Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12]([N:15]1[C:19]2=[N:20][CH:21]=[N:22][C:23]([NH2:24])=[C:18]2[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:16]1)([CH3:14])[CH3:13])C1C=CC=CC=1.[BrH:32].CCOCC>C(O)(=O)C>[BrH:32].[NH2:10][CH2:11][C:12]([N:15]1[C:19]2=[N:20][CH:21]=[N:22][C:23]([NH2:24])=[C:18]2[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:16]1)([CH3:14])[CH3:13]
Reactant: CC(C)(CNC(=O)OCc1ccccc1)n1nc(-c2ccccc2)c2c(N)ncnc21
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)(CN)n1nc(-c2ccccc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 1D (85 mg, 0.2 mmol) was treated with 1 mL of 33% solution of HBr in glacial acetic acid. The reaction was stirred at room temperature for 1 hour. Dry ether was then added to the mixture leading to the formation of a precipitate. It was collected by filtration, rinsed thoroughly with Et2O and dried. 50 mg of the compound were redissolved in 50 mL of water and freeze dried for two days. A white solid was obtained. 1H NMR (ppm, DMSO-d6): δ 1.73 (s, 6H), 2.34 (s, 3H), 3.59 (br q, J=5.67 Hz, 2H), 7.33 (d, J=7.89 Hz, 2H), 7.53 (d, J=8.07 Hz, 2H), 7.95 (br s, 3H), 8.40 (s, 1H). 13C NMR (ppm, DMSO-d6): δ 20.93, 24.83, 46.51, 61.41, 98.47, 128.33, 128.76, 129.80, 138.82, 144.85, 149.49, 152.83, 154.21. LCMS (+esi): 297 (M-Br−).
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.C1(C)C=CC=CC=1.[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](Br)[CH:23]=1>O>[F:3][C:4]([F:12])([F:13])[C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][C:24]1[CH:23]=[C:22]([Br:21])[CH:27]=[CH:26][CH:25]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Brc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(Oc2cccc(Br)c2)c1
Reaction time: 18 h
Yield: 45 %

Procedure:
The reaction is performed in a 1 L 3-necked flask equipped with a mechanical stirrer, a Dean-Stark trap topped with a condenser and a nitrogen bubbler, and a stopper. The flask is flushed with nitrogen and charged firstly with potassium hydroxide (22.4 g, 0.4 mol), α,α,α-trifluoro-m-cresol (64.8 g, 0.4 mol), and toluene (500 mL). The mixture is stirred and heated at reflux for 2 h, during which time water collected in the trap (ca. 6mL). 1,3-Dibromobenzene (50 mL, 0.42 mol) and cuprous chloride (39.6 g, 0.4 mol) are added to the reaction mixture, and heating at reflux is continued for another 18 h. Then it is analyzed by capillary GC, which shows ca.45% of the title product along with ca.12.5% of the product resulting from dialkylation, with the rest being starting materials. The reaction mixture is filtered with the aid of ether (200 mL), and washed successively with 2×100 mL portions of 5% HCl (to remove any residual copper impurities), water, and brine. It is dried with (MgSO4) and concentrated on the rotary evaporator to a red oily residue. Fractional distillation afforded 47 g (38%) of the title compound, distilling at 113-117° C. @ 1 mm. Also, 112 g (10.5%) of the dialkylation product is obtained, distilling at 160-165° C. @ 1 mm. Other fractions from the distillation show mixtures containing the desired product, but no further effort is made to obtain the rest of it.
Reaction SMILES: [O-]S([O-])=O.[Na+:5].[Na+].C([O-])(O)=O.[Na+].[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:23][CH3:24])=[C:17]([S:19](Cl)(=[O:21])=[O:20])[CH:18]=1>O.O1CCOCC1>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([O:23][CH3:24])=[C:17]([S:19]([O-:21])=[O:20])[CH:18]=1.[Na+:5]
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Br)cc1S(=O)[O-]
Temperature: 70 °C
Reaction time: 1.33 h

