Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.Cl[CH2:16][C:17]12[CH2:24][CH2:23][CH2:22][N:21]1[CH2:20][CH2:19][CH2:18]2>>[N:21]12[CH2:22][CH2:23][CH2:24][C:17]1([CH2:16][NH:1][C:2]1[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH2:20]2
Reactant: Nc1cccc2c([N+](=O)[O-])cccc12
Reactant: ClCC12CCCN1CCC2
Product: O=[N+]([O-])c1cccc2c(NCC34CCCN3CCC4)cccc12
Yield: 45.3 %

Procedure:
1-Amino-5-nitronaphthalene and 5-chloromethyl-1-azabicyclo[3.3.0]octane were reacted in the same manner as in Example 3 to obtain the titled compound in a yield of 45.3%.
Reaction SMILES: [Li]CCCC.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[Se:16][CH:17]=[CH:18][CH:19]=2)=[C:11]([F:20])[C:10]=1[F:21])[CH3:7].[CH:22](N1CCOCC1)=[O:23]>C1COCC1.ClCCl.Cl>[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[Se:16][C:17]([CH:22]=[O:23])=[CH:18][CH:19]=2)=[C:11]([F:20])[C:10]=1[F:21])[CH3:7]
Reactant: O=CN1CCOCC1
Reactant: CCOc1ccc(-c2ccc[se]2)c(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc(C=O)[se]2)c(F)c1F
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
7.6 ml (44.4 mmol) of TMP are initially introduced at −20° C. in THF, and 26.7 ml (42.4 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 25 min at this temperature, a solution of 11.7 g (38.6 mmol) of 2-(4-ethoxy-2,3-difluorophenyl)selenophene in 80 ml of THF is added. When the addition is complete, the batch is warmed to RT over the course of 45 min and left at this temperature for 20 min. The solution is cooled to −40° C., and N-formylmorpholine is added. The reaction mixture is warmed to RT and stirred for 4.5 h. The solution is diluted with a lot of dichloromethane, and 2 N hydrochloric acid is added. The mixture is briefly stirred vigorously, and the organic phase is separated off. The aqueous phase is extracted with dichloromethane, and the combined organic phases are washed with water. The solution is dried using sodium sulfate and concentrated to dryness. The residue is digested in cold ethanol, and the solid is filtered off with suction. Drying in vacuo gives 5-(4-ethoxy-2,3-difluorophenyl)selenophene-2-carbaldehyde as a violet solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:33])[CH2:9][C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.[C:34]1([C@H:40]([NH2:42])[CH3:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:34]1([C@H:40]([NH:42][C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:21]3[CH:20]=[CH:19][C:18]([C@@H:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH3:17])[CH2:9][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[O:33])=[CH:23][CH:22]=3)=[CH:29][CH:28]=2)=[O:31])[CH3:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2C)ccn1
Product: Cc1cc(C(=O)C[C@@H](c2ccc(-c3ccc(C(=O)N[C@H](C)c4ccccc4)cc3)cc2)c2ccccc2C)ccn1

Procedure:
In analogy to example 89, step 2, from 4′-[(S)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid (example 95, step 1) and (R)-(+)-1-phenylethylamine was prepared the title compound as a white foam, MS (ESI+): m/z=539.4 ([M+H]+).
Reaction SMILES: C(O[C:4]([C:6]1[N:10]=[C:9]([CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)[O:8][N:7]=1)=[O:5])C.[CH2:19]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][NH2:34])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[N:13]12[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]1)[CH:11]([C:9]1[O:8][N:7]=[C:6]([C:4](=[O:5])[NH:34][CH2:33][CH2:32][CH:29]3[CH2:28][CH2:27][N:26]([CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:31][CH2:30]3)[N:10]=1)[CH2:12]2
Reactant: CCOC(=O)c1noc(C2CN3CCC2CC3)n1
Reactant: NCCC1CCN(Cc2ccccc2)CC1
Product: O=C(NCCC1CCN(Cc2ccccc2)CC1)c1noc(C2CN3CCC2CC3)n1
Temperature: 100 °C

