Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])=[N+:2]=[N-:3].[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[CH:10].O[C@H]([C@@H]1C([O-])=C(O)C(=O)O1)CO.[Na+].O>S([O-])([O-])(=O)=O.[Cu+2].C(O)CCC>[C:11]1([C:9]2[N:3]=[N:2][N:1]([CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])[CH:10]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Reactant: C#Cc1ccccc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCCCO
Product: C[Si](C)(C)Cn1cc(-c2ccccc2)nn1
Reaction time: 96 h

Procedure:
(Azidomethyl)trimethylsilane (1.6 g, 12.38 mmol), ethynylbenzene (1.30 g, 12.73 mmol), copper(II) sulfate (0.06 g, 0.376 mmol) and sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate (0.135 g, 0.681 mmol) were added to a 1:2 solution of water:butan-1-ol. The reaction was stirred for 4 days and t-butanol and water were removed, producing a 4-phenyl-1-((trimethylsilyl)methyl)-1H-1,2,3-triazole solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][NH:22][C:23]([CH2:25][O:26]C(=O)C)=[O:24])[CH2:16][CH2:15][CH2:14]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][NH:22][C:23](=[O:24])[CH2:25][OH:26])[CH2:16][CH2:15][CH2:14]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OCC(=O)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(CO)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
Acetic acid {[(R)-6-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamoyl}-methyl ester (0.1 g) was dissolved in 10 mL methanol, and 2 mL of 2M aqueous NaOH was added. The reaction mixture was heated to 60° C. with stirring for 20 minutes, then cooled and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate, and the organic layer was separated, dried (MgSO4), and concentrated under reduced pressure. The oily residue was recrystallized from methyl tert-butyl ether/hexanes (1:1) to 80 mg of N—[(R)-6-(3-fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-2-hydroxy-acetamide, MS (M+H)=378.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][N:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[O:27].Cl[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36]>O1CCCC1.O>[CH3:36][O:35][C:30]1[CH:29]=[C:34]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][N:20]([CH3:19])[C:21]2=[O:27])[CH:33]=[CH:32][CH:31]=1
Reactant: CN1CCCCCC1=O
Reactant: COc1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: COc1cccc(C2CCCCN(C)C2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
Diisopropylamine (152 g) in tetrahydrofuran (150 ml) was added over 30 minutes to 15% butyl lithium in hexane (641 g, 1.50 mole) under nitrogen at 20°-25° C. with cooling and the mixture stirred 30 minutes at room temperature. N-methylcaprolactam (63.6 g) in tetrahydrofuran (60 ml) was added over 5 minutes below 25° C. with cooling, the mixture was stirred for one hour at room temperature and then o-chloroanisole (71.3 g) was added over 20 minutes keeping the temperature below 30° C. The reaction mixture was stirred for two hours, water (2. l.) was added, the product was extracted into ethyl acetate (2×1 l.), the extracts were combined, washed with 2 N hydrochloric acid (1. l.) and water (500 ml) and evaporated under reduced pressure to give 27.1 g oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:10])[OH:9].[CH2:11](O)[CH2:12][CH2:13]O>C1CCCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]1[O:10][CH2:13][CH2:12][CH2:11][O:9]1
Reactant: Cc1ccccc1B(O)O
Reactant: OCCCO
Solvent: C1CCCCC1
Product: Cc1ccccc1B1OCCCO1

Procedure:
A mixture of 1.75 g of 2-methyl phenylboronic acid trimer, 30 ml of cyclohexane, and 0.5 ml of 1,3-propanediol is heated under reflux for 6 hours. The mixture is washed with water and extracted with pentane. The organic phases are dried and concentrated under reduced pressure. In this way 1.8 g of desired product is obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([OH:15])=[C:7]([CH2:16][C:17]([CH3:19])=[CH2:18])[C:6]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].[I:29]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)C.O>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:9][C:8]2[O:15][C:17]([CH2:19][I:29])([CH3:18])[CH2:16][C:7]=2[C:6]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:3])[CH3:2]
Reactant: II
Reactant: C=C(C)Cc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CI)O2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.6 %