Procedure:
To a solution of Na2SO3 (1.42 g) and NaHCO3 (0.948 g) in H2O (17 ml) at 70° C. was added a solution of 5-bromo-2-methoxybenzene-1-sulfonyl chloride (2 g) in dioxane (17 ml) dropwise. The reaction mixture was stirred at 70° C. for 80 minutes and cooled to room temperature. The solvent was removed under vacuum to yield sodium 5-bromo-2-methoxybenzenesulfinate as white solid. The solid was placed under high vacuum overnight and used without further purification.
Reaction SMILES: [CH3:1][NH:2]C.C=O.[ClH:6].[CH2:7]([N:14]1[C:22]2[C:21]([N:23]3[CH2:32][CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24]3)=[CH:20][N:19]=[CH:18][C:17]=2[CH:16]=[C:15]1[CH3:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.IC.[C-]#N.[Na+]>C(O)C.CN(C)C=O.O.C(O)(=O)C>[ClH:6].[ClH:6].[CH2:7]([N:14]1[C:22]2[C:21]([N:23]3[CH2:32][CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24]3)=[CH:20][N:19]=[CH:18][C:17]=2[C:16]([C:1]#[N:2])=[C:15]1[CH3:33])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cc2cncc(N3CCc4ccccc4C3)c2n1Cc1ccccc1
Reactant: CNC
Agent: C=O
Agent: Cl
Agent: [C-]#N
Solvent: CCO
Solvent: CC(=O)O
Solvent: CI
Product: Cc1c(C#N)c2cncc(N3CCc4ccccc4C3)c2n1Cc1ccccc1
Reaction time: 8 h
Yield: 7 %

Procedure:
Dimethylamine (1.05 ml, 2.1 mmol), acetic acid (0.81 ml), and formaldehyde (0.042 ml) were added to a solution of 2-(1-benzyl-2-methyl-1H-pyrrolo[3,2-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (600 mg, 1.71 mmol) prepared in Example 44 in ethanol (5 ml). The resulting mixture was refluxed under stirring overnight and concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography. The resulting compound (300 mg, 0.73 mmol) was dissolved in ethanol (2 ml). Iodomethane (0.091 ml, 0.46 mmol) was added to the solution, which was stirred overnight at room temperature. The resulting white product (100 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (3 ml). Sodium cyanide (34 mg, 0.72 mmol) was added to the solution, which was then stirred for 5 hours at 100° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography, dissolved in ether, and then saturated with hydrochloric acid gas to give the titled compound as a white solid (25 mg, 34.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:3]=1.Cl[CH2:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH2:31][CH2:32][CH2:33][S:34]3(=[O:36])=[O:35])=[CH:3][C:4]=2[N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[O:9])[CH2:11][CH2:12]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3N3CCOCC3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3N3CCOCC3)CC2)c(C)c1

Procedure:
Using [4-amino-2-(morpholin-4-yl)phenyl][4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 151 and 3-chloropropane-1-sulfonyl chloride (0.08 mL) and by the reaction and treatment in the same manner as in Preparation Example 78, the title compound (82 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[F:38])[C:5]2=[CH:4][CH:3]=1.Cl.[CH3:41][NH:42][CH3:43].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C)C1C=CN=CC=1.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:29])[N:42]([CH3:43])[CH3:41])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[F:38])[C:5]2=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CC(C)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2F)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
A mixture of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-chloro-2-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg), dimethylamine hydrochloride (8.5 mg), 4-dimethylamino pyridine (18 mg), EDCl (21 mg) and DIPEA (129 mg) in THF (4 mL) was stirred at room temperature overnight. Then the solvent was removed and the residue was separated by preparative HPLC to give title compound as white solid (7 mg).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:24]=[CH:23][C:22]4[N:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=5)[S:27][C:21]=4[C:20]3=[O:38])=[CH:15][C:14]=2[O:39][CH3:40])[CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:24]=[CH:23][C:22]4[N:25]=[C:26]([C:28]5[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:32][CH:33]=5)[S:27][C:21]=4[C:20]3=[O:38])=[CH:15][C:14]=2[O:39][CH3:40])[CH2:9]1
Reactant: COc1cc(-n2ccc3nc(-c4ccc(C(F)(F)F)cc4)sc3c2=O)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-n2ccc3nc(-c4ccc(C(F)(F)F)cc4)sc3c2=O)ccc1OC1CNC1
Reaction time: 1 h
Yield: 84.6 %

Procedure:
Dissolve 3-{2-methoxy-4-[4-oxo-2-(4-trifluoromethyl-phenyl)-4H-thiazolo[5,4-c]pyridin-5-yl]-phenoxy}-azetidine-1-carboxylic acid tert-butyl ester (1.3 g, 2.27 mmol) in dichloromethane (12 mL) and slowly add trifluoroacetic acid (6 mL). Stir the mixture for one hour and then evaporate. Apply the residue to a 10 g SCX column with dichloromethane. Wash the column with methanol then elute the material using 1:1 dichloromethane:2N ammonia/methanol. Concentrate to give 0.909 g (85%) of the desired product as a white solid. MS/ES m/z 474.0 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C(Cl)(Cl)Cl>[CH2:28]([NH:33][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)CN
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2ncc(C(=O)NCC(C)(C)C)c(=O)n12
Reaction time: 0.08 h
Yield: 62.2 %

