Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)[CH:25]=[CH:24][C:3]=1[O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[C:6]1=[O:23].[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[F:1][C:2]1[CH:27]=[C:26]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)[CH:25]=[CH:24][C:3]=1[O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[C:6]1=[O:23]
Reactant: Cc1nnc(-c2ccc(O[C@H]3CCN(C4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c(F)c2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(O[C@H]3CCN(C4CCNCC4)C3=O)c(F)c2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-tert-butyl 4-(3-(2-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (680 mg, 1.48 mmol) was dissolved in CH2Cl2 (10 mL) and TFA (4 mL) was added and stirred at ambient temperature for 1 hour and then concentrated in vacuo to afford crude (S)-3-(2-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)-1-(piperidin-4-yl)pyrrolidin-2-one 2,2,2-trifluoroacetate as an oil which was taken forward without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1.CO>N1C=CC=CC=1.[Cu]I.[Cu]>[CH:21]1([C:13]2[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:11][C:10]3[C:15](=[C:16]([C:17]([NH:19][CH3:20])=[O:18])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([O:42][C:39]5[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=5)=[CH:3][CH:4]=4)[N:9]=3)[CH:14]=2)[CH2:23][CH2:22]1
Reactant: Oc1ccc(F)cc1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: c1ccncc1
Product: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 150 °C
Yield: 16.5 %

Procedure:
A mixture of Compound (1) (50 mg, 0.11 mmol), potassium carbonate (30 mg, 0.22 mmol), copper(I) iodide (10 mg, 0.05 mmol), copper (6.9 mg, 0.11 mmol) and 4-fluorophenol (18 mg, 0.16 mmol) in pyridine (1 mL) was heated to 150° C. for 16 h in a sealed-tube. After cooling to RT, MeOH (5 mL) was added and the mixture was filtered through celite and washed with more MeOH. The filtrate was concentrated in vacuo to give a crude mixture which was purified by reverse phase flash column chromatography eluting with ACN/water (10-100%) to give 5-cyclopropyl-2-[4-(4-fluorophenoxy)phenyl]-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide (2) (9 mg, 17%) as a pale yellow solid. ESI-MS m/z calculated for [M+H]+: 495.15; found: 495.12.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.CC(O)=O.O>CCO>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][C:3]([C:5]2[N:6]=[CH:7][C:8]3[C:9](=[O:27])[N:10]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=4[O:25][CH3:26])[CH:11]=[CH:12][C:13]=3[C:14]=2[OH:15])=[O:4])=[CH:31][CH:30]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Cn2ccc3c(O)c(C(=O)NCc4ccc(F)cc4)ncc3c2=O)c(OC)c1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
A mixture of 7-(2,4-dimethoxy-benzyl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (15 mg, 0.041 mmol) and 4-fluorobenzylamine (0.020 mL, 0.14 mmol) in EtOH (2 mL) was refluxed for 16 h. After cooling the mixture to r.t., AcOH (0.1 mL) and water (2 mL) were added. The resulting precipitate was isolated by filtration, washed with cold MeOH/H2O (5 mL, 1:1), and purified by silica gel chromatography (0-2% MeOH/CH2Cl2) to give 15 mg of the title compound. MS: (+) m/z 464.35 (M+1).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:18]=[C:19]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[CH:20]=[N:21][CH:22]=2)=[CH:12][CH:11]=3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.S(Cl)(Cl)(=O)=O.[CH3:45][CH:46]([CH3:52])[CH2:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[CH3:45][CH:46]([CH3:52])[CH2:47][S:48]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:18]=[C:19]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[CH:20]=[N:21][CH:22]=2)=[CH:12][CH:11]=3)[CH2:2][CH2:3]1)(=[O:50])=[O:49]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: O=S(=O)(Nc1cncc(-c2ccc3ncc(N4CCNCC4)nc3c2)c1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)CS(=O)(=O)N1CCN(c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.4 %

