Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(B(CC)[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)C.[OH-].[K+].[Cl-].[NH4+]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.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(OCC)(=O)C.O>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: CCB(CC)c1cccnc1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cccnc2)cc1
Yield: 52.8 %

Procedure:
In tetrahydrofuran (100 ml), methyl 4-bromobenzoate (5.04 g) and diethyl-3-pyridylborane (Chem. Pharm. Bull., 33, 4755, 1985) (2.30 g) were dissolved, followed by the addition of tetrabutylammonium bromide (2.51 g), potassium hydroxide (2.63 g), tetrakis(triphenylphosphine)palladium (O) (1.8 g) and water (1 ml) under an argon atmosphere. The resulting mixture was heated under reflux for 2 hours. After ice cooling, an aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The organic layer so separated was dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by chromatography on a silica gel column (hexane: ethyl acetate=1:1). The solvent was then distilled off. To the residue, methanol and IN aqueous hydrochloric acid in ethanol were added. The solvent was distilled off again. Tetrahydrofuran was added to the residue and the solid so precipitated was collected by filtration. After drying, the title compound (1.76 g, 45%) was obtained as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[N:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[C:25]([C:27]1[C:28]([NH2:36])=[N:29][C:30]([CH2:33][O:34][CH3:35])=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:36])=[N:29][C:30]([CH2:33][O:34][CH3:35])=[CH:31][CH:32]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(COC)nc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COCc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 41.4 %

Procedure:
To a mixture of (4-benzyloxy-phenyl)-acetohydroximoyl chloride (19 mg, 0.069 mmol) described in Manufacturing Example 1-1-3 and tetrahydrofuran (1 mL) were added 3-ethynyl-6-methoxymethyl-pyridin-2-ylamine (8.6 mg, 0.053 mmol) described in Manufacturing Example 26-1-7 and triethylamine (15 μL, 0.11 mmol) at room temperature, which was stirred for 5.5 hours at room temperature. Water was added at room temperature to the reaction mixture, which was then extracted with ethyl acetate-tetrahydrofuran (3:2). The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:3) to obtain the title compound (8.8 mg, 41%).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]2[OH:19])=[C:8]([Cl:20])[CH:7]=1)[CH3:5].[OH-].[Na+]>CO>[Cl:20][C:8]1[CH:7]=[C:6]([CH:4]([CH3:5])[C:3]([OH:21])=[O:2])[CH:11]=[CH:10][C:9]=1[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]1[OH:19]
Reactant: COC(=O)C(C)c1ccc(C[C@@H]2CCCC[C@@H]2O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)c1ccc(C[C@@H]2CCCC[C@@H]2O)c(Cl)c1
Yield: 80.3 %

Procedure:
3 g of methyl-2-[3-chloro-4-(cis-2-hydroxycyclohexane-1-yl methyl)phenyl]propionate was incorporated with 80 ml of an aqueous methanol containing 1.2 g of sodium hydroxide and then refluxed under heat for two hours. After the end of the reaction, the reaction mixture was treated to remove the solvent therefrom at a reduced pressure, incorporated with 50 ml of water and washed with 50 ml of ethyl acetate, after which the aqueous layer was adjusted to a pH of 2 with conc. hydrochloric acid, extracted with 50 ml of ethyl acetate, washed with water, dried and then freed of the solvent thereby to obtain 2.3 g (yield 80%) of oily 2-[3-chloro-4-(cis-2-hydroxycyclohexane-1-yl methyl)phenyl]propionic acid having the following instrumental analyses.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12]>[Rh]>[CH3:1][C:2]1([CH3:13])[NH:11][C@H:10]2[C@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][C:3]1=[O:12]
Reactant: CC1(C)Nc2ccccc2NC1=O
Agent: [Rh]
Product: CC1(C)N[C@@H]2CCCC[C@@H]2NC1=O

