Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:19][CH2:18][C:17]2([CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20]2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:19][CH2:18][C:17]4([CH2:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[O:20]4)[CH2:16][CH2:15]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)Cc3ccccc3O4)nn2)n1

Procedure:
The object product (49 mg, 56%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (50 mg), 3H-spiro[1-benzofuran-2,4′-piperidine] (50 mg) and potassium carbonate (50 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>OS(C(F)(F)F)(=O)=O>[Br:19][C:3]1[C:4]2[CH2:8][O:7][C:6](=[O:9])[C:5]=2[CH:10]=[CH:11][C:2]=1[Br:1]
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1OCc2c1ccc(Br)c2Br
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a flask containing a stir bar was added commercially available 5-bromo-2-benzofuran-1(3H)-one (12.0 g, 56.3 mmol) and NBS (15 g, 84 mmol). Triflic acid (50 mL) was added at 0° C. and the resulting mixture was stirred for 2 days. TLC analysis of the reaction mixture showed a complete reaction; the reaction mixture was poured into an ice and the organic layer separated. The organic layer was washed with aq. NaCl, water, dried over Na2SO4, filtered and concentrated to dryness, it was then absorbed onto silica gel and subjected for purification over a silica column to give the title compound.
Reaction SMILES: C([O:8][C:9]1[C:10]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:10]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: NS(=O)(=O)c1ncccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NS(=O)(=O)c1ncccc1O

Procedure:
A solution of 263.7 g of 3-benzyloxy-pyrid-2-ylsulfonamide in 2.5 l of methanol is hydrogenated with the addition of 26 g of 5% Pd/C catalyst. After 23.8 l of hydrogen have been absorbed, the catalyst is filtered off. After evaporation of the methanol, 3-hydroxypyrid-2-ylsulfonamide remains in the form of a crystalline mass. Melting point 162°-164° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:24])[C:5]1=[O:34].C(N(C(C)C)CC)(C)C.[N:44]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[O:24])[C:5](=[O:34])[N:4]3[CH2:3][CH2:2][NH:1][C:50]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[O:51])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(4-morpholinyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.052 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (5 mL) under nitrogen was treated with 4-morpholinecarbonyl chloride (0.008 mL, 0.068 mmol) at 40° C. for 1 h then 3½ h at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was triturated with Et2O:MeOH, filtered, washed with 2:1 Et2O:MeOH, and dried in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.3 (s, 1 H), 3.10 (s, 2 H), 3.13-3.22 (m, 8 H), 3.27-3.33 (m, 1 H), 3.42-3.50 (m, 4 H), 3.55 (d, J=10.67 Hz, 2 H), 3.63-3.73 (m, 2 H), 3.78 (d, J=4.49 Hz, 1 H), 3.93-4.05 (m, 2 H), 4.14 (s, 2 H), 4.30 (t, J=6.67 Hz, 2 H), 7.11-7.19 (m, 2 H), 7.39-7.47 (m, 2 H), 8.34 (s, 1 H), 8.57 (d, J=1.12 Hz, 1 H), 9.88 (br. s., 1 H), 10.38-10.48 (m, 1 H); ES+ MS: 583 (M+H+).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[C:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:4]=1.I[CH3:21]>C1COCC1>[CH3:21][N:12]([CH2:11][C:10]#[C:9][C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCC#Cc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CC#Cc1cccnc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.6 %

Procedure:
To a solution of sodium hydride (60% dispersion in mineral oil, 30 mg, 0.95 mmol) in anhydrous THF (3 mL) at 0° C. was added a solution of 47 (109 mg, 0.47 mmol) in anhydrous THF (2 mL) dropwise over 15 min. To the resultant solution was added a solution of iodomethane (150 μL, 2.42 mmol) in THF (5 mL) over 10 min, the ice bath was removed and the solution was stirred at ambient temperature for 16 h. The reaction was stopped by the addition of water (5 mL) and the aqueous fraction was extracted with EtOAc (3×20 mL), washed with water, dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (EtOAc/Hex, 25/75, Rf=0.18) to afford the title compound 49 (69 mg, 60% yield) as a yellow oil: 1H NMR (CDCl3) δ 8.65 (s, 1H), 8.52 (m, 1H), 7.69 (m, 1H), 7.24 (m, 1H), 4.29 (s, 2H), 2.97 (s, 3H), 2.97 (s, 9H); LRMS (ESI) m/z calcd for C14H19N2O2 [M H]+ 247. found 247.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](Br)[CH2:9][CH2:10][CH3:11]>CO.O>[CH2:8]([NH:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCBr
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCNCC(=O)O
Yield: 41.6 %

