Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.Cl.[CH3:9][C:10]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[N:25][O:26][CH3:27])[C:21]([NH:23][CH3:24])=[O:22]>O>[CH3:9][C:10]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[C:20](=[N:25]\[O:26][CH3:27])/[C:21]([NH:23][CH3:24])=[O:22]
Reactant: CNC(=O)C(=NOC)c1ccccc1COc1cc(C)ccc1C
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Toluene (3 ml) and conc. hydrochloric acid (0.61 g, 6 mmol) were added to 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (0.98 g, E/Z=75/25), and the mixture was stirred at 80° C. for 2 hours. After completion of the reaction, water (150 ml) was added. The mixture was extracted with methylene chloride (50 ml) twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crystals (1.01 g, E/Z=95/5). The crystals were recrystallized from toluene to give (E)-2-[2-(2,5-dimethylphenoxymethyl)-phenyl]-2-methoxyimino-N-methylacetamide (0.72 .g, Yield 71.5%) as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.N[CH2:32][C:33]1C=NC=C[CH:38]=1>>[N:8]1[CH:38]=[CH:33][CH:32]=[C:11]([CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH:12]=1
Reactant: NCc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCc1cccnc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 3-(aminomethyl)pyridine instead of 1-BOC-3-aminopyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (1H, br. s.) 10.28 (1H, s) 8.73 (1H, t, J=6.05 Hz) 8.55 (1H, d, J=1.76 Hz) 8.45 (1H, dd, J=4.78, 1.66 Hz) 8.02 (1H, d, J=5.47 Hz) 7.81 (1H, d, J=5.47 Hz) 7.67-7.74 (1H, m) 7.50 (1H, d, J=5.47 Hz) 7.28-7.38 (2H, m) 6.84 (1H, d, J=5.47 Hz) 6.42 (1H, dd, J=3.42, 1.85 Hz) 4.48 (2H, d, J=6.05 Hz)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)(=[O:4])=[O:3].[H-].[Na+].CS(O[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>ClCCl.CO>[C:35]([O:34][C:32](=[O:33])[NH:31][CH:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][N:10]2[C:9]3[CH:15]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12][C:11]2=[O:14])[CH2:26][CH2:27]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CS(=O)(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(S(C)(=O)=O)cc32)CC1
Yield: 66 %

Procedure:
6-(Methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one (Intermediate 101) (280 mg, 1.23 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (1.62 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) gave the product in 66% yield as a yellow gum.
Reaction SMILES: [C:1]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([NH:16][C:17]3[C:18]4[N:19]([CH:24]=[CH:25][N:26]=4)[N:20]=[C:21](Cl)[CH:22]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=2)[C:38]([O:40][CH3:41])=[O:39])O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14]([NH:16][C:17]3[C:18]4[N:19]([CH:24]=[CH:25][N:26]=4)[N:20]=[C:21]([C:35]4[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=4)[C:38]([O:40][CH3:41])=[O:39])[CH:22]=3)[CH:13]=[CH:12][CH:11]=2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)C1CCN(c2cccc(Nc3cc(Cl)nn4ccnc34)n2)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2cc(Nc3cccc(N4CCC(C(C)(C)C)C4)n3)c3nccn3n2)c1
Reaction time: 0.15 h
Yield: 11.8 %

