Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10](O)=[O:11])=[O:6])[CH2:2][CH3:3].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:59][C@@H:60]([CH2:75][C:76]1[CH:81]=[C:80]([F:82])[CH:79]=[C:78]([F:83])[CH:77]=1)[C@H:61]([OH:74])[CH2:62][NH:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([CH:71]([CH3:73])[CH3:72])[CH:66]=1>CN(C=O)C>[F:82][C:80]1[CH:81]=[C:76]([CH:77]=[C:78]([F:83])[CH:79]=1)[CH2:75][C@H:60]([NH:59][C:10](=[O:11])[C:9]1[CH:13]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:21][CH2:22][CH3:23])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:8]=1)[C@H:61]([OH:74])[CH2:62][NH:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([CH:71]([CH3:73])[CH3:72])[CH:66]=1
Reactant: CC(C)c1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2nccs2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(C(C)C)c2)cc(-c2nccs2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[(Dipropylamino)carbonyl]-5-(1,3-thiazol-2-yl)benzoic acid is dissolved in DMF (8 mL), and diisopropylethylamine (456 μL, 2.6 mmol), HATU (342 mg, 0.9 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-isopropylbenzyl)amino]butan-2-ol dihydrochloride (350 mg, 0.83 mmol) are added. The reaction stirred at room temperature 1 h. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) provides the title compound as the free base. The residue is dissolved in diethyl ether (5 mL) and 1N hydrochloric acid in diethyl ether (2 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 663.3 [M+H]+.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[CH:8][N:7]=[C:6]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[C:5]=12.CN(C=O)C.[Br:28]N1C(=O)CCC1=O>O>[Br:28][C:9]1[N:4]2[N:3]=[N:2][N:1]=[C:5]2[C:6]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccn3nnnc23)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3nnnc23)CC1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
A 3 L round bottom flask was charged with tert-butyl 4-(tetrazolo[1,5-a]pyrazin-8-yl)piperazine-1-carboxylate (500 g, 1.6 mol) and DMF (2 L). To the above was added N-bromosuccinimide (320 g, 1.8 mol) in portions at 10° C. The resulting mixture was stirred at 10° C. for 0.5 h. Work-up: the reaction mixture was poured into water (3 L). The resulting crystalline solid was collected by filtration, washed with water (300 mL), and dried to afford 500 g (79%) of the product as a red solid. MS m/z: 384 (M+H+).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[N:7][C:8]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:10]=1[Sn](C)(C)C.[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[Br:1][C:10]1[CH:9]=[C:8]([C:15]([F:18])([F:17])[F:16])[N:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: BrBr
Reactant: COc1cnc(C(F)(F)F)cc1[Sn](C)(C)C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cnc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine (0.52 ml, 10 mmol) was added via syringe to a stirred solution of 3-methoxy-6-trifluoromethyl-4-trimethylstannylpyridine (1.7 g, 5 mmol) in dichloromethane (25 ml). The reaction mixture was stirred for 30 min at room temperature and treated with saturated aqueous Na2SO3 (15 ml). The phases were separated. The aqueous layer was extracted with dichloromethane (2×15 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (hexane:ethyl acetate 0-15%) to afford 4-bromo-3-methoxy-6-trifluoromethylpyridine as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][C@@H:20]3[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]3[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:12]=[CH:11]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:62][CH2:63][CH2:64][Cl:65]>CC(C)=O>[Cl:65][CH2:64][CH2:63][CH2:62][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][C@@H:20]3[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])[C@H:21]3[O:22][C:23](=[O:28])[C:24]([CH3:26])([CH3:27])[CH3:25])[CH:12]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2cccc3ccn(CCc4ccc(O)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2cccc3ccn(CCc4ccc(OCCCCl)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[2-(4-hydroxyphenyl)ethyl]-7-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indole (0.2 g), cesium carbonate (0.17 g) and 1-bromo-3-chloropropane (0.05 mL) in acetone (4 mL) was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1) to give 1-{2-[4-(3-chloropropoxy)phenyl]ethyl}-7-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indole (0.21 g). This material was dissolved in acetonitrile (6 mL). To the solution was added sodium iodide (46 mg), and the mixture was heated for reflux overnight. To the reaction mixture were added tris(hydroxymethyl)aminomethane (0.31 g) and ethanol (4 mL), and the mixture was stirred at 60° C. for 2 days. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: methylene chloride/methanol=30/1-5/1) to give 1-[2-(4-{3-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl-amino]propoxy}phenyl)ethyl]-7-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indole (0.13 g). This material was dissolved in methanol (3 mL). To the solution were added water (0.3 mL) and lithium hydroxide monohydrate (24 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction method on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (71 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1.Cl.[CH2:15](OCC)[CH3:16]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH2:15][CH3:16])=[O:12])=[CH:2]1
Reactant: CCOCC
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1c[nH]c2ccccc12
Yield: 158.3 %

