Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][NH:17][C:18]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.S(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[C:3]2[N:4]([C:18]([CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:17][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(NNC(=O)C3CCOCC3)c(Cl)nc2c1
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(c1)nc(Cl)c1nnc(C3CCOCC3)n12
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 99.1 %

Procedure:
To a mixture of 1.20 g of methyl 3-chloro-2-[2-(tetrahydro-2H-pyran-4-ylcarbonyl)hydrazino]quinoxaline-6-carboxylate and 36 mL of acetonitrile was added 0.5 mL of thionyl chloride, followed by stirring at 90° C. for 4.5 hours. The solvent was evaporated under reduced pressure, to the obtained residue was added water, and the solid was collected by filtration and dried under reduced pressure to obtain 1.13 g of methyl 4-chloro-1-(tetrahydro-2H-pyran-4-yl)[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:24]#[N:25])=[CH:11][C:12]2[N:13]([C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:16][N:17]=2)[CH:14]=1.B.C1COCC1>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH2:24][NH2:25])=[CH:11][C:12]2[N:13]([C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:16][N:17]=2)[CH:14]=1
Reactant: N#Cc1cc2nnc(N3CCOCC3)n2cc1-c1ccc(Cl)cc1Cl
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: NCc1cc2nnc(N3CCOCC3)n2cc1-c1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 5 %

Procedure:
In a sealed flask, a solution of the crude 6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-[1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile in THF (1 mL) was cooled to 0° C. (ice bath) then treated with BH3.THF complex (1.0 M solution in THF, 0.73 mL, 0.73 mmol). The reaction mixture was heated at 40° C. for 1 h, cooled to RT, and diluted in MeOH (large excess). The mixture was concentrated under vacuum, and the remaining residue was suspended in 2.0 M HCl, and shaken for 15 min. After evaporation to dryness, the remaining residue was purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 5 mg, 0.008 mmol, 5%) as a white solid. MS: 378 [M+1]+; HPLC: AtRet=1.15.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])/[C:4](/[CH2:9][NH:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:5]\[CH2:6][CH2:7][CH3:8]>[B-](F)(F)(F)F.C1C2C=CC1C=C2.C1C2C=CC1C=C2.[Rh]>[CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH2:9][NH:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCC/C=C(/CNOCc1ccccc1)C(=O)OC
Agent: [Rh]
Agent: C1=CC2C=CC1C2
Agent: F[B-](F)(F)F
Product: CCCC[C@@H](CNOCc1ccccc1)C(=O)OC
Reaction time: 24 h
Yield: 94.5 %

Procedure:
A ˜1:1 mixture of (E) and (Z)-2-[[(phenylmethoxy)amino]methyl]-2-hexenoic acid methyl ester (3.95 g, 15 mmol), bis(norbornadiene)rhodium(I)tetrafluoroborate (56.1 mg, 0.15 mmol) and (1S,1′S,2R,2′R)-TangPhos (47.3 mg, 0.165 mmol) in de-oxygenated methanol (90 mL) in a Parr bottle is hydrogenated under H2 (45-55 psi) at RT for 24 hours. The reaction mixture is concentrated on Rotavap under reduced pressure (20 mbar) until no further solvent distills. The residue liquid is dissolved in a mixture of ethyl acetate/heptane (50/50, 10 mL) and filtered through a silica gel pad (˜12 g). The silica gel pad is rinsed with a mixture of ethyl acetate/heptane (50/50, 200 mL). The filtrates are combined and concentrated on Rotavap under reduced pressure (20 mbar) until no further solvent distills to afford 2-[[(phenylmethoxy)amino]methyl]-(2S)-hexanoic acid methyl ester (3.76 g, yield: 94%, S:R=98.0:2.0) as a liquid.
Reaction SMILES: [CH2:1]([N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:17]([NH2:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:10]1[C:11](=[O:16])[CH2:12][CH:13]([NH:25][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:14]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCN
Reactant: CCCCCCCCCN1C(=O)C=CC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCN1C(=O)CC(NCCCCCCCC)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-nonyl maleimide (0.01 M) prepared as described in Example 12 above, octylamine (0.01 M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) was stirred for 24 hours at room temperature. Acetonitrile was removed under vacuum to leave a residual liquid product which was flash chromatographed (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product.
Reaction SMILES: [C:1]([C:9]1[C:10]([N+:23]([O-:25])=[O:24])=[C:11]([C:15](C)([C:19](O)=O)[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>C(O)(=O)C>[C:1]([C:9]1[C:10]([N+:23]([O-:25])=[O:24])=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)(C(=O)O)c1cccc(C(=O)c2ccccc2)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1[N+](=O)[O-]
Yield: 17.8 %

