Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]([CH2:12][C:13]3[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=3)[CH:9]=[CH:10][N:11]=2)=[CH:3][CH:2]=1.[N:20]([C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:33][CH3:34])=[C:21]=[O:22]>C(Cl)Cl.CN(C=O)C>[CH3:34][O:33][C:24]1[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[CH:28][C:23]=1[NH:20][C:21]([NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:14]=1)=[O:22]
Reactant: Nc1cccc(Cn2ccnc2-c2ccncc2)c1
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1cccc(Cn2ccnc2-c2ccncc2)c1

Procedure:
To a solution of 3-(2-Pyridin-4-yl-imidazol-1-ylmethyl)-phenylamine (50 mg, 0.2 mmol) in DCM (4.0 mL) and DMF (1.0 mL) is added 2-isocyanato-1-methoxy-4-trifluoromethyl-benzene (43 mg, 0.2 mmol) and allowed to react overnight. The resulting crude was concentrated under reduced pressure and the residue is purified by column chromatography (DCM:MeOH) to afford 1-(2-methoxy-5-trifluoromethyl-phenyl)-3-[3-(2-pyridin-4-yl-imidazol-1-ylmethyl)-phenyl]-urea as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH3:31]
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Reactant: CCCBr
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(CCCC(=O)OC)cc1-c1cc(CCCC(=O)OC)ccc1O
Yield: 91.1 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 0.475 ml (5.181 mmol) of propyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 5 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 20 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 50/1) to obtain 202 mg (0.4720 mmol, 91%) of 2-propoxy-2'-hydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 0.94 (3H, t, CH3), 1.6-2.2 (6H, m, 3CH2), 2.36 (4H, t, 2CH2), 2.65 (4H, t, 2CH2), 3.66 (6H, s, 2CH3), 3.99 (2H, t, CH2), 6.60 (1H, s, OH), 6.8-7.3 (6H, m, arom-H) MS (FAB): 427 (M-H)-
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19][C:20]([CH3:23])=[N:21][N:22]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19][C:20]([CH3:23])=[N:21][N:22]=1
Reactant: Cc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3O)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
A mixture of ((2S,5R)-6-(benzyloxy)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (0.2 g, 0.6 mmol) and 10% Pd/C (0.2 g) in THF (20 mL) was stirred under H2 atmosphere at rt for 3 hrs. The reaction mixture was then filtered and concentrated to afford (2S,5R)-6-hydroxy-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (0.13 g, 92%) as a white solid, which was used directly in the next step. ESI-MS (EI+, m/z): 225 [M+H]+.
Reaction SMILES: [SH:1][CH:2]([CH2:5][SH:6])[CH2:3][OH:4].[C:7]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[SH:6][CH2:5][CH:2]1[CH2:3][O:4][C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[S:1]1
Reactant: OCC(S)CS
Reactant: COC(=O)CCC(=O)c1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CCC1(c2ccccc2)OCC(CS)S1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 2,3-dimercapto-1-propanol (2.3 g, 0.019 mol), methyl 3-benzoylpropionate from Example 67 (3.7 g, 0.019 mol) and boron trifluoride etherate (0.5 ml) in methylene chloride (50 ml). The crude product was chromatographed on silica gel using 1% acetone/toluene as eluent to give 1.0 g (31%) of product.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18](=[O:20])[NH:17][C:16]=2[CH:21]=1.Cl[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]2[O:19][C:18](=[O:20])[N:17]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:16]=2[CH:21]=1
Reactant: Cc1ccn2c(C)c(-c3ccc4oc(=O)[nH]c4c3)nc2c1
Reactant: CC(C)(C)OC(=O)CCl
Product: Cc1ccn2c(C)c(-c3ccc4oc(=O)n(CC(=O)OC(C)(C)C)c4c3)nc2c1
Yield: 38 %