Procedure:
A mixture of N-(6-(3-tert-butylpyrrolidin-1-yl)pyridin-2-yl)-6-chloroimidazo[1,2-b]pyridazin-8-amine (400 mg, 1.08 mmol), methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (425 mg, 1.62 mmol), Pd2(dba)3 (64 mg, 0.11 mmol), X-phos (105 mg, 0.22 mmol) and Na2CO3 (343 mg, 3.24 mmol) in dioxane (5 mL) and water (5 mL) was heated to reflux for 15 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 25% acetonitrile/75% water (0.1% TFA, v/v) initially, proceeding to 50% acetonitrile/50% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give methyl 3-(8-(6-(3-tert-butylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (60 mg, 12%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.74 (s, 1H), 8.55 (s, 1H), 8.21-8.11 (m, 3H), 7.86 (s, 1H), 7.63-7.47 (m, 2H), 6.27 (d, 1H, J=5.4 Hz), 6.14 (d, 1H, J=7.2 Hz), 3.96 (s, 3H), 3.71-3.68 (m, 1H), 3.48-3.42 (m, 2H), 3.19-3.13 (m, 1H), 2.16-1.98 (m, 2H), 1.82-1.78 (m, 2H). 0.93 (s, 9H). LC-MS: 471, [M+H]+, tR=2.275 min, HPLC: 96.55% at 214 nm, 96.14% at 254 nm, tR=5.449 min.
Reaction SMILES: CS(OC[C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)(=O)=O.CS(Cl)(=O)=O.O(CC1C=CC(CO)=CC=1)C1C=CC=CC=1.[Na].[C:35]1([C:41]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[N:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1.CN(C=O)C>[N:8]1[CH:9]=[CH:10][N:11]=[CH:12][C:7]=1[CH:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:42]=[C:41]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)OCc1cnccn1
Agent: CS(=O)(=O)Cl
Agent: OCc1ccc(COc2ccccc2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1cnccn1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A solution of 2-(methanesulfonyloxymethyl)pyrazine (5 mmole), (prepared from 2′-(pyrazin-2-yl)styrene according to the procedure in EP 02257, followed by treatment with methanesulfonyl chloride, according to a procedure in Can. J. Chem. 1999, 77 (4) 463 in 20 ml THF was added dropwise to the sodium salt of ethyl N-(diphenylmethylene)glycinate (5 mmole) in 20 ml DMF cooled in an ice bath. The mixture was allowed to warm to room temperature during 4 hrs. The reaction mixture was partitioned between ether and water. The aqueous layer was separated and reextracted with ether (75 ml). The combined ethereal extracts were washed with brine and dried over MgSO4. Evaporation of the solvent afforded a residue which was chromatographed on silica and eluted with acetone:hexane (1:3) to afford 1.27 g (78%) of ethyl 2-(pyrazin-2-yl)-N-(diphenylmethylene)glycinate.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[C:10]([CH2:12][C:13]3[C:14](=[O:25])[C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[C:17](=[O:20])[C:18]=3[CH3:19])[CH:9]=[CH:8][C:7]=2[O:26]C(=O)C)[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+]>CO.O>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[C:10]([CH2:12][C:13]3[C:14](=[O:25])[C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[C:17](=[O:20])[C:18]=3[CH3:19])[CH:9]=[CH:8][C:7]=2[OH:26])[CH2:3][CH2:2]1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)NC3CC3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)NC3CC3)c2)=C(C)C1=O
Yield: 55.6 %

Procedure:
N-Cyclopropyl-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.050 g, 0.121 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.023 g, 0.0673 mmol, 56%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:6])[CH3:2].[O-]S([O-])(=O)=O.[Mg+2].C(O)(=O)C.[Cl:26][CH2:27][CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:28][CH2:27][Cl:26])[CH3:6])[CH3:2]
Reactant: O=CCCl
Reactant: CCOC(=O)C(C)NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C(C)N(CCCl)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 2-benzylamino-propionic acid ethyl ester (24.72 g, 1 eq.) in 114 mL of dry DCM under nitrogen was added MgSO4 (10.80 g, 0.75 eq.). The reaction was cooled to 0° C. then acetic acid (6.82 mL, 1 eq) and the above solution of chloroacetaldehyde in dry DCM (solution I) were added. Sodium triacetoxyborohydride (38 g, 1.5 eq.) was added portionwise. The reaction was stirred for 2 h at 0° C. The crude was carefully quenched with 160 mL of a saturated aqueous solution of NaHCO3. Then 75 mL of an aqueous solution of NaOH (2N) was added. The aqueous layer was extracted twice with 120 mL of DCM. The combined organic layers were washed twice with 120 mL of a saturated aqueous solution of NaHCO3, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 100/0 to 93/7) to afford 2-[benzyl-(2-chloro-ethyl)-amino]-propionic acid ethyl ester (27.40 g, yield=85%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[CH:17][NH:18]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH:24]([CH3:33])[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26].CC(C)([O-])C.[Na+]>C1COCC1>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[CH:17][N:18]4[CH:24]([CH3:33])[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1cccc2[nH]ccc12)N1CCN(C2CCCC2)CC1
Reactant: CC(Br)C(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C(=O)c1ccccc1)n1ccc2c(C(=O)N3CCN(C4CCCC4)CC3)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.1 %

