Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:29])[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]2[C@@H:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH2:13][O:12][C:11]2=[O:26])=[CH:5][C:4]=1[O:27][CH3:28].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.[NH4+].[Cl-]>C(Cl)Cl>[N:31]1([C:1]([O:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]3[C@@H:14]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=4)[CH2:13][O:12][C:11]3=[O:26])=[CH:5][C:4]=2[O:27][CH3:28])=[O:29])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1ccc(C[C@H]2COC(=O)[C@@H]2Cc2ccc(OC(=O)Cl)c(OC)c2)cc1OC
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc(C[C@H]2COC(=O)[C@@H]2Cc2ccc(OC(=O)N3CCCC3)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.8 %

Procedure:
To the above solution 4-(((3R,4R)-4-(3,4-dimethoxybenzyl)-2-oxotetrahydrofuran-3-yl)methyl)-2-methoxyphenyl carbonochloridate (124 mg, 0.33 mmol, 1.0 eq) in DCM (15 mL) was added TEA (67 mg, 0.66 mmol, 2.0 eq), followed by pyrrolidine (65 mg, 0.60 mmol, 1.5 eq) at 0° C. The mixture was stirred at rt over 2 days, basified with sat. aq. NH4Cl (30 mL), and extracted with DCM (30 mL×3). The combined organic layers were dried over MgSO4, filtered and concentrated. The resulting residue was purified by prep-HPLC to afford 4-(((3R,4R)-4-(3,4-dimethoxybenzyl)-2-oxotetrahydrofuran-3-yl)methyl)-2-methoxyphenyl pyrrolidine-1-carboxylate (71.0 mg, 45.4% from two steps). LRMS (M+H+) m/z calculated 470.2, found 469.9. 1H NMR (CDCl3, 400 MHz) δ 7.00 (d, 1H), 6.74-6.78 (m, 2H), 6.64-6.70 (m, 1H), 6.50-6.56 (m, 2H), 4.12-4.17 (m, 1H), 3.82-3.90 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.56-3.60 (m, 2H), 3.44-3.48 (m, 2H), 2.97 (d, 2H), 2.48-2.68 (m, 4H), 1.90-1.98 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13](=O)[CH2:14][CH3:15])=[C:6](OS(C)(=O)=O)[CH:7]=1.Cl.Cl.[CH2:19]([NH:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:13]([CH2:14][CH3:15])=[N:27][N:26]2[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: NNCc1ccccc1
Reactant: CCC(=O)c1ccc(Br)cc1OS(C)(=O)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nn(Cc2ccccc2)c2cc(Br)ccc12
Temperature: 135 °C
Yield: 40.9 %

Procedure:
Methanesulfonic acid 5-bromo-2-propionyl-phenyl ester (5.00 g, 16.3 mmol) was combined with benzylhydrazine dihydrochloride (4.45 g, 22.8 mmol) and sodium acetate (4.01 g, 48.9 mmol) in xylenes (30 mL). The reaction mixture was heated to 135° C. for two days using a Dean Stark apparatus. The reaction was cooled to room temperature, diluted with dichloromethane (75 mL), and washed with water (75 mL) and 1N aqueous hydrochloric acid (75 mL). The organic extracts were dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel eluting with 4:1 hexanes/ethyl acetate to yield 2.10 g of 6-bromo-1-benzyl-3ethyl-1H-indazole (41% yield). 1H NMR (400 MHz, CDCl3) δ 1.39 (t, 3, J=7.7), 2.96 (q, 2, J=7.7), 5.48 (s, 2), 7.14-7.23 (m, 3), 7.26-7.31 (m, 3), 7.42 (s, 1), 7.54 (d, 1, J=8.5). 13C NMR (100 MHz, CDCl3) δ 13.70, 20.37, 52.68, 112.12, 120.77, 121.69, 121.83, 123.34, 126.97, 127.76, 128.75, 136.74, 141.37, 147.60. IR 3064, 3031, 2970, 2934, 2875, 1606, 1504, 1497, 1454, 1236, 1048, 831, 701 cm1. Analysis calculated for C16H15BrN2 : C, 60.97; H, 4.80; N, 8.89. Found: C, 61.21; H, 4.92; N, 8.73.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[O:4][N:3]=1.CN(C)CCN(C)C.C([Li])CCC.[C:21](=[O:23])=[O:22].Cl>C1(C)C=CC=CC=1.CCCCCC.O.C(OCC)C>[CH3:1][C:2]1[N:6]=[C:5]([CH2:7][C:21]([OH:23])=[O:22])[O:4][N:3]=1
Reactant: O=C=O
Reactant: Cc1noc(C)n1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1noc(CC(=O)O)n1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