Procedure:
5-(3,7-Dimethylimidazo[1,2-a]pyridin-2-yl)-3-t-butoxycarbonylmethyl-2-benzoxazolinone (1.5 g) was prepared in substantially the same manner as that of Example 47 from 5-(3,7-dimethylimidazo[1,2-a]pyridin-2yl)-2-benzoxazolinone (2.8 g) and t-butyl chloroacetate (2.25 g). mp. 198°-200° C. (dec.).
Reaction SMILES: C(OC([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[CH:11][CH:10]=1)=O)(C)(C)C.Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O:19][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc(OCc2ccncc2)c2ccccc12

Procedure:
4-tert-Butyloxycarbonylamino-1-naphthol (41) can be alkylated with 4-chloromethylpyridine hydrochloride in a non-protic solvent, such as acetonitrile, with a base, such as powdered potassium carbonate, at temperatures between 60-80° C. Purification of the product 4-tert-butyloxycarbonylamino-1-(pyridin-4-yl-methyl)naphthalene (44) can be accomplished by silica gel chromatography. Removal of the BOC-protecting group can be accomplished with HCl in a non-protic solvent, such as dioxane, to provide 1-amino-4-(pyridin-4-yl-methoxy)naphthalene (43) as the hydrochloride salt.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[F:21][C:22]([F:32])([F:31])[C@H:23]([NH2:30])[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[F:32][C:22]([F:21])([F:31])[C@H:23]([NH:30][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: N[C@H](c1cccnc1)C(F)(F)F
Product: O=C(N[C@H](c1cccnc1)C(F)(F)F)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (R)-2,2,2-trifluoro-1-pyridin-3-yl-ethylamine (CAN 1212813-98-3) as starting materials. MS (EI): m/e=443.1 [M+H]+.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:29]=[CH:28][C:9]([C:10]([C:12]2[C:21]([O:22]C)=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:17]3)=[O:11])=[CH:8][CH:7]=1>C(Cl)Cl.[Cl-].[Na+].O>[F:5][C:6]1[CH:29]=[CH:28][C:9]([C:10]([C:12]2[C:21]([OH:22])=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:17]3)=[O:11])=[CH:8][CH:7]=1
Reactant: COc1ccc2cc(S(N)(=O)=O)ccc2c1C(=O)c1ccc(F)cc1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(O)ccc2c1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
Boron tribromide (55.7 ml, 1M solution in methylene chloride) was added to a suspension of 5-(4-fluorobenzoyl)-6-methoxy-2-naphthalenesulfonamide (5 g, 14 mmol), [prepared as described in example 1], in methylene chloride (100 ml) at 0° C. After 30 minutes, the reaction mixture was poured into brine and the product was extracted into methylene chloride. The organic layer was washed with brine, dried over sodium sulfate, and concentrated to dryness in vacuo. The crude product was purified by chromatography (silica gel, gradient elution, 20-80% ethyl acetate/hexane) to afford 4.0 g of 5-(4-fluorobenzoyl)-6-hydroxy-2-naphthalenesulfonamide as a solid (83% yield).
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][C:8]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:7][CH2:6]1)=O.[C:16]([O:20][C:21](=[O:35])[CH2:22][CH2:23][N:24]([CH2:28][C:29]1[S:30][C:31]([CH3:34])=[CH:32][CH:33]=1)[C:25]([NH2:27])=[S:26])([CH3:19])([CH3:18])[CH3:17]>CO>[C:16]([O:20][C:21](=[O:35])[CH2:22][CH2:23][N:24]([CH2:28][C:29]1[S:30][C:31]([CH3:34])=[CH:32][CH:33]=1)[C:25]1[S:26][CH:2]=[C:3]([CH:5]2[CH2:10][CH2:9][C:8]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:7][CH2:6]2)[N:27]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1ccc(CN(CCC(=O)OC(C)(C)C)C(N)=S)s1
Reactant: O=C(CBr)C1CCC2(CCCCC2)CC1
Solvent: CO
Product: Cc1ccc(CN(CCC(=O)OC(C)(C)C)c2nc(C3CCC4(CCCCC4)CC3)cs2)s1