Procedure:
In 200 ml of a mixed solvent of diethyl ether-water (3:1) was dissolved 10.0 g of 4-acetoxy-3,5-di-t-butyl-2-(2-methyl-2-propenyl)phenol synthesized according to the procedure described in JP 7-330759/95 and combined with 5.3 g of sodium bicarbonate and 12.0 g of iodine, and the mixture was stirred at room temperature for 20 minutes. Then, the reaction mixture was combined with a saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated to give 13.2 g of 5-acetoxy-4,6-di-t-butyl-2-iodomethyl-2-methyl-2,3-dihydrobenzofuran (rotamer mixture) as a colorless oil (yield 95%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[CH2:7]([O:9][P:10]([O:14]CC)[O:11][CH2:12][CH3:13])[CH3:8]>>[CH2:7]([O:9][P:10]([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:14])[O:11][CH2:12][CH3:13])[CH3:8]
Reactant: CCOP(OCC)OCC
Reactant: BrCCCCBr
Product: CCOP(=O)(CCCCBr)OCC

Procedure:
In another method, 1,4-dibromobutane is heated with triethylphosphite to give diethyl-4-bromobutylphosphonate, for example, as described by Eberhard and Westheimer, 1965. The resultant bromide is then reacted with, for example, biphenyl-4-carboxylic acid in dimethylformamide, in the presence of potassium carbonate. Again, the phosphate ester groups, e.g., ethyl groups, are removed e.g., with trimethylsilylbromide or left in place. An example of such a method is illustrated in the following scheme.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH3:14])=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].C(N(C(C)C)CC)(C)C>[I-].[K+].O1CCCC1>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][CH2:2][C:3]([NH:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[CH3:14])=[O:4])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: COc1ccc(C)c(NC(=O)CCl)c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C)c(NC(=O)CNc2ccc(F)c(Cl)c2)c1
Yield: 86.7 %

Procedure:
2-Chloro-N-(5-methoxy-2-methylphenyl)-acetamide (3 g), 3-chloro4-fluoroaniline (7.56 g), diisopropylethylamine (13.8 ml), potassium iodide (0.005 g) and anhydrous tetrahydrofuran (20 ml) were heated together at 105° C. in a sealed tube for 19 hours. The mixture was then cooled and concentrated. Purification of the residue by silica gel chromatography (eluting with 1:1 iso-hexane/ethyl acetate) gave the sub-title compound (3.93 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=2)=[O:21])=[CH:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:37]Br>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=2)=[O:21])=[C:11]([Br:37])[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CN1CCn2cc(C(=O)NCc3ccc(F)c(Cl)c3)c(OCc3ccccc3)c2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCn2c(Br)c(C(=O)NCc3ccc(F)c(Cl)c3)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 8-(benzyloxy)-N-(3-chloro-4-fluorobenzyl)-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo-[1,2-a]pyrazine-7-carboxamide (0.23 g, 0.51 mmol) and sodium bicarbonate (0.52 g, 6.13 mmol) in dichloromethane (50 mL) at 0° C., a solution of bromine in dichloromethane (0.5 M, 1.1 mL, 0.55 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate. Collection and concentration of appropriate fractions provided the titled product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:33])=[CH:4][C:5]([Cl:32])=[C:6]([C:8]2[C:9](=[O:31])[N:10]([CH:28]([CH3:30])[CH3:29])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:12]=3)[CH:7]=1.[F:34][C:35]1[CH:36]=[C:37]([N:41]=[C:42]=[O:43])[CH:38]=[CH:39][CH:40]=1>C1COCC1>[Cl:32][C:5]1[C:6]([C:8]2[C:9](=[O:31])[N:10]([CH:28]([CH3:29])[CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH:12]=3)=[CH:7][C:2]([NH:1][C:42]([NH:41][C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([F:34])[CH:36]=2)=[O:43])=[C:3]([F:33])[CH:4]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: COc1ccc(CNc2cc3c(cn2)cc(-c2cc(N)c(F)cc2Cl)c(=O)n3C(C)C)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2cc3c(cn2)cc(-c2cc(NC(=O)Nc4cccc(F)c4)c(F)cc2Cl)c(=O)n3C(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.9 %