Procedure:
A mixture of 3-ethoxycarbonyl-5-(quinuclidin-3-yl)-1,2,4-oxadiazole (0.2 g) and 1-benzyl-4-(2-aminoethyl)piperidine (0.26 g) was stirred and heated at 100° C. for 2 hours. The cooled mixture was chromatographed on alumina eluting with chloroform to give 5-(quinuclidin-3-yl)-3-[{2-(1-benzylpiperidin-4-yl)ethyl}carbamoyl]-1,2,4-oxadiazole as an oil. The compound was treated with an ethanol solution of hydrogen chloride, the solution was evaporated in vacuo and the residue was powdered with ether to give 5-(quinuclidin-3-yl)-3-[{2-(1-benzylpiperidin-4-yl)ethyl}carbamoyl]-1,2,4-oxadiazole dihydrochloride (0.2 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[Cl:14])[NH:7][C:6]=1[CH3:15].[H-].[Na+].[CH3:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[Cl:14])[N:7]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:30][CH:29]=2)[C:6]=1[CH3:15]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: COC(=O)Cc1c(C)[nH]c2nccc(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2)c2nccc(Cl)c12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a cooled (0° C.) stirred solution of (4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (0.1 g, 0.42 mmol) in dry DMF (2.5 ml) is added sodium hydride (0.019 g of a 60% dispersion in mineral oil, 0.47 mmol). After stirring at room temperature for 5 hours, the reaction mixture is re-cooled to 0° C. and treated with 4-methylsulfonylbenzyl bromide (0.105 g, 0.42 mmol). The resulting mixture is stirred and allowed to warm to room temperature overnight. The reaction mixture is diluted with water (3 ml) and extracted with ether (3×15 ml). The organic portions are combined, washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting crude residue is loaded on a pre-packed packed Isolute™ silica column and eluted with iso-hexane:ethyl acetate (1:8) to yield the titled compound as a white powder. (MH+ 407).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[C:4]#[N:5].O.N>O1CCOCC1.C(O)C.[Ni].O>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH2:4][NH2:5]
Reactant: Cc1ccc(-c2ccccc2)cc1C#N
Agent: [Ni]
Agent: N
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2ccccc2)cc1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
1.0 g (5.17 mmol) of 2-methyl-5-phenylbenzonitrile (produced in the same manner as in the above-mentioned Reference Production Example 1 (2)) was dissolved in a mixed solvent of 8 ml of 1,4-dioxane and 8 ml of ethanol, and to this solution was added 1.0 g of a suspension of 2 ml of 28 wt % ammonia water and Raney nickel W2 (manufactured by Aldrich; 50 wt % in water). This mixture was stirred for 8 hours at room temperature under hydrogen atmosphere, then, filtrated through celite, and the celite was washed with ethanol and water. The filtrate and washed solution was combined and concentrated under reduced pressure, and the residue was distilled by using Kugelrohl distillation apparatus (0.5 mmHg, set temperature: 216° C.), to obtain 842 mg (4.27 mmol) of 2-methyl-5-phenylbenzylamine.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]([C:6]([OH:8])=[O:7])=O.[C:9]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])[CH3:10]>>[O:11]=[C:9]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:10]/[C:4](=[CH:3]\[CH2:2][CH3:1])/[C:6]([OH:8])=[O:7]
Reactant: CC(=O)c1cccnc1
Reactant: CCCC(=O)C(=O)O
Product: CC/C=C(\CC(=O)c1cccnc1)C(=O)O