Procedure:
A mixture of 29.8 mg (0.1 mmol) (4-cyclopentyl-piperazin-1-yl)-(1H-indol-4-yl)-methanone (intermediate 2), 32 mg (0.15 mmol) 2-bromo-1-phenyl-propan-1-one (commercially available) and 28.8 mg (0.3 mmol) sodium-tert-butoxide in 2 mL THF was shaken at room temperature for 16 h. After evaporation to dryness the residue was dissolved in methanol/DMF and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/NEt3. The combined product fractions were evaporated to yield 2.6 mg of the title compound. MS (m/e): 430.5 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:10]2)=[CH:5][CH:4]=1.Br.[CH3:26][O:27][C:28]([C:30]1[CH2:31][NH:32][CH2:33][CH2:34][CH:35]=1)=[O:29].C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH3:26][O:27][C:28]([C:30]1[CH2:31][N:32]([CH2:13][CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10]2)[CH2:33][CH2:34][CH:35]=1)=[O:29]
Reactant: COc1ccc2c(c1)CC(COS(=O)(=O)c1ccc(C)cc1)CC2
Reactant: COC(=O)C1=CCCNC1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=CCCN(CC2CCc3ccc(OC)cc3C2)C1
Reaction time: 18 h

Procedure:
To a solution of 5.19 g (15 mmol) of p-toluene-sulphonic acid (7-methoxy-1,2,3,4-tetrahydro-naphth-2-ylmethyl) ester in 75 ml of dimethylformamide there are added first 3.66 g (16.5 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrobromide (guvacoline hydrobromide) and then 6.78 g (52.5 mmol) of N-ethyl-N,N-diisopropylamine. The mixture is stirred at 60° for 18 hours and then concentrated by evaporation under a high vacuum. Water is added to the residue and extraction is carried out with diethyl ether. The organic phases are washed with water and extracted with 2N hydrochloric acid. The hydrochloric acid extracts are rendered alkaline at reduced temperature with sodium hydroxide solution (30%) and are extracted with dichloromethane, whereupon the combined organic phases are dried over sodium sulphate and concentrated by evaporation under reduced pressure. 1-[(7-methoxy-1,2,3,4-tetrahydro-naphth-2-yl)methyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester is obtained in the form of a light-yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:7]=[O:8])=[CH:4][S:5][CH:6]=1.[C:9]1([CH2:15][CH2:16][CH2:17][Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:1][C:2]1[C:3]([CH:7]([OH:8])[CH2:17][CH2:16][CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][S:5][CH:6]=1
Reactant: O=Cc1cscc1Br
Reactant: Br[Mg]CCCc1ccccc1
Product: OC(CCCc1ccccc1)c1cscc1Br

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 4-bromo-thiophene-3-carbaldehyde and 3-phenyl-propyl magnesium bromide.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[C:8]([N:18]1C(C2C=CC=CC=2)O1)([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>C(Cl)Cl>[C:8]([NH:18][NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: COC(CN)OC
Reactant: O=C(OCc1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: COC(CNNC(=O)OCc1ccccc1)OC
Temperature: 23 °C
Reaction time: 18 h
Yield: 43.2 %