Procedure:
A solution of 3-(5-amino-2-chloro-4-fluorophenyl)-1-isopropyl-7-((4-methoxybenzyl)amino)-1,6-naphthyridin-2(1H)-one (0.11 g, 0.236 mmol) in THF (5 mL) was treated with TEA (0.1 mL) and 3-fluorophenyl isocyanate (0.032 mL, 0.259 mmol) and stirred at RT for 5 h. The mixture was concentrated to dryness, treated with DCM and the solid collected via filtration and dried to afford 1-(4-chloro-2-fluoro-5-(1-isopropyl-7-((4-methoxybenzyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (94 mg, 66% yield). MS (ESI) m/z: 604.1 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][CH:8]2[C@:17]3([OH:18])[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].[CH3:24][CH:25]([CH3:30])[CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[OH:18][C@:17]12[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[N:11]([C:27](=[O:28])[CH2:26][CH:25]([CH3:30])[CH3:24])[CH2:10][CH2:9][CH:8]2[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O[C@]12CCCC[C@@H]1NCCC2Nc1ccccc1
Reactant: CC(C)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CC(=O)N1CCC(Nc2ccccc2)[C@@]2(O)CCCC[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (4aR,8aS)-4-(phenylamino)octahydroquinolin-4a(2H)-ol (20 mg, 0.081 mmol) in 1:1 CH2Cl2:sat'd. aq. NaHCO3 (3 mL) was added 3-methylbutanoyl chloride (0.049 g, 0.406 mmol). The mixture was stirred at rt for 1 hr. The mixture was diluted with sat'd. aq. NaHCO3 and CH2Cl2 and extracted 3× with CH2Cl2. The combined organics were dried (anted. Na2SO4), filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (400 MHz, CDCl3) δ 7.22-7.40 (m, 5H), 4.38 (d, 1H, J=10.4 Hz), 3.96 (d, 1H, J=10.2 Hz), 3.35 (t, 1H, J=9.4 Hz), 2.62-2.85 (m, 2H), 1.15-2.40 (m, 12H), 0.81-0.99 (m, 6H). HRMS (ES) m/z M+H calc'd:331.2380. found: 331.2379.
Reaction SMILES: C(OC(C)C)(C)C.[CH3:8][C:9]1[N:10]([CH2:44][O:45][CH3:46])[C:11]([CH3:43])=[C:12]([C:32]([O:34]COC(=O)C(C)(C)C)=[O:33])[CH:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:14]=1[C:15]([O:17][CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:16]>O>[CH3:43][C:11]1[N:10]([CH2:44][O:45][CH3:46])[C:9]([CH3:8])=[C:14]([C:15]([O:17][CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:23])[CH3:24])=[O:16])[CH:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]=1[C:32]([OH:34])=[O:33]
Reactant: COCN1C(C)=C(C(=O)OCOC(=O)C(C)(C)C)C(c2ccccc2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Solvent: O
Solvent: CC(C)OC(C)C
Product: COCN1C(C)=C(C(=O)O)C(c2ccccc2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.1 %

Procedure:
To 20 ml of isopropyl ether saturated with water were added 545 mg of bis(pivaloyloxymethyl) 1,4-dihydro-2,6-dimethyl-1-methoxymethyl-4-phenyl-3,5-pyridinedicarboxylate obtained in Example 10 and 100 mg of Lipase B, and the system was stirred at 25 ° C. for 5 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane=1/1) to obtain 328 mg (yield: 76%) of (+)-1,4-dihydro-2,6-dimethyl -1-methoxymethyl-4-phenyl-5-pivaloyloxymethoxycarbonyl-3-pyridinecarboxylic acid as a colorless crystal.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1.[H][H]>CO.[C].[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:7]2[CH:6]=[N:5][C:4]3[C:8]2=[N:9][CH:10]=[N:11][C:3]=3[NH:2][CH3:1])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CNc1ncnc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CNc1ncnc2c1ncn2-c1ccc(N)cc1
Yield: 71.1 %