Procedure:
2-bromo-1-spiro[5.5]undec-3-yl-ethanone (200 mg, 0.7 mmol) in MeOH (2 mL) was treated with 3-[1-(5-methyl-thiophen-2-ylmethyl)-thioureido]-propionic acid tert-butyl ester (250 mg, 0.8 mmol) following a method analogous to General Procedure C to produce 3-[(5-methyl-thiophen-2-ylmethyl)-(4-spiro[5.5]undec-3-yl-thiazol-2-yl)-amino]-propionic acid tert-butyl ester after workup and purification (45 mg). This propionate ester derivative (45 mg, 0.09 mmol) was hydrolyzed using NaOH (0.5 mL of 2.0N aq solution in 1 mL of 1:1:MeOH:THF) following a method analogous to General Procedure G1 to produce 3-[(5-methyl-thiophen-2-ylmethyl)-(4-spiro[5.5]undec-3-yl-thiazol-2-yl)-amino]-propionic acid after workup (15 mg, 33% yield). LC-MS m/z: 433 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 6.80 (d, 1H), 6.59 (d, 1H), 6.11 (s, 1H), 4.60 (s, 2H), 3.75 (t, 2H), 2.71 (t, 2H), 2.51 (m, 1H), 2.43 (s, 3H), 1.82 (m, 2H), 1.71 (m, 2H), 1.50 (m, 2H), 1.3-1.5 (m, 7H), 1.27-1.13 (m, 5H). Sodium salt of the title compound could be prepared from the title compound following a method analogous to General Procedure H.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:12][CH2:13][CH2:14][C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH2:12][CH2:13][CH2:14][CH:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[OH:23])=[CH:24][CH:25]=1
Reactant: O=C(CCCN1CCCC1Cc1ccc(Cl)cc1)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(CCCN1CCCC1Cc1ccc(Cl)cc1)c1ccc(F)cc1

Procedure:
Stir 0.8 g of 2-(4-chlorobenzyl)-1-[3-(4-fluorobenzoyl)propyl]pyrrolidine at room temperature for 3 hours with 0.5 g of sodium borohydride in 8 ml of methanol/2 ml of water. Concentrate the resulting reaction mixture and then take up the concentrate with water/diethyl ether. Dry the ethereal phase over sodium sulfate and distil off the solvent to obtain the title compound as light-brown viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][C:11]=3[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[N+:26]([O-])([OH:28])=[O:27]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:26]([O-:28])=[O:27])[C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:18][C:11]=3[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2ccc(OC(C)C)cc12
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc([N+](=O)[O-])c(OC(C)C)cc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 32 %

Procedure:
Ethyl 2-(4-chlorophenyl)-5-isopropoxybenzofuran-3-carboxylate 4 (30 g, 0.084 mol) was dissolved in chloroform (75 mL) and the resulting solution was cooled in an ice bath. Nitric acid (55 mL) was also dissolved in chloroform (75 mL) and cooled in an ice bath. The acid solution was added dropwise to the solution of ethyl 2-(4-chlorophenyl)-5-isopropoxybenzofuran-3-carboxylate over 1 hour, and the reaction mixture was then stirred at 0° C. for 1.5 hrs. The reaction mixture was then diluted with water (60 mL) and the layers were separated. The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil which was purified by column chromatography (5/1 PE/EA) to afford ethyl 2-(4-chlorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate as a brown solid (11 g, 32%).
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH2:29])=[O:28]>>[C:27]([C:26]1[CH:25]=[C:24]([NH:23][C:18](=[O:20])[C:17]2[CH:16]=[CH:15][C:14]([S:11]([N:1]3[C:10]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:4][CH2:3][CH2:2]3)(=[O:12])=[O:13])=[CH:22][CH:21]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])[NH2:29]
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: NC(=O)c1cccc(N)c1
Product: NC(=O)c1cccc(NC(=O)c2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2)c1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 3-aminobenzamide (36 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 10-50 EtOAc in dichloromethane. The resulting solid was triturated with dichloromethane/hexanes to give N-(3-carbamoylphenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide as a white solid. Yield: 35 mg (31%). 1H-NMR: 10.58 (s, 1H), 8.22-8.20 (m, 1H), 8.08 (d, J=8.5 Hz, 2H), 7.95 (s, 1H), 7.92-7.88 (m, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.62 (t, J=8.0 Hz, 2H), 7.43 (t, J=7.5 Hz, 1H), 7.35 (s, 1H), 7.24-7.08 (m, 3H), 3.84-3.80 (m, 2H), 2.46 (t, J=7.0, 2H), 1.67-1.59 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([CH3:13])=[CH:4][C:3]=1[CH:14]([CH3:22])[C:15](N1CCCC1)=[O:16].Cl.C1(N=C=NC2CCCCC2)CCCCC1>C(O)(=O)C>[CH3:22][CH:14]1[C:3]2[CH:4]=[C:5]([CH3:13])[C:6]([N:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)=[CH:7][C:2]=2[O:1][C:15]1=[O:16]
Reactant: Cc1cc(C(C)C(=O)N2CCCC2)c(O)cc1N1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc2c(cc1N1CCCC1)OC(=O)C2C
Reaction time: 1 h