Procedure:
Aminoacetaldehyde dimethyl acetal (0.430 g, 3.95 mmol) was added to a solution of N-CBZ-3-phenyl-oxaziridine (1.11 g, 4.35 mmol) (prepared as described in Tetrahedron Let. 1993, 6859, the disclosure of which is entirely incorporated herein by reference) in CH2Cl2 (20 mL) at 23° C. The resulting yellow solution was stirred at 23° C. for 18 h, and it then was concentrated under reduced pressure. Purification of the residue by flash column chromatography (3% CH3OH/CH2Cl2) provided 1-CBZ-2-(2,2-dimethoxyethyl)-hydrazine (0.434 g, 43%) as a pale yellow oil: Rf =0.40 (5% CH3OH/CH2Cl2); IR (thin film) 3317, 1721, 1456 cm-1 ; 1H NMR (C6D6) δ 2.96 (bs, 2H), 3.06 (bs, 6H), 3.97 (bs, 1H), 4.37 (bs, 1H), 4.97 (bs, 2H), 5.87 (bs, 1H), 6.98-7.18 (m, 5H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH:16]=1)=[N:13][O:14][N:15]=2)(=O)=O.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CN(C=O)C>[N:15]1[O:14][N:13]=[C:12]2[CH:16]=[C:8]([CH2:7][CH2:6][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:9]=[CH:10][C:11]=12
Reactant: CS(=O)(=O)OCCc1ccc2nonc2c1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: c1cc2nonc2cc1CCN1CCNCC1
Yield: 96.9 %

Procedure:
5-[2-(Methanesulfonyloxy)ethyl]benzofurazan (242 mg, 1 mmol) and piperazine (0.86 g, 10 mmol) in DMF (9 ml) were stirred together at room temperature for 19 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with CH2Cl2 /CH3OH/NH3 (Aq.); 90:10:1 to give the piperazine as a yellow solid (225 mg, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([OH:12])[CH2:10][CH3:11])=[C:5]([CH3:13])[CH:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[C:5]([CH3:13])[CH:4]=1
Reactant: CCC(O)c1cnc(OC)cc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCC(=O)c1cnc(OC)cc1C
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(6-methoxy-4-methyl-pyridin-3-yl)-propan-1-ol (445 mg, 2.45 mmol, 1 eq.) in CHCl3 (10 ml) is added activated manganese dioxide (4.3 g, 49 mmol, 20 eq.) in one portion at RT. The reaction mixture is heated at reflux for 48 h. After cooling to RT, the mixture is filtered through Celite® (filter material) and concentrated under reduced pressure. The resulting crude residue is purified by column chromatography on silica gel eluting with 10% EtOAc/iso-hexane to yield 1-(6-methoxy-4-methyl-pyridin-3-yl)-propan-1-one as a white solid. MS: m/z 180.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 1.2 (t, 3H), 2.55 (s, 3H), 2.95 (q, 2H), 4.00 (s, 3H), 6.60 (s, 1H), 8.65 (s, 1H).
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[O:3]1.O>C1COCC1>[F:13][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:4]=2[O:3]1
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)OC(F)(F)O2
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of 2,2-difluorobenzo[d][1,3]dioxol-5carbaldehyde (125 g, 0.67 mol) in anhydrous THF (400 mL) was added NaBh4 (28 g, 0.74 mol) in portions at 0° C. The mixture was stirred for 1 h at 0° C., then poured into 500 mL of water. The mixture was extracted with ethyl acetate (200 mL×3). The organic phase was dried over Na2SO4 and concentrated in vacuo to give (2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol as colorless oil (120 g, 95%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([CH2:11][C:12]([CH3:15])([SH:14])[CH3:13])[CH2:7][CH2:6]2)[O:4]CC1.Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH3:15][C:12]([SH:14])([CH3:13])[CH2:11][N:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1
Reactant: CC(C)(S)CN1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(S)CN1CCC(=O)CC1
Temperature: 70 °C
Yield: 96.6 %