Procedure:
Indole-3-acetic acid (3.5 g, 20 mmol) was dissolved in ethanol (70 Cm3) and a solution of hydrogen chloride in diethyl ether (12 cm3, 12 mmol) was added. The reaction was heated to reflux for 5 hand upon cooling the solvent was removed under reduced pressure to provide ethyl indole-3-acetate (4 g, 19 mmol, 98%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10](B(O)O)[CH:9]=[N:8][C:7]=12)[CH3:2].O1CCOCC1.Br[C:22]1[S:23][C:24]2[C:30]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[C:29]([C@H:38]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:28]([CH3:49])=[CH:27][C:25]=2[N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:45]([O:44][C@@H:38]([C:29]1[C:28]([CH3:49])=[CH:27][C:25]2[N:26]=[C:22]([C:10]3[CH:9]=[N:8][C:7]4[N:6]([N:5]=[CH:4][C:3]=4[CH2:1][CH3:2])[CH:11]=3)[S:23][C:24]=2[C:30]=1[C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[C:39]([O:41][CH2:42][CH3:43])=[O:40])([CH3:46])([CH3:47])[CH3:48]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: CCc1cnn2cc(B(O)O)cnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc4c(CC)cnn4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of the crude 3-ethylpyrazolo[1,5-a]pyrimidin-6-ylboronic acid in dioxane (˜0.18M, 0.68 mL, 0.123 mmol) was added (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (50 mg, 0.101 mmol), Pd(PPh3)4 (12 mg, 0.010 mmol) and 2M potassium carbonate (0.20 mL, 0.404 mmol) was heated in a microwave at 110° C. for 1 h. Reaction mixture was stored overnight at rt, diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 30% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C30H32ClN4O3S: 563.2 (M+H+); Found: 563.3 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][CH2:21]Cl.O>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([O:12][CH2:19][O:20][CH3:21])=[CH:10][N:11]=2)[CH2:2][CH2:3]1
Reactant: COCCl
Reactant: Oc1ccc(OCC2CC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(OCC2CC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-(cyclopropylmethoxy)pyridin-3-ol (855 mg) and potassium carbonate (1.44 g) in DMF (15 mL) was added chloromethyl methyl ether (0.635 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (789 mg) as an oil.
Reaction SMILES: [Li+].[OH-].C(OC([C:8]1[C:13]([Cl:14])=[CH:12][C:11](=[O:15])[N:10]([CH3:16])[C:9]=1[NH:17][CH3:18])=O)C.Cl>CO.C1COCC1>[Cl:14][C:13]1[CH:8]=[C:9]([NH:17][CH3:18])[N:10]([CH3:16])[C:11](=[O:15])[CH:12]=1
Reactant: CCOC(=O)c1c(Cl)cc(=O)n(C)c1NC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(Cl)cc(=O)n1C
Temperature: 25 °C
Reaction time: 43 h
Yield: 60.1 %

Procedure:
An aqueous solution of LiOH (2N, 400 mmol, 200 mL) was slowly added at 0° C. to a stirring solution of example 31c (16.0 g, 65.6 mmol) in MeOH/THF (200 mL/100 mL). The reaction mixture was allowed to warm to room temperature and stirred for 43 h. The solution was adjusted to neutral pH with 1N HCl and extracted with EtOAc. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give 6.8 g (60%) of clean desired product as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 6.87 (q, 1H, J=4.4 Hz), 5.63 (s, 1H), 5.35 (s, 1H), 3.25 (s, 3H), 2.72 (d, 3H, J=4.4 Hz). MS (ES) [m+H] calc'd for C7H9ClN2O, 173, 175; found 173, 175.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10](=O)[CH2:11][CH2:12][C:13](=O)[CH3:14]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([N:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:9])[N:7]=1
Reactant: Nc1cccc(Cl)n1
Reactant: CC(=O)CCC(C)=O
Product: Cc1ccc(C)n1-c1cccc(Cl)n1
Yield: 54.9 %