Procedure:
A mixture containing 8.16 g (0.04 mole) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 6.2 ml (0.044 mol) of triethylamine in 240 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 3.25 ml (0.04 mol) of methyl chloroformate in 20 ml of chloroform is dropped to the above solution at -16° C. during 10 minutes. After stirring for 5 minutes, 3.83 g (0.044 mol) of neopentylamine dissolved in 10 ml of chloroform are dropped to the above solution at -10° C. during 5 minutes. After stirring at -10° C. for 1 hour, the reaction mixture is washed 3 times with 80 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 80 ml of water each. The organic phase is dried over anhydrous sodium sulfate and then evaporated to give 6.8 g (62.2%) of the named product as yellow crystals after recrystallization from ethanol, m.p.: 191°-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH3:9].[Br:10]Br>C(Cl)(Cl)(Cl)Cl.[Fe].II>[Br:10][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:9])[C:4]=1[Cl:8]
Reactant: Cc1c(Cl)cccc1Cl
Reactant: BrBr
Agent: [Fe]
Agent: II
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c(Cl)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.2 %

Procedure:
Treat a mixture of 2,6-dichlorotoluene (50.0 g, 0.31 mol), iodine (0.10 g, 0.39 mmol), and 325 mesh iron powder (0.70 g, 12.5 mmol) in CCl4 (60 mL) dropwise with bromine (52.8 g, 0.33 mol) over 20 minutes and is stir for 3 hours at room temperature. Pour the mixture into ice water and extract with 1,2-dichloroethane. Wash the organic layer with saturated sodium bisulfite and dry using Na2SO4. Remove the solvent in vacuo to afford 76.01 g (100%) 1-bromo-2,4-dichloro-3-methyl-benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:29])[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21](=[O:24])[C:22]=3[CH3:23])[CH:13]=[CH:12][C:11]=2[O:30]C(=O)C)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])O.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:29])[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21](=[O:24])[C:22]=3[CH3:23])[CH:13]=[CH:12][C:11]=2[OH:30])[CH:5]=[CH:4][N:3]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccnc(Cl)c3)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)Nc3ccnc(Cl)c3)c2)=C(C)C1=O
Yield: 79.1 %

Procedure:
N-(2-Chloropyridin-4-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.079 g, 0.163 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 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 recrystallized from ether to obtain the titled compound (0.057 g, 0.129 mmol, 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][CH2:23][NH:22][C:21]2=[O:25])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][C@@H:11]1[CH2:13][C@@H:12]1[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].[N:32]#[C:33]Br>C(Cl)Cl>[CH3:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:33]#[N:32])[CH2:16][CH2:15]2)=[N:6][CH:5]=[C:4]([N:20]2[CH2:24][CH2:23][NH:22][C:21]2=[O:25])[CH:3]=1
Reactant: Cc1cc(N2CCNC2=O)cnc1OCC[C@@H]1C[C@@H]1C1CCNCC1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(N2CCNC2=O)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(5-methyl-6-{2-[(1S,2R)-2-piperidine-4-ylcyclopropyl]ethoxy}pyridine-3-yl)imidazolidin-2-one (12 mg, 0.035 mmol) in 1.5 mL of DCM was added K2CO3 (14.5 mg, 0.105 mmol, in 0.5 mL of water) at room temperature followed by addition of cyanogen bromide (0.014 mL of 3M soln in DCM, 0.042 mmol) via syringe at room temperature. The mixture was then stirred for 30 min at room temperature and then diluted with 2 mL DCM. The solution was washed with sat'd NaHCO3 aq. soln, separated, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. The crude product was used without further purification. LCMS (ESI) m/z 370 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:37](=[O:38])[C:36]4[CH:40]=[CH:41][CH:42]=[C:34]([Cl:33])[CH:35]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4cccc(Cl)c4)c3)csc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (35.4 mg, 0.108 mmol) (from Example 3 supra) in THF (3 mL) were added diisopropylethyl-amine (28 mg, 0.216 mmol) (Aldrich) and then 3-chlorobenzoyl chloride (28 mg, 0.161 mmol) (Aldrich). The reaction was stirred at room temperature for 20 minutes before it was concentrated to remove the solvent. The residue was diluted with EtOAc (40 mL), washed with aqueous 1N NaOH (10 mL), brine (2×10 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (hexanes/EtOAc, 75/25 to 50/50) to give 3-[3-(3-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 38.2 mg, 75.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[H-].[Na+].[CH2:12]([OH:14])[CH3:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:14][CH2:12][CH3:13])=[CH:4][N:3]=1
Reactant: CCO
Reactant: ClCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Product: CCOCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
2-Chloro-5-chloromethyl-pyridine (1 g, 6.2 mmol) was dissolved in 15 ml dry ethanol. After cooling in an ice bath NaH (248 mg 60%, 6.2 mmol) was added to this solution. The reaction was warmed to rt and stirred for 16 hours. After this time the reaction was quenched with 15 ml ice-water and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography using 5%-10% ethyl acetate in hexane to afford 400 mg of 2-Chloro-5-ethoxymethyl-pyridine (yield 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][C:29]=4[C:36]4[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=4)[CH2:23][CH2:22]3)[CH:18]=[CH:17][C:12]=2[C:13]([O:15]C)=[O:14])[CH:5]=[N:6][C:7]=1[NH:8][CH3:9].[Li+].[OH-]>O1CCCC1.CO.ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][C:29]=4[C:36]4[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=4)[CH2:23][CH2:22]3)[CH:18]=[CH:17][C:12]=2[C:13]([OH:15])=[O:14])[CH:5]=[N:6][C:7]=1[NH:8][CH3:9]
Reactant: CNc1ncc(Oc2cc(N3CCN(CC4=C(c5ccc(Cl)cc5)CC(C)(C)CC4)CC3)ccc2C(=O)OC)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNc1ncc(Oc2cc(N3CCN(CC4=C(c5ccc(Cl)cc5)CC(C)(C)CC4)CC3)ccc2C(=O)O)cc1Cl
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 377G (0.295 g) in tetrahydrofuran (5 mL) and methanol (2 mL) was added 1.0M aqueous LiOH (1.452 mL) and the reaction was heated to 55° C. After stirring for 3 hours, the reaction was cooled, diluted with dichloromethane (75 mL) and water (15 mL) and quenched with 1N aqueous HCl (1.45 mL). The organic layer was separated, washed with brine (15 mL), dried over magnesium sulfate, filtered, and concentrated to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](O)=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>O1CCCC1>[OH:13][CH2:12][CH:10]1[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CO)C1
Reaction time: 4 h