Procedure:
To a stirred solution of the 1-(8-aza-1,4-dioxaspiro[4.5]dec-8-yl)-2-methylpropane-2-thiol (Synthesis, 1999, 7, 1106) (1.15 g, 4.98 mmol) in THF (12 mL) was added 6 N HCl (12 mL). The mixture was heated at 70° C. overnight, then poured into saturated Na2CO3. The mixture was extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and evaporated. The residue was dissolved in EtOAc and acidified by adding HCl/EtOAc until no more solid formed. The solvent was decanted and the solid was then partitioned between EtOAc and satd Na2CO3. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried over Na2SO4 and evaporated to give the title compound (0.90 g, 4.81 mmol, 97%) as a green oil. 1H NMR (300 MHz, CDCl3) δ 2.96 (t, J=6.0, 4H), 2.52 (s, 2H), 2.41 (t, J=6.0, 4H), 1.34 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1B1OC(C)(C)C(C)(C)O1)([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][C:32](=[O:53])[NH:33][C:34]([C:36]1[S:37][C:38]([S:51][CH3:52])=[C:39]([S:41]([C:44]2[CH:45]=[N:46][CH:47]=[C:48](Br)[CH:49]=2)(=[O:43])=[O:42])[CH:40]=1)=[NH:35])([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:26])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[C:48]1[CH:47]=[N:46][CH:45]=[C:44]([S:41]([C:39]2[CH:40]=[C:36]([C:34]([NH:33][C:32]([O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:53])=[NH:35])[S:37][C:38]=2[S:51][CH3:52])(=[O:43])=[O:42])[CH:49]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccc(COCC(=O)OC(C)(C)C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cncc(-c2c(C)cccc2COCC(=O)OC(C)(C)C)c1
Temperature: 80 °C

Procedure:
The procedure as in Example 1: step c was followed using [3-Methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-acetic acid tert-butyl ester (252.2 mg, 0.62 mmol, Example 131: step d), {[4-(5-Bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (75.9 mg, 0.15 mmol, Example 128: step a), Pd(PPh3)4 (35 mg, 0.03 mmol), aqueous Na2CO3 (2M, 1 mL), ethanol (1 mL) and toluene (2 mL). The reaction was heated to 80° C. for 24 hours. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and removal of the solvents in vacuo was followed by purification by flash column chromatography (SiO2) (30% EtOAc in hexanes) of the residue yielded the title compound (460 mg) as a brown oil. ESI-MS (m/z): Calcd. for C30H37N3O7S3: 648.2 (M+1) found: 647.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[K+].[CH3:14][O:15][C:16](=[O:21])[CH2:17]C([O-])=O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[O:12])[CH2:17][C:16]([O:15][CH3:14])=[O:21]
Reactant: O=C(O)Cc1ccc(F)cc1F
Reactant: COC(=O)CC(=O)[O-]
Agent: [K+]
Product: COC(=O)CC(=O)Cc1ccc(F)cc1F

Procedure:
The title compound was prepared from 2-(2,4-difluorophenyl)acetic acid and 3-methoxy-3-oxopropanoic acid potassium salt according to the procedure for the preparation of Example 170, part A. 1H NMR (300 MHz, CDCl3): δ 3.54 (2H, s), 3.76 (3H, s), 3.86 (2H, s), 6.83-6.90 (2H, m), 7.13-7.19 (1H, m).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.C(N(CC)CC)C>ClCCl.O>[CH:12]([C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](C=O)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 33.6 %

Procedure:
DMSO (1.4 mL, 19.69 mmol) in dichloromethane (2 mL) was added dropwise to a solution of oxalyl chloride (0.86 mL, 9.85 mmol) in dichloromethane (10 mL) at −78° C. After 10 min at −78° C., (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (1.8 g, 8.95 mmol) in dichloromethane (6 mL) was added dropwise. After the resulting mixture was stirred at −78° C. for 30 min, triethylamine (6.2 mL, 44.75 mmol) was added and the mixture was stirred at −78° C. for 45 min then at room temperature for 30 min. Water was added to the reaction mixture and the two layers were separated. The organic layer was washed with water, dried over sodium sulfate, filtered and the solvent removed. The crude material was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate/hexanes to afford 0.6 g of (R)-tert-butyl 3-formylpyrrolidine-1-carboxylate as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 3.54 (dd, 1H), 3.32-3.21 (m, 2H), 3.12 (m, 2H), 2.04 (m, 2H), 1.39 (s, 9H).