Procedure:
A mixture of 3.0 g (0.0075 mole) of 2-(3-benzoyl-2-nitrophenyl)-2-methylpropanedioic acid, 20 ml of acetic acid and 20 ml of 20% sulfuric acid was heated at reflux under a nitrogen atomsphere overnight. The dark solution was concentrated and the residue was treated with 200 ml of 2N potassium carbonate. The mixture was triturated with diethyl ether and then filtered to remove insoluble material. The filtrate layers were separated and the aqueous layer was washed with diethylether. The aqueous solution was treated with charcoal, filtered through celite and the filtrate made acidic with 13 ml of conc. sulfuric acid. The solid which precipitated was collected by filtration and recrystallized from 2-propanol-water to yield 0.4 g (18%) of white powder, m.p. 177°-179° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[CH:21][N:20]=1>>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)[CH:22]=[CH:21][N:20]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccnc(F)c1
Product: N#Cc1cc(-c2ccnc(F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, light brown solid (59 mg, 77%), MS (ISP) m/z=307.4 [(M+H)+], mp 289° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 2-fluoro-pyridin-4-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:18]1C[CH2:21][CH2:20][CH2:19]1.C(Cl)(=O)C=C>CC(C)=O>[C:19]([O:10][CH2:9][CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:18])[CH:20]=[CH2:21]
Reactant: OCCSc1ccccc1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=CC(=O)OCCSc1ccccc1
Temperature: -30 °C
Yield: 62 %

Procedure:
To a 500 mL three-neck round bottom flask equipped with mechanical stirrer were charged 2-hydroxyethyl phenyl sulfide (33.0 g, 0.21 mol), anhydrous triethylamine (45 mL, 0.32 mol), and anhydrous tetrahydrofuran (160 mL). The solution was cooled in a −30° C. acetone/dry ice bath under nitrogen blanket for 15 mins. Acryloyl chloride (22 mL, 0.27 mol) was added into the vigorously stirred cold solution through an addition funnel over 30 min. After the addition, the reaction mixture was stirred in the cold acetone bath for additional four hours followed by quenching with the addition of 2M HCl (200 mL). The mixture was extracted with diether ether (150 mL×3) and the combined organic layer was washed with DI water (200 mL×3), aqueous sodium bicarbonate (200 mL×2), and dried over MgSO4. Filtration and removal of solvents under reduced pressure gave the crude product as a light brown oil which was purified on silica gel using Hexanes/Ethyl acetate (50/1, v/v) as eluent to give the final product as a colorless oil (27.4 g, 0.13 mol, yield: 62%), H1 NMR (CDCl3): δ 7.44 (2H), 7.33 (2H), 7.24 (1H), 6.41 (1H), 6.12 (1H), 5.85 (1H), 4.35 (2H), 3.21 (2H).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6](=[O:17])[CH2:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH3:4]>O1CCOCC1.COC(C)(C)C>[CH2:3]([O:5][C:6](=[O:17])[CH:7]([Br:1])[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH3:4]
Reactant: CCOC(=O)CC(=O)c1ccccc1C
Reactant: BrBr
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: CCOC(=O)C(Br)C(=O)c1ccccc1C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
Bromine (1.65 g, 10.3 mmol, 1.03 equiv) was added drop-wise to a stirred solution of 3-oxo-3-o-tolyl-propionic acid ethyl ester (2.06 g, 10.0 mmol, 1.0 equiv) in 1,4-dioxane (25 mL) at ambient temperature. The mixture was stirred for 1 hour and then diluted with tert-butyl methyl ether (50 mL). The resultant solution was washed sequentially with water, aqueous potassium carbonate solution and saturated aqueous sodium chloride solution. The collected organic was dried over magnesium sulphate, filtered, and concentrated under vacuum to afford 2.74 g (96%) of 2-bromo-3-oxo-3-o-tolyl-propionic acid ethyl ester as a dark brown residue. 1H NMR (400 MHz, CDCl3) δ: 7.66 (d, 1H), 7.46-7.37 (m, 1H), 7.28 (m, 2H), 5.62 (s, 1H), 4.29-4.22 (q, 2H), 2.52 (s, 3H), 1.28-1.19 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[CH:11]=[C:10]([CH3:15])[CH:9]=2)=[CH:4][CH:3]=1.P(Br)(Br)([Br:18])=O>C1(C)C=CC=CC=1>[Br:18][C:12]1[CH:11]=[C:10]([CH3:15])[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)[nH]c(=O)c1
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Product: Cc1cc(Br)nc(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-4-methyl-1H-pyridin-2-one (1.1 g, 5 mmol) and phosphoryl bromide (4.63 g, 16 mmol) in toluene (9.5 mL) according to the general procedure Ia to d preparation of bromides. Obtained as a light brown solid (1.0 g, quant., 74% purity). MS (ISP) 282.0 [(M+H)+], 284.0 [(M+2+H)+] and 286.0 [(M+4+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[NH:9][C:8]2([CH3:14])[CH3:13].[H-].[Na+].CI.O.[C:20](C#N)(C)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:20])[C:8]2([CH3:14])[CH3:13]
Reactant: CC(=O)C#N
Reactant: COc1cccc2c1C(=O)NC2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: COc1cccc2c1C(=O)N(C)C2(C)C

