Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].C[N:17]([CH3:20])[CH:18]=O>>[CH3:6][C:3]1[C:4]2[N:5]=[CH:18][N:17]([C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[C:4]#[N:5])[C:20]=2[CH:8]=[CH:9][CH:2]=1
Reactant: N#Cc1ccccc1F
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cccc2c1ncn2-c1ccccc1C#N
Reaction time: 20 h

Procedure:
The title A compound (133 mg, 1.01 mmol), 2-fluorbenzonitrile (164 μL, 1.51 mmol) and finely ground potassium carbonate (279 mg, 2.02 mmol) were combined in 1 mL of N,N-dimethylformamide and heated to 80°. After stirring for 20 hours, the dimethylformamide was removed in vacuo and the brown solid residue was partitioned between saturated sodium bicarbonate and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were dried over magnesium sulfate, filtered and the solvent removed. The residue was purified by flash chromatography (20 g silica gel, eluted with ethyl acetate, hexane) to provide 160 mg of the title B compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10](O)[CH2:11][O:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[F:44]C(F)(C(F)(F)F)C(F)(F)C(F)(F)S(F)(=O)=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@H:10]([F:44])[CH2:11][O:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O[C@H](COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: F[C@@H](COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h

Procedure:
After dissolving (R)-1-benzyloxy-3-trityloxypropan-2-ol (CAS 83526-68-5) (10.45 g) in toluene (50 ml), nonafluoro-1-butanesulfonyl fluoride (7.95 ml) was added and the mixture was cooled on ice. Next, 1,8-diazabicyclo[5.4.0]undeca-7-ene (6.63 ml) was added dropwise while stirring. The mixture was stirred for 30 minutes on ice, and then for 3 hours and 30 minutes at room temperature. The reaction mixture was directly purified by silica gel column chromatography to obtain the title compound (7.52 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)=[N:4][N:3]=1.[NH:25]1[CH2:37][CH2:36][CH:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:26]1.O>CN1CCCC1=O>[C:32]([O:31][C:29]([CH:28]1[CH2:36][CH2:37][N:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=3)[C:5]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=3)=[N:4][N:3]=2)[CH2:26][CH2:27]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Reactant: CC(C)(C)OC(=O)C1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nnc(N3CCC(C(=O)OC(C)(C)C)CC3)c3ccc(C#N)cc23)cc1Cl
Temperature: 170 °C
Yield: 56.6 %

Procedure:
1-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine (2 g) prepared in Example 1 and t-butyl isonipecotate (2 g) were dissolved in 20 ml of N-methyl-2-pyrrolidone. The obtained solution was heated at 170° C. for 5 hours and cooled, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The obtained residue was subjected to silica gel column chromatography and eluted with toluene/tetrahydrofuran (10:1) to give 1.6 g of 1-(4-tert-butoxycarbonyl-piperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([O:21][C:2]2[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: OC1CCCCC1
Product: CS(=O)(=O)c1ccc(OC2CCCCC2)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1(a)) and cyclohexanol. The crude material was purified by preparative HPLC to yield the title compound as a white solid. MS (m/e): 297.3 ([M−H]−, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH2:18])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[C:26](=O)[O:27][C:28]2=[O:33].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][N:18]3[C:26](=[O:27])[C:25]4[C:29](=[CH:30][CH:31]=[CH:32][C:24]=4[O:23][CH2:22][O:21][CH3:20])[C:28]3=[O:33])[C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Reactant: COCOc1cccc2c1C(=O)OC2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCOc1cccc2c1C(=O)N(CC1OCCc3c1sc(N)c3C(=O)OC(C)(C)C)C2=O
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A mixture of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.15 g, 0.53 mmol) and 4-methoxymethoxy-isobenzofuran-1,3-dione (135 mg, 0.64 mmol) was dissolved in distilled acetonitrile (7 ml) under nitrogen. The flask was cooled in an ice bath with stirring and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.12 g, 0.64 mmol), and triethylamine (0.22 ml, 1.59 mmol) were added. The reaction was warmed to ambient temperature and stirred for 18 h. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate (40 ml). The organic layer was washed with 1% hydrochloric acid (2×10 ml), saturated sodium bicarbonate (10 ml), and brine (10 ml). The resulting solution was dried (Na2SO4), filtered, and the solvent evaporated in vacuo which afforded 0.18 g of a crude 2-amino-7-(4-methoxymethoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester which was used without further purification.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]([F:25])([F:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>CS(C)=O>[F:25][C:10]([F:9])([F:24])[C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][C:20]3([O:23][CH2:2]3)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1
Reactant: O=C1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc(N2CCC3(CC2)CO3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
Trimethylsulfoxonium iodide (2.00 g, 9.02 mmol) was gradually added to a suspension of sodium hydride (361 mg, 9.02 mmol) in dimethylsulfoxide (30 ml), and the mixture was stirred at room temperature for 1 hour. To which a solution of 1-(4-trifluoromethylphenyl)piperidin-4-one (2.00 g, 8.2 mmol) in DMSO (10 ml) was added, and the mixture was stirred overnight. The reaction mixture was poured into ice water, and extracted with diethyl ether. The extract was washed with brine, dried over sodium sulfate, and then filtered. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1) to afford 6-(4-trifluoromethylphenyl)-1-oxa-6-azaspiro[2,5]octane (1.51 g, yield 72%) as a pale yellow crystalline powder.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH2:22][O:23][CH2:24][CH3:25].O>CN(C)C=O>[N:1]([CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH2:22][O:23][CH2:24][CH3:25])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCN=[N+]=[N-]
Temperature: 25 °C

