Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:14])[CH:12]=[CH2:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Fe].O>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:14])[CH:12]=[CH2:13])[CH:7]=[CH:8][CH:9]=1
Reactant: C=CC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Product: C=CC(=O)Nc1cccc(N)c1
Temperature: 25 °C

Procedure:
For example, N-(3-nitrophenyl)acrylamide 2 is reduced in the presence of iron powder, FeSO4 and water, preferably upon heating, more preferably upon heating to reflux. The reaction mixture is cooled to RT and the solution is made basic, such as to a pH>12, preferably to a pH of about 13-14 to give N-(3-aminophenyl)acrylamide 3.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[C:4]([Cl:12])[N:3]=1.[N+:13]([O-])([O-:15])=[O:14].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([Cl:12])[N:3]=1
Reactant: O=c1[nH]c2cc(Cl)nc(Cl)c2[nH]1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2c(Cl)nc(Cl)c([N+](=O)[O-])c2[nH]1
Temperature: 125 °C

Procedure:
To a solution of 4,6-dichloro-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (0.6 g, 2.94 mmol) from Step C in conc. H2SO4(15 mL) was added KNO3 (2.97 g, 29.4 mmol) and the reaction mixture was heated at 125° C. for 2 h. After cooling, the reaction was mixed with ice and the solid precipitate was isolated by filtration and washed with cold H2O to give the title compound. MS: m/z=290 (M+I+CH3CN).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([C:19](O)=[O:20])[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:22][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([CH2:19][OH:20])[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1cccc2ccc(-c3cccc(C(F)(F)F)c3)nc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc2ccc(-c3cccc(C(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a solution of 2-(3-(trifluoromethyl)phenyl)quinoline-8-carboxylic acid (1.5 g, 4.72 mmol) in THF (50 ml) was added LiAlH4 (0.36 g, 9.46 mmol) in portions at 0° C. The mixture was stirred at room temperature overnight, quenched with water and concentrated to dryness. The residue was diluted with water and extracted with ethylacetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. Purification by column chromatography (1:10 ethylacetate in pentane) gave the product as a yellow oil (0.69 g, 48% yield).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH3:25])[C:8]([C:21]([F:24])([F:23])[F:22])([O:16][Si](C)(C)C)[C:9]=1[NH:10]2.[OH-].[K+].CCO>C1COCC1.O>[Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([CH3:25])[C:8]([C:21]([F:22])([F:23])[F:24])([OH:16])[C:9]=1[NH:10]2
Reactant: CC1CCc2c([nH]c3ccc(Cl)c(Cl)c23)C1(O[Si](C)(C)C)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC1CCc2c([nH]c3ccc(Cl)c(Cl)c23)C1(O)C(F)(F)F
Temperature: 60 °C
Yield: 19.7 %

Procedure:
5,6-Dichloro-2-methyl-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.15 g, 0.3 mmol) was dissolved in THF (5 mL) and a solution of KOH (0.068 g, 1.2 mmol) in water (5 mL) was added followed by EtOH (2 mL). The reaction mixture was heated at 60° C. for 6 h, diluted with water (10 mL) and extracted into EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude residue which was purified by column chromatography [EtOAc-hexane (1:4) as eluant] to provide the title compound (0.02 g, 20%). 1H NMR (500 MHz, CDCl3, δ in ppm) (mixture of two diastereomers) 8.35 (br s, 1H), 8.28 (br s, 1H), 7.26 (d, J=8.5 Hz, 2H), 7.19 (d, J=8 Hz, 2H), 3.26-2.98 (m, 4H), 2.51 (s, 1H), 2.46-2.42 (m, 1H), 2.35 (s, 1H), 2.26 (m, 1H), 2.12-1.97 (m, 3H), 1.84-1.78 (m, 1H), 1.21-1.18 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:9][S:10](Cl)=[O:11]>>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][S:10]([CH3:9])=[O:11])=[CH:3][CH:4]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CS(=O)Cl
Product: CS(=O)Nc1ccc(Cl)nc1

Procedure:
The title compound is prepared from 5-amino-2-chloropyridine and methanesulfinyl chloride following a procedure analogous to that described for Intermediate 3 (Step 1). LC (method 1): tR=0.82 min; Mass spectrum (ESI+): m/z=191 [M+H]+.
