Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=O)[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[NH2:26])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[ClH:28]>C(#N)C>[ClH:28].[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]3[NH:26][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccccc1NC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: Cl
Solvent: CC#N
Product: O=c1[nH]c2cc(Br)cc3c2n(c1=O)C(Cc1nc2ccccc2[nH]1)CC3
Temperature: 50 °C
Yield: 73 %

Procedure:
A solution of 9-bromo-5-(o-aminophenylcarbamoylmethyl)-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (Example 99) (250 mg, 0.5 mmol) in a mixture of acetonitrile (10 mL) and concentrated hydrochloric acid (2 mL) was heated at 50° C. for 5 h and concentrated. The residue was washed with distilled water and diethyl ether and dried in vacuo to give 150 mg of the title compound (73%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.15 (s, 1H), 7.80 (dd, 2H, J=6.3, 3 Hz), 7.54 (dd, 2H, J=6.3, 3 Hz), 7.28 (bs, 1H), 7.25 (bs, 1H), 5.26~5.35 (m, 1H), 3.41~3.50 (m, 2H), 3.07 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.90 (dm, 1H, J=17.1 Hz), 2.19 (dm, 1H, J=13.5 Hz), 1.90~2.05 (m, 1H).
Reaction SMILES: CC(C)([S@@]([NH:6][C@@H:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:8]1[CH:9]=[C:10]([P:14]([CH3:19])(=[O:18])[O:15][CH2:16][CH3:17])[CH:11]=[CH:12][CH:13]=1)=O)C>Cl.O1CCOCC1>[NH2:6][C@@H:7]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:8]1[CH:9]=[C:10]([P:14]([CH3:19])(=[O:18])[O:15][CH2:16][CH3:17])[CH:11]=[CH:12][CH:13]=1
Reactant: CCOP(C)(=O)c1cccc([C@@H](N[S@@](=O)C(C)(C)C)c2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOP(C)(=O)c1cccc([C@@H](N)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 3-((S)—((S)-1,1dimethylethylsulfinamido)(phenyl)methyl)phenyl(methyl)phosphinate, 25-c, (25 g, 76% purity, 48.7 mmol) was dissolved in HCl/dioxane (150 ml, 4 mol/L) and the mixture was stirred at room temperature for 2 h. The mixture was then concentrated under vacuum and the residue was dissolved in H2O (90 ml) and HCl (10 ml). The aqueous phase was extracted with EA (80 ml×5). The pH of the aqueous phase was adjusted to about pH=12 and extracted with EA (100 ml*3). The organic layer was dried over Na2SO4. The solvent was removed to provide crude product, 25-d, (10.55 g) and the crude product was used for the next step directly.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][O:25][CH3:26])[CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:27]([O:29]C)=[O:28])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][O:25][CH3:26])[CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:27]([OH:29])=[O:28])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COCC1CCCN(c2nc3cc(C(=O)OC)ccc3nc2-c2ccc(F)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCC1CCCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccc(F)cc2)C1
Reaction time: 0.13 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-(4-fluorophenyl)-3-(3-(methoxymethyl)piperidin-1-yl)quinoxaline-6-carboxylate (152.3 mg, 0.37 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (44.7 mg, 1.12 mmol, 3.00 equiv) in water (1.5 mL) dropwise with stirring. The resulting solution was stirred for 4 h at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with water. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solids were collected by filtration and the crude product (240 mg) was purified by Prep-HPLC under the following conditions (AGILENT Pre-HPLC (UV-Directed)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (45% CH3CN up to 60% in 8 min, hold 60% in 5 min, up to 100% in 0.1 min, hold 100% in 1.4 min); Detector, uv 220&254 nm. This resulted in 89 mg (61%) of 2-(4-fluorophenyl)-3-(3-(methoxymethyl)piperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9](=O)[CH3:10])=[C:6]([Cl:12])[N:5]=[CH:4][N:3]=1.[CH3:13][NH:14][NH2:15].C([O-])(=O)C.[Na+]>CC#N>[Cl:12][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[N:14]([CH3:13])[N:15]=[C:9]([CH3:10])[CH2:8][C:7]=12
Reactant: CNN
Reactant: CC(=O)Cc1c(Cl)ncnc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1=NN(C)c2ncnc(Cl)c2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 122 %