Procedure:
Sodium azide (14.7 g) was added to a solution of 1-(2-chloroethyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (22.8 g prepared according to the method of Part F) in N,N-dimethylformamide (75 mL). The reaction mixture was heated at reflux for several hours and then allowed to cool to ambient temperature overnight. The reaction mixture was poured into water (100 ml) and then extracted 3 times with ethyl acetate. The extracts were combined, washed 3 times with water, dried over magnesium sulfate, filtered and then concentrated to dryness under vacuum to provide crude 1-(2-azidoethyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=3)=[CH:13][C:8]=2[C:9]([O:11]C)=[O:10])[CH:4]=[N:3]1.[OH-].[Li+].Cl>C(O)(C)C.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([CH3:23])[CH:22]=3)=[CH:13][C:8]=2[C:9]([OH:11])=[O:10])[CH:4]=[N:3]1
Reactant: COC(=O)c1cc(-c2cncc(C)c2)ccc1-c1cnn(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1cncc(-c2ccc(-c3cnn(C)c3)c(C(=O)O)c2)c1
Temperature: 80 °C

Procedure:
To a mixture of methyl 2-(1-methyl-1H-pyrazol-4-yl)-5-(5-methylpyridin-3-yl)benzoate (2-4, 0.216 g, 0.703 mmol, 1.0 equiv) in isopropanol/water (3:1, 4 mL) was added 1M lithium hydroxide solution (0.773 mL, 0.773 mmol, 1.1 equiv) and the reaction was heated to 80° C. for 15 minutes in the microwave. The reaction mixture was cooled and the pH was adjusted to ˜7 by the addition of 1N HCl. The reaction mixture was concentrated and the solids azeotroped from toluene to afford the product as a solid. ESI+ MS [M+H]+ C12H15N3O2: 308.02 found, 308.36 required.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].O>CN(C)C=O>[CH3:18][C:12]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)([CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)n1cnc([N+](=O)[O-])c1
Reaction time: 0.33 h

Procedure:
To a solution of 4-nitro-1H-imidazole (10 g) in N,N-dimethylformamide (150 mL) was added sodium hydride (60% in mineral oil, 4.2 g) in an ice bath, and the mixture was stirred at the same temperature for 20 min. To the reaction mixture was added ethyl 2-bromo-2-methylpropanoate (20 mL) at the same temperature, and the mixture was stirred overnight at 50° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (12 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[N:12]=[C:11]([C:21]([N:23]3[CH2:27][CH2:26][S:25][CH2:24]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C(N3CCS(=O)C3)=[O:48])C=2)C=C(F)C=1.ClC1C=CC=C(C(OO)=O)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[N:12]=[C:11]([C:21]([N:23]3[CH2:27][CH2:26][S:25](=[O:48])[CH2:24]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1)N1CCS(=O)C1
Reactant: Cc1cc(-n2nc(C(=O)N3CCSC3)cc2-c2cc(F)cc(Cl)c2)ccn1
Agent: O=C(OO)c1cccc(Cl)c1
Product: Cc1cc(-n2nc(C(=O)N3CCS(=O)C3)cc2-c2cc(F)cc(Cl)c2)ccn1

Procedure:
55 mg (0.14 mmol) of the compound of Example 23 is reacted analogously to the synthesis of the compound of Example 6 with 34 mg (0.14 mmol, 70%) of meta-chloroperbenzoic acid for 2 hours at room temperature. After the crude product is purified by means of preparative HPLC (mobile solvent: acetonitrile/water gradient), 53 mg (93% of theory) of the title compound is obtained.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:18]=[CH:17][C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2].C(O)(=O)C.[BH4-].[Na+]>CS(C)=O>[N+:1]([CH2:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])/C=C/c1ccc(Oc2ccccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.9 %

