Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH2:10][C:11](OCC)=[O:12])=[C:4]([N+:16]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl.CC#N.O.FC(F)(F)C(O)=O>C(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[O:9][CH2:10][C:11](=[O:12])[NH:16][C:4]=2[CH:3]=1
Reactant: CCOC(=O)COc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC#N
Solvent: CCO
Product: O=C1COc2cc(Cl)c(Cl)cc2N1
Temperature: 85 °C
Reaction time: 20 h

Procedure:
Ethyl [(4,5-dichloro-2-nitrophenyl)oxy]acetate (36.0 g, 0. 122 mol) was dissolved in 400 mL of ethanol and treated with SnCl2.2H2O (138.0 g, 0.612 mol). This mixture was magnetically stirred and heated to 85° C. in an oil bath. After 20 hours, HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) showed that all of the starting material (Rt=7.8 min) was gone and that two new compounds had formed: the desired product (Rt=6.2 min) and the hydroxamic acid of the desired product (Rt=5.9 min). An additional 138.0 g of SnCl2.2H2O (0.612 mol) and 90 mL of concentrated HCl were added and stirred at 85° C. for seven hours, after which time HPLC showed that only the desired product remained. The reaction mixture was poured into 5.5 L of 5% aqueous HCl and stirred for 20 minutes, resulting in precipitation of the product. The solid was filtered off and air-dried on a vacuum funnel for one hour. The solid was transferred to a 1 L round bottom flask and suspended in 500 mL of absolute ethanol. The solvent was removed by rotary evaporation to azeotrope off the last traces of water and the resulting white solid was dried under high vacuum to give 6,7-dichloro-2H-1,4-benzoxazin-3(4H)-one (22.2 g. 0.102 mol, 83%) as a fine white powder. MS (ES) m/e 218 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][C:7]=1[F:15])([CH3:5])[CH3:4].[CH3:16][C@@H:17]1[CH2:19][O:18]1.O>O1CCCC1.CCOCC>[CH:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][N:12]2[CH2:16][C@H:17]([OH:18])[CH3:19])=[CH:8][C:7]=1[F:15])([CH3:5])[CH3:4]
Reactant: CC(C)c1cc2[nH]ccc2cc1F
Reactant: C[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc2c(ccn2C[C@@H](C)O)cc1F
Reaction time: 1 h
Yield: 27 %

Procedure:
A suspension of 0.05 g of sodium hydride dispersion in 10 ml of tetrahydrofuran was treated with 0.23 g of 6-isopropyl-5-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.18 ml of (R)-methyloxirane the reaction mixture was stirred at room temperature for 70 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 15 g of silica gel with toluene-ethyl acetate (19:1). 0.08 g (27%) of (R)-1-(6-isopropyl-5-fluoro-indol-1-yl)-propan-2-ol was obtained as a yellow oil.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[C:12]1(=[O:30])[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[S:24])[NH2:23])[C:15](=[O:25])[C:14]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:13]12>>[C:15]1(=[O:25])[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[S:24][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:23]=2)[C:12](=[O:30])[C:13]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:14]12
Reactant: O=C1c2ccccc2CC1Br
Reactant: NC(=S)CCCCCN1C(=O)c2ccccc2C1=O
Product: O=C1c2ccccc2C(=O)N1CCCCCc1nc2c(s1)Cc1ccccc1-2

Procedure:
2-Bromo-1-indanone, 6-phthalimidohexanethioamide
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([S:13](Cl)(=[O:15])=[O:14])=[CH:3]1.[CH3:17][NH:18][CH3:19]>C(O)C>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([S:13]([N:18]([CH3:19])[CH3:17])(=[O:15])=[O:14])=[CH:3]1
Reactant: Cn1cc(S(=O)(=O)Cl)c(=O)c2ccccc21
Reactant: CNC
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cn(C)c2ccccc2c1=O

Procedure:
A mixture of 1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonyl chloride (2.4 g) and a solution of dimethylamine in ethanol (33% w/w; 50 ml) was stirred at room temperature for 30 minutes. The precipitated solid was filtered off and then boiled with dichloromethane (100 ml). The mixture was filtered and the filtrate evaporated to dryness to provide a white solid which was crystallised from methanol to give the novel compound 1,N,N-trimethyl-4-oxo-1,4-dihydroquinoline-3-sulphonamide, m.p. 225°-226°.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[C:14]([O:26][CH3:27])[CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[I-:28].[K+].II.[N+]([O-])(OC(C)(C)C)=O>C(#N)C.[Cu](I)I>[I:28][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:24])([CH3:23])[CH3:25])([CH3:21])[CH3:20])=[C:14]([O:26][CH3:27])[CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: [I-]
Reactant: COc1cc(-c2ccc(N)c3c2CNC3=O)ccc1O[Si](C)(C)C(C)(C)C
Agent: I[Cu]I
Agent: CC(C)(C)O[N+](=O)[O-]
Agent: II
Solvent: CC#N
Product: COc1cc(-c2ccc(I)c3c2CNC3=O)ccc1O[Si](C)(C)C(C)(C)C
Yield: 62 %