Procedure:
In 1,000 mL of methanol, 13.0 g (48 mmol) of methyl-[9-(4-nitrophenyl)-9H-purin-6-yl]amine was suspended, and 1.8 g of 10% palladium carbon was added thereto, and the suspension was stirred in a hydrogen atmosphere at 60° C. for six hours. The palladium carbon was removed by Celite filtration, and the product was concentrated under reduced pressure, and the obtained crude product was purified by a silica gel column (ethyl acetate:methanol=9.1) to obtain 8.2 g (70%) of a target product as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH:19]([CH2:24][F:25])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:36]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[CH:35][C:34]([F:51])=[CH:33][C:32]=1B1OC(C)(C)C(C)(C)O1)(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.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:26]([O:29][CH2:30][C:31]1[C:36]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[CH:35][C:34]([F:51])=[CH:33][C:32]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH:19]([CH2:24][F:25])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:28])[CH3:27]
Reactant: CN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1CF
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)C(CF)C4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 48.6 %

Procedure:
A reaction vessel was charged with a mixture of 336g (1 g, 2.4 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (1.3 g, 2.68 mmol), PdCl2(dppf) (190 mg, 0.24 mmol), K3PO4 (1 g, 4.8 mmol), and NaOAc (390 mg, 4.8 mmol) in MeCN (15 mL) and water (1.5 mL). It was bubbled with nitrogen for 30 min and then heated at 110° C. for 3 h. The solvent was evaporated in vacuum and the residue was purified on silica gel column chromatography eluting with 5:1 methylene chloride/methanol to afford 336h (0.80 g, 45%). MS: [M+H]+ 686.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:7]([CH3:15])[CH:8]([F:14])[C:9](OCC)=[O:10])([CH3:6])=[O:5])[CH3:2].[OH-].[NH4+:17]>C(O)C>[NH2:17][C:9](=[O:10])[CH:8]([F:14])[CH:7]([P:4]([CH3:6])(=[O:5])[O:3][CH2:1][CH3:2])[CH3:15]
Reactant: [NH4+]
Reactant: CCOC(=O)C(F)C(C)P(C)(=O)OCC
Agent: [OH-]
Solvent: CCO
Product: CCOP(C)(=O)C(C)C(F)C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.7 %

Procedure:
To a solution of ethyl 3-[ethoxy(methyl)phosphoryl]-2-fluorobutanoate (3.0 g, 12.4 mmol) in ethanol (15 mL) was added concentrated ammonium hydroxide (14.8 M, 1.3 mL, 19 mmol). The solution was stirred for 24 h at room temperature and then at 50° C. for 2 hours. Another portion of concentrated ammonium hydroxide (14.8 M, 0.5 mL, 7 mmol) was added and the mixture was stirred at room temperature for three days and then evaporated to give 2.4 g (91%) of a diastereomeric mixture of ethyl 3-amino-2-fluoro-1-methyl-3-oxopropyl(methyl)phosphinate as a clear oil. 1H NMR (400 MHz, CDCl3) δ5.9-6.7 (m, 2H), 4.9-5.6 (m, 1H), 4.0-4.2 (m, 2H), 2.5-2.8 (m, 1H), 1.2-1.6 (m, 9H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)([O-:22])=[O:21]>[OH-].[K+].C(O)C>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:27][C:26]2[CH:29]=[CH:30][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccc([N+](=O)[O-])cc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 67.7 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.19 g, 0.74 mmol) was reacted with 4-nitrobenzaldehyde (0.112 g, 0.74 mmol) in 1.5 mL of 4% KOH in ethanol for 3 hours at room temperature to afford 0.195 g (68%) of the title compound as a fine tan powder, mp 184-185° C.: CI-MS m/e 389 (M+), 390 (M+ +1);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:11][CH2:10][C@H:9]([CH2:12][OH:13])[CH2:8]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:13][CH2:12][C@H:9]1[CH2:10][CH2:11][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H]1CCN(c2ccccn2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CCN(c2ccccn2)C1
Temperature: 25 °C