Procedure:
To a solution of N-{5-[3-(1-piperazinyl)-6-quinoxalinyl]-3-pyridinyl}benzenesulfonamide (0.20 mmol) and triethylamine (0.20 mmol) in dichloromethane (2 ml) was added a sulfonyl chloride such as 2-methyl-1-propanesulfonyl chloride (0.22 mmol). The reaction stirred for 18 hours at ambient temperature and purified on silica by column chromatography (80% ethyl acetate/hexanes). The desired fractions were combined and concentrated to give the title compound (22 mg, 20%) as an off-white solid. MS(ES)+ m/e 567.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH2:6][C:7](O)=[O:8])[CH3:2].C(OCCCl)=O.[NH2:17][NH:18][C:19]([NH2:21])=[S:20].Cl>O1CCCC1.O.C(N(CC)CC)C>[NH2:21][C:19]([NH:18][NH:17][C:7](=[O:8])[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:10])=[S:20]
Reactant: CCOC(=O)CCC(=O)O
Reactant: NNC(N)=S
Agent: Cl
Agent: O=COCCCl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC(=O)NNC(N)=S
Reaction time: 0.5 h

Procedure:
To a solution of succinic acid monoethyl ester (22.0 g) and triethylamine (16.8 g) in tetrahydrofuran (150 ml) was added dropwise chloroethyl formate (18.0 g) at −20° C. After stirring for 30 min., pulverized thiosemicarbazide (13.7 g) was added and the mixture was stirred at room temperature for 7 hrs. Water was added to the reaction mixture, acidified with 2N hydrochloric acid and extracted with chloroform. The aqueous layer was separated and sodium chloride was added. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residual crystals were recrystallized from dichloromethane-ethanol to give ethyl 4-[2-(aminocarbothioyl)hydrazino]-4-oxobutanoate as colorless prism crystals (8.23 g, 25%). melting point: 143–144° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[O:4].[CH3:13][O:14][C:15](OC)(OC)[CH2:16][O:17][CH3:18]>C(OC(=O)C)(=O)C>[CH3:12][O:11][C:9](=[O:10])[C:8](=[C:16]([O:17][CH3:18])[CH2:15][O:14][CH3:13])[C:6](=[O:7])[CH2:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: COCC(OC)(OC)OC
Reactant: COC(=O)CC(=O)CC(=O)OC
Solvent: CC(=O)OC(C)=O
Product: COCC(OC)=C(C(=O)CC(=O)OC)C(=O)OC

Procedure:
Dimethyl 1,3-acetonedicarboxylate (20.0 g, 115 mmol) is dissolved in a solution of 1,1,1,2-tetramethoxy-ethane (23.8 g, 158 mmol) and acetic anhydride (420 mL) and the solution is heated to reflux for 4 hours. The mixture is concentrated under reduced pressure. Toluene (200 mL) is added and the solvent removed under reduced pressure to yield the title compound.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)#[N:2].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15]N.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.NCCCCN.CC[O-].[Na+]>C(O)C>[N:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][C:1]2[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:2]=2)=[CH:6][CH:7]=1
Reactant: N#CCCc1ccncc1
Reactant: NCCCCN
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCO
Product: c1cc(CCC2=NCCCCN2)ccn1
Yield: 93.6 %

Procedure:
The mixture of 4-[2-cyanoethyl]pyridine (1.32 g, 0.01M), 1,4-diaminobutane (0.88 g, 0.01M) and 1,4-diaminobutane di-p-toluenesulfonate (4.32 g, 0.01M) was heated at about 190° to about 200° C. for 4 hrs. The residue was stirred with ethanol (20 ml) which contained EtONa (0.02M) and filtered. The filtrate was concentrated and distilled at 0.07 mmHg and a temperature of about 180° to about 200° C. to give 4,5,6,7-tetrahydro-2[2-(4-pyridyl)ethyl]-1H-1,3-diazepine (1.9 g, 93% yield).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([C:29](=O)[CH2:30][O:31][CH3:32])[C:25](OC)=[O:26])=[CH:19][CH:18]=1)#[N:10].O1CCOCC1>CO>[CH3:32][O:31][CH2:30][C:29]1[N:4]=[C:2]([CH3:3])[NH:5][C:25](=[O:26])[C:24]=1[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:12]2[C:11]([C:9]#[N:10])=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:18][CH:19]=1
Reactant: CC(=N)N
Reactant: COCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of acetamidine hydrochloride (3.4 g) in methanol (30 mL) was added sodium methoxide (28% methanol solution, 10.3 g) at 0° C., a solution of methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-4-methoxy-3-oxobutanoate in methanol (60 mL)-1,4-dioxane (20 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, and water (50 mL) and 50% aqueous acetic acid solution were added to the residue and adjusted to pH 5. The obtained crystallized product was collected by filtration and washed with water to give the title compound as colorless crystals (5.27 g, 86%).
Reaction SMILES: [CH2:1]([N:8](C(OC(C)(C)C)=O)[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([NH:8][CH:9]1[CH2:10][C:11]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:12]=2[CH2:13][CH2:14][CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2ccc(O)cc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Oc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Reaction time: 1 h