Procedure:
In a similar manner to Step 4 of Example 140, 7-amino-4-(4-tert-butyldimethylsilyloxy-3-methoxyphenyl)isoindolinone (43.0 mg, 0.110 mmol) was dissolved in acetonitrile (6 mL), and the solution was treated with potassium iodide (29.2 mg, 0.176 mmol), copper iodide (33.5 mg, 0.896 mmol), iodine (44.7 mg, 0.896 mmol) and tert-butyl nitrate (0.059 mL, 0.50 mmol), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=5/1) to obtain 7-iodo-4-(4-tert-butyldimethylsilyloxy-3-methoxyphenyl)isoindolinone (33.8 mg, yield 62%).
Reaction SMILES: [C:1]([O-])(=[O:3])C.[Cl-].[Mg+2].[Cl-].P([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[C:36]3[N:35]=[CH:34][N:33]=[C:31](N)[C:30]=3[N:29]=[CH:28]2)[C@H:24](O)[C@@H:23]1[OH:38])(OP(OP(O)(O)=O)(O)=O)(=O)O.C([O-])(=O)C.[Na+].NO>C(O)C(N)(CO)CO.O>[CH2:31]1[N:33]=[CH:34][NH:35][C:36]2[N:27]([CH:25]3[O:26][CH:22]([CH2:21][OH:20])[CH:23]([OH:38])[CH2:24]3)[CH:28]=[N:29][C:30]=2[C@@H:1]1[OH:3]
Reactant: CC(=O)[O-]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: NC(CO)(CO)CO
Agent: NO
Agent: [Cl-]
Solvent: O
Product: OCC1OC(n2cnc3c2NC=NC[C@H]3O)CC1O
Reaction time: 0.05 h

Procedure:
Acetate kinase levels were measured essentially according to the method described by Brown et al., Journal of General Microbiology 102:327-336; 1977. Briefly, reaction constituents (all from Sigma chemicals) were prepared, and added to a microcentrifuge tube as follows: 12.5 μl of 200 mM magnesium chloride, 50 μl of 100 mM ATP, 30 μl of 200 mM sodium acetate, 50 μl of hydroxylamine solution (see below), and 30 μl of water. All of these solutions except for magnesium chloride are made in 50 mM Tris buffer, pH 8.0. The tube was placed into a 37° C. dry block and equilibrated for 3 minutes. Next, 100 μl of diluted cell-free extract (dilutions range between 1:2 and 1:50) was added, the contents mixed, and the reaction allowed to proceed for 10 minutes. The reaction was stopped by adding 450 μl of ferric chloride reagent (see below), and the tube was placed on ice for 10 min. The tube was then centrifuged in a microcentrifuge for 2 min, and absorbance at 540 nanometers determined versus a blank containing all of the above constituents except for 100 μl of deionized water in place of the enzyme preparation.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10]C(=O)[O:8][C:7](=O)[C:6]=2[CH:13]=1.[CH3:14][NH2:15]>O1CCCC1>[NH2:10][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:13][C:6]=1[C:7]([NH:15][CH3:14])=[O:8]
Reactant: CN
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Solvent: C1CCOC1
Product: CNC(=O)c1cc(F)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
6-Fluoro-2H-3,1-benzoxazine-2,4(1H)-dione (200 mg, 1.104 mmol) was dissolved in dry tetrahydrofuran (THF) (10 mL), at which time methyl amine (3.31 mL, 6.63 mmol) was added. The reaction was stirred at room temperature for 1 h, then concentrated under vacuum. The crude product was purified on silica (Biotage, 40% EtOAc/hexene) to afford the title compound (120 mg, 65%) as a white solid. LC-MS (ES) m/z=169.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:29])[CH2:14][NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27]C)=[O:26])[CH:20]=2)=[O:17])[CH:11]([C:30](=[O:36])[NH:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:10][CH:9]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)(=[O:39])=[O:38].[OH-].[K+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13](=[O:29])[CH2:14][NH:15][C:16](=[O:17])[NH:18][C:19]2[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=2)[C:25]([OH:27])=[O:26])[CH:11]([C:30](=[O:36])[NH:31][CH2:32][CH:33]([CH3:34])[CH3:35])[CH2:10][CH:9]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)(=[O:38])=[O:39]
Reactant: COC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)NCC(C)C)CC(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)CNC(=O)C1CC(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 45.9 %