Procedure:
In a manner analogous to that described above, by an aldol condensation of 2-oxo-n-valeric acid with 3-acetylpyridine there is obtained γ-oxo-α-[(E)-propylidene]-3-pyridinebutyric acid, MS: 219 (M+H)+. Ring closure with hydrazine yields 4-propyl-6-(3-pyridyl)-3(2H)-pyridazinone, MS: 215 (M)+, which is converted into the corresponding chloride, 3-chloro-4-propyl-6-(3-pyridyl)pyridazine, MS: 233 (M)+. Hydrazinolysis to 3-hydrazino-4-propyl-6-(3-pyridyl)pyridazine, MS: 229 (M)+, and condensation with diethyl (3-pyridyl)malonate yields ethyl rac-8-propyl-α-(3-pyridylmethyl)-6-(3-pyridyl)-s-triazolo[4,3-b]pyridazine-3-acetate, which is converted by basic saponification into the above acid, MS: 388 (M)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([Cl:25])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:12]([O:11][C:10](=[O:16])[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:20]2[C:21]([Cl:25])=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=2)[CH:4]=1)([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CN)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(CNc2nc(Cl)ncc2Cl)c1
Yield: 92.3 %

Procedure:
To a solution of tert-butyl [3-(aminomethyl)phenyl]carbamate (0.50 g, 2.2 mmol) and 2,4,5-trichloropyrimidine (0.45 g, 2.5 mmol) in N,N-dimethylformamide (6 mL) was added potassium carbonate (0.62 g, 4.5 mmol). The resultant mixture was stirred overnight at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, and concentrated. The resulted residue was triturated with methylene chloride and hexanes to give the desired product as an off-white powder (0.75 g, 90%). LCMS for C12H11Cl2N4O2 (M-tBu+H)+: m/z=313.0, 315.0.
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[C:5]([C:11]#[N:12])=[N:6][C:7]([I:10])=[CH:8][N:9]=1>C(O)CCC>[I:10][C:7]1[N:6]=[C:5]2[C:11]([NH2:12])=[N:2][NH:1][C:4]2=[N:9][CH:8]=1
Reactant: NN
Reactant: N#Cc1nc(I)cnc1Cl
Solvent: CCCCO
Product: Nc1n[nH]c2ncc(I)nc12
Temperature: 110 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
0.74 ml (9.8 mmol) of hydrazine is added to 2.6 g (9.80 mmol) of a solution of 3-chloro-6-iodopyrazine-2-carbonitrile in 15 ml of butanol. The reaction mixture is heated at 110° C. for 5 hours and then left at room temperature overnight. The suspended solid is filtered, rinsed with butanol and then dried in an oven at 50° C. to yield 2.2 g (86%) of 5-iodo-1H-pyrazolo[3,4-b]pyrazine-3-amine in the form of a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([OH:15])=[O:14])[C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:21][CH2:22]O>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([O:15][CH2:21][CH3:22])=[O:14])[C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Cc1nc2cc(O)ccc2cc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2ccc(O)cc2nc1C
Temperature: 75 °C