Procedure:
The product from Example 12a (20 g, 156 mmol) was treated with hexane-2,5-dione (18.3 mL, 156 mmol) for 2 h following the procedure from Example 2a giving the title compound (17.7 g 55%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=[O:7])[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C(O)(=O)C.[N+:16]([O-])([OH:18])=[O:17]>C(OC(=O)C)(=O)C>[N+:16]([C:10]1[CH:9]=[CH:8][C:3]2[C:4]([CH:6]=[O:7])=[CH:5][S:1][C:2]=2[CH:11]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1csc2ccccc12
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=Cc1csc2cc([N+](=O)[O-])ccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 9 g of benzo[b]thiophene-3-carboxaldehyde in 50 ml of acetic anhydride was cooled to 0° C. by means of an external ethanol/ice bath. A solution of 40 ml of acetic acid and 20 ml of fuming nitric acid was added at such a rate to maintain the temperature of the reaction at 0°-5° C. Following the addition of the reagents, the reaction mixture was stirred for 1.5 hours. The reaction mixture was poured into 500 ml of ice and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The resulting oil was treated with ethanol. A solid formed, which was recovered by filtration providing 1.3 g of 6-nitrobenzo[b]thiophene-3-carboxaldehyde, m.p. 187°-192° C.
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6](=O)[C@@H:7]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:8]([CH3:13])[C:9]([F:12])([F:11])[F:10])C.Cl>C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([NH:14][C@H:7]([CH2:6][OH:5])[C@@H:8]([CH3:13])[C:9]([F:10])([F:11])[F:12])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: CCOC(=O)[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)[C@H](C)C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]([C@@H](CO)NS(=O)(=O)c1ccc(Cl)cc1)C(F)(F)F
Reaction time: 12 h
Yield: 70.9 %

Procedure:
A solution of lithium borohydride (2.0 M in THF, 0.34 mL) was added to a solution of (2S,3S)-2-(4-chloro-benzenesulfonylamino)-4,4,4-trifluoro-3-methyl-butyric acid ethyl ester (126 mg, 0.34 mmol) in THF (5 mL) and stirred for 12 h. Careful addition of 2N HCl (aq) was performed until pH<2. Organic solvent was removed in vacuo. The aqueous layer was extracted with EtOAc (2×20 mL) and organic layers were combined and washed with brine. The organic layer was dried over Na2SO4 and solvent removed in vacuo. The crude solid was purified by flash chromatography (20% EtOAc/hexanes) to provide a white solid (80 mg) in 71 % yield. Mass Spectrum (−ESI): 330.0 [M−H]−.
Reaction SMILES: [Cl:1][C:2]([Cl:19])([Cl:18])[CH2:3][O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15]CC)=[O:14])[CH2:9][CH2:8]1)=[O:6]>[OH-].[K+].C(O)C.O>[Cl:19][C:2]([Cl:1])([Cl:18])[CH2:3][O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1)=[O:6]
Reactant: CCOC(=O)C1CCN(C(=O)OCC(Cl)(Cl)Cl)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCC(Cl)(Cl)Cl)CC1
Yield: 43 %

Procedure:
Ethyl 1-(2,2,2-trichloroethoxycarbonyl)piperidine-4-carboxylate (158 g, 0.48 mol) was dissolved in a 2 N potassium hydroxide-ethanol solution (500 mL) and water (500 mL), followed by heating under reflux for about 1 hour. After cooling, to the reaction mixture was added water (300 mL), followed by extraction with ethyl acetate (300 mL×3). The aqueous layer was added a 10% aqueous citric acid solution, followed by extraction with ethyl acetate (500 mL×3), and the acidic fraction extracted was washed with saturated brine (300 mL). The resultant was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated. The residue was washed with hexane to obtain 62.9 g of 1-(2,2,2-trichloroethoxycarbonyl)piperidine-4-carboxylic acid as a colorless crystal (yield 43%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C(F)(F)F)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCCc3ccccc3)c3cc(C(F)(F)F)sc3n2)cc1

Procedure:
The reaction procedure as above wherein phenethylamine is reacted with 4-(4-chloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-(4-phenethylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-yl)-benzoic acid methylester.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.[Na].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[NH:15][S:16]([C:19]1[N:29]=[C:22]2[N:23]=[C:24]([CH3:28])[CH:25]=[C:26](Cl)[N:21]2[N:20]=1)(=[O:18])=[O:17].Cl>CO.C(Cl)Cl.CO>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[NH:15][S:16]([C:19]1[N:29]=[C:22]2[N:23]=[C:24]([CH3:28])[CH:25]=[C:26]([O:2][CH3:1])[N:21]2[N:20]=1)(=[O:18])=[O:17]
Reactant: Cc1cc(Cl)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C)nc2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn12
Reaction time: 0.17 h

Procedure:
A sodium methoxide-methanol solution was made by dissolving 0.3 g (13 mg-atom) of sodium metal into 20 ml of absolute methanol. To this solution was added 1.0 g (2.5 mmol) of N-(2,6-dichlorophenyl)-7-chloro-5-methyl-1,2,4-triazolo-[1,5-a]pyrimidine-2-sulfonamide. A mild exotherm ensued and the reaction was complete within 10 min as determined by TLC (20 percent methanol-methylene chloride). The solution was acidified with 6N aqueous HCl and the resulting white solid collected. Recovered 0.9 g (93 percent) of a white powder; mp 214°-215° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2].[NH2:24][CH2:25][CH:26]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH:24][CH2:25][CH:26]4[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(C(=O)OC(C)(C)C)C4)cc3)oc12