Procedure:
7-methoxy-3,3-dimethyl-2,3-dihydro-isoindol-1-one (3.16 g) is dissolved in THF (50 mL) and NaH (7.88 g) is added batchwise. After 5 min methyl iodide (7.18 mL) is added. After 18 h at 0° C. the reaction mixture is combined with H2O/AcCN as well as Isolute and purified by RP HPLC.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][C@@H:9](OC(OC)=O)[C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:21][CH2:20][CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C(O[C@H]1[C@@H]2O[C@@H]2[C@@]2(C)C(=C[C@@H](OC(OC)=O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][CH:9]=[C:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:18][CH2:19][CH2:20][O:21]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCCO4)CC[C@H]3[C@H]12
Agent: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Yield: 45.3 %

Procedure:
The procedure of Example 17 was repeated except that 40.2 mg (0.0798 mmole) of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate was used in lieu of 43.6 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate to give 15.5 mg of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate. In addition, 14.2 mg of the starting compound 20-(1,3-dioxolan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate was recovered. The yield of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate was 70% based on consumed 20-(1,3-dioxolan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.CN(C=O)C.[Na+].[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O-:27])(=O)=[O:25])=[CH:20][CH:19]=1)[C:14]#[C:15][CH3:16]>C(Cl)Cl>[CH2:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([Cl:4])(=[O:27])=[O:25])=[CH:20][CH:19]=1)[C:14]#[C:15][CH3:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC#CCOc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a stirred solution of oxalyl chloride (47.8 ml, 0.545 mol) at 0° C. in 240 mL of CH2Cl2 was added a DMF (43.0 ml) solution of 4-but-2-ynyloxy-benzenesulfonic acid sodium salt in a drop wise manner. The reaction mixture was stirred at 0° C. for 30 min and then let warm to room temperature and stirred for 18 h. The reaction was then poured into ice and extracted with hexanes. The organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide 42.0 g (95%) of the desired product as yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13]O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C1(=O)[NH:19]C(=O)C2=CC=CC=C12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl.O.NN>C1COCC1.CCO.C(Cl)Cl.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH2:19])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCC1CCN(c2ccncc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: NN
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: NCC1CCN(c2ccncc2)CC1
Temperature: 75 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
A solution of 1-(4-pyridyl)piperidine-4-methanol (5.87 g, 30.6: mmol), phthalimide (4.59 g, 31.2 mmol), and triphenylphosphine (8.10 g, 30.9 mmol) in 125 mL of THF at −5° C. was treated with a solution of diethyl azodicarboxylate (5.38 g, 30.9 mmol) in THF (40 mL). After 16 h, the mixture was poured into EtOAc and 1 N HCl. The aqueous layer was washed with EtOAc (2×), pH adjusted to 12 by addition of 5 N NaOH, and washed with EtOAc (3×). The combined organic extracts were dried (K2CO3) and concentrated, yielding 8.45 g (86%). The crude material (5.47 g, 17.0 mmol) was then treated with hydrazine hydrate (3.5 mL, 60.0 mmol) in EtOH (50 mL). The mixture was heated at 75° C. for 5 h, cooled, diluted with CH2Cl2 (100 mL), and cooled to 0° C. The solid was removed by filtration; and the filtrate was concentrated, yielding 3.32 g of the title compound which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH3:16])(O)[C:10](OCC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:1]([O:8][CH:9]([CH3:16])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(O)OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(CO)OCc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