Procedure:
To a solution of N-benzyl-N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (500 mg) in ethyl acetate (5 ml) was added 4N hydrogen chloride in ethyl acetate (5 ml) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The mixture was poured into a mixture of saturated aqueous sodium hydrogencarbonate and ethyl acetate, followed by being made basic with saturated aqueous sodium hydrogencarbonate. After separation, the organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to give crude 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]3[N:33]4[C:29]([S:30][CH:31]=[CH:32]4)=[N:28][C:27]=3[CH3:34])=[O:25])[CH2:18]2)=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(Cl)cc2)s1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Product: Cc1nc(C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c(-c2ccc(Cl)cc2)s1

Procedure:
prepared by reaction of 5-(4-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:21]N(C)C=O.[H-].[Na+].CI>O>[CH3:21][N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:20])[CH3:19]
Reactant: CN(C)C=O
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
A 12.5 g portion of N-[3-(3-methyl-1,2,4-triazolo [4,3-b]pyridazin-6-yl)phenyl]acetamide was added to 500 ml of dimethylformamide under argon. A 2.47 g portion of sodium hydride (50% in oil) was added, this mixture was stirred one hour, then 3.2 ml of methyl iodide was added. This mixture was stirred for 2.5 days, then poured into 1.5 liters of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and concentrated in vacuo. The residue was chromatographed as described in Example 1. Fractions 8-15 were combined, concentrated and the solid recrystallized from dichloromethane-hexane, giving 8.5 g of the desired product, mp 200°-203° C.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:11](=[O:42])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[N:25]([C:38](=[O:41])[NH:39][CH3:40])[CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][NH:39][C:38]([N:25]1[CH2:26][CH:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=2)[CH:21]2[N:20]([C:18](=[O:19])[CH:13]([NH:12][C:11](=[O:42])[CH:9]([NH:7][CH3:6])[CH3:10])[C:14]([CH3:16])([CH3:17])[CH3:15])[CH2:24][CH2:23][CH:22]12)=[O:41]
Reactant: CNC(=O)N1CC(COc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)N1CC(COc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)C(C)NC)C(C)(C)C
Reaction time: 1.5 h
Yield: 54.1 %

Procedure:
A solution of carbamate 90 (175 mg, 0.29 mmol) in DCM (10 mL) was treated with TFA (4 mL) at 0° C. After 1.5 h, the reaction mixture was concentrated, diluted with EtOAc, washed successively with saturated aqueous NaHCO3, and brine dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by reverse phase HPLC (2″ Dynamax® C18; 10% ACN/water to 70% ACN/water containing 0.1% HOAc, 30 min; Flow: 40 mL/min). The product-containing fractions were combined, frozen, and lyophilized to afford 91 (80 mg, 55%) as a white flocculent solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]([O:23]CC)=O)[N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:30][CH2:29]1.C[Al](C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:26])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]([N:38]3[CH2:37][CH2:36][N:35]([CH2:34][CH:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH2:40][CH2:39]3)=[O:23])[N:17]=2)(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: CCOC(=O)c1noc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)n1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)no2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using ethyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,2,4-oxadiazole-3-carboxylate (35 mg, 0.09 mmol), 1-[(1-methylpiperidin-4-yl)methyl]piperazine (34 mg, 0.17 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (3 mL). A portion of the crude product was purified using prep method D.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](F)[N:11]=2)=[O:9])=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1.[C:18]([N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([Br:17])=[CH:6][C:7]=1[C:8]([C:10]1[N:11]=[C:12]([N:28]2[CH2:29][CH2:30][CH2:31][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]2)[CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Nc1ncc(Br)cc1C(=O)c1cccc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc(C(=O)c3cc(Br)cnc3N)n2)CC1
Temperature: 95 °C
Yield: 59 %