Procedure:
To a stirred solution of 1-(4,6-dichloropyrimidin-5-yl)propan-2-one (940 mg) in dry MeCN (10 mL), methyl hydrazine (232 mg) and sodium acetate (715 mg) were added. The reaction mixture was stirred at room temperature for 24 hours before being quenched with water (100 mL). Aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. Evaporation of solvents under reduced pressure gave crude 5-chloro-1,3-dimethyl-1,4-dihydropyridazino[3,4-d]pyrimidine (1.1 g) as white solid which was used as was. 1H NMR (DMSO-d6): δ 2.06 (s, 3H), 3.2 (s, 3H), 3.55 (s, 2H), 8.33 (s, 1H).
Reaction SMILES: [H-].[B].[Al].[CH2:4]([O:11][CH2:12][C:13]#[C:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Pd]>[CH2:4]([O:11][CH2:12][CH:13]=[CH:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: OC(C#CCOCc1ccccc1)C(F)(F)F
Agent: [Pd]
Agent: [Al]
Agent: [B]
Product: OC(C=CCOCc1ccccc1)C(F)(F)F

Procedure:
Next, a hydride of boron or aluminum or palladium catalyst is allowed to act on 5-benzyloxy-1,1,1-trifluoro-3-pentyne-2-ol (compound (3)) to obtain 5-benzyloxy-1,1,1-trifluoro-3-pentene-2-ol (E)-(5) or (Z)-(5). This is acetylated or isobutylated and then thereon is allowed lipases or lipases-producing microorganism to act to obtain optically active (R)-5-benzyloxy-1,1,1-trifluoro-3-pentene-2-ol [(R)-(E)-5] or [(R)-(Z)-5] and optically active (S)-2-acetoxy (or butoxy)-5-benzyloxy-1,1,1-trifluoro-3-pentene [(S)-(E)-6 or (S)-(Z)-6].
Reaction SMILES: C(Br)(Br)(Br)Br.[C:6]([O:10][C:11]([N:13]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18](O)[C:17]([C:25]2[C:29]([F:30])=[CH:28][O:27][C:26]=2[CH2:31][OH:32])=[CH:16][CH:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[C:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]2[C:17]([C:25]3[C:29]([F:30])=[CH:28][O:27][C:26]=3[CH2:31][O:32]2)=[CH:16][CH:15]=1)=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2c(F)coc2CO)c1O
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1OCc1occ(F)c1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
Carbon tetrabromide (2.74 g) was added to an ice-cooled solution of methyl 6-bis-(tert-butoxycarbonyl)amino-3-(4-fluoro-2-hydroxymethylfuran-3-yl)-2-hydroxybenzoate (Intermediate 99, 1.98 g) and triphenylphosphine (2.16 g) in DCM (70 mL). The mixture was stirred for 30 minutes and then concentrated in vacuo. The residue was dissolved in acetone (80 mL) and cesium carbonate (13.4 g) was added. The reaction mixture was heated at reflux for 30 minutes, cooled and then concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate in cyclohexane, with a gradient of 0-30%. The resultant product was triturated with cyclohexane to give methyl 7-bis-(tert-butoxycarbonyl)amino-1-fluoro-4H-furo[2,3-c]chromene-6-carboxylate (1.21 g) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:25])=[N:5][C:6]2[N:7]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16].[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C.CCOC(C)=O>[N:26]([CH2:2][C:3]1[C:4]([CH3:25])=[N:5][C:6]2[N:7]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CCl)c(C)nc2n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CN=[N+]=[N-])c(C)nc2n1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
To a stirred solution of crude ethyl 6-(chloromethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (448 mg, 1.12 mmol) in DMF (5 mL) was added NaN3 (110 mg, 1.69 mmol). The reaction was heated to 50° C. for 1 h. After cooling, the reaction was diluted with EtOAc and extracted with H2O and brine before drying over MgSO4. Filtration and concentration under reduced pressure gave ethyl 6-(azidomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (450 mg, 100% crude yield) as a yellow oil.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=1)([OH:3])=O.[CH2:17]([O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)[CH3:18].C1C=C2N=NN(O)C2=CC=1.O.C(N=C=NC(C)C)(C)C>CN(C)C=O>[CH2:17]([O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:1](=[O:3])[CH2:4][C:5]2[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=2)=[CH:26][CH:27]=1)[CH3:18]
Reactant: CC(C)(Sc1nc(CC(=O)O)cs1)C(=O)O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(NC(=O)Cc2csc(SC(C)(C)C(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An operation similar to that of Example 461-5 was performed 3 times using 2-{[4-(carboxymethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin obtained in Example 461-4 and 4-aminophenylacetic acid ethyl ester. To a suspension of the obtained resin in dimethylformamide (30 mL) were added HOBT monohydrate (0.92 g), diisopropylcarbodiimide (0.93 ml) and 4-aminophenylacetic acid ethyl ester (1.1 g), and the mixture was stirred at room temperature overnight. The resin was collected by filtration from the reaction mixture, washed once each with dimethylformamide and methanol, twice with dimethylformamide, once with methanol, three times with tetrahydrofuran and finally once with methanol, and vacuum dried to give the title pale-brown resin (3.1 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:40]=[C:14]3[N:15](CC4C=CC(OC)=CC=4)[CH:16]=[N:17][C:18]([O:19][C:20]4[C:21]([F:30])=[C:22]5[C:26](=[CH:27][CH:28]=4)[NH:25][C:24]([CH3:29])=[CH:23]5)=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2]>C1COCC1.CN1CCN(C)C1=O.[Pd]>[CH2:1]([O:3][C:4](=[O:41])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:40][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C:20]4[C:21]([F:30])=[C:22]5[C:26](=[CH:27][CH:28]=4)[NH:25][C:24]([CH3:29])=[CH:23]5)[C:13]=3[CH:12]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc3c(Oc4ccc5[nH]c(C)cc5c4F)ncn(Cc4ccc(OC)cc4)c-3n2)cc1
Agent: [Pd]
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2cc3c(Oc4ccc5[nH]c(C)cc5c4F)ncnc3[nH]2)cc1