Procedure:
In a manner analogous with the foregoing, 3,3-dimethyl-3,4-dihydroquinoxalin-2-one is hydrogenated at about 130° C. and 1500 psi in the presence of rhodium (5%) on charcoal in 2 hours, to yield cis-3,3-dimethyl-decahydroquinoxalin-2-one.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>>[CH2:13]([NH:18][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CCN
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NCCC(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and isoamylamine as starting materials to give the aimed compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:29]=1[C:23]1([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:22][CH:21]2[CH2:30][C:31]([O:33]CC)=[O:32]>>[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:29]=1[C:23]1([CH2:24][CH2:25][N:26]([C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:14])[F:13])[CH2:27][CH2:28]1)[CH2:22][CH:21]2[CH2:30][C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Product: O=C(O)CC1CC2(CCN(C(=O)Cc3ccccc3C(F)(F)F)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 2-(2-(trifluoromethyl)phenyl)acetic acid and ethyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate. LC-MS Method 1 tR=1.83, min, m/z=468, 466
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:19])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[C:12]([NH:19][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.1 %

Procedure:
To a mixture of N2-(3-chlorophenyl)-4-(trifluoromethyl)pyrimidine-2,5-diamine (150 mg), pyridine (84 μL) and dichloromethane (3 mL) was added benzenesulfonylchloride (129 mg) under ice-cooling, followed by stirring at room temperature for 6 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate), and the obtained residue was solidified from a mixed solvent of hexane and ethyl acetate to obtain N-{2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide (174 mg) as a white powder.
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>CO.O1CCCC1>[OH:15][C:14]1[C:9](=[O:8])[NH:10][N:11]=[C:12]([CH2:23][CH2:24][C:25]2[CH:26]=[N:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=2)[CH:13]=1
Reactant: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cn1
Solvent: C1CCOC1
Solvent: CO
Product: O=c1[nH]nc(CCc2ccc(C(F)(F)F)nc2)cc1O
Yield: 26 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-{[6-(trifluoromethyl)pyridin-3-yl]ethynyl}pyridazine (Intermediate 9) except that the reaction was carried out in a mixture of methanol and tetrahydrofuran (1:1). The resulting crude product was purified by preparative HPLC under acidic conditions to afford 4-hydroxy-6-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}pyridazin-3(2H)-one as a cream solid (26% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:11])=[CH:2]1.ClN1[C:26](=[O:27])[CH2:25][CH2:24]C1=O.BrCCCO.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:27]1[C:2]2=[C:3]([C:10]([O:12][CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:11])[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[N:1]2[CH2:24][CH2:25][CH2:26]1
Reactant: O=C(OCCN1CCCCC1)c1c[nH]c2ccccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: OCCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCCN1CCCCC1)c1c2n(c3ccccc13)CCCO2

Procedure:
2-(1-Piperidyl)ethyl 1 H-indole-3-carboxylate was treated initially with N-chlorosuccinimide (1.5 equivalents) for 2 h, then with 3-bromo-1-propanol (3 equivalents) for 21 h, followed by anhydrous potassium carbonate in acetone, using the method described in Example 1b. The crude product was purified using the same chromatography conditions as in Example 1b to afford the title compound. (E4) as a pale yellow oil (15%). This was converted to its oxalate salt and crystallised from acetone mp 174°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[NH:25][C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=2[N:30]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:35][C:33]2[CH:32]=[CH:31][C:29]3[N:30]=[C:26]([NH:25][C:16]4[C:15]5[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=5)[N:19]=[CH:18][N:17]=4)[S:27][C:28]=3[CH:34]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)c5ccc(Cl)cc5)cc4s3)c2cc1OC

Procedure:
4-Chloro-N-[2-(6,7-dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl ]benzamide was prepared from p-chlorobenzoyl chloride (15 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 2 (yellowish solid, 41 mg, 83 μmol, 74%). LC/ESI-MS: m/z=492 [M(35Cl)+H]+; m/z=490 [M(35Cl)−H]−; Rt=3.45 min.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][C:13]([CH3:17])([CH3:16])[CH2:14]O.N1C=CC=CC=1>O=S(Cl)Cl>[CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:12][C:13]([CH3:17])([CH3:16])[CH3:14])=[O:5]
Reactant: CC(C)(C)CO
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc(Br)ccc1C(=O)OCC(C)(C)C
Yield: 67.9 %