Procedure:
A mixture of (2-amino-5-bromopyridin-3-yl)(6-fluoropyridin-2-yl)methanone (190 mg, 0.64 mmol), 1-Boc-homopiperazine (0.14 ml, 0.70 mmol) and potassium carbonate (310 mg, 2.24 mmol) in dimethylformamide (4 ml) was heated at 95° C. for 48 hours. The reaction mixture was cooled down to room temperature and concentrated in vacuo. The residue was slurried in EtOAc and K2CO3 was filtered off. The mother liquors were concentrated in vacuo. The resulting residue was purified on silica gel by flash column chromatography (ISCO Companion|, 12 g column, 0-20% EtOAc/Petrol) to give the title compound as a yellow solid (180 mg, 59% yield).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[Cl:30]C1C=CC=CC=1>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][Cl:30])=[CH:4][C:3]=1[F:9]
Reactant: Clc1ccccc1
Reactant: Cc1cnc(Br)c(F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Product: Fc1cc(CCl)cnc1Br
Yield: 42 %

Procedure:
10.00 g (52.63 mmol) of 6-bromo-5-fluoro-3-methylpyridin (cf. F. L. Setliff, Organic Preparations and Procedures International 1971, 3, 217-222), 12.18 g (68.42 mmol) of N-bromosuccinimide and 0.86 g (5.26 mmol) of 2,2′-azobis(2-methylpropanenitrile) in 1 of chlorobenzene are boiled under reflux for 6 hours. The reaction mixture is washed with saturated aqueous sodium sulphite solution and sodium bicarbonate solution and then dried over sodium sulphate and concentrated under reduced pressure. Column chromatography of the residue on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (1:20) gives 6.0 g (42% of theory) of 6-bromo-3-chloromethyl-5-fluoropyridine.
Reaction SMILES: C(O[C@H:15]1[O:62][C@H:61]([CH2:63][O:64][C:65](=[O:77])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[C@H:46]([O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C@H:31]([O:32][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C@H:16]1[O:17][C:18](=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=O)CCCCCCCCCCC.[C:78]([OH:81])(=[S:80])[CH3:79].[Sn](Cl)(Cl)(Cl)Cl.Cl>C1(C)C=CC=CC=1>[C:78]([S:80][C@H:15]1[O:62][C@H:61]([CH2:63][O:64][C:65](=[O:77])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH3:76])[C@H:46]([O:47][C:48](=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C@H:31]([O:32][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C@H:16]1[O:17][C:18](=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:81])[CH3:79]
Reactant: CCCCCCCCCCCC(=O)OC[C@H]1O[C@H](OC(=O)CCCCCCCCCCC)[C@H](OC(=O)CCCCCCCCCCC)[C@@H](OC(=O)CCCCCCCCCCC)[C@H]1OC(=O)CCCCCCCCCCC
Reactant: CC(O)=S
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)OC[C@H]1O[C@H](SC(C)=O)[C@H](OC(=O)CCCCCCCCCCC)[C@@H](OC(=O)CCCCCCCCCCC)[C@H]1OC(=O)CCCCCCCCCCC
Reaction time: 1 h
Yield: 21 %

Procedure:
To compound 1 (20.0 g, 18.2 mmol) and thioacetic acid (27.0 mL, 20 eq.) in dry toluene (80 mL) under argon was added tin (IV) chloride (21.3 mL) dropwise at room temperature. The reaction was monitored by Tlc carefully. After 1 h, 600 mL of 1M aqueous HCl was added to the vigorously stirred mixture and the resulting mixture was filtered through Celite to remove the emulsion of tin salts. The mixture was diluted with pentane (800 mL), washed with water (2×400 mL), saturated sodium hydrogen carbonate (300 mL) and water (300 mL), dried with Na2SO4 and concentrated. The residue was purified by column chromatography three times (SiO2, pentane/EtOAc 20:1, 30:1, 40:1) to give 1-S-acetyl-2,3,4,6-tetra-O-lauroyl-1-thio-α-D-galactopyranose (3.65 g, 21%). 1H-Nmr data (CHCl3): δ 6.26 (d, 1H, J 5.5 Hz, H-1), 5.47 (dd, 1H, J 11.0 Hz, 5.5 Hz, H-2), 5.46 (d, 1H, J 3.5 Hz, H-4), 5.04 (dd, 1H, J 11.0 Hz, 3.5 Hz, H-3), 4.17 (t, 1H, J 6.5 Hz, H-5), 4.06 (d, 2H, J 6.5 Hz, H-6a and H-6b), 2.38 (t, 8H, J 7.0 Hz, --COCH2 --), 2.40 (s, 3H, -SAc), 0.87 (t, 15H, J 7.0 Hz, --CH3).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N+:12]([O-])[CH:13]=1.CN(C)C(Cl)=O.O>C(#N)C>[CH3:7][C:8]1[C:13]([C:5]#[N:6])=[N:12][C:11]([O:15][CH2:16][C:17]([F:20])([F:18])[F:19])=[CH:10][CH:9]=1
Reactant: Cc1ccc(OCC(F)(F)F)[n+]([O-])c1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: O
Solvent: CC#N
Product: Cc1ccc(OCC(F)(F)F)nc1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 29.1 %