Procedure:
A mixture of 1.8 g (6 mmoles) of 2-[2-hydroxy-5-methyl-4-(pyrrolidin-1-yl)-phenyl]-propionic acid pyrrolidide, 2 ml of glacial acetic acid and 2 ml of concentrated hydrochloric acid is boiled under reflux for 40 minutes. The reaction mixture is concentrated by evaporation in vacuo, water is added to the residue, the pH is adjusted to 5 with dilute sodium hydroxide solution and extraction with ether is carried out 3 times. The combined ethereal extracts are dried over sodium sulphate and concentrated in vacuo to 10 ml. 1.2 g (6 mmoles) of N,N'-dicyclohexylcarbodiimide are added thereto and the mixture is left at room temperature for one hour; the residue is filtered off, subsequently washed with ether, and the filtrate is concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with petroleum ether/ether. Subsequent recrystallisation of the pure fractions from ether/petroleum ether yields 3,5-dimethyl-6-(pyrrolidin-1-yl)-benzofuran-2(3H)-one having a melting point of 68°-69°.
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)=[CH:15][CH:14]=1)=[O:11])[CH2:2][CH3:3].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:21][C:22]2[NH:26][CH:25]=[CH:24][N:23]=2)[CH2:36][C:32]2[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=2)=[CH:17][CH:18]=1)=[O:11])[CH2:28][CH3:29]
Reactant: CCCN(CCC)CCCCNC(=O)Nc1ccc(CNCc2ncc[nH]2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCNC(=O)Nc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.4 %

Procedure:
The compound (101 mg) obtained in Example 12-3 was dissolved in anhydrous methanol (4.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (41.8 mg) and sodium cyanoborohydride (47.1 mg). The solution was adjusted to pH 5 by addition of acetic acid, followed by stirring at room temperature for 20 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and subjected to extraction with chloroform. The extract was dried with magnesium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (80.3 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([N:12]=[C:13](SC)SC)[S:9][C:7]=2[N:8]=1.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][N:2]([CH3:18])[C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([NH:12][C:13]3[O:31][C@:23]4([CH2:22][N:21]=3)[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]4)[S:9][C:7]=2[N:8]=1
Reactant: CSC(=Nc1nc2cnc(N(C)C)nc2s1)SC
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ncc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2n1
Temperature: 100 °C
Yield: 74.9 %