Procedure:
A! A 32% solution of sodium hydroxide (123 ml) was added to a mixture of glycin (50 g, 0.66 mole) and butyl bromide (75 ml, 0.66 mole) in methanol (600 ml) and water (600 ml), the reaction mixture was refluxed for 24 hours, then the solvend was evaporated under vacuum. The crude was dissolved in ethanol, the salts were filtered off 3 times, and the solvent was evaporated under vacuum. The resulting crude was purified by flash chromatography (eluent: chloroform/methanol/concentrated ammonia 6:4:0.5) yielding 36 g of N-butyl-glycine.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([C:18]2[NH:19][CH:20]=[C:21]([CH3:23])[N:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:12]1([C:18]2[N:19]([C:2]3[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=3[N+:9]([O-:11])=[O:10])[CH:20]=[C:21]([CH3:23])[N:22]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Cc1c[nH]c(C2CCCCC2)n1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cn(-c2cc(F)ccc2[N+](=O)[O-])c(C2CCCCC2)n1

Procedure:
15.9 g (0.1 mol) 2,4-Difluoro-nitrobenzene, 16.5 g 2-Cyclohexyl-4-methylimidazole, 30 g potassium carbonate, and 150 ml acetonitrile were heated 24 hours at 60° C. After cooling the product was filtered off, washed with 100 ml acetonitrile, evaporated to dryness and chromatographed on silica gel with 5% MeOH/CH2Cl2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][CH2:22][S:23]([C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C(Br)(Br)(Br)[Br:35]>ClCCl>[Br:35][CH2:21][CH2:22][S:23]([C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24]
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1ccc(S(=O)(=O)CCO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)CCBr)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 g of 4-(2-hydroxyethylthio)benzonitrile was reacted via Procedure R to yield 4-(2-hydroxyethylsulfonyl)benzonitrile. 3.0 g of triphenylphosphine was added to a solution of 2 g of 4-(2-hydroxyethylsulfonyl)benzonitrile and 4.7 g of carbon tetrabromide in dichloromethane at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (0-70% ethyl acetate/hexane) to afford 4-(2-bromoethylsulfonyl)benzonitrile. 250 mg of 4-(2-bromoethylsulfonyl)benzonitrile was used in Procedure P with imidazole to give 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzonitrile. 300 mg of 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(2-(1H-imidazol-1-yl)ethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 467.1 (M)+.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([CH3:30])([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][CH:15]=1)[CH2:7][C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)C.[OH-].[Na+]>C(O)C>[C:25]([O:24][C:22](=[O:23])[C:21]([CH3:30])([CH3:29])[CH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:6]([CH2:7][C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][C:4]([OH:31])=[O:3])=[CH:15][CH:16]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)CN(Cc1ccc(CC(C)(C)C(=O)OC(C)(C)C)cc1)Cc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(CN(CC(=O)O)Cc2ccco2)cc1
Temperature: 80 °C