Procedure:
Trimethylsilyl cyanide (0.19 mL, 1.40 mmol) is added dropwise a solution of 5-methyl-2-(2,2,2-trifluoroethoxy)pyridine 1-oxide (0.14 g, 0.70 mmol, Step-2) and dimethylcarbamoyl chloride (0.1 mL, 1.05 mmol) in acetonitrile (10 mL) is stirred at room temperature for 2 days. Then trimethylsilyl cyanide (0.19 mL, 1.40 mmol) and dimethylcarbamoyl chloride (0.1 mL, 1.05 mmol) is added to the reaction mixture and refluxed with stirring for 20 hours. After cooling to room temperature, the reaction mixture is poured into water, extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (2:1 to 1:1) to give 44 mg (29% yield) of the title compound as colorless oil.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:33])[NH:12][C:13]2[C:14](=[O:32])[O:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([O:23][CH:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[C:17]=3[CH3:31])=[CH:7][C:6]=1[CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37])(=O)C>C(N(CC)CC)C.CO>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:12][C:13]2[C:14](=[O:32])[O:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([O:23][CH:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[C:17]=3[CH3:31])=[O:33])=[CH:7][C:6]=1[CH2:34][CH:35]=[C:36]([CH3:38])[CH3:37]
Reactant: CC(=O)Oc1ccc(C(=O)Nc2cc3ccc(OC4CCN(C)CC4)c(C)c3oc2=O)cc1CC=C(C)C
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)=CCc1cc(C(=O)Nc2cc3ccc(OC4CCN(C)CC4)c(C)c3oc2=O)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
General procedure IV for the preparation of compounds 31a-g: Compound 29a (52 mg, 0.1 mmol) was dissolved in 10% triethylamine/methanol (3 mL). The solution was stirred at room temperature overnight and concentrated. The residue was purified by column chromatography on silica by using methylene chloride and methanol (10:1) to give 31a as a white, amorphous solid (37 mg, 73%). 1H NMR (500 MHz, DMSOd6) δ 9.22 (s, 1H), 8.47 (s, 1H), 7.68˜7.66 (m, 2H), 7.53 (d, J=8.7, 1H), 7.11 (d, J=8.9, 1H), 6.90 (d, J=8.7, 1H), 5.30 (m, 1H), 4.57 (m, 1H), 3.27 (d, J=7.3, 2H), 2.62˜2.54 (m, 2H), 2.34˜2.28 (m, 2H), 2.22 (s, 3H), 2.21 (s, 3H), 1.96˜1.92 (m, 2H), 1.76˜1.72 (m, 2H), 1.71 (s, 3H), 1.69 (s, 3H). 13C NMR (125 MHz, DMSOd6) δ 165.3, 158.8, 158.4, 156.6, 149.5, 131.9, 129.2, 127.8, 127.7, 126.8, 126.0, 124.0, 122.3, 121.3, 114.6, 113.4, 112.7, 110.8, 72.1, 51.8, 45.7, 30.2, 27.9, 25.6, 17.7, 8.2. IR (film) νmax 3421, 1703, 1666, 1601, 1528, 1504, 1366, 1248, 1178, 1150, 1094, 1040 cm−1. HRMS (ESI+) m/z Calc for [M+H+] C28H33N2O5 477.2389. found: 477.2397.