A solution of 4.0 g (40.8 mmol) of 3,5-dimethyl-1,2,4-oxadiazole and of 6.0 ml of N,N,N',N'-tetramethylethylenediamine (TMEDA) in 100 ml of dry toluene was prepared in a 250 ml three-necked glass vessel equipped with a thermometer, a gas inlet tube through which dry nitrogen was introduced continuously and a pressure equalized dropping funnel. The magnetically stirred solution was cooled to -75° C. with an acetone-carbon dioxide bath and by means of the dropping funnel, a solution of approximately 40 mmol of n-butyllithium in 20 ml of n-hexane was added slowly to keep the reaction mixture below -65° C. Afterwards the reaction mixture was stirred for another 60 minutes at -55° to -60° C. Subsequently, the reaction mixture was transferred with a bent ground glass tube to a second vessel containing powdered carbon dioxide covered with a layer of dry diethyl ether and after standing a few hours, the carbon dioxide had practically disappeared from the mixture. 100 ml of water were added, followed by addition of 1 N hydrochloric acid with stirring until a pH of 8 was attained. The layers were separated and the organic layer was discarded and the aqueous layer was shaken twice with 25 ml of diethyl ether. The pH of the aqueous layer was brought to 2.0 with 1 N hydrochloric acid and seven extractions with about 25 ml portions of ethyl acetate at pH 2.0 resulted in almost complete removal of the desired product from the aqueous layer. The extracts were combined, dried over anhydrous magnesium sulfate, and filtered and the filtrate was concentrated in vacuo to a small volume until a crystalline white precipitate appeared. Thin-layer chromatography showed that the supernatant liquid still contained a considerable amount of the desired product and no by-products and the solvent was then completely removed in vacuo. The practically colorless residue was dried to constant weight to obtain 4.2 g (72% yield) of the product with a purity of at least 96% estimated by TLC and PMR spectrum. Recrystallization of the product was effected by dissolution in a minimum volume of chloroform, followed by slow addition of petroleum ether (b.p. 80°-110° C.) until a turbidity appear to obtain 3.6 g of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid with a melting point of about 95° C. (slow decarboxylation sets in at about 90° C.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:36])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[CH:25][CH:24]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:33][C:31]([F:32])([F:34])[C:30]([NH:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][C:20](=[O:36])[C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:15][CH:16]=2)=[CH:28][CH:27]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)CCc3ccc(NC(=O)C(F)(F)F)cc3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1ccc(NC(=O)C(F)(F)F)cc1)c1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A suspension of 4-(4-{3-[4-(2,2,2-trifluoroacetylamino)phenyl]propionyl}-phenyl)piperazine-1-carboxylic acid tert-butyl ester (2.5 g, 4.95 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and diluted with water. The resultant white solid was collected, washed with water, dried in vacuo to give the title compound (1.93 g, 96%). The product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[O:15][C:16]2[C:22]([C:23](OC)=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[NH3:27]>CO>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[O:15][C:16]2[C:22]([C:23]([NH2:27])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: N
Reactant: COC(=O)c1cccc2nc(-c3ccc(-c4ccccn4)cc3F)oc12
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(-c4ccccn4)cc3F)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 84 %

Procedure:
Methyl 2-(2-fluoro-4-(pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxylate (500 mg, 1.40 mmol) was added to ammonia in methanol (30 ml) and the mixture was stirred at room temperature for 3 days. The solid was filtered, washed with methanol and ammonium hydroxide, dried in vacuum. 400 mg of 2-(2-fluoro-4-(pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide as a solid was obtained, yield 84%. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.5-7.54 (m, 2H), 7.87-8.04 (m, 5H), 8.21-8.23 (m, 3H), 8.47 (s, 1H), 8.76 (s, 1H); LC-MS (ESI) m/z: 334 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH3:14][O:15][C:16]1[CH:21]=[C:20]([C:22]2[NH:26][C:25]([CH3:27])=[N:24][N:23]=2)[CH:19]=[CH:18][C:17]=1[NH2:28]>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:28][C:17]1[CH:18]=[CH:19][C:20]([C:22]2[NH:26][C:25]([CH3:27])=[N:24][N:23]=2)=[CH:21][C:16]=1[O:15][CH3:14])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1ccc(F)cc1Cl
Reactant: COc1cc(-c2nnc(C)[nH]2)ccc1N
Solvent: CC#N
Product: COc1cc(-c2nnc(C)[nH]2)ccc1NC(=O)NC(=O)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The solution of equivalent amounts of 2-chloro-4-fluorobenzoyl isocyanate was added dropwise to the solution of 35 mg of 2-methoxy-4-(5-methyl-4H-[1,2,4]triazol-3-yl)phenylamine in 3 ml of acetonitrile and the mixture was stirred at room temperature for 30 minutes. The solid was then filtered off with suction, stirred with t-butyl methyl ether, filtered off with suction and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH2:29]([O:31][C:32](=[O:35])[CH2:33]Br)[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:29]([O:31][C:32](=[O:35])[CH2:33][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=3[CH:27]=2)[C:11]([F:12])([F:13])[F:14])[CH:4]=1)[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)COc1ccc(Cl)c(C(C)C(O)(c2ccc3c(c2)N(C)C(=O)CO3)C(F)(F)F)c1

Procedure:
In analogy to Example 1, step 5, 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4) was reacted with ethylbromoacetate and cesium carbonate to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=500.2 [M−H+].
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([NH:44][CH2:45][C:46](O)=[O:47])(OC(C)(C)C)=O.CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C.CCN(CC)CC>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:46](=[O:47])[CH2:45][NH2:44])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NCC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound (31.8 mg) obtained in Example 25 in DMF (2.0 ml), Et3N (8.4 μl ) was added, Boc-glycine (21 mg) and WSC.HCl (23 mg) were added at room temperature and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, and dried, and the solvent was evaporated under reduced pressure, and then the residue was purified by preparative HPLC. A 4 N hydrogen chloride/ethyl acetate solution was further added thereto, and the reaction mixture was stirred for 1 hour, and then the solvent was evaporated. The obtained residue was dissolved in ethyl acetate, washed with an aqueous saturated sodium hydrogen carbonate solution and brine, dried, and then the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:61]1[CH:70]=[CH:69][C:64]([C:65]([O:67][CH3:68])=[O:66])=[CH:63][C:62]=1[F:71]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:71][C:62]1[CH:63]=[C:64]([CH:69]=[CH:70][C:61]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[C:65]([O:67][CH3:68])=[O:66]
Reactant: COC(=O)c1ccc(Br)c(F)c1
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2CCN(C)CC2)c(F)c1
Temperature: 105 °C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
To 1-methylpiperazine (980 μl, 8.80 mmol) in toluene (15 ml) was added tris(dibenzylidene acetone)dipalladium (201 mg, 0.22 mmol), BINAP (550 mg, 0.88 mmol), and cesium carbonate (4.30 g, 13.2 mmol). The mixture was stirred for 30 minutes before the addition of methyl 4-bromo-3-fluorobenzoate (2.05 g, 8.80 mmol), after which, the temperature was increased to 105° C. and stirred for an additional 18 h. The mixture was cooled and filtered through Celite, washed with ethyl acetate, and the resultant filtrate concentrated in vacuo to afford an orange oil. The residue was purified by column chromatography eluting with 5% methanol in dichloromethane. Pure fractions were concentrated to afford (1.80 g, 81%) of methyl 3-fluoro-4-(4-methylpiperazin-1-yl)benzoate as a colorless oil. 1H NMR (400 MHz, CD3OD): 7.78-7.73 (d, 1H), 7.64-7.59 (d, 1H), 7.09-7.03 (m, 1H), 3.86 (s, 3H), 3.26-3.20 (m, 4H), 2.65-2.59 (m, 4H), 2.35 (s, 3H). MS (EI) for C13H17FN2O2: 253 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[S:31]1[C:35]([C:36]([NH:38][NH2:39])=O)=[N:34][CH:33]=[N:32]1.ClCCl.CO>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:36]([C:35]3[S:31][N:32]=[CH:33][N:34]=3)=[N:38][N:39]=[C:14]2[CH2:13]1)=[O:11]