Procedure:
7-Hydroxy-2-methylquinoline-3-carboxylic acid (860 mg, 4.24 mmol) was dissolved in EtOH (29 mL) and H2SO4 (0.3 mL) was added. The reaction was heated at 75° C. for 23 h before being concentrated onto silica. Purification (FCC, SiO2, 0-5%, MeOH/DCM) afforded the title compound as a yellow solid sulfate salt (1.128 g, 81%).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=[NH:9])=[O:8])[CH3:2].[H-].[Na+].I[CH2:24][CH3:25]>CN(C)C=O.O>[CH2:24]([N:9]=[S:7]([CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:8])[CH3:25]
Reactant: CCN(CC)CCCS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN=S(=O)(CCCN(CC)CC)c1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of S-(3-diethylaminopropyl)-S-(4-nitrophenyl)sulfoximine (10 mmol) in dimethylformamide is added to a stirred suspension of 60% sodium hydride-oil dispersion (10 mmol) at ambient temperature. After stirring for 30 min the mixture is warmed to 50° C. for 30 min and then cooled to ambient temperature. Iodoethane (10 mmol) is added dropwise to the reaction mixture and stirred at ambient temperature for 30 min and then warmed to 50° C. for 1 hr. The reaction mixture is diluted with water and extracted with methylene chloride. The methylene chloride extract is concentrated in vacuo and the residue partitioned between methylene chloride-1N hydrochloric acid. The acid layer is separated and basified with 50% sodium hydroxide solution and extracted with methylene chloride. The methylene chloride extract is washed with water, dried, and concentrated to obtain the title compound.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[N:11]=[CH:10][CH:9]=[N:8][C:7]=1[S:6]2.[CH3:17][O:18][C:19](Cl)=[O:20].CI>>[C:19]([N:13]1[C:12]2[N:11]=[CH:10][CH:9]=[N:8][C:7]=2[S:6][C:5]2[C:14]1=[CH:15][CH:16]=[CH:3][CH:4]=2)([O:18][CH3:17])=[O:20]
Reactant: COC(=O)Cl
Reactant: COc1ccc2c(c1)Sc1nccnc1N2
Solvent: CI
Product: COC(=O)N1c2ccccc2Sc2nccnc21
Yield: 23 %

Procedure:
By following the conditions of Example 4, but substituting 1,4-diazaphenothiazine for 7-methoxy 1,4-diazaphenothiazine and methylchloroformate for methyl iodide, the title compound, m.p. 137°-138° was obtained in a 23% yield.
Reaction SMILES: [CH:1]1([C@H:7]([NH2:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:10]1[C:12]([CH3:14])([CH3:13])[CH2:11]1>>[CH:1]1([C@H:7]([NH:9][CH2:11][C:12]([CH3:14])([CH3:13])[OH:10])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CO1
Reactant: C[C@@H](N)C1CCCCC1
Product: C[C@@H](NCC(C)(C)O)C1CCCCC1

Procedure:
(1R)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((1R)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-((1R)-1-Cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl)amine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to afford 2-(2-methyl-4-nitrophenylimino)-3-((1R)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]C)=O)[CH2:3][CH2:2]1.[CH3:12][NH:13][NH2:14]>C(O)C>[CH3:12][N:13]([C:8](=[O:10])[CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[NH2:14]
Reactant: CNN
Reactant: COC(=O)CN1CCOCC1
Solvent: CCO
Product: CN(N)C(=O)CN1CCOCC1
Temperature: 95 °C
Yield: 49.6 %

Procedure:
In a 25 mL, sealed tube, methyl 2-morpholinoacetate (0.5 g, 1.0 eq.) was dissolved in ethanol (5 mL) at RT. Methylhydrazine (0.16 g, 1.1 eq.) was introduced dropwise at RT and the reaction mixture was refluxed at 95° C. for 48 h. The reaction mixture was concentrated under reduced pressure (40° C., 20 mm Hg) to afford the crude N-methyl-2-morpholinoacetohydrazide (0.27 g) which was used without further purification in the following step.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1)[CH3:2].[CH3:21][O-].[Na+].IC>CO.C(Cl)Cl>[CH2:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([O:16][CH3:21])[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1)[CH3:2]
Reactant: CCc1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CI
Product: CCc1ncsc1CSc1nc(OC)cc(C(F)(F)F)n1
Temperature: 65 °C
Yield: 60 %