Procedure:
Hydrogenation of 0.50 g (0.91 mMol) of 4-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoic acid ethyl ester in 150 ml of THF and 15 ml of 1,3-dimethyl-2-imidazolidinone in the presence of 0.2 g of Pd/C (10%; “Engelhard 5125”), filtration and concentration gives the crude product. Stirrng in THF/water, filtration and washing with water gives the title compound; MS-ES+: (M+H)+=431; elemental analysis for C, H, N, and ,F within 0.4%; of calculated value.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:14]3[NH:13][C:12]4[CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][CH2:19][C:11]=4[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[Br-].[CH:33]1([Zn+])[CH2:36][CH2:35][CH2:34]1>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:33]1([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]3[CH:16]=[CH:15][C:14]4[NH:13][C:12]5[CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:19][C:11]=5[C:10]=4[CH:9]=3)=[CH:4][C:3]=2[C:28]([F:31])([F:29])[F:30])[CH2:36][CH2:35][CH2:34]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc21
Reactant: [Zn+]C1CCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCC4)c(C(F)(F)F)c3)cc21
Temperature: 90 °C

Procedure:
To a solution of ethyl 2-(7-(4-chloro-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (202.8 mg, 0.449 mmol) in tetrahydrofuran (1 mL) was added 0.5 M cyclobutylzinc(II) bromide solution in tetrahydrofuran (8.98 mL, 4.49 mmol) and bis(tri-t-butylphosphine)palladium (46.8 mg, 0.090 mmol) at room temperature. The mixture was heated at 90° C. for 63 h. The mixture was then quenched with 1 N aqueous HCl solution and filtered through Celite®. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine solution to remove excess HCl and concentrated under reduced pressure. The residue was purified by HPLC. The combined fractions were triturated with saturated aqueous sodium bicarbonate solution to basic solution and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and acidified to pH 4. The organic layer was washed with water until the aqueous layer was neutral. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the title compound as a pink solid (32.3 mg). LCMS m/z=444.6 [M+H]+; NMR (400 MHz, DMSO-d6) δ ppm 1.78-1.87 (m, 1H), 1.93-2.02 (m, 1H), 2.03-2.12 (m, 1H), 2.16-2.28 (m, 4H), 2.34 (dd, J=15.98, 9.03 Hz, 1H), 2.60-2.75 (m, 4H), 3.41-3.51 (m, 1H), 3.74-3.84 (m, 1H), 5.12 (s, 2H), 6.70 (dd, J=8.78, 2.46 Hz, 1H), 6.92 (d, J=2.40 Hz, 1H), 7.19 (d, J=8.84 Hz, 1H), 7.66-7.78 (m, 3H), 10.46 (s, 1H), 12.20 (bs, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[N:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][CH:26]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:31][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:21]3[S:20][CH:24]=[CH:23][N:22]=3)[N:30]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2nccs2)n1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2nccs2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 6-(thiazol-2-yl)picolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.77 min.; [M+H]+: 409.94 g/mol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C.[NH4+].