Reaction SMILES: C([O:20][CH2:21][C@H:22]1[O:36][C@H:26]([O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:25]([O:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@@H:24]([O:46][C:47](=[O:54])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:23]1[O:55][C:56](=[O:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.OS(O)(=O)=O>CO>[C:28]([O:27][C@H:26]1[O:36][C@H:22]([CH2:21][OH:20])[C@@H:23]([O:55][C:56](=[O:63])[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C@H:24]([O:46][C:47](=[O:54])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:25]1[O:37][C:38](=[O:45])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O[C@H]1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=C(O[C@H]1O[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
6-O-Trityl-1,2,3,4-tetra-O-benzoyl-α-D-mannopyranose (5 g, 6.0 mmol), was dissolved in MeOH. H2SO4 (conc.) (150 μL) was carefully added, and the solution was stirred at room temperature overnight. The solution was poured into ice-water (300 mL) and extracted with EtOAc (80 mL). The organic layer was separated and washed with brine (80 mL), followed by NaHCO3 (sat.). The solution was dried (Na2SO4), filtered and the solvent evaporated. The crude product was purified using column chromatography (SiO2; Hex:EtOAc, 500:50 to 200:200) to yield 1.79 g of the white solid product (50%). 1H NMR (300 MHz, CDCl3) δ: 8.20-8.12 (m, 4H, Ar), 8.02-7.98 (m, 2H, Ar), 7.87-7.84 (m, 2H, Ar), 7.70-7.26 (m, 27H, Ar), 6.63 (d, 1H, J1,2=2.1, H-1), 6.12 (dd, 1H, J3,2=3.3, J3,4=10.2, H-3), 6.02 (dd, 1H, J4,3=10.0, J4,5=10.0, H-4), 5.89 (dd, 1H, J1,2=1.8, J2,3=3.1, H-2), 4.25 (ddd, 1H, H-5), 3.90-3.76 (m, 2H, H-6).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[CH3:23][O:24][C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH3:23][O:24][C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:27][N:26]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)c(OC)n1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Product: COc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)c(OC)n1
Temperature: 100 °C
Reaction time: 12 h
Yield: 29.6 %

Procedure:
To 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (40 mg, 0.126 mmol), 2,4-dimethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidine (67 mg, 0.252 mmol), palladium acetate (1.4 mg, 0.0063 mmol), S-Phos (5.2 mg, 0.0126 mmol) and potassium phosphate (53.5 mg, 0.252 mmol), dimethylformamide (1 ml) was added, followed by being degassed under ultrasonic irradiation. This was stirred at 100° C. for 12 hours, followed by addition of water, and the resulting solid was filtered, which was washed with ethyl acetate, to obtain the desired compound as a colorless solid (15.7 mg, yield 30%).
Reaction SMILES: [C:1]([O:4][C@H:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6](Cl)=[O:7])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:20][O:21][C:22]([C@@H:24]1[CH2:29][N:28]([CH3:30])[CH2:27][CH2:26][NH:25]1)=[O:23].O>C(Cl)Cl>[CH3:20][O:21][C:22]([C@@H:24]1[CH2:29][N:28]([CH3:30])[CH2:27][CH2:26][N:25]1[C:6](=[O:7])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:23]
Reactant: CC(=O)O[C@@H](C(=O)Cl)C(C)(C)C
Reactant: COC(=O)[C@@H]1CN(C)CCN1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C)CCN1C(=O)[C@H](OC(C)=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a stirred solution of (2R)-1-chloro-3,3-dimethyl-1-oxobutan-2-yl acetate (0.247 g, 1.41 mmol) in CH2Cl2 (10 mL) was added triethylamine (0.39 mL, 2.83 mmol) and a solution of (S)-methyl-4-methylpiperazine-2-carboxylate (0.150 g, 0.943 mmol) in CH2Cl2 (3 mL) dropwise. The reaction mixture was stirred at room temperature for 30 minutes. Water (10 mL) was then added to quench the reaction and the reaction mixture was extracted with CH2Cl2 (2×25 mL). The combined organic layers were separated, washed with water (2×50 mL) dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (0.12 g) as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([O:28][CH3:29])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([O:28][CH3:29])[CH:11]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCCCCC(=CC(=O)OCC)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)OCC)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1OC

Procedure:
A solution of 27.92 g (66.4 mmol) of ethyl 3-(4-t-butyldimethylsilyloxymethyl-2-methoxyphenyl)-2-octenoate [prepared as described in step (iii) above] in 200 ml of ethyl acetate was vigorously stirred for 8 hours in the presence of 1.58 g of 10% palladium-on-charcoal in a stream of hydrogen. At the end of this time, the catalyst was filtered off, and the filtrate was concentrated by evaporation under reduced pressure, to give 28.25 g (a quantitative yield) of the title compound as an oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:3]=1.C(N(CC)CC)C.C(Cl)Cl>[Pd].CO>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:3]=1
Reactant: Cc1ccc(-c2nc(C)c(C)c(Cl)n2)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(-c2ncc(C)c(C)n2)cc1
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A mixture of 4,5-dimethyl-6-chloro-2-(4-methylphenyl)pyrimidine (6.2 g), triethylamine (3.2), and palladium on carbon (200 mg) in 100 ml of methanol was stirred overnight under hydrogen. Methylene chloride was added, the solid filtered off through celite, and solvent removed from the filtrate under reduced pressure. Tetrahydrofuran was added to the residue, and triethylamine hydrochloride filtered off. Solvent was removed from the filtrate under reduced pressure, giving 4.4 g of 4,5-dimethyl-2-(4-methylphenyl)pyrimidine, m.p. 114° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:31]([O:38][C:39](=[O:42])[CH2:40][NH2:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C:10]([NH:41][CH2:40][C:39]([O:38][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:42])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-pyridyl)propanoic acid (55.0 g), glycine benzyl ester tosylate (69.7 g), and diphenylphosphoryl azide (46.7 ml) in N,N-dimethylformamide (550 ml) was added dropwise N,N-diisopropylethylamine (75.6 ml) at 4° C. The mixture was warmed to room temperature and stirred for 3 hours. The resulting mixture was poured into ice-cold saturated aqueous sodium hydrogencarbonate solution (700 ml). The mixture was extracted twice with ethyl acetate (total 1.3 L) and washed successively with water (400 ml×2), saturated aqueous ammonium chloride solution (200 ml), aqueous sodium hydrogencarbonate solution (300 ml×2), and brine (40 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (77.4 g) as pale brown crystals.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16](=O)[CH3:17])=O)C1C=CC=CC=1>CC(O)C.[Pd]>[CH3:17][C@@H:16]1[CH:15]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14][CH2:13][CH2:12][NH:11]1
Reactant: CC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(C)O
Product: C[C@H]1NCCCC1NC(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
(R)-6-(Benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)-2-hexanone (306) (14.3 g, 39.3 mmol) was divided in 2 equal batches and each batch was dissolved in IPA (70 mL), combined with 10% Pd/C (5.5 g), and hydrogenated on a Parr shaker at 50 psi pressure for 12 hours. The batches were combined, filtered through celite and concentrated in vacuo to give (R)-tert-butyl 2-methylpiperidin-3-ylcarbamate (307), (8.2 g, 38 mmol, 97% yield) as a clear oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][N:31]([C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[C:38](=[O:40])[CH3:39])=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:37])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: COC[C@H](C)NCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Product: COC[C@H](C)N(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
A suspension of urea 334 (66 mg, 0.127 mmol) in acetic anhydride (2 ml) was stirred at rt for 2 days. The reaction mixture was quenched by addition of methanol and water, and partitioned with AcOEt. After separation, the organic layer was collected, washed with water, 1N NaOH (×4), water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude solid was purified by flash column chromatography on silica gel (eluent 2% of ammonium hydroxyde in MeOH/DCM: 05/90 to 10/90) to afford the compound 335 (46 mg, 0.08 mmol, 64% yield) as an off-white fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): mixture of rotamers, 8.70 (s, 1H), 8.58-8.48 (m, 2H), 8.34 and 8.30 (2s, 1H), 8.27 and 8.19 (2d, J=8.3 Hz, 1H), 7.85-7.69 (m, 2H), 7.38 (t, J=9.0 Hz, 1H), 7.20 (bd, J=9.0 Hz, 1H), 6.67-6.54 (m, 2H), 4.74-4.16 (m, 3H), 3.41-3.22 (m, 2H), 3.15 and 3.13 (2s, 3H), 2.59-2.52 (m, 1H), 2.16 and 1.96 (2s, 3H), 1.09 and 1.04 (2d, J=6.9 Hz, 3H), 0.72-0.58 (m, 2H), 0.50-0.36 (m, 2H). MS (m/z): 564.4 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.