Reactant: NNC(=O)c1ncns1
Reactant: O=C1CN(C(=O)c2ccc(F)c(Cl)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc(F)c(Cl)c1Cl)N1CCn2c(nnc2-c2ncns2)C1
Temperature: 120 °C

Procedure:
4-[(2,3-Dichloro-4-fluorophenyl)carbonyl]-2-piperazinone (I34) (0.25 g, 0.859 mmol) was dissolved in dichloromethane (DCM) (2.147 ml) and stirred under an argon atmosphere. Triethyloxonium tetrafluoroborate (0.196 g, 1.031 mmol) was added and the solution was left to stir for 40 minutes. A clear solution formed. 1,2,4-Thiadiazole-5-carbohydrazide (I80) (0.149 g, 1.031 mmol) was added and the solution was left to stir under argon for 60 minutes and then the solvent was removed under reduced pressure. 1-Butanol (2.147 ml) was added and the solution was left to reflux at 120° C. under an argon atmosphere for 5 hours. The solvent was removed under reduced pressure to afford a crude light orange solid of 0.56 g. TLC (DCM/MeOH 90:10): showed amide remained but some product had been formed. The crude material was purified by flash chromatography (Biotage SP4, 50 g cartridge) with a gradient of MeOH 0-10% in DCM. The solvent was removed under reduced pressure to afford desired product but still containing some impurities. The isolated material was then purified by MDAP and the solvent was removed under reduced pressure and transferred to a vial. The material was triturated with ether to afford desired product in 5.7 mg.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1SC.[C:25]([C:28]1[CH:29]=[CH:30][C:31]([NH:48][CH2:49][CH3:50])=[C:32]([N:34]=[C:35]2[N:39]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:38](=[O:47])[CH2:37][S:36]2)[CH:33]=1)(=[O:27])[CH3:26]>>[C:25]([C:28]1[CH:29]=[CH:30][C:31]([NH:48][CH2:49][CH3:50])=[C:32]([N:34]=[C:35]2[N:39]([CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:38](=[O:47])[C:37](=[C:14]3[CH:15]=[CH:16][C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:13]3[CH3:12])[S:36]2)[CH:33]=1)(=[O:27])[CH3:26]
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SCC(=O)N1Cc1ccccc1
Reactant: CSc1ccc2ccccc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2C=Cc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 102, 1-methyl-2-methylthioquinolinium p-toluenesulfonate was condensed with 2-(5-acetyl-2-ethylaminophenylimino)-3-benzylthiazolidin-4-one to afford the title compound. 1H-NMR (CDCl3): δ 7.66–7.71 (2H, m), 7.43–7.56 (4H, m), 7.20–7.38 (7H, m), 6.53 (1H, d), 5.20 (2H, s), 3.78 (3H, br s), 3.07 (2H, q), 2.51 (3H, s), 1.06 (3H, t); MS(ESI): 509 (MH+).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[C:15]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[C:16]2[C:21](=[CH:22][C:23]=1[Cl:24])[N:20]=[C:19]([O:25][CH3:26])[C:18]([O:27][CH3:28])=[N:17]2.O[CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:13][C:14]1[C:15]([N:29]([CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[S:30]([CH3:33])(=[O:32])=[O:31])=[C:16]2[C:21](=[CH:22][C:23]=1[Cl:24])[N:20]=[C:19]([O:25][CH3:26])[C:18]([O:27][CH3:28])=[N:17]2
Reactant: COc1nc2cc(Cl)c(Cl)c(NS(C)(=O)=O)c2nc1OC
Reactant: OCc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1nc2cc(Cl)c(Cl)c(N(Cc3cccnc3)S(C)(=O)=O)c2nc1OC