Procedure:
A The process is performed as described in Example 1A, but starting with 2 g of (2RS,4SR,5RS)-5-(2-fluorophenyl)-2-isobutylcarbamoyl-1-{2-[3-(3-methoxycarbonylphenyl)ureido]acetyl}-4-(4-nitrophenyl)sulphonylpyrrolidine and 0.16 g of potassium hydroxide in a mixture of 60 cm3 of methanol and 20 cm3 of distilled water. After treatment, 0.9 g of (2RS,4SR,5RS)-3-(3-{2-[5-(2-fluorophenyl)-2-isobutylcarbamoyl-4-(4-nitrophenyl)sulphonyl-1-pyrrolidinyl]-2-oxoethyl}ureido)benzoic acid is obtained [Rf=0.2; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 383 K, δ in ppm): 0.94 (d, J=6.5 Hz, 6H: C(CH3)2); 1.89 (mt, 1H: CH); from 2.65 to 3.00 (2 mts, 1H each: CH2 at 3); 3.08 (mt, 2H: NCH2); 3.72 and 3.91 (broad d and d respectively, J=17 Hz, 1H each: COCH2N); 4.21 (mt, 1H: H4); 4.83 (t, J=7.5 Hz, 1H: H2); 5.71 (d, J=3 Hz, 1H: H5); from 6.95 to 7.65 (mt, 6H:aromatic H); 8.02 (mt, 1H: aromatic H (H2: ortho to the COOH)); 8.18 (broad t, J=8 Hz, 1H: H of the aromatic at 5 (H6)); 8.25 (d, J=8.5 Hz, 2H: H of the aromatic at 4 (H meta to the NO2)); 8.42 (d, J=8.5 Hz, 2H: H of the aromatic at 4 (H ortho to the NO2))].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)[O:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:13]=[CH:14][C:15]=1[NH2:16]
Reactant: COc1cc(OC2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(OC2CCOCC2)ccc1N
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Step C A suspension of 4-(3-methoxy-4-nitrophenoxy)tetrahydro-2H-pyran (0.4 g, 1.6 mmol) and Pd/C (Aldrich, 10%, 0.1 g) in ethyl acetate (10 mL) was vigorously shaken in a Parr under atmosphere of H2 (50 psi) for 0.5 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 2-methoxy-4-(tetrahydro-pyran-4-yloxy)-phenylamine as a light yellow oil (0.3 g, 85%).
Reaction SMILES: Cl.Cl[CH:3]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22][SH:23].[H-].[Na+]>O1CCCC1>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22][S:23][CH:3]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: SCc1ccc(Cl)c(Cl)c1
Reactant: ClC(CCc1ccccc1)Cn1ccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(CSC(CCc2ccccc2)Cn2ccnc2)cc1Cl

Procedure:
600 Mg. of 1-(2-chloro-4-phenylbutyl) imidazole hydrochloride was added to a fully reacted mixture of 1.1 g. of 3,4-dichlorobenzylmercaptan and 400 mg. of 56% sodium hydride dispersion in mineral oil in 30 ml. of tetrahydrofuran. After stirring under reflux for 12 hours the solvent was evaporated under vacuum and 150 ml. of ether was added. The resulting mixture was washed twice with water and the ethereal solution dried and evaporated to afford 1-[2-(3,4-dichlorobenzylthio)-4-phenylbutyl]imidazole, as an oil. This material was converted to the oxalate salt by treatment of an ethereal solution wih oxalic acid in ether until precipitation was complete, which salt was recrystallized from acetone/ethyl acetate as colorless flakes (660 mg.), m.p. 143.5°-146° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH2:16][CH3:17])[CH2:14][N:13]([C:18]4[N:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=4)[CH2:12]3)=[C:8]([C:26]([NH2:28])=[O:27])[CH:7]=[N:6][N:5]2[CH:29]=1.[CH3:30][N:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:33][C:32]1=[O:46].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CN(C)C=O>[C:24]([C:21]1[CH:22]=[N:23][C:18]([N:13]2[CH2:14][C@H:15]([CH2:16][CH3:17])[C@H:11]([NH:10][C:9]3[C:4]4[N:5]([CH:29]=[C:2]([C:35]5[CH:34]=[CH:33][C:32](=[O:46])[N:31]([CH3:30])[CH:36]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:26]([NH2:28])=[O:27])[CH2:12]2)=[N:19][CH:20]=1)#[N:25]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)ccc1=O
Reactant: CC[C@H]1CN(c2ncc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC[C@H]1CN(c2ncc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(=O)n(C)c3)cc12
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 44.2 %