Procedure:
To a solution of 2-(4-((E)-2-nitro-vinyl)-phenoxy)-pyridine (9.9 g, 41 mmol) described in Manufacturing Example 209-1-2, acetic acid (2.5 g) and dimethyl sulfoxide (60 mL) was added sodium borohydride (770 mg, 20 mmol) while the temperature was held at 30° C. or lower, which was stirred for 15 minutes at room temperature. This reaction solution was partitioned into ethyl acetate and water while the temperature was held at 30° C. or lower. The organic layer was separated and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (4.5 g, 45%).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12](=O)[CH3:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][N:29]([CH:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[S:8][CH:9]=3)[CH3:13])[CH2:28][CH2:27]2)[CH:21]=1)=[O:18]
Reactant: CC(=O)c1csc(-c2ccccc2)n1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C(C)c3csc(-c4ccccc4)n3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 1-(2-phenyl-1,3-thiazol-4-yl)ethanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 434.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][C:4](=[O:13])[CH:3]=1.[Br:14][C:15]([CH2:17]Br)=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:17][C:15]([Br:14])=[CH2:16])=[CH:9][CH:10]=2)[O:5][C:4](=[O:13])[CH:3]=1
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Reactant: C=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(Br)COc1ccc2c(C)cc(=O)oc2c1
Yield: 89 %

Procedure:
4-Methyl-7-hydroxycoumarin (2.00 g., 11.4 m mole) was refluxed with freshly-distilled 2,3-dibromopropene (2.72 g., 13.6 m mole), anhydrous potassium carbonate (3.15 g., 22.8 m mole), and acetone (80 ml.) for four hours. The reaction mixture was treated as described for the preparation of Example I, Part 1-A to obtain 4-methyl-7-(2'-bromoallyloxy) coumarin as an off-white solid (3.70 g.) that contained some excess 2,3-dibromopropene. Recrystallization of a portion (500 mg.) from ligroin (b.p. 100°-120° C.) gave needles (394 mg., 89% yield) of m.p. 109.5°-110.5° C. An analytical sample of m.p. 110°-111° C. was obtained by recrystallization from methanol.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][O:15][C@@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.C[O-].[Na+]>CO.ClCCl.CO>[O:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C@H:6]1[O:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OCc2ccccc2)OC[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O[C@@H]1[C@@H](OCc2ccccc2)OC[C@@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A suspension of compound 3 (20 g) in dry methanol:dichloromethane (2:1, 400 ml) containing sodium methoxide in methanol (0.46 g. Na in 100 ml of methanol) was stirred at room temperature until starting product disappeared (tlc). The solution was then made neutral with mixed-bed resin (50 ml, BioRad AG501-X8), filtered and evaporated to dryness to give 4 (10.2 g, 76%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:16]1[O:19][C@H:17]1[CH3:18].C(Cl)Cl.CO>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]([OH:19])[CH3:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@H]1CO1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CO
Product: C[C@H](O)CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 8 h
Yield: 64 %

Procedure:
1-(4-Nitro-phenyl)-piperazine (2.0 g, 0.0096 mol) was dissolved in Methanol (50.0 mL) and the reaction mixture was placed in a sealed tube. (S)-(−)-Propylene Oxide (0.841 g, 0.0145 mol) was then added at room temperature and the reaction was allowed to stir overnight. The mixture was then reduced en vacuo and the product was isolated by Isco flash column chromatography (DCM/MeOH) to afford 1.63 grams of (S)-1-[4-(4-Nitro-phenyl)-piperazin-1-yl]-propan-2-ol as a yellow solid. (M+H)=266.20.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:14]=1[C:25]1[N:26]=[CH:27][NH:28][CH:29]=1)[CH3:12]>>[CH2:11]([C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:14]=1[C:25]1[N:26]=[CH:27][N:28]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:29]=1)[CH3:12]
Reactant: CCc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CCc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 28 %