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Diethyl azodicarboxylate (90 μl, 0.57 mmol) was added to a stirred solution of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide (200 mg, 0.57 mmol - see Preparation 3), 3-(hydroxymethyl)pyridine (55 gl, 5 0.57 mmol), and triphenylphosphine (149 mg, 0.57 mmol) in dry tetrahydrofuran (12 ml) under nitrogen at 23° C. After 8 hours, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (gradient elution with ether/methanol) to give N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(3-pyridylmethyl)methanesulphonamide (145 mg, 57%) as a white solid, m.p. 217° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[O:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=[C:8](Cl)[CH:7]=1.[CH2:26]([C:33]#[N:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1(C)C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[O:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=[C:8]([CH:26]([C:33]#[N:34])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:7]=1
Reactant: O=c1c2ccccc2sc2cc(Cl)cc(Oc3cc(Cl)cc(Cl)c3)c12
Reactant: N#CCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: N#CC(c1ccccc1)c1cc(Oc2cc(Cl)cc(Cl)c2)c2c(=O)c3ccccc3sc2c1
Yield: 30.1 %

Procedure:
2 g (4.9 mmol) of 1-(3',5'-dichlorophenoxy)-3-chlorothioxanthone, 0.86 g of benzyl cyanide, 2.03 g of potassium carbonate and 20 ml of DMSO are stirred at 80° C. for 6 hours. The mixture is discharged into 2N HCl/tetrahydronfuran/toluene, and the organic phase is separated off, dired over sodium sulfate and evaporated. Chromatography on silica gel using methylene chloride gives 0.72 g (30%) of product, melting point 145°-155° C.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[C:19]([CH3:22])[C:18]=2[N:23]=O)=[CH:13][CH:12]=1.O>C(O)C>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:21][N:20]=[C:19]([CH3:22])[C:18]=2[NH2:23])=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2[nH]nc(C)c2N=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2[nH]nc(C)c2N)cc1
Reaction time: 0.25 h

Procedure:
6.80 g of sodium dithionite was added to a mixture of 1.23 g of 5-(4-methoxy-phenyl)-3-methyl-4-nitroso-1H-pyrazole (Example 22(c)) and 50 ml of water at 70° C., and the reaction mixture was stirred for 15 minutes. 5 ml of ethanol was added and the reaction mixture was stirred for 10 minutes. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Trituration with ether gave the title compound as a beige solid, melting point 120–122° C., C11H13N3O (203.24), MS (ESI, method B) 204 (M+H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH3:31][CH:32]([CH3:36])[CH2:33][CH:34]=[O:35]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:34]([OH:35])[CH2:33][CH:32]([CH3:36])[CH3:31])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)CC=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(F)cnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)CC(O)c1cc2cc(F)cnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a suspension of 1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine (10 g, 36.2 mmol) in dry tetrahydrofuran (400 mL) at −78° C. was added a n-butyllithium solution in n-hexane (2.5 M, 21.7 mL, 54.3 mmol) dropwise. The mixture was stirred at −78° C. for 30 min and then treated with 3-methyl-butyraldehyde (7 mL, 65.2 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 20% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-butan-1-ol as a colorless oil (9.4 g, 71%): LC/MS m/e calcd for C20H22N2O4S [M+H]+ 363.43, observed 362.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[NH:33][C:32](=[O:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[NH:33][C:32](=[O:34])[O:31][N:30]=4)=[CH:27][CH:28]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc(-c2noc(=O)[nH]2)cc1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc(-c2noc(=O)[nH]2)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
120 mg (purity 93%, 0.37 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 2.2B) and 1.2 eq. of 3-(4-aminophenyl)-1,2,4-oxadiazol-5(4H)-one (Example 1.5A) were reacted according to General Method 1. Yield: 23 mg (13% of theory)