[Cl-].OP(O)(O)=O>C1COCC1.CC1C=CC=CC=1.CCCCCCC.O>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([B:26]([OH:31])[OH:27])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2)CC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To tert-butyl 4-(4-bromophenyl)-1-piperazinecarboxylate (118.30 g, 346.9 mmol) in dry THF/MePh (1/1, 1.5 L) at −78° C. under dry nitrogen was added n-BuLi (2.5 M, 160 mL, 398.9 mmol) dropwise and the reaction was stirred at −78° C. for 20 minutes. Triisopropyl borate (96.1 mL, 416.3 mmol) was added dropwise and the reaction was warmed to 0° C. and stirred for 2 hours. Aqueous sat. NH4Cl (400 mL), water (100 mL) and 1 equivalent of H3PO4 (20 ML) were added and the mixture stirred for 15 minutes and then concentrated to a volume of approximately 200 mL (at which stage the mixture became bluish and a precipitate formed). A dropping funnel was charged with heptane (800 mL) and the solvent was added to the reaction mixture with vigorous stirring over a period of one hour and the resulting suspension was stirred overnight. The suspension was filtered, washed with heptane (2×200 mL), and dried over the weekend in vacuo to afford 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenylboronic acid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]2)=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C.Cl>ClC1C=CC=CC=1>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]#[N:14])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(C#N)cc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1ccc2ccc(O)cc2c1
Yield: 94 %

Procedure:
To a solution of 7-methoxynaphthalene-2-carbonitrile (6 g) in chlorobenzene (60 ml) was added aluminum chloride (15.3 g) at room temperature and the mixture was heated under refluxing for 30 min. After completion of the reaction, the reaction mixture was ice-cooled and ice, ethyl acetate and conc. hydrochloric acid were added, and the mixture was stirred. The organic layer was separated and concentrated. To the obtained residue was added hexane and the resultant solid was collected by filtration and dried under reduced pressure to give the title compound (5.21 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@@H:4](/[CH:5]=[CH:6]/[C:7](=[O:9])[CH3:8])[C@H:3]1[C:10](Cl)=[O:11].[CH:14]([OH:17])([CH3:16])[CH3:15]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[C@@H:4](/[CH:5]=[CH:6]/[C:7](=[O:9])[CH3:8])[C@H:3]1[C:10]([O:17][CH:14]([CH3:16])[CH3:15])=[O:11]
Reactant: CC(C)O
Reactant: CC(=O)/C=C/[C@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: c1ccccc1
Product: CC(=O)/C=C/[C@H]1[C@@H](C(=O)OC(C)C)C1(C)C

Procedure:
Using the procedure of Example 3, 6 g of (1R,cis) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylic acid chloride and 2.7 ml of isopropanol were reacted to obtain 1.96 g of isopropyl (1R,cis) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-39°±5° (c=0.2% in benzene).
Reaction SMILES: C1(S[CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:15]=[CH:16][C:17]=3[O:21][CH2:22][CH3:23])[S:10]2(=[O:12])=[O:11])C=CC=CC=1.S(Cl)([Cl:36])(=O)=O>ClCCl>[Cl:36][CH2:8][N:9]1[C:19](=[O:20])[C:18]2[C:13](=[C:14]([O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:15]=[CH:16][C:17]=2[O:21][CH2:22][CH3:23])[S:10]1(=[O:12])=[O:11]
Reactant: CCOc1ccc(OCC(=O)OC(C)(C)C)c2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOc1ccc(OCC(=O)OC(C)(C)C)c2c1C(=O)N(CCl)S2(=O)=O
Yield: 95 %