Procedure:
A solution of 785 mg (1.83 mmol) of tert-butyl 3-(4-{[(2-ethoxy-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate (Example I-9) in 15 ml of ethanol is admixed with 5.5 ml (5.5 mmol) of 1 N aqueous sodium hydroxide solution and heated at 80° C. for 1 h. After cooling, the mixture is concentrated under reduced pressure and the residue is taken up in a little water, acidified with 1 N hydrochloric acid and extracted 3× with ethyl acetate. The combined organic extracts are washed 2× with sat. NaCl solution, dried over sodium sulphate and freed from the solvent under reduced pressure. This gives 728 mg (99%) of N-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-(2-furylmethyl)glycine.
Reaction SMILES: C(O[C:4]([C:6]1[O:7][C:8]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:9][N:10]=1)=[O:5])C.[CH2:20]([NH2:22])[CH3:21]>CO.O1CCCC1>[C:16]([O:15][C:13](=[O:14])[NH:12][CH2:11][C:8]1[O:7][C:6]([C:4](=[O:5])[NH:22][CH2:20][CH3:21])=[N:10][N:9]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: CCN
Reactant: CCOC(=O)c1nnc(CNC(=O)OC(C)(C)C)o1
Solvent: CO
Solvent: C1CCOC1
Product: CCNC(=O)c1nnc(CNC(=O)OC(C)(C)C)o1
Reaction time: 1.5 h

Procedure:
To a solution of 5-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]-1,3,4-oxadiazole-2-carboxylic acid ethyl ester (prepared as described in JOC (1995), 60(10), 3112-20) (0.150 g) in methanol (5 ml) was added a solution of 2.0M ethylamine in tetrahydrofuran (3 ml). The solution was left standing at 20° C. for 1.5 h. The solvent was removed by evaporation using a stream of nitrogen to give the title compound as a yellow gum (0.139 g).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([CH2:19][C:20](O)=[O:21])#N.C(N)C1C=CC=CC=1>C(O)(=O)C>[CH:1]1([N:6]2[C:7]3[N:8]=[C:9]([S:15][CH3:16])[N:10]=[CH:11][C:12]=3[CH:13]=[CH:19][C:20]2=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCC(=O)O
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Solvent: NCc1ccccc1
Solvent: CC(=O)O
Product: CSc1ncc2ccc(=O)n(C3CCCC3)c2n1
Temperature: 25 °C

Procedure:
A mixture of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (9), (1 g, 4.2 mmol), 1.2 equivalent of cyanoacetic acid, and a catalytic amount of benzylamine was taken into acetic acid and refluxed for about 6 h. After completion of the reaction by TLC, the reaction mixture was cooled to room temperature and product precipitated from the reaction mixture. Additional product was precipitated from the reaction mixture via the addition of hexane. The resultant solid was collected, washed with saturated NaHCO3, water, and subsequently dried under vacuum. The resultant crude product (10) was recrystallized in 2-propanol.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([CH:20]=O)[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[CH:35]([NH2:38])([CH3:37])[CH3:36].CC(O)=O.C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([CH2:20][NH:38][CH:35]([CH3:37])[CH3:36])[CH2:16][CH2:15]2)=[O:7])=[CH:33][CH:34]=1
Reactant: CC(C)N
Reactant: O=C[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCCCC4)cc32)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NC[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCCCC4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 12.2 %

Procedure:
A suspension of (E)-4-fluoro-N-(1-(cis-4-formylcyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (75 mg, 0.162 mmol) in MeOH (3.2 mL) was cooled to 0° C. under nitrogen atmosphere. To this mixture was added isopropylamine (0.208 mL, 2.432 mmol) followed by AcOH (0.056 mL, 0.973 mmol). The resulting mixture was stirred for 15 minutes. Solid sodium cyanoborohydride (15.28 mg, 0.243 mmol) was added in one portion, and the resulting mixture was stirred for 18 hours at RT. The reaction mixture was quenched with water (10 mL), and the aqueous layer was extracted with DCM (30 mL). The organic layer was collected, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (10-30% of 90/10/1 DCM/MeOH/NH4OH in DCM) to afford (E)-4-fluoro-N-(1-(cis-4-((isopropylamino)methyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (10 mg, 12.20% yield). MS m/z=506.2 [M+H]. Calc'd for C30H40FN5O: 505.3.
Reaction SMILES: N[C:2]1[N:6](C2C(Cl)=CC(C(F)(F)F)=CC=2Cl)[N:5]=[C:4](C#N)[CH:3]=1.[F:21][C:22]([F:33])([F:32])[S:23]([N:25]1C(=O)CCC1=O)=[O:24]>C(N(CC)CC)C>[F:21][C:22]([F:33])([F:32])[S:23]([NH:25][N:6]1[CH:2]=[CH:3][CH:4]=[N:5]1)=[O:24]
Reactant: O=C1CCC(=O)N1S(=O)C(F)(F)F
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: CCN(CC)CC
Product: O=S(Nn1cccn1)C(F)(F)F