Procedure:
Borane dimethyl sulfide complex (4.5 mL, 15.0 mmol) was slowly added to 1-(tertiary butoxycarbonyl)azetidine-3-carboxylic acid (1.0 g, 5.0 mmol) dissolved in a distilled tetrahydrofuran solution (20 mL) at 0° C., and the mixture was stirred at the same temperature for 4 hours. Thereafter, 1N HCl aqueous solution (70 mL) was slowly added at 0° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate (3*30 mL), and the organic layer was washed with a saturated sodium chloride solution and distilled water once, respectively and dried over anhydrous magnesium sulfate. The solvent was removed by reduced pressure evaporation to obtain the desired compound tertiary butyl 3-(hydroxymethyl)azetidine-1-carboxylate.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([F:15])[CH:5]=1.[Cl:16][C:17]1[C:22]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:21][CH:20]=[C:19]([C:28]([F:31])([F:30])[F:29])[N:18]=1>>[Cl:16][C:17]1[C:22]([CH:23]=[CH:24][C:25]([NH:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([F:15])[CH:5]=2)=[O:26])=[CH:21][CH:20]=[C:19]([C:28]([F:29])([F:30])[F:31])[N:18]=1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc1F
Yield: 97.7 %

Procedure:
N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide HCl salt (467 mg, 1.84 mmol) was reacted with 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (420 mg, 1.67 mmol) to give the title compound (737 mg, 98%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]2[C:13]([CH3:20])=[C:14]([N:19]3[CH2:30][C:25]4[C:24](=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23]3)[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1
Reactant: BrCc1ccccc1CBr
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)C(C)(C)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)c(N2Cc3ccccc3C2)c(C)c2c1OC(C)(C)C2c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.3 %

Procedure:
A mixture of 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine (1.00 g, 3.55 mmol), 1,2-bis(bromomethyl)benzene (1.03 g, 3.91 mmol), potassium carbonate (540 mg, 3.91 mmol), and N,N-dimethylformamide (20 ml) was stirred at room temperature for 1 hour. Water was added into the reaction mixture and the product was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 10:1) to obtain 208 mg (15% yield) of the title compound. Melting point: 164-166° C. (Ethyl acetate-hexane)
Reaction SMILES: [CH2:1]([C:8]1[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][C:11]([CH2:12]O)=[CH:10][C:9]=1[S:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BrH:26]>O>[CH2:1]([C:8]1[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][C:11]([CH2:12][Br:26])=[CH:10][C:9]=1[S:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br
Reactant: CSc1cc(CO)cc(S(N)(=O)=O)c1Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CSc1cc(CBr)cc(S(N)(=O)=O)c1Cc1ccccc1

Procedure:
4-Benzyl-3-methylthio-5-sulfamylbenzyl alcohol (10 g; prepared as described in Example 1) is while stirring added in portions to acetic acid saturated with dry hydrogen bromide (50 ml), and the mixture is stirred for 24 hours. The resulting solution is diluted with water (100 ml) and cooled to precipitate crude 4-benzyl-3-methylthio-5-sulfamylbenzyl bromide. After recrystallization from methanol it is obtained with a melting point of 149°-150° C.