Procedure:
By the method of part E of Example 45 2-phenylthiomethyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin (1.92 g) was reacted with sulfuryl chloride (0.54 g) in dichloromethane at about 5° C. and purified with hexane affording 2-chloromethyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin, 1.54 g, 95% yield, mp 117°-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[N:17]=1)=[O:9]
Reactant: Nc1nc(-c2cc(F)ccc2F)cs1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1nc(-c2cc(F)ccc2F)cs1)c1cc(Cl)ccc1O
Yield: 36.5 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-4-(2,5-difluorophenyl)thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH3:7][O:8][P:9]([O:12]C)[O:10][CH3:11]>C(O)C(C)C>[CH3:7][O:8][P:9]([O:10][CH3:11])([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])=[O:12]
Reactant: C=CC(=O)OC
Reactant: COP(OC)OC
Solvent: CC(C)CO
Product: COC(=O)CCP(=O)(OC)OC
Temperature: 80 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
86 g of methylacrylate and 100 g of isobutanol are mixed under nitrogen at room temperature and heated to 80° C. 124 g of trimethylphosphite are added dropwise to the reaction solution in the course of 1 hour. The reaction mixture is stirred for 5 hours at reflux temperature and the solvent (remainder of isobutanol and isobutyl methyl ether) is removed by vacuum distillation. The crude product is obtained in a yield of 173 g with a 94.1% purity, which corresponds to a theoretical yield of 83.0%. The boiling point is 104°-106° C. at 0.93 mbar.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([OH:16])[C:8]([OH:17])=[C:7]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2].Br[CH2:25][CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]2[O:17][CH2:25][CH2:26][CH2:27][O:16][C:9]2=[C:10]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2]
Reactant: BrCCCBr
Reactant: CCOC(=O)Cn1c(C(=O)OCC)c(O)c(O)c1C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C(=O)OCC)c2c(c1C(=O)OCC)OCCCO2
Temperature: 105 °C
Reaction time: 12 h
Yield: 83.3 %

Procedure:
To a 500-mL round-bottom flask containing a stir bar and an argon atmosphere was added diethyl 1-(2-ethoxy-2-oxoethyl)-3,4-dihydroxy-1H-pyrrole-2,5-dicarboxylate (48.00 g, 146 mmol), 1,3-dibromopropane (29.48 g, 146 mmol), anhydrous potassium carbonate (50.36 g, 364 mmol), and anhydrous dimethylformamide (DMF) (250 mL). The reaction was heated to 105° C. and became lime green after about 30 minutes. The reaction was stirred for 12 hours, during which, it became yellow, and was cooled to room temperature. The mixture was poured into DI water (500 mL), the solids were collected via vacuum filtration, and washed with several portions of DI water. The solids were recrystallized from hot methanol to yield 44.90 g (80%) of a yellow solid. mp 139.7-139.9° C.; 1H NMR (300 MHz, CDCl3): δ 5.43 (s, 2H), 4.30 (q, 4H, J=7.7 Hz), 4.22 (q, 2H, J=8.0 Hz), 4.20 (t, 6H, J=63 Hz), 2.25 (p, 2H, J=6.3 Hz), 1.34 (t, 6H, J=7.7 Hz), 1.28 (t, 3H, J=8.0 Hz); 13C NMR (75 MHz, CDCl3): δ 169.6, 161.0, 142.7, 114.1, 71.7, 61.5, 60.9, 48.0, 33.4, 14.5, 14.4; HRMS (EI): Calcd for C17H23NO8 ([M]+), 369.1424, found m/z, 369.1417; Anal. Calcd for C17H23NO8: C, 55.28; H3, 6.28; N, 3.79%, found: C, 55.29; H, 6.37; N, 3.80
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)(=O)=O.O.[NH2:18][NH2:19]>O>[NH:18]([CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)[NH2:19]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: NN
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(NN)C1
Temperature: 95 °C
Yield: 88.9 %

Procedure:
A suspension of tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (Preparation 35, 7.11 g, 28.3 mmol) in neat hydrazine monohydrate (13.7 mL, 283 mmol) was heated to 95° C. for 18 hours. The reaction was cooled to room temperature, then water (100 mL) was added and the mixture extracted with dichloromethane (5×100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a the title compound as a clear oil (4.71 g, 89%). The compound was used without further purification in the next step.