Procedure:
As described in EP-A 1 331 222, 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carbonitrile (II) is sulfinylated using N-trifluoromethylsulfinylsuccinimide as the sulfinylating agent in the presence of triethylamine and without the addition of a chlorinating agent. The intermediate N-trifluoromethylsulfinylamino-pyrazole is isolated and under the conditions of a Thia-Fries rearrangement transformed into the final product 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylsulfinyl)-pyrazole-3-carbonitrile.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[NH3:17].O>ClCCl>[NH2:17][S:2]([C:5]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3]
Reactant: N
Reactant: COC(=O)c1ccc(OC)cc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(OC)cc1S(N)(=O)=O
Temperature: -10 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
A solution of 554 g of the compound of Example 4 in 5 L of dichloromethane was cooled to -40° C. and 79 g of anhydrous ammonia was added at this temperature. The reaction mixture was allowed to warm to -10° C., stirred 1 hour, then poured into 6 L of water. The organic phase was separated and filtered. The filter cake was washed with dichloromethane and dried giving 356 g of crude product. A 180 g portion was recrystallized from methanol to give 130 g of the title compound, m.p. 139°-142° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].IC.[C:12](=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:12]
Reactant: Cc1cccc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C)cccc1Br
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of 2-bromo-6-methylphenol (0.520 g, 2.78 mmol) in 15 ML of acetone was added iodomethane (0.338 mL, 5.42 mmol) and potassium carbonate (0.768 g, 5.56 mmol). The reaction was heated to reflux and stirred overnight. Ammonium chloride (sat.) was added and the mixture was extracted with diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford 456 mg of 1-bromo-2-methoxy-3-methylbenzene as a clear oil. To a solution of 1-bromo-2-methoxy-3-methylbenzene (0.123 g, 0.61 mmol) in 3 mL of THF at −70° C. was added n-butyllithium (1.6 M in hexanes, 0.46 mL, 0.73 mmol) dropwise. The reaction stirred at −70° C. for 30 minutes and was then allowed to warm up to −20° C. Ammonium chloride (sat.) was added and the mixture was extracted with ethyl acetate, dried over sodium sulfate and filter to give 96 mg crude material. The crude material was purified by column chromatography (3/1 hexanes/ethyl acetate) to afford 40 mg of 2-methoxy-3-methylphenylboronic acid as a white solid. MS(ES+): 167.0 (M+H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][CH2:12][C:11](=[N:14][O:15][CH3:16])[CH2:10]1)=O)(C)(C)C.CCOCC>C(OCC)(=O)C>[ClH:1].[CH3:16][O:15][N:14]=[C:11]1[CH2:12][CH2:13][NH:9][CH2:10]1
Reactant: CON=C1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CON=C1CCNC1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
7 ml of a 3M hydrogen chloride solution in ethyl acetate was added to 2.3 g of ice-cooled 1-(t-butoxycarbonyl)-3-methoxyiminopyrrolidine, and the mixture was stirred at about 40° C. for one hour. After completion of the reaction, the solvent was stripped off from the reaction mixture and ether was added to the residue. The crystals which formed were collected by filtration and washed with ether, giving 1.5 g of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:31][CH:30]([CH3:32])[CH2:29][CH2:28][N:21]([CH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[CH:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1
Reactant: CC(C)CCN(Cc1nccs1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCN(Cc1nccs1)C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Trifluoroacetic acid (2.7 ml, 35 mmol) is added to a solution of 4-{(3-methyl-butyl)-[(thiazol-2-yl)-methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.55 mmol) in dichloromethane (2.7 ml). The reaction is stirred for 1 hour at room temperature. The reaction is concentrated, loaded onto a SCX-2 (5 g) column, and washed with water (50 ml) and methanol (50 ml). The product is then eluted off with 2M ammonia in methanol (100 ml) and concentrated on a rotary evaporator to yield (0.14 g) of N-(3-methylbutyl)-N-[(1,3-thiazol-2-yl)methyl]piperidin-4-amine: mass spectrum (ion spray): m/z=268 (M+1); 1H NMR (CDCl3): δ=7.67 (1H, d), 7.22 (1H, d), 3.95 (2H, s), 3.16-3.09 (2H, m), 2.67-2.49 (5H, m), 1.81 (2H, brd), 1.69-1.57 (2H, m), 1.50-1.32 (4H, m), 0.87 (6H, d).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[N:2]=1.Cl[CH:9]([CH:15]=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>CCO>[N:7]1[CH:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:2]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:1]2
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Nc1cccnn1
Solvent: CCO
Product: CCOC(=O)c1cnc2cccnn12
Temperature: 25 °C
Yield: 40.8 %