A solution of ethyl 2-benzyloxylactate (9.5 g, 45.6 mmole) in anhydrous tetrahydrofuran (30 mL) was added dropwise during 30 minutes to a stirred solution of lithium aluminum hydride (1.06 g, 28 mmole) in anhydrous tetrahydrofuran (56 mL) at room temperature under argon atmosphere. Next, the mixture was stirred for 3 hours at 60° C. After cooling to 30° C., freshly prepared saturated solution of sodium sulfate (10 mL) was slowly added. The mixture was filtered and the solvent was distilled under reduced pressure. The residue was dissolved in dichloromethane (100 mL) and the solution was dried with anhydrous magnesium sulfate. The solvent then was distilled under reduced pressure. The residue was subjected to fractional vacuum distillation giving 6.2 g of colorless liquid product. NMR (d6-DMSO): 1.90 ppm (d, —CH3, 3H), 3.20–3.50 ppm (bm, —CH— and —CH2—, 3H), 4.53 ppm (s, —CH2—, 2H), 4.63 ppm (t, —OH, 1H), 7.33 ppm (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][C:25]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[C:33]([CH3:34])[C:25]=3[CH3:24])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cc1cccc(C(=O)O)c1C
Product: Cc1cccc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)c1C

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 2,3-dimethyl-benzoic acid. LC-MS (basic): tR=0.83 min; [M+H]+=465.2.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[NH2:34][C:35]([C@@H:37]1[CH2:41][CH2:40][C@H:39]([C:42]2[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=2)[N:38]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:36].[C:56]1([C@H:62](O)[CH3:63])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>C1COCC1>[NH2:34][C:35]([C@@H:37]1[CH2:41][CH2:40][C@H:39]([C:42]2[CH:47]=[CH:46][C:45]([O:48][C@@H:62]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH3:63])=[CH:44][CH:43]=2)[N:38]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:36]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@H]1C(N)=O
Reactant: C[C@@H](O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccc([C@H]2CC[C@@H](C(N)=O)N2C(=O)OC(C)(C)C)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
Polystyrene supported PPh3 (100 mg, 1.5 mmol) and DIAD (30 mg, 1.5 mmol) were added to a solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-1-pyrrolidinecarboxylate (D13, 30 mg, 0.10 mmol) in dry THF (1 ml) at 0° C. After 15 min (1R)-1-phenylethanol (24.4 mg, 0.2 mmol) was added and the reaction mixture was stirred at 0° C. for 2 h. The resin was filtered off and the solvent was evaporated. The crude material was purified by chromatography on silica gel using cyclohexanes/ethyl acetate (8:2) to afford the title compound (20 mg, 48%); Rt (HPLC): 5.70 min, 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.31 (s, 9H); 1.53 (d, 3H); 1.65-1.78 (m, 1H); 1.79-1.92 (m, 1H); 1.93-2.03 (m, 1H); 2.07-2.21 (m, 1H); 4.50 (br. s., 1H); 4.70 (br. s., 1H); 5.41-5.50 (m, 1H); 6.78 (d, 2H); 6.91 (s, 1H); 7.23 (br. s., 1H); 7.31 (br. s., 2H); 7.39 (br. s., 4H); 7.44 (br. s., 1H).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:24])([CH3:23])[C:17]=3[CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:26]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[NH:21][C:20](=[O:22])[O:19][C:18]([CH3:23])([CH3:24])[C:17]=3[CH:25]=2)=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccccc3)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccccc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-(4-phenylmercapto-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[CH2:18]/[C:19](=[N:27]\[OH:28])/[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=3)=[CH:13][CH:12]=2)[N:8]=[N:7]1)C.[OH-].[Li+].Cl>O1CCOCC1.O>[OH:28]/[N:27]=[C:19](/[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=1)\[CH2:18][CH:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:8]=[N:7][N:6]([CH2:5][C:4]([OH:36])=[O:3])[CH:10]=2)=[CH:12][CH:13]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35]
Reactant: CCOC(=O)Cn1cc(-c2ccc(C(C/C(=N\O)c3ccnc(C)c3)c3ccccc3C)cc2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(/C(CC(c2ccc(-c3cn(CC(=O)O)nn3)cc2)c2ccccc2C)=N/O)ccn1
Temperature: 120 °C