Procedure:
Using General Esterification Method C; 2-methyl-4-bromo-benzoic acid (1.82 g, 8.47 mmols) was refluxed for 3 h with 10 mL SOCl2. The resulting solution was concentrated under reduced pressure and the crude acyl chloride combined with 2,2-dimethylpropanol (0.75 g, 8.47 mmols) and pyridine (1.4 mL, 16.9 mmols) to give the title compound (1.64 g, 68%) after work-up and column chromatography (2-5% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@:13]1([OH:46])[CH2:21][C@H:20]([CH2:22]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:19][C@@H:18]2[C@H:14]1[CH2:15][N:16]([C:34](=[O:45])[C@H:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:43][CH3:44])[CH3:36])[CH2:17]2>CN(C)C=O.O>[N:1]([CH2:22][C@@H:20]1[CH2:19][C@@H:18]2[C@@H:14]([CH2:15][N:16]([C:34](=[O:45])[C@H:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])[CH3:36])[CH2:17]2)[C@@:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH3:5])([OH:46])[CH2:21]1)=[N+:2]=[N-:3]
Reactant: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](COS(=O)(=O)c3ccc(C)cc3)C[C@@](O)(c3ccccc3OC)[C@@H]2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](CN=[N+]=[N-])C[C@@](O)(c3ccccc3OC)[C@@H]2C1
Temperature: 20 °C
Reaction time: 20 h
Yield: 99.4 %

Procedure:
1.68 g of sodium azide are added to a solution, which has been brought to 50° C., of 9.0 g (3aS,4S,6R,7aR)-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]-6-tosyloxymethylperhydroisoindol-4-ol in 50 cm3 of dimethylformamide. The reaction mixture is stirred at 20° C. for 20 hours and then diluted with 350 cm3 of water and subjected to extraction with 100 cm3 of ethyl acetate. The organic phase is washed with 100 cm3 of water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). 7.0 g of (3aS,4S,6R,7aR)-6-azidomethyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol are obtained in the form of a thick white foam.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:4]=[C:3]1[C:18]([OH:20])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][C:46]1[C:47](=[O:56])[NH:48][CH:49]=[C:50]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:51]=1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:52]([C:50]1[CH:51]=[C:46]([NH:45][C:18]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][C:9]=3[O:11][C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[O:20])[C:47](=[O:56])[NH:48][CH:49]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: Cn1c(C(=O)O)cc2cccc(Oc3ccncc3)c21
Reactant: CC(C)(C)c1c[nH]c(=O)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(C(=O)Nc2cc(C(C)(C)C)c[nH]c2=O)cc2cccc(Oc3ccncc3)c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.2 %

Procedure:
1-Methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid (145 mg, 0.542 mmol) and HATU (206 mg, 0.542 mmol) were combined in DMF (1 mL) and stirred 5 min at room temperature. The above aminopyridinone (90 mg, 0.542 mmol) was added to the reaction mixture followed by N,N-diisopropylethylamine (283 microL, 1.63 mmol). The solution was stirred at room temperature for 72 h then poured into saturated aqueous NaHCO3. The aqueous layer was extracted with chloroform and the combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica-gel chromatography (2% ammonium hydroxide, 50% ethyl acetate in hexane) provided 1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-2-oxo-1,2-dihydropyridin-3-yl)-amide (163 mg, 73%) as a white solid: mp: 236-238° C. (dec.); ESI MS m/z 417 [C24H24N4O3+H]+; HPLC>97%, tR=14.74 min.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH:5](Br)[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][C:16]3[N:17]([CH2:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[C:18](=[O:31])[N:19]([CH2:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:20](=[O:23])[C:21]=3[N:22]=2)=[CH:10][CH:9]=1)Br)C.CC(C)([O-])C.[K+].C>C(O)(C)(C)C.O>[CH:25]1([CH2:24][N:19]2[C:20](=[O:23])[C:21]3[N:22]=[C:14]([C:11]4[CH:10]=[CH:9][C:8]([C:6]#[C:5][C:4]([OH:40])=[O:3])=[CH:13][CH:12]=4)[NH:15][C:16]=3[N:17]([CH2:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:18]2=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)C(Br)C(Br)c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)C#Cc1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.4 %

