehyde (0.95 mL, 6.9 mmol), and K2CO3 (1.15 g, 8.33 mmol) in MeOH (35 mL) was heated at reflux overnight. The reaction was cooled to ambient temperature and the volatiles evaporated at reduced pressure. The residue was diluted with water and the product extracted with EtOAc. The combined organic extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (Analogix® 40×150 column, 10%-70% EtOAc/hexanes) to yield 0.89 g (50%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.67-7.60 (m, 1H), 7.53-7.48 (m, 1H), 7.47-7.42 (m, 1H), 2.67 (qd, J=7.5, 1.6, 2H), 1.29 (t, J=7.5, 3H). MS (DCI+) m/z 260 (M+H).
Reaction SMILES: [C:1](O)(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:24][C:25]([CH3:38])([CH2:36][CH3:37])[C:26](=[O:35])[C:27]([CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][NH:30]1)=[O:28]>C(Cl)Cl>[C:1]([N:30]1[CH:29]([C:27](=[O:28])[C:26](=[O:35])[C:25]([CH3:38])([CH3:24])[CH2:36][CH3:37])[CH2:34][CH2:33][CH2:32][NH:31]1)(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: CCC(C)(C)C(=O)C(=O)C1CCCNN1
Reactant: C#CCCCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCCC(=O)N1NCCCC1C(=O)C(=O)C(C)(C)CC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.8 %

Procedure:
To a solution of 5-hexynoic acid (0.467 g, 4 mmol) in 10 ml CH2Cl2 was added triethylamine (0.56 ml, 4 mmol), followed by isobutyl chloroformate (0.53 ml, 4 mmol) at 0° C. After stirring for 5 minutes, a solution of 3,3-dimethyl-1-perhydropyridazinyl pentane-1,2-dione (0.424 g, 2 mmol) in 1 ml CH2Cl2 was added. The reaction was gradually warmed up to room temperature. The crude material was subject to silica gel purification to yield final product as clear oil (0.385 g, 63%). 1H NMR (CDCl3, 400 MHz) δ 0.91 (t, 3H, J=7.0); 1.26 (s, 6H); 1.76(m, 8H); 2.28 (m, 2H); 2.50 (m, 2H); 2.88 (m, 2H); 3.60 (m, 1H); 4.50 (m, 2H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[NH:13][C:12]1=[O:19])[CH2:8]2.Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.[H-].[Na+].Cl>>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH:16]([CH3:17])[CH3:18])[N:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:12]1=[O:19])[CH2:10]2
Reactant: CC(C)c1cn(C2C3CC4CC(C3)CC2C4)c(=O)[nH]1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C)c1cn(C2C3CC4CC(C3)CC2C4)c(=O)n1Cc1ccccn1

Procedure:
1—This material was obtained as described in example 23 from 1-adamantan-2-yl-4-isopropyl-1,3-dihydro-imidazol-2-one (obtained in example 8, 100 mg) by alkylation with 2-chloromethylpyridine hydrochloride (73 mg) with the following modification: 2.5 equivalents of NaH dispersion (42 mg) was used such as to compensate for the HCl content in the alkylating agent. 1-Adamantan-2-yl-4-isopropyl-3-pyridin-2-ylmethyl-1,3-dihydro-imidazol-2-one was obtained as a light yellow gum (64 mg). MS (ESI): 352.2 (MH+).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH:5]=[CH:4]1.[CH3:27][O:28][CH2:29][CH2:30][C:31](O)=[O:32]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[C:6]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][CH2:29][O:28][CH3:27])[CH2:24][CH2:25]2)[CH:5]=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1
Reactant: COCCC(=O)O
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2ccoc3cccc2-3)CC1

Procedure:
The title compound, off-white solid (74 mg, 72%), MS (ISP) m/z=413.4 [(M+H)+], mp 154° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-4-yl-piperidin-1-yl)-ethyl]-cyclohexyl-amine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 3-methoxypropionic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].Br[CH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[O:8][CH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(COc2ccc([N+](=O)[O-])c(F)c2)c1
Reaction time: 3 h