Procedure:
To a solution of 2-{[(4-ethyl-1,3-thiazol-5-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (500 mg, 1.56 mmol) in anhydrous methanol (10 mL) was added dropwise a solution of 30% sodium methoxide in methanol (310 μL, 1.71 mmol) at 0° C. The mixture was heated to 65° C. for 1 hour. Iodomethane (220 μL, 3.43 mmol) was added at room temperature, and the reaction was heated overnight at 65° C. The solvent was evaporated, and the residue was extracted three times with dichloromethane/water. The combined organic phases were washed with brine, dried over magnesium sulfate, and evaporated to afford a crude oil. The residue was dissolved in DCM and purified on silica gel using DCM/MeOH (0 to 10%) to afford 4-ethyl-5-({[4-methoxy-6-(trifluoromethyl)pyrimidin-2-yl]sulfanyl}methyl)-1,3-thiazole (315 mg, 60% yield). 1H NMR (500 MHz, MeOH-d4): δ 1.21 (t, J=7.5 Hz, 3H), 2.79 (q, J=7.5 Hz, 2H), 3.40 (s, 3H), 4.74 (s, 2H), 6.76 (s, 1H), 8.89 (s, 1H). LRMS (ES+) m/z 336 (100%, M+1).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[C:12](=[O:20])[C:13]([CH2:17][CH2:18]Cl)=[C:14]([CH3:16])[N:15]=[C:10]3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][O:28][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:30][CH2:31][N:32]([CH2:18][CH2:17][C:13]4[C:12](=[O:20])[N:11]5[C:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)=[CH:8][S:9][C:10]5=[N:15][C:14]=4[CH3:16])[CH2:33][CH2:34]3)=[N:27][O:28][C:24]=2[CH:23]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1nc2scc(-c3ccccc3)n2c(=O)c1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2scc(-c3ccccc3)n2c(=O)c1CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 20 °C

Procedure:
In 50 ml de N,N-dimethylformamide, 3.12 g (10.2 mmoles) of 3-phenyl-6-(2-chloroethyl)-7-methyl-thiazolo[3,2-a]pyrimidin-5-one, 2.23 g (10.2 mmoles) of 6-fluoro-3-(4-piperidinyl)-benzisoxazol, 4.50 g (32.5 mmoles) of potassium carbonate and a catalytic amount of potassium iodide were suspended. The reaction mixture was heated for 18 hours at a temperature ranging between 85° and 90° C., cooled to 20° C. and poured into 100 ml of water. The solid formed was purified on silica gel column, using acetonitrile/methanol as eluent. 2.1 g of 6-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-3-phenyl-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one, mp 76°-91° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([C:24](OC)=[O:25])[CH2:17][CH2:16][CH:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH2:14]2)[N:9]1C(=O)C(F)(F)F.[OH-].[Na+].C(OCC)C>C1COCC1>[OH:25][CH2:24][C:8]1([CH3:7])[CH2:17][CH2:16][CH:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH2:14]2)[NH:9]1
Reactant: COC(=O)C1(C)CCC2CC=CC=C2N1C(=O)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(CO)CCC2CC=CC=C2N1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a suspension of lithium aluminum hydride (1.12 g, 29.5 mmol) in THF (10 mL) was added dropwise 2-methyl-N-trifluoroacetyl-2-methoxycarbonyltetrahydroquinoline (8.88 g, 29.5 mmol) in THF (90 mL) over 25 min, while the reaction temperature was maintained at 40°~45° C. The mixture was heated at 60° C. for 1 h and the excess reagent was decomposed by slow addition of aqueous THF at 0° C. Aqueous sodium hydroxide was added and stirred for 30 min followed by addition of diethyl ether. The organic layer was separated, washed with brine three times, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 3:1 hexane/ethyl acetate to give 4.97 g of 2-hydroxymethyl-2-methyltetrahydroquinoline (95%): 1H NMR (270 MHz, CDCl3) δ6.98 (m, 2H), 6.64 (td, 1H, J=7.3, 1 Hz), 3.73 (bs, 1H), 3.47 (s, 2H), 2.76 (m, 2H), 1.93 (bs, 1H), 1.86 (m, 1H), 1.61 (m, 1H), 1.19 (s, 3H).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([OH:15])=O.[NH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH2:34][C:33]1=[O:42]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[N:35]1([C:13]([C:16]2[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=2)[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:15])[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH:32][C:33](=[O:42])[CH2:34]1
Reactant: CN(Cc1cccc(C(=O)O)c1)C(=O)OC(C)(C)C
Reactant: O=C1CNc2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(Cc1cccc(C(=O)N2CC(=O)Nc3ccccc32)c1)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 27.2 %