[NH4+].[Cl-]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: ClCc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCOCc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperidine (708 mg, 3.09 mmol) in anhydrous THF (15 mL) was cooled to 0° C., and NaH (60% dispersion in oil, 148 mg, 3.7 mmol, 1.2 equiv.) was added all at once. Alkoxide formation was effected by stirring at room temperature for 2 h under N2, then 4-chlorobenzyl chloride (597 mg, 3.7 mmol, 1.2 equiv.) and tetra-n-butylammonium iodide (114 mg, 0.31 mmol, 0.1 equiv.) were added. The mixture was stirred at room temperature for 20 h. Saturated aqueous NH4Cl solution was added, and the product was extracted into EtOAc. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by CC (SiO2, hexane/EtOAc 4:1) to afford, after evaporation, 1-(tert-butoxycarbonyl)-4-[2-(4-chlorobenzyloxy)ethyl]piperidine (974 mg, 89%) as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.30 (d, 2H, J=8.4 Hz), 7.24 (d, 2H, J=6.8 Hz), 4.45 (s, 2H), 4.05 (d, 2H, J=13.2 Hz), 3.49 (t, 2H, J=6.0 Hz), 2.67 (t, 2H, J=12.8 Hz), 1.63 (d, 2H, J=13.6 Hz), 1.55 (m, 3H), 1.44 (s, 9H), 1.11 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10](OC)[C:9]([C:13]([F:16])([F:15])[F:14])=[N:8][C:5]2=[N:6][CH:7]=1.[NH3:17]>CO>[NH2:17][C:7]1[N:6]=[C:5]2[N:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[NH:10][C:4]2=[CH:3][C:2]=1[Cl:1]
Reactant: N
Reactant: COn1c(C(F)(F)F)nc2ncc(Cl)cc21
Solvent: CO
Product: Nc1nc2nc(C(F)(F)F)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 2.5 g. portion of 6-chloro-1-methoxy-2-(trifluoromethyl)-1-H-imidazo [4,5-b] pyridine was dissolved in 25 ml. of methanol, and the solution was saturated with gaseous ammonia. The reaction mixture was stirred at ambient temperature for 2 hours, and additional ammonia was periodically bubbled through the liquid phase. The solvent was then removed under vacuum, and the solid residue was taken up in ethyl ether and the solution was stirred with anhydrous magnesium sulfate and charcoal. The solids were then removed by filtration, and the filtrate was evaporated to dryness to yield about 2 g. of 5-amino-6-chloro-2-(trifluoromethyl)-1H-imidazo [4,5-b] pyridine, which was recrystallized from chloroform-methanol. The purified product melted at 241° -242° C. , and it was identified conclusively by infrared, nuclear magnetic resonance, mass spectroscopy and elemental microanalysis. The analytical results were as follows.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]([CH2:7][NH:8][CH:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.N1C2C=CC=C(CO)[C:34]=2N=N1.C(O)(C)(C)C.[I-].[I-].[Sm+2]>C1C=CC=CC=1>[CH3:16][O:15][C:13](=[O:14])[CH2:12][CH:11]1[CH2:10][CH:9]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=2)[N:8]([CH2:7][C:6]2[CH:27]=[CH:28][C:3]([C:2]([F:29])([F:30])[F:1])=[CH:4][CH:5]=2)[CH2:34]1
Reactant: OCc1cccc2[nH]nnc12
Reactant: COC(=O)/C=C/CC(NCc1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Agent: [I-]
Agent: [Sm+2]
Solvent: CC(C)(C)O
Solvent: c1ccccc1
Product: COC(=O)CC1CC(c2ccc(C(F)(F)F)cc2)N(Cc2ccc(C(F)(F)F)cc2)C1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
The amine from Step 4 (400 mg, 0.9 mmol) was dissolved in benzene and benzotriazolemethanol (135 mg, 0.9 mmol) was added followed by powdered molecular sieves (470 mg). This was stirred overnight, the molecular sieves removed by filtration through Celite and the filtrate concentrated in vacuo. The residue was dissolved in THF (25 mL) and anhydrous t-butanol (0.17 mL, 0.9 mmol) was added. This solution was added dropwise via cannula onto a solution of samarium diiodide (27 mL, 2.7 mmol, 0.1M in THF) which was pre-cooled to −78° C. The mixture was stirred (−78° C. 0° C.) overnight then quenched with aq. K2CO3 and extracted with ethyl acetate. The organic extracts were washed with water, dried (MgSO4) and evaporated. The residue was purified on silica using 30-50% CH2Cl2 in iso-hexane to elute isomer a (245 mg) and isomer b (100 mg).