Procedure:
A mixture of 6-bromo-4-(((3S,4S)-1-(5-cyanopyrimidin-2-yl)-4-ethylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.044 mmol, from Step 1), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (31.0 mg, 0.132 mmol, from Step 2), and PdCl2(dppf)-CH2Cl2 adduct (7.17 mg, 8.79 μmol) was pumped under vacuum and backfilled with nitrogen three times. A 2 M aqueous solution of potassium phosphate tribasic (0.066 mL, 0.132 mmol) and N,N-dimethylformamide (0.5 mL) were added. The mixture was immediately pumped under vacuum and backfilled with nitrogen three times, sealed and placed in a 90° C. heating block for 3 h, then cooled to room temperature. The mixture was filtered to remove the insoluble material. The filtrate was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 0-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (9.4 mg, 44% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.16 (d, J=7.4 Hz, 1H), 8.77 (d, J=3.0 Hz, 1H), 8.67 (d, J=3.0 Hz, 1H), 8.28 (d, J=2.5 Hz, 1H), 8.21 (s, 1H), 8.13 (d, J=2.0 Hz, 1H), 8.00-7.90 (m, 1H), 7.25 (d, J=1.5 Hz, 1H), 6.48 (d, J=9.4 Hz, 1H), 5.09-4.91 (m, 1H), 4.09-3.94 (m, 2H), 3.85 (d, J=12.4 Hz, 1H), 3.51 (s, 3H), 2.66-2.55 (m, 1H), 1.64 (quin, J=7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H); MS (ES+) m/z: 484.2 (M+H); LC retention time: 1.19 min (analytical LCMS Method I).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]1([C:41]1[CH:46]=[C:45]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([CH2:54][CH3:55])=[CH:50][CH:49]=2)[C:44]([Cl:56])=[CH:43][C:42]=1[CH:57]=[CH2:58])O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=[O:60].O[Li].O>C1COCC1.CO.O>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:41]1[C:42](=[CH:43][C:44]([Cl:56])=[C:45]([CH2:47][C:48]3[CH:49]=[CH:50][C:51]([CH2:54][CH3:55])=[CH:52][CH:53]=3)[CH:46]=1)[CH:57]([OH:60])[CH2:58]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@]1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1ccc(Cc2cc3c(cc2Cl)C(O)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reaction time: 6 h

Procedure:
To (2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-(4-chloro-5-(4-ethylbenzyl)-2-vinylphenyl)tetrahydro-2H-pyran-2-ol (120 mg, 0.15 mmol) was added TFA (1.5 mL) at −10° C. After the reaction mixture was stirred for 6 h, the solvent was removed under vacuum and aqueous saturated NaHCO3 (10 mL) was added to the residue. The aqueous layer was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine and dried over Na2SO4. Removal of the solvent afforded the crude product, which was dissolved in 1.9 mL of a mixture of THF:CH3OH:H2O (2:3:1) followed by addition of 6 mg of LiOH.H2O at room temperature. After stirring for 2 h, the volatiles were removed using a rotary evaporator. The residue, after being dissolved in ethyl acetate, was washed with brine (10 mL×2), 5% aqueous KHSO4 (10 mL) and finally with brine (10 mL) prior to drying over Na2SO4. The volatiles were removed and the resulting oil was purified by preparative TLC to obtain 44 mg of the title product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([N+:16]([O-])=O)=[CH:8][CH:7]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH2:16])=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)COc1ccc([N+](=O)[O-])c2ccccc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)COc1ccc(N)c2ccccc12
Yield: 90.4 %