Procedure:
A mixture of pyridazin-3-amine (9.51 g, 0.1 mol) and 2-ethyl 2-chloro-3-oxopropanoate (22.5 g, 0.15 mol) in EtOH (20 mL) was stirred at reflux overnight. The mixture was allowed to cool to RT and concentrated in vacuo to remove EtOH. The residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was slurried in isopropyl ether (50 mL) with stirring for 30 min, collected by filtration and dried in vacuo to afford ethyl imidazo[1,2-b]pyridazine-3-carboxylate (7.8 g, 40.8% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([N:14](C(OC(C)(C)C)=O)[CH3:15])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:24]>ClCCl.C(O)(C)C>[ClH:24].[CH3:1][O:2][C:3](=[O:23])[CH:4]([NH:14][CH3:15])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C(COCc1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: CNC(COCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Benzyloxy-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid methyl ester (0.6 g, 1.86 mmol) was dissolved in dichloromethane and then added slowly into a mixture of hydrochloric acid in isopropyl alcohol ([5M], 3 mL). The reaction mixture was stirred for 2 hours at room temperature. The solvent was then evaporated and the residue was kept on high vacuum atmosphere overnight to yield a crude product as an oil. The crude product was stored in the freezer as an oil.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@H:13]2[O:18][C@@:17]3([C:26]4[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=5)[CH:25]=4)[CH2:20][O:19]3)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]2[OH:39])(=O)=O)=CC=1.[C:40]([O-])(=[O:42])[CH3:41].[Na+].O>CN(C=O)C>[C:40]([O:11][CH2:12][C@H:13]1[O:18][C@@:17]2([C:26]3[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]4[CH:35]=[CH:34][C:31]([CH2:32][CH3:33])=[CH:30][CH:29]=4)[CH:25]=3)[CH2:20][O:19]2)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]1[OH:39])(=[O:42])[CH3:41]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COC(C)=O)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 80 °C
Yield: 38.1 %

Procedure:
To a solution of ((1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′-trihydroxy-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-6′-yl)methyl 4-methylbenzenesulfonate (20 mg, 0.034 mmol) in 1 mL of DMF, was added sodium acetate (36 mg, 0.44 mmol). The solution was warmed to 80° C. and kept at the same temperature overnight. 5 mL of water was added and the solution was extracted with ethyl acetate. The combined organic layers were washed with brine prior to drying over sodium sulfate. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 6 mg of title compound. 1H NMR (CD3OD, 400 MHz) δ 7.37 (s, 1H), 7.19 (s, 1H), 7.11 (s, 4H), 5.12 (d, J=13.0 Hz, 1H), 5.08 (d, J=13.0 Hz, 1H), 4.32 (dd, J=11.6, 2.0 Hz, 1H), 4.17-4.09 (m, 3H), 3.99-3.94 (m, 1H), 3.77-3.68 (m, 2H), 3.43 (dd, J=9.8, 8.6 Hz, 1H), 2.60 (q, J=7.6 Hz, 2H), 1.99 (s, 3H), 1.20 (t, J=7.6 Hz, 3H); MS ESI (m/z) 485 (M+Na)+, calc. 462.