Procedure:
2.8 g (4.1 mmol) 3-[4-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]phenyl}-2,3-dibromo-propionic acid ethyl ester (part a of this example) was added to 56 mL of 1M potassium t-butoxide in t-butanol (Aldrich) at room temperature. The mixture was stirred at room temperature for 2.5 hours, then 0.10 mL water was added. The solution was stirred for an additional hour then 1 g charcoal was added in 250 mL water. The mixture was stirred for 30 minutes then filtered. The filtrate was acidified with conc. hydrochloric acid (pH=1), then the resulting suspension was stirred for 15 minutes, filtered then washed with 3×50 mL water. The solid was dried under reduced pressure to give 1.63 g (81%) of title compound; 1H-NMR (DMSO-d6)δ: 8.15 (d, J=8.0 Hz, phenyl CH, 2H), 7.73 (d, J=8.0 Hz, phenyl CH, 2H), 3.87 (d, J=6.6 Hz, CH2N, 2H), 3.74 (d, J=6.8 Hz, CH2N, 2H), 1.88 (br s, c-hexyl CH, 1H), 1.4-1.8 (m, c-hexyl CH, CH2, 11H), 0.8-1.2 (m, c-hexyl CH2, 10 H); MS (ES−): 487 (M-1), 443 (M-1-CO2).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:15][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCOCOCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCOCOCCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of 48.40 g of 5-(2-methoxyethoxy)methoxy-1-pentanol (prepared as described in Preparation 39) and 100.19 g of carbon tetrabromide dissolved in 500 ml of methylene chloride was added 79.32 g of triphenylphosphine, whilst ice-cooling (at 5° to 8° C.). The mixture was stirred at room temperature for one hour, after which the solvent was removed by evaporation under reduced pressure. Diethyl ether was then added. The insoluble materials were filtered off and the filtrate was concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 850 g of silica gel and 57.87 g of the title compound were obtained from the fractions eluted with a 1:9 by volume mixture of ethyl acetate and hexane, as a colorless oil.
Reaction SMILES: [NH2:1]/[C:2](=[N:16]\[OH:17])/[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH2:18]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([O:34][CH2:35][C:36](O)=[O:37])[CH2:30][CH2:29]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH2:1]/[C:2](=[N:16]\[O:17][C:36](=[O:37])[CH2:35][O:34][CH:31]1[CH2:32][CH2:33][N:28]([C:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])[CH2:29][CH2:30]1)/[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1/C(N)=N/O
Reactant: O=C(O)COC1CCN(C(=O)OCc2ccccc2)CC1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1/C(N)=N/OC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
The title compound was prepared by a similar method to Preparation 5 from tert-butyl (Z)-(2S)-2-[amino(hydroxyimino)methyl]-1-piperidinecarboxylate [see Preparation 4] and 2-(1-[(benzyloxy)carbonyl]-4-piperidyloxy)acetic acid [see Preparation 92] to afford tert-butyl (Z)(2S)-2-[amino([2-(1-[(benzyloxy)carbonyl]-4 piperidyloxy)acetyl]oxyimino)methyl]-1-piperidinecarboxylate as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:23]([CH3:24])[O:22][C@@H:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:11]([OH:25])[C@@H:10]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:29]C(OCC)(OCC)C)[CH3:28]>CN(C=O)C>[C:27]([O:25][C@@H:11]1[C@H:10]([OH:26])[C@@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:23]([CH3:24])[O:22][C@H:12]1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:29])[CH3:28]
Reactant: CCOC(C)(OCC)OCC
Reactant: COc1ccc(O[C@@H]2O[C@@H](C)[C@H](OCc3ccccc3)[C@@H](O)[C@H]2O)cc1
Solvent: CN(C)C=O
Product: COc1ccc(O[C@@H]2O[C@@H](C)[C@H](OCc3ccccc3)[C@@H](O)[C@H]2OC(C)=O)cc1
Temperature: 50 °C
Reaction time: 0.83 h