Procedure:
To a solution of (4-{4-[(−)-3-[(E)-hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-phenyl}-[1,2,3]triazol-1-yl)-acetic acid ethyl ester (35 mg) in a mixture of dioxane (1 mL) and water (1 mL) was added lithium hydroxide (14 mg) and the reaction mixture heated by microwave irradiation to 120° C. for 20 min. The solution was adjusted to approximately pH 3 by using 1 M aqueous hydrochloric acid and then extracted over a sat. solution of brine (50 mL) with ethyl acetate (3×50 mL). The combined organic phases were dried over sodium sulfate and the crude reaction product purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of dichloromethane/methanol (100:0 to 90:10). Light yellow solid. MS (ESI−): m/z=454.1 ([M−H]−).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=O)[CH2:7][N:8]1[C:12]([CH3:13])=[C:11]([CH2:14][C:15]2[CH:23]=[C:22]([CH3:24])[C:21]([O:25][CH3:26])=[C:20]3[C:16]=2[CH2:17][CH2:18][CH2:19]3)[C:10]([CH3:27])=[N:9]1)C.Cl.[C:31]([NH2:34])(=[NH:33])[CH3:32].[O-]CC.[Na+]>C(O)C>[CH3:26][O:25][C:21]1[C:22]([CH3:24])=[CH:23][C:15]([CH2:14][C:11]2[C:10]([CH3:27])=[N:9][N:8]([CH2:7][C:6]3[N:33]=[C:31]([CH3:32])[NH:34][C:4](=[O:3])[CH:5]=3)[C:12]=2[CH3:13])=[C:16]2[C:20]=1[CH2:19][CH2:18][CH2:17]2
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(=O)Cn1nc(C)c(Cc2cc(C)c(OC)c3c2CCC3)c1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1c(C)cc(Cc2c(C)nn(Cc3cc(=O)[nH]c(C)n3)c2C)c2c1CCC2
Temperature: 72.5 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To the solution of 4-[4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-3-oxo-butyric acid ethyl ester (1.0 gm, 0.0025 mole) in Ethanol (60 ml), Acetamidine hydrochloride (0.71 gm, 0.0075 mole) was added. Further to this, Sodium ethoxide (0.51 gm, 0.0075 mole) was added at 5-10° C. and then stirred at 70-75° C. for 2 hours. The Ethanol was distilled under vacuum and residue was partitioned between Ethyl acetate (100 ml) and water (100 ml). Further aqueous layer was extracted with Ethyl acetate (2×100 ml). The combined volume of Ethyl acetate layer was reduced to 20 ml and then filtered to give 800 mg of desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=2)[NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:27][C:22]1[CH:21]=[C:20]([CH:10]([NH:11][C@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH:25]=[CH:24][C:23]=1[CH3:26]
Reactant: Cc1ccc(C(N[C@@H](C)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(N[C@@H](C)c2ccccc2)c2cccc(N)c2)cc1C
Yield: 77.8 %

Procedure:
In a similar manner to that described in Example (1b), a solution of isomer B of N-[(3-nitrophenyl)-(3,4-dimethylphenyl)methyl]-N-[(S)-1-phenylethyl]amine (1.19 g) in methanol (20 ml), nickel chloride hexahydrate (1.57 g) and sodium borohydride (500 mg) were reacted, to afford isomer B of the title compound (849 mg) as a colorless oil.