Procedure:
2-Fluoro-4-hydroxynitrobenzene (3 g) is added portionwise to a stirred suspension of sodium hydride (0.9 g, 60% dispersion in mineral oil) in dry dimethylformamide (50 mL) under nitrogen. After stirring for 20 minutes methyl 3-bromomethylbenzoate is added in one portion and stirring continued for 3 hours. The reaction mixture is evaporated to dryness and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase is washed three times with water (50 mL),dried over magnesium sulphate and evaporated to give a yellow solid which is crystallised from a mixture of ethyl acetate and cyclohexane (1:3 v/v) to give methyl 3-(3-fluoro-4-nitrophenoxymethyl]benzoate (4.95 g) as a white solid.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:18][CH2:19][C@H:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:15][O:14][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[CH:2][N:18]([CH2:19][C@H:20]([OH:22])[CH3:21])[C:5]=3[C:6]=2[CH:7]=1
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)CC2
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)CC2
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
A solution of 2 g of (RS)-2-(2-oxoethyl)-7-methoxy-1-tetralone and 100 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 2.78 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 25 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 2.25 g (94%) of (R)-1-(4,5-dihydro-8-methoxy-1H-benz[g]indol-1-yl)-propan-2-ol were obtained as a brown oil which was used directly in the next reaction.
Reaction SMILES: [N+:1]([C:4]([N+:29]([O-:31])=[O:30])([CH2:11][O:12][CH2:13][O:14][CH2:15][C:16]([N+:26]([O-:28])=[O:27])([N+:23]([O-:25])=[O:24])[CH2:17][CH2:18][C:19](OC)=[O:20])[CH2:5][CH2:6][C:7](OC)=[O:8])([O-:3])=[O:2].O>B.C1COCC1>[N+:1]([C:4]([N+:29]([O-:31])=[O:30])([CH2:11][O:12][CH2:13][O:14][CH2:15][C:16]([N+:23]([O-:25])=[O:24])([N+:26]([O-:28])=[O:27])[CH2:17][CH2:18][CH2:19][OH:20])[CH2:5][CH2:6][CH2:7][OH:8])([O-:3])=[O:2]
Reactant: COC(=O)CCC(COCOCC(CCC(=O)OC)([N+](=O)[O-])[N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])C(CCCO)(COCOCC(CCCO)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dimethyl 4,4,10,10-tetranitro-6,8-dioxatridecane-1,13-dioate (28.8 g) was dissolved in 139 mL of BH3.THF with ice-cooling and under a nitrogen atmosphere. The solution was stirred at room temperature for 3 days, after which time 27 mL of water was added slowly and the mixture was heated at 60° C. for 5 minutes. After cooling, the mixture was poured into 200 mL of water, and the product was extracted with ether. The ether solution was washed with aqueous sodium bicarbonate solution, then with water, and dried (MgSO4) After removal of the solvent, the crude product was recrystallized from dichloromethane. Yield: 19.9 g (79%); M.P. 72.5°-3.5° C. 1H NMR spectrum (CDCl3 /TMS): δ 4.76 (s, 2H); 4.41 (s, 4H); 2.69 (m, 4H); 1.59 (m. 4H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=2[OH:22])[CH2:9]1)(OC(C)(C)C)=O.Cl>>[Br:21][C:19]1[CH:18]=[CH:17][C:16]([OH:22])=[C:15]([CH:20]=1)[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cc(Br)ccc2O)C1
Agent: Cl
Product: Oc1ccc(Br)cc1C[C@@H]1CNCCO1

Procedure:
Deprotection of N-Boc-(R)-2-(5-bromo-2-hydroxybenzyl)morpholine, using hydrogen chloride (4M, in methanol), afforded the morpholine example 1 as an off-white solid (51 mg, 100%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]([CH3:25])[C:21](=[O:26])[CH:20]=1>CN(C)C=O.O>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][N:22]([CH3:25])[C:21](=[O:26])[CH:20]=1
Reactant: Cn1ccc(CN)cc1=O
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1=O
Yield: 86.2 %

Procedure:
(4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (130 mg, 0.40 mmol), 4-aminomethyl-1-methyl-1H-pyridin-2-one (55 mg, 0.40 mol) were coupled in N,N-dimethylformamide (2 mL) at room temperature. The reaction mixture is diluted with water and the precipitate is collected by Büchner filtration and then dried under house vacuum to give (4Z)-6-iodo-4-({[(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione as an orange solid (0.15 g, 88%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][C@@H:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:19]([CH3:21])[CH3:20].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:17][C@@H:18]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 94.4 %