Procedure:
As described for 1f, 1-fluoro-4-nitro-benzene was converted, using 5-ethyl-3-(4-fluoro-phenyl)-4-(1H-imidazole-4-yl)-isoxazole (100 mg, 0.39 mmol) instead of 4-(1H-imidazol-4-yl)-3-phenyl-isoxazole was converted to the title compound (43 mg, 28%) which was obtained as an off-white solid. MS: m/e=379.1.1 [M+H]+.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1COCC1.[NH4+].[Cl-].[CH3:17][C:18]([Si:21]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[O:22][CH2:23][C@@H:24]([NH:32][C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:25]/[CH:26]=[CH:27]\[C:28](OC)=[O:29])([CH3:20])[CH3:19]>C(Cl)Cl>[CH3:20][C:18]([Si:21]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[O:22][CH2:23][C@@H:24]([NH:32][C:33](=[O:34])[O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH2:25]/[CH:26]=[CH:27]\[CH2:28][OH:29])([CH3:17])[CH3:19]
Reactant: COC(=O)/C=C\C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC[C@H](C/C=C\CO)NC(=O)OCc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 97.3 %

Procedure:
In a 500 ml round-bottomed flask methyl (2Z,5S)-6-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-5-({[(phenylmethyl)oxy]carbonyl}amino)-2-hexenoate D5 (3.58 g) was dissolved in dry DCM (122 ml) and the solution cooled at −78° C. To this solution DIBAL-H 1 M in THF (33.7 ml, 33.7 mmol) was added dropwise and the mixture left under stirring at −78° C. for 5 hours. After this time a saturated NH4Cl aqueous solution (250 ml) was added and the reaction mixture filtered through a celite pad the solid was washed with DCM (5×200 ml) and the resulting filtrate transferred into a separatory funnel. The phases were separated and the aqueous one back extracted with DCM (3×100 mls). The collected organic phases were dried (Na2SO4) and solvent removed under reduced pressure to give an oil. This crude was purified by column chromatography on silica gel (SP4 SNAP 340 g, Cy/EtOAc from 100/0 to 80/20). Collected fractions gave the title compound D6 (3.3 g) as colorless thick oil. HPLC (walk-up): rt=7.30 min. C30H37NO4Si requires 503. 1H NMR (400 MHz, CDCl3-d6) δ (ppm): 7.74-7.30 (m, 15 H), 5.71 (m, 1 H), 5.52 (m, 1 H), 5.80-5.61 (m, 1 H), 561-3.36 (m, 1 H), 5.20-4.94 (m, 2 H), 4.25-3.98 (m, 2 H), 3.91-372 (m, 1 H), 3.72-3.58 (m, 2 H), 2.50-2.26 (m, 2 H), 1.07 (s, 9 H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]1)[CH2:5]2.[C:17]1([S:27](Cl)(=[O:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C1COCC1>[C:17]1([S:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][C:6]2([C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11]2)[CH2:5]3)(=[O:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: Nc1ccc2c(c1)CC1(C2)NC(=O)NC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NC(=O)C2(Cc3ccc(NS(=O)(=O)c4cccc5ccccc45)cc3C2)N1

Procedure:
To a stirred solution of 50 mg (0.23 mmol) (±)-5′-amino-spiro[imidazolidine-4,2′-indane]-2,5-dione (described in Intermediate 6) in THF (3 mL) was added 1-naphthalenesulfonyl chloride (53 mg, 0.24 mmol) and triethylamine (0.034 mL, 0.24 mmol). After 30 min the reaction mixture was concentrated to dryness. The residue was dissolved in DMF and purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound as a white solid. MS: m/z=408 (M+1). HRMS: m/z=408.1019; calculated m/z=408.1013 for C21H17N3O4S.
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:20].[I-:27].[Na+].CC(=O)CC>CCOCC>[I:27][CH2:2][CH2:3][C@H:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:20]
Reactant: [I-]
Reactant: Cc1cc(OC(=O)OC(C)(C)C)ccc1O[C@H](CCCl)c1ccccc1
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: Cc1cc(OC(=O)OC(C)(C)C)ccc1O[C@H](CCI)c1ccccc1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
A dry 1-L R.B. flask was charged (R)-3-chloro-1-phenyl-1-(2-methyl-4-((tert-butoxycarbonyl)oxy)phenoxy)propane (18.00 g, 47.80 mmol), sodium iodide (90.0 g, 600 mmol) and 2-butanone (550 mL). The reaction flask was protected from light. The reaction mixture was stirred at reflux temperature under nitrogen for 16 hours. The mixture was cooled to room temperature and poured into ether (1 L). The insoluble inorganic salts (white precipitate) were removed by filtration. The filtrate was concentrated under reduced pressure and the crude residue was dissolved in diethyl ether (1 L). The ethereal layer was washed with cold saturated sodium bisulfite solution (2×200 mL), water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to flash chromatography, eluting with 20% ethyl acetate in hexane to provide 20.5 grams (91%) of the desired compound.