Procedure:
The title compound was prepared from 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (INTERMEDIATE 36) and tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate by a procedure analogous to that described in EXAMPLE 1. Mass spectrum (ESI) 489.3 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][C:17]1[C:25]2[C:21](=[N:22][O:23][N:24]=2)[CH:20]=[C:19]([CH2:26][CH3:27])[C:18]=1Br)(=[O:15])=[O:14].[Cu](C#N)[C:31]#[N:32].N>N1C=CC=CC=1>[CH3:1][N:2]([CH3:29])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:16][C:17]1[C:25]2[C:21](=[N:22][O:23][N:24]=2)[CH:20]=[C:19]([CH2:26][CH3:27])[C:18]=1[C:31]#[N:32])(=[O:15])=[O:14]
Reactant: CCc1cc2nonc2c(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)c1Br
Reactant: N#C[Cu]C#N
Agent: N
Solvent: c1ccncc1
Product: CCc1cc2nonc2c(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)c1C#N

Procedure:
A mixture of 4.6 g of 5-dimethylamino-N-(5-bromo-6-ethyl-2,1,3-benzoxadiazol-4-yl)-1-naphthalenesulfonamide and 1.3 g of copper cyanide is heated for 8 hours at 120° in 30 ml of pyridine. The mixture is poured onto aqueous ammonia solution, worked up in the customary manner and 5-dimethylamino- N-(5-cyano-6-ethyl-2,1,3-benzoxadiazol-4-yl)-1-naphthalenesulfonamide is obtained.
Reaction SMILES: Cl[CH:2]1[C:6]2=[N:7][C:8]3[N:9]([CH2:21][CH3:22])[CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[O:4][CH2:3]1>CO.[Pd]>[CH2:21]([N:9]1[C:8]2[N:7]=[C:6]3[CH2:2][CH2:3][O:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10]1)[CH3:22]
Reactant: CCOC(=O)c1cn(CC)c2nc3c(cc2c1=O)OCC3Cl
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cn(CC)c2nc3c(cc2c1=O)OCC3
Yield: 89.6 %

Procedure:
300 mg of the crude ethyl 3-chloro-5-ethyl-8-oxo-2,3,5,8-tetrahydrofuro[3,2-b]-1,8-naphthyridine-7-carboxylate (Compound XII where R1 =R3 =C2H5) obtained above was dissolved in 30 ml of methanol, which was reduced over 5% palladium black (200 mg) under atmospheric pressure. After reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to obtain 240 mg of crude ethyl 5-ethyl-8-oxo-2,3,5,8-tetrahydrofuro[3,2-b]-1,8-naphthyridine-7-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](F)[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.C([N:28](CC)CC)C.C([O-])(=O)C.[NH4+]>O1CCOCC1>[NH2:28][C:6]1[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c([N+](=O)[O-])c2F)c1=O
Reactant: CCN(CC)CC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c([N+](=O)[O-])c2N)c1=O
Temperature: 90 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
To stirred solution of 200 grams (0.519 mole) of 3-(4-chloro-2,6-difluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 1000 mL of dioxane was added 150 mL (1.091 moles) of triethylamine in one portion. Upon completion of addition, the mixture was vigorously stirred and 400 grams (5.189 moles) of ammonium acetate was added in one portion. The reaction mixture was heated to 90° C. where it stirred for two hours. The reaction mixture was allowed to cool to ambient temperature where it stirred for about 18 hours. The resulting suspension was collected by filtration and washed with dioxane. The filtrate was concentrated under reduced pressure to yield a viscous dark oil. The oil was poured into ice-water. The resulting solid was collected by filtration and washed with water. The solid was dried under reduced pressure and then at ambient temperature for about 18 hours, yielding 195.1 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[CH2:20][N:21]2[CH2:25][CH2:24][O:23][C:22]2=[O:26])[CH:7]=1)C.[OH-].[Li+]>CO.O>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:27])=[O:3])[CH:11]=[CH:10][CH:9]=2)=[C:14]([CH2:20][N:21]2[CH2:25][CH2:24][O:23][C:22]2=[O:26])[CH:15]=1
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C)cc2CN2CCOC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(Oc2cccc(CC(=O)O)c2)c(CN2CCOC2=O)c1

Procedure:
Hydrolysis of {3-[4-methyl-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid ethyl ester with lithium hydroxide in MeOH and H2O at 60° C. provided the desired product.