Procedure:
WSC.HCl (640 mg, 3.4 mmol) and 4-(dimethylamino)pyridine (330 mg, 2.7 mmol) were added to a solution of tert-butyl N-(3-carboxybenzyl)-N-methylcarbamate (700 mg, 2.6 mmol) and 1,2,3,4-tetrahydroquinoxalin-2-one (440 mg, 2.9 mmol) in dichloromethane (20 ml). The mixture was stirred for 18 h, reduced in vacuo and taken up in ethyl acetate. This solution was washed with 0.3N potassium hydrogen sulphate and saturated sodium hydrogen carbonate solutions, dried and reduced. Chromatography (50% EtOAc/50% 60-80 pet.ether) afforded tert-butyl N-(3-(1,2,3,4-tetrahydroquinoxalin-3-on-1-carbonyl) benzyl)-N-methylcarbamate (280 mg, 27%) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[CH3:27].CO.[OH-].[Na+]>N1C=CC=CC=1.O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:1][S:28]([C:23]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:21]([F:20])[CH:22]=2)(=[O:29])=[O:30])[C:3]([C:9]([C:11]2[C:12]3[CH:19]=[CH:18][NH:17][C:13]=3[N:14]=[CH:15][CH:16]=2)=[O:10])=[N:4][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Reactant: Nc1cc(Cl)cnc1C(=O)c1ccnc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2ccnc3[nH]ccc23)cc1F

Procedure:
Prepared from 18 mg (0.066 mmol) of (3-amino-5-chloro-pyridin-2-yl)-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methanone and 48 mg (0.25 mmol) of 3-fluoro-4-methyl-benzenesulfonyl chloride in 0.10 mL pyridine using procedure x. After the sulfonylation was complete, 2 mL methanol, 0.5 mL water and 32 mg sodium hydroxide were used. Yield: 20 mg of a yellow solid. LC-MSD, m/z for C20H14ClFN4O3S [M+H]+=445.0, 447.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([O:27]C)=[O:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[OH-].[Na+].Cl>C(O)C.O1CCCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([OH:27])=[O:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: COC(=O)c1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(F)cc3F)cc1CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OC2)c1ccc(F)cc1F

Procedure:
A solution of methyl 2-((2,4-difluorophenyl)(methyl)carbamoyl)-4H-thieno[3,2-c]chromene-8-carboxylate, sodium hydroxide (115 mg, 2.9 mmol) in ethanol (20 mL), tetrahydrofuran (20 mL) and water (20 mL) was stirred at room temperature for 16 hr. The reaction mixture was acidified to pH=2 with concentrated hydrochloric acid, and the organic solvents were removed in vacuo. The resulting aqueous solution was extracted with ethylacetate. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated to afford 2-((2,4-difluorophenyl)(methyl)carbamoyl)-4H-thieno[3,2-c]chromene-8-carboxylic acid (1.0 g). LCMS (ESI) m/z: 402.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>CO>[OH:13][CH2:12][CH2:14][NH:15][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:11][CH:10]=1
Reactant: NCCO
Reactant: COC(=O)c1ccc(O)cc1
Solvent: CO
Product: O=C(NCCO)c1ccc(O)cc1

Procedure:
A mixture of 80 g of methyl 4-hydroxybenzoate and 120 ml of ethanolamine was heated at 150° C. for five hours during which time 14.2 ml of methanol was distilled off. The excess ethanolamine was removed in vacuo, and the residue was treated with two 150 ml portions of chloroform. The chloroform was removed in vacuo and the residual oil dissolved in acetone from which the product crystallized to give 45.3 g of N-(2-hydroxyethyl)-4-hydroxybenzamide.