Procedure:
4-Methoxyphenyl 4-O-benzyl-α-L-rhamnopyranoside (4.06 g, 11.28 mmol) and 1,1,1-triethoxyethane (2.20 g, 2.47 mL, 13.53 mmol) are dissolved in 75 mL of DMF and stirred for 50 min at 50° C. DMF was removed in vacuo. The residue was dissolved in AcOH/H2O (4:1, v/v) and stirred for 10 min at room temperature. The acetic acid is removed in vacuo and the crude product was purified by column chromatography (3:1 hexane/EtOAc) yielding 4.51 g (98%, 2 steps) of 12 as a colorless oil: [α]D: −69.4 (c=1.25, CHCl3). IR (thin film, CHCl3): 3005, 2933, 1739, 1503, 1374, 1126, 1041 cm−1. 1H NMR (CDCl3, 300 MHz) δ 1.34 (d, J=6.0 Hz, 3H), 2.19 (s, 3H), 2.41 (b, 1H), 3.44 (t, J=9.3 Hz, 1H), 3.76 (s, 3H), 3.92 (m, 1H), 4.31 (d, J=9.0 Hz, 2H), 4.74 (d, J=12.6 Hz, 2H), 4.87 (d, J=12.6 Hz, 2H), 5.29 (m, 1H), 5.36 (s, 1H), 6.82 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 7.33 (m, 5H). 13C NMR (CDCl3, 75 MHz) 18.1, 21.2, 55.7, 68.1, 70.0, 72.6, 75.3, 81.6, 96.3, 114.5, 117.6, 127.8, 127.8, 128.4, 138.0, 149.9, 154.9, 170.6. MALDI-HRMS: m/z [M+Na]+ calcd 425.1571, obsd 425.1565.
Reaction SMILES: [CH2:1](OC1N=C(O)C2C(=CC=C(I)C=2)N=1)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH2:47]([O:49][C:50]1[N:59]=[C:58]([O:60][C@H:61]2[CH2:65][N:64]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@H:63]([C:73]([O:75][CH3:76])=[O:74])[CH2:62]2)[C:57]2[C:52](=[CH:53][CH:54]=[C:55](I)[CH:56]=2)[N:51]=1)[CH3:48].C([B-](F)(F)F)=C.[K+]>C1COCC1.CCO.CCOC(C)=O.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>[CH2:47]([O:49][C:50]1[N:59]=[C:58]([O:60][C@H:61]2[CH2:65][N:64]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@H:63]([C:73]([O:75][CH3:76])=[O:74])[CH2:62]2)[C:57]2[C:52](=[CH:53][CH:54]=[C:55]([CH:1]=[CH2:2])[CH:56]=2)[N:51]=1)[CH3:48]
Reactant: CCOc1nc(O)c2cc(I)ccc2n1
Reactant: CCOc1nc(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)c2cc(I)ccc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C=C[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=Cc1ccc2nc(OCC)nc(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)c2c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
A solution of 2-ethoxy-6-iodoquinazolin-4-ol (2.94 g, 9.30 mmol) and 1-tent-butyl 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.28 g, 9.30 mmol) in THF (150 ml) was cooled to 0° C. and treated with Ph3P (2.93 g, 11.16 mmol). DEAD (4.42 ml, 11.16 mmol) was added dropwise, and the mixture was stirred at 20° C. for 4 h. After evaporation of the volatiles, the residue was purified on silica gel (gradient elution, 0-5% EtOAc/(EtOAc:DCM=5:95)) to furnish a 6:4 mixture of 1-tert-butyl 2-methyl (2S,4R)-4-[(2-ethoxy-6-iodoquinazolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate and 1-text-butyl 2-methyl (2S,4R)-4-(2-ethoxy-6-iodo-4-oxoquinazolin-3(4H)-yl)pyrrolidine-1,2-dicarboxylate (3.8 g) LCMS (ES+) m/z 544 (M+H)+. This material was dissolved in EtOH (40 mL) and treated with TEA (0.83 mL, 5.98 mmol). Potassium vinyltrifluoroborate (0.80 g, 5.98 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.32 g, 0.399 mmol) were added, and the mixture was stirred at 90° C. for 2 h. The mixture cooled, diluted with EtOAc and washed with aqueous HCl (1 N) and brine. The organic phase was dried over Na2SO4, filtered and concentrated to give a residue that was purified on silica (gradient elution, 0-20% EtOAc/DCM) to yield the title compound as an oil (1.38 g, 33%). LCMS (ES+) m/z 444 (M+H)+.