Procedure:
A mixture of N-[(benzyloxy)carbonyl]glycine (, 2.4 g, 11.5 mmol), tert-butyl D-valinate hydrochloride (2.4 g, 11.4 mmol) and N-methylmorpholine (2.53 ml, 22.9 mmol) in DCM (20 ml) was stirred at room temperature. TBTU (4.79 g, 14.9 mmol) was added and the mixture was stirred for three days. The solvent was removed under reduced pressure. Water was added and the mixture was extracted two times with toluen. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography using DCM:EtOAc:aceton 4:1:1 as eluent to give 3.92 g (94%) of the title compound. NMR (500 MHz, CD3COOD) 0.88-0.99 (m, 6H), 1.48 (s, 9H), 2.08-2.19 (m 1H), 3.85 (ABq, 2H), 4.24 (d, 1H), 5.12 (ABq, 2H), 7.28-7.41 (m, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([O:16]CC)=[O:15])[CH2:11][C@H:10]1[CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:21])=[N-]>CC([O-])=O.CC([O-])=O.[Pd+2].CCOCC>[C:1]([O:5][C:6]([NH:8][C@:9]1([C:14]([OH:16])=[O:15])[CH2:11][C@H:10]1[CH:12]1[CH2:13][CH2:21]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=[N+]=[N-]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)O)C[C@H]1C1CC1
Temperature: -15 °C
Yield: 106.3 %

Procedure:
A 30 mL ether solution of (1R,2S)-ethyl 1-(tert-butoxycarbonylamino)-2-vinylcyclopropanecarboxylate (1.0 g, 3.9 mmol, prepared as described in WO2005037214) in a 500 mL round-bottomed flask equipped with a stir bar was first cooled in an acetone-ice bath to approx. −15° C., then an ether solution of diazomethane (33 ml, 20 mmol) was added in one portion to the above solution. While stirring vigorously and keeping the reaction open to air, Pd(OAc)2 (0.088 g, 0.39 mmol) was added to in one portion to the reaction at −15° C. After the active effervescence subsided, the reaction was allowed to stir for another 5 min at −15° C. and concentrated down to fairly clean crude product. The crude could be further purified with flash chromatography on silica (eluent=hexanes/EtOAc 5:1), giving the titled compound as a colorless thick oil (1.0 g, 95% yield). 1H-NMR (400 MHz, CDCl3) δ 5.10 (br s, 1 H), 4.18-4.24 (m, 2 H), 1.60-1.64 (m, 2 H), 1.44 (s, 9 H), 1.27 (t, 3 H), 1.05-1.11 (m, 1 H), 0.83-0.89 (m, 1H), 0.47-0.58 (m, 2 H), 0.30-0.34 (m, 2 H). LCMS (APCI+) 170.0 (MH+−Boc).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][C:11](=[O:13])[CH3:12])=[O:3].[CH3:24][O:25][C:26](=[O:44])[C@@H:27]([NH2:43])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([Cl:42])[CH:36]=2)=[CH:31][CH:30]=1>>[CH3:24][O:25][C:26](=[O:44])[C@@H:27]([NH:43][C:2]([C:4]1[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=2)[CH:7]=[CH:8][C:9]=1[O:10][C:11](=[O:13])[CH3:12])=[O:3])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([Cl:42])[CH:36]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Reactant: CC(=O)Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1OC(C)=O
Yield: 90.6 %