Procedure:
A mixture of dimethyl 5-(dimethylamino)thiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (90 mg, 0.301 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (83 mg, 0.361 mmol) and cesium carbonate (196 mg, 0.60 mmol) in DMF (1.0 mL) was heated to 100° C. for 1.5 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo, and the crude residue was purified by silica gel chromatography (2-40% 9:1 methanol: ammonium hydroxide-chloroform) to afford (R)—N5,N5-dimethyl-N2-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-yl)thiazolo[5,4-d]pyrimidine-2,5-diamine (81 mg, 71% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.07 (br. s., 1H) 8.50 (s, 1H) 4.01 (d, J=9.54 Hz, 1H) 3.67 (d, J=9.54 Hz, 1H) 3.39 (dd, J=14.93, 1.63 Hz, 1H) 3.23 (s, 6H) 2.71-3.10 (m, 5H) 2.10-2.24 (m, 2H) 1.68-1.84 (m, 1H) 1.46-1.68 (m, 2H). MS (LC/MS) R.T.=0.87; [M+H]+=360.23.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[CH:11][C:10]([C:21]([O:23]CC)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(OC)c2)n(-c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2cc(C(=O)O)nn2-c2cccc(Cl)c2)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1.50 g (4.20 mmol) of the compound of Example 31A are provided in 20 ml of 1,4-dioxane, 20 ml (20 mmol) of a 1N solution of lithium hydroxide in water are added, and the mixture is stirred at 70° C. for 1 h. The mixture is concentrated, a 1N aqueous hydrogen chloride solution is subsequently added to the residue until the pH is acidic, the mixture is extracted with ethyl acetate, and the combined organic phases are dried over magnesium sulfate, filtered and concentrated. 1.32 g (92% of theory) of the title compound are obtained.
Reaction SMILES: C[Mg]Br.[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:32])[C:14]([N:17]2[C:22](=[O:23])[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:20]([CH:30]=[O:31])[O:19][CH2:18]2)([CH3:16])[CH3:15])[CH:8]=[C:9]([Cl:11])[CH:10]=1.[Cl-].[NH4+].[C:35](OCC)(=O)C>CCOCC.O1CCCC1>[Cl:4][C:5]1[CH:6]=[C:7]([NH:12][C:13](=[O:32])[C:14]([N:17]2[C:22](=[O:23])[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[C:20]([CH:30]([OH:31])[CH3:35])[O:19][CH2:18]2)([CH3:16])[CH3:15])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: CC(C)(C(=O)Nc1cc(Cl)cc(Cl)c1)N1COC(C=O)=C(c2ccccc2)C1=O
Reactant: CCOC(C)=O
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)C1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cc(Cl)cc(Cl)c2)CO1

Procedure:
Methylmagnesium bromide (1.7 ml of a 3M solution in ether) was added dropwise to a stirred solution of N-(3,5-dichlorophenyl)-2-(6-formyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (1.0 g) in dry tetrahydrofuran under an inert atmosphere at -5° C. After 1 hour at that temperature, ammonium chloride solution (saturated) and ethyl acetate were added. The organic phase was washed (brine), dried (magnesium sulphate) and evaporated. The residue was purified by dry column chromatography on silica gel, eluting with dichloromethane/ethyl acetate to give N-(3,5-dichlorophenyl)-2[2,3-dihydro-6-(1-hydroxyethyl)-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl]-2-methylpropanamide (compound 123, 0.27 g) as a cream solid, m.p. 85-88° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:22]=[CH:23][C:24]=3[C:25]#[N:26])[C:20]=2Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:22]=[CH:23][C:24]=3[C:25]#[N:26])[C:20]=2[N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: N#Cc1cnn2c(Cl)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cnn2c(N3CCOCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Temperature: 160 °C
Yield: 90 %

Procedure:
A solution of 50 mg (0.138 mmol) of 6-(4-benzyloxy-phenyl)-7-chloro-pyrazolo[1,5-a]pyrimidine-3-carbonitrile in 2 mL of dimethylformamide in a 5 mL microwave vessel, was added 25 mg (0.18 mmol) of potassium carbonate, followed by 15 mg (0.166 mmol) of morpholine, and the mixture was heated in a microwave synthesizer (Emrys system from Personal Chemistry, 300 W) at 160° C. for 5 min. Since analysis by LC-MS indicated product formation, the reaction mixture was diluted with ethyl acetate, washed with brine (2 times), dried over sodium sulfate and concentrated to give a residue which was purified via reverse-phase chromatography using Gilson to afford (after lyophilization) desired 6-(4-benzyloxy-phenyl)-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile (90% purity) as indicated by 1H NMR; LC-MS—calcd for C24H21N5O2 [M++H]+: 412.17, found: 412.1.