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(N(CC)CC)C.[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[C:12]1([CH2:11][O:18][C:19]([N:2]([CH3:1])[NH2:3])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cold, stirred solution of 36.8 (0.8 mol; 42.49 ml) methylhydrazine and 161.6 g (1.6 mol, 224 ml) triethylamine in 700 ml tetrahydrofuran were added dropwise 136.5 g (0.8 mol, 113.6 ml) benzylchloroformate. After stirring at room temperature overnight, the tetrahydrofuran was evaporated and the residue was worked up with ethylacetate/water (pH=9.0. Insoluble material was removed by filtration and the organic phase was washed (H2O), dried (MgSO4) and evaporated. The oily residue was stirred with 1 1. of ether, the etherial solution was decanted from insoluble material and evaporated to give 61 g of an oil which was dissolved in 200 ml MeOH containing 25 ml conc. HCl. After evaporation to dryness, the residue was recrystallized from EtOH/ ethylacetate to give 22.0 g of the hydrochloride of 2 as colorless crystals. This material was dissolved in water and the pH was adjusted to 9.0. Extraction with ethylacetate, drying of the organic phase (MgSO4) and evaporation yielded 19.0 g of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]1[N:9]2[CH:4]([NH:5][S:6](=[O:16])(=[O:15])[C:7]3[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=32)[CH2:3][CH2:2]1.[CH3:17][N:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[S:19]([CH3:22])(=[O:21])=[O:20].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:16]=[S:6]1(=[O:15])[C:7]2[CH:13]=[C:12]([O:14][C:27]3[CH:28]=[CH:29][C:24]([CH2:23][N:18]([CH3:17])[S:19]([CH3:22])(=[O:20])=[O:21])=[CH:25][CH:26]=3)[CH:11]=[CH:10][C:8]=2[N:9]2[CH2:1][CH2:2][CH2:3][CH:4]2[NH:5]1
Reactant: CN(Cc1ccc(B(O)O)cc1)S(C)(=O)=O
Reactant: O=S1(=O)NC2CCCN2c2ccc(O)cc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(Cc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1)S(C)(=O)=O
Reaction time: 8 h

Procedure:
A suspension composed of 5.74 mg (3.37 mmol) of 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c]-[1,2,4]benzothiadiazin-7-ol 5,5-dioxide, 926 mg (4.04 mmol) of (4-{[methyl(methylsulphonyl) amino]methyl}phenyl)boronic acid, 920 mg (5.06 mmol), of copper(II) acetate, 817 μl (10.10 mmol) of pyridine and about 4 g of 4 Å molecular sieve in 50 ml of CH2Cl2 is stirred overnight. The reaction mixture is filtered, rinsing with CH2Cl2/MeOH (1/1). The filtrate is concentrated and then directly placed on a silica column which is eluted with a CH2Cl2/MeOH 95/5 system. The fractions containing the expected product are combined and evaporated, and the residue is taken up in ethyl ether. After filtering off the solid, the title product is recovered in the form of white powder.