Procedure:
2-(S)-[(4-Acetoxy-4′-trifluoromethyl-biphenyl-3-carbonyl)-amino]-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester (278 mg) was prepared from acetic acid 3-chlorocarbonyl-4′-trifluoromethyl-biphenyl-4-yl ester (171 mg, 0.5 mmol) and 2-(S)-amino-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester (155 mg, 0.5 mmol) following the general procedure M.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:14])[CH2:12][CH3:13])=[CH:10][C:5]=2[O:4][C:3]1=[O:15].[CH3:16]N(CN(C)C)C.C(OC(=O)C)(=O)C>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:14])[C:12](=[CH2:16])[CH3:13])=[CH:10][C:5]=2[O:4][C:3]1=[O:15]
Reactant: CCC(=O)c1ccc2c(c1)oc(=O)n2C
Reactant: CN(C)CN(C)C
Solvent: CC(=O)OC(C)=O
Product: C=C(C)C(=O)c1ccc2c(c1)oc(=O)n2C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
0.01 mole of 3-methyl-6-propionylbenzoxazolinone and 0.04 mole of bis(dimethylamino)methane are introduced into a 150-cm3 ground-necked flask equipped with a reflux condenser and a magnetic stirrer. 15 cm3 of acetic anhydride are added dropwise and the mixture is heated to 100° C. for 5 hours. After being cooled, the reaction mixture is poured into 5 volumes of ice-cold water. The mixture is acidified and stirred for one hour, and the product is drained, washed with water to neutrality, dried and recrystallized in hexane.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:19]([CH:40](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[OH:41])[O:18][C@@H:11]1[O:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:9][C@H:10]1[C@@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:19]([CH2:40][OH:41])[O:18][C@@H:11]1[O:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCCO[C@H]1O[C@H](C(O)C(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NCCO[C@H]1O[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 100 mL round bottom flask, 2-azidoethyl 2,3,4-tri-O-benzoyl-6-trityl-α-D-mannopyranoside (1.1 g, 1.368 mmol) was dissolved in CH2Cl2 (10 mL). To the above solution was added TFA (10 mL, 130 mmol). After stirring at 25° C. for 18 hr, the mixture was diluted with CH2Cl2 (20 mL), washed with brine (10 mL) and sat NaHCO3 till pH ˜7. The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (40 g), eluting with 0-100% EtOAc in hexane, to to give the title compound. LC-MS Method A: m/e=579.12 [M+18] and 584.10 [M+Na]; Rt=2.22 min. 1H NMR (CDCl3) δ 7.2-8.2 (m, 15H), 6.0 (dd, 1H), 5.9 (t, 1H), 5.7 (m, 1H), 5.2 (br-s, 1H), 4.1-4.2 (m, 2H), 3.85 (m, 1H), 3.7-3.8 (m, 2H), 3.6 (m, 1H, 3.5 (m, 1H).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:14][C:13]([CH2:22][C@H:23]1[CH2:27][O:26][C:25](=[O:28])[NH:24]1)=[CH:12][CH:11]=2)=[O:7])C>C(O)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:22][C@H:23]3[CH2:27][O:26][C:25](=[O:28])[NH:24]3)[CH:14]=2)[NH:9][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: CCOC(=O)c1[nH]c2ccc(C[C@H]3COC(=O)N3)cc2c1CCN(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCc1c(C(=O)O)[nH]c2ccc(C[C@H]3COC(=O)N3)cc12
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 299.8 %

Procedure:
To a solution of 1.4 g (24.9 mmoles) of KOH in 30 ml of ethanol was added 2.8 g (7.8 mmoles) of (S)-3-(2-dimethylaminoethyl)-5-[2-oxo-1,3-oxazolidin-4-ylmethyl]-1H-indol-2-carboxylic acid ethyl ester. The resulting solution was heated at reflux temperature for one hour. It was cooled and the solvent evaporated to dryness. The residue was dissolved in 6 ml of water and washed three times with 10 ml of dichloromethane. The aqueous solution was cooled to 5° C., adjusted to pH 6 with glacial acetic acid, stirred for 30 minutes at that temperature and the water evaporated to dryness. The residue was redissolved in 30 ml of water and 5 g of ionic exchange resin (Dowex 50WX8-400) added. The mixture was left under stirring at room temperature for 24 hours. The resin was filtered and it was washed with water. For desorption the resin was suspended with 20 ml of a 10% aqueous solution of ammonia and stirred at room temperature for 5 hours. Once that time had elapsed it was filtered and washed with water. The water was evaporated to dryness under reduced pressure to give 7.75 g (94%) of the title acid as a yellow crystalline solid:
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:28])[N:4]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:5]([CH3:19])=[CH:6][C:7]=1[C:8]([N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C:2]1[C:3](=[O:28])[N:4]([CH2:20][C:21]([OH:23])=[O:22])[C:5]([CH3:19])=[CH:6][C:7]=1[C:8]([N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:9]
Reactant: Cc1cc(C(=O)N(CC(C)C)CC(C)C)c(O)c(=O)n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)N(CC(C)C)CC(C)C)c(O)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 32 h

Procedure:
To a solution 3-hydroxy-4-diisobutylaminocarbonyl-6-methyl-1-tert-butyloxycarbonylmethyl-2-pyridinone from step 5 above (0.61 g) in CH2Cl2 (4 mL) was added TFA (2 mL) and the solution was stirred at ambient temperature for 32 h. The solvents were removed in vacuo to give the title compound (0.6 g; HPLC RT=13.56 min, method B).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[N:1]1([C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCCc4ccccc43)c2cc1OC
Yield: 91 %

Procedure:
Utilizing a procedure analogous to that described in Example 2, this product was prepared in 91% yield from 1,2,3,4-tetrahydroquinoline (2 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 130°-131° C.; LC-MS: 322 (MH+); anal. RP18-HPLC RT: 4.08 min.).