Procedure:
(4-Nitro-naphthalen-1-yloxy)-acetic acid methyl ester (0.90 g) and 10% Pd/C (90 mg) in MeOH (150 ml) is stirred at room temperature under 1 atmosphere of hydrogen for 4 h. The mixture is then filtered through Celite® and evaporated to dryness to provide (4-amino-naphthalen-1-yloxy)-acetic acid methyl ester (0.72 g). MS 232 (M+1).
Reaction SMILES: [OH:1][C:2]1([C:11]([OH:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]1[C:4]([OH:6])=[O:5].[C:14](O)(=O)C.[BH4-].[Na+].Cl>O1CCCC1>[CH3:14][O:1][C:2]1([C:11]([OH:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]1[C:4]([OH:6])=[O:5]
Reactant: CC(=O)O
Reactant: O=C(O)C1C=CC=CC1(O)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(C(=O)O)C=CC=CC1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Anhydrous 2-methoxyphthalic acid (640 mg), which was prepared with using anhydrous 2-hydroxyphthalic acid by the same procedure as reference example 12, was suspended in tetrahydrofuran (20 ml). Acetic acid (430 mg) and sodium borohydride (135 mg) were added to the suspension. The mixture was stirred for 30 min. at room temperature and for 2 hr. at 50° C. The reaction solution was cooled. 1N hydrochloric acid (7 ml) was added to the cooled solution. The solution was stirred for 15 min. The reaction solution was evaporated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1→1:1) to give the title compound (314 mg) having the following physical data.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][S:4][CH2:5][C:6]1([O:18][CH2:17][CH2:16][O:15]1)[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1>C1COCC1>[F:20][C:2]([F:1])([F:19])[CH2:3][S:4][CH2:5][C:6]1([O:15][CH2:16][CH2:17][O:18]1)[C:7]1[CH:8]=[CH:9][C:10]([CH2:11][NH2:12])=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(C2(CSCC(F)(F)F)OCCO2)cc1
Solvent: C1CCOC1
Product: NCc1ccc(C2(CSCC(F)(F)F)OCCO2)cc1
Temperature: 60 °C
Yield: 101.7 %

Procedure:
To a solution of 4-[2-(2,2,2-trifluoroethylthio)-1,1-(ethylenedioxy)ethyl]-benzonitrile (248 mg, 0.8 mmol) in anhydrous THF (8 mL) under nitrogen, add borane-tetrahydrofurane complex (9.8 mL, 9.8 mmol) and heat at 60° C. for 3 h. Cool to room temperature and quench with methanol dropwise. Concentrate in vacuo and purify by SCX chromatography to obtain the title compound (250 mg, 99%). MS (ES+) m/z: 308 (M+H)+.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[C:25](O)[CH:24]=1.C([N+]#[C-])(C)C>C(OCC)(=O)C>[N+:29]([C:28]1[CH:23]=[CH:24][C:25]([O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])=[CH:26][CH:27]=1)([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: [C-]#[N+]C(C)C
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Yield: 53.4 %

Procedure:
A solution of 6.0 g (20 mM) N-carbobenzoxy-L-phenylalanine, 3.3 g (24 mM) p-nitrophenol, and 1.6 g (24 mM) isopropyl isonitrile in 50 ml ethyl acetate was held at 60°C for 40 hours, and then evaporated. The residue was dissolved in ethanol, and the solution stored in a refrigerator until crystals formed. The crystals were filtered out, washed with petroleum ether, and dried. 4.5 g N-Carbobenzoxy-L-phenylalanine p-nitrophenyl ester was obtained (53% yield). M.P. 125.5° - 127°C. [α]D25 = -8.0° (C = 2.2, in chloroform).
Reaction SMILES: [I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([O:18]CC)=O)=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[OH-].[K+].C(N(C(C)C)C(C)C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:54]([C:56]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[C:57]=1[NH2:58])[CH3:55]>C(O)C>[CH2:54]([C:56]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[C:57]=1[NH:58][C:16]([C:12]1[C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[N:11][C:2]([I:1])=[N:3][C:4]=3[C:5]=2[N:14]([CH3:15])[N:13]=1)=[O:18])[CH3:55]
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(I)nc1-2
Reactant: CCc1cccc(CC)c1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(I)nc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (4.0 g, 10.4 mmol) prepared as described in WO2004/104007 was dissolved in anhydrous ethanol (150 mL) and treated with potassium hydroxide (5.83 g, 104 mmol.) at RT for 24 hour. The white precipitate formed during the reaction was collected by filtration. The solid was then suspended in anhydrous dimethylformamide (5.0 mL) and treated with N-ethyl-N,N-diisopropylamine (10 ml) and O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (4.5 g, 14.1 mmol). The mixture was then treated with 2,6-diethylaniline (2.3 ml, 14.1 mmol) and stirred at room temperature overnight. The solvent was removed under reduced pressure and the crude was purified by column chromatography to afford the title compound.