Procedure:
(S)-(1-(Pyridin-2-yl)pyrrolidin-3-yl)methanol (1.683 mmol, 0.3 g) and triethylamine (5.05 mmol, 0.702 ml, 0.511 g) were stirred in DCM (10 ml) at 0° C. Methanesulfonyl chloride (2.52 mmol, 0.195 ml, 0.289 g) was added and the reaction allowed to warm to room temperature over 1 hour. The reaction mixture was washed with water, dried over Na2SO4 and concentrated at reduced pressure to afford (S)-(1-(pyridin-2-yl)pyrrolidin-3-yl)methyl methanesulfonate. (0.38 g)
Reaction SMILES: [CH3:1][NH:2][CH3:3].N1CCOCC1.Cl[C:11]1[C:16]([Br:17])=[CH:15][N:14]=[C:13]([CH2:18][OH:19])[CH:12]=1.ClC1C(CO)=NC=CC=1Cl>C(O)C>[CH3:1][N:2]([CH3:3])[C:11]1[C:16]([Br:17])=[CH:15][N:14]=[C:13]([CH2:18][OH:19])[CH:12]=1
Reactant: CNC
Reactant: OCc1cc(Cl)c(Br)cn1
Agent: OCc1nccc(Cl)c1Cl
Solvent: C1COCCN1
Solvent: CCO
Product: CN(C)c1cc(CO)ncc1Br

Procedure:
Substituting 33% w/w dimethylamine in ethanol (15 ml) for morpholine and 4-chloro-5-bromo-2-hydroxymethylpyridine (5 g) for 3,4-dichloro-2-hydroxymethylpyridine and using corresponding molar proportions of the other reagents in the method of Example 3D gave after chromatography (silica, chloroform:methanol, 98:2) 4-dimethylamino-5-bromo-2-hydroxymethylpyridine, 3.62 g, as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2([C:13]#[N:14])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-:15].[K+].OO>CC(O)C.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2([C:13]([NH2:14])=[O:15])[CH2:11][CH2:12]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N#CC1(c2cccc([N+](=O)[O-])c2)CC1
Reactant: [OH-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: OO
Agent: [Cl-]
Solvent: CC(C)O
Product: NC(=O)C1(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 63 %

Procedure:
To a solution of 1-(3-nitrophenyl)cyclopropanecarbonitrile (1.6 g, 8.50 mmol) in 2-Propanol (50 ml) was added triethylbenzylammonium chloride (0.058 g, 0.255 mmol) and 25% aq KOH solution (5 ml). Resulting solution was stirred for 5 min. and H2O2 (10 ml, 98 mmol, ca. 30% solution in water) was added. Reaction mixture was heated at 50° C. for 4 h. Solvent was evaporated in vacuo and residue was suspended in water (200 ml). Precipitate was filtered and dried to obtain 1-(3-nitrophenyl)cyclopropane carboxamide (1.104 g, 5.36 mmol, 63% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C1C(=O)N([I:16])C(=O)C1.C(O)(C(F)(F)F)=O>CC#N.CCOC(C)=O>[F:1][C:2]1[C:7]([I:16])=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(F)ccn1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(I)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 4-fluoropyridin-2-amine (336 g, 2.5 mol) and NIS (745 g, 2.75 mol) in MeCN (9 l) was treated with TFA (114 g, 1 mol). The reaction mixture was then stirred at room temperature for 8 h. The reaction mixture was diluted with EtOAc (10 l), washed with sat. aq. Na2S2O3 (2×5 l), brine (4×5 l). The combined organic layers were dried over Na2SO4, filtered and concentrated to get the crude product. The crude product was purified by recrystallization from EtOAc/pentane (1/10) to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, 1H), 6.45 (s, 2H), 6.33 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].CC(C)=[O:20]>>[C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]([OH:20])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)cc1
Reactant: CC(C)=O
Product: N#Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Temperature: 0 °C
Yield: 70 %

Procedure:
To an ice cold solution of 4-(4-cyano-phenoxy)-benzaldehyde (2.0 g, 8.9 mmol) in acetone (10 mL), the Jone's reagent (7 mL) was added slowly drop wise until reaction completes. Acetone was removed completely and diluted with water. The mixture was extracted with ethyl acetate. the combined organic layers were dried over anhydrous sodium sulphate and concentrated to get the title compound (1.5 g, 70%)
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1([F:18])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:17])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]([O:10][CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C(O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
To a solution of 128 mg of (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylacetic acid in 3 ml of dimethylformamide, 81 mg of carbonyldiimidazole was added and stirred for 30 minutes. Then 121 mg of 4-hydroxy-1-t-butoxycarbonylpiperidine and 10 mg of sodium hydride were added successively, followed by another 30 minutes' stirring. The reaction liquid was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue obtained was purified on silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to provide 121 mg of the title compound.