Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([CH:13]([CH3:15])[CH3:14])[O:9]2)=[CH:4][CH:3]=1.[CH:24](O)=O>C(OCC)(=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[C:6](=[O:23])[C:5]3[CH:4]=[CH:3][C:2]4[NH:1][CH:24]=[N:12][C:11]=4[C:10]=3[O:9][C:8]=2[CH:13]([CH3:14])[CH3:15])=[CH:21][CH:20]=1
Reactant: CC(C)c1oc2c(N)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Reactant: O=CO
Solvent: CCOC(C)=O
Product: CC(C)c1oc2c(ccc3[nH]cnc32)c(=O)c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
7,8-Diamino-3-(4-chlorophenyl)-2-isopropyl-chromen-4-one (43 mg, 0.13 mmol) is dissolved in formic acid (1.5 ml), and the solution is heated at reflux for 1 h. The reaction mixture is cooled to room temperature, diluted with ethyl acetate (40 ml) and washed with saturated sodium bicarbonate solution (2×30 ml), water (40 ml) and saturated brine (30 ml). The organic layer is dried (MgSO4), filtered and evaporated to give a pale yellow solid. This is triturated with n-hexane/ethyl acetate/dichloromethane and filtered to give a colourless powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[N:2]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])[N:2]=1
Reactant: Nc1cccnn1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 9.3 %

Procedure:
To a solution of pyridazine-3-amine (2.00 g, 21.0 mmol) and pyridine (5.10 ml, 63.1 mmol) in tetrahydrofuran (100 ml) was added 2,2,2-trichloroethyl chloroformate (4.34 ml, 31.5 mmol) with ice-cooling, the mixture was stirred for 50 minutes with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product (530 mg, 9.3%) as a solid.
Reaction SMILES: [CH:1](/[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=1>CC(N(C)C)=O.[Cu]>[CH:1](/[C:9]1[N:10]([C:21]2[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=2)[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C(=C/c1nc2ccccc2[nH]1)\c1ccccc1
Reactant: FC(F)(F)c1cccnc1Cl
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1cccnc1-n1c(/C=C/c2ccccc2)nc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 4.6 %

Procedure:
To a stirred solution of (E)-2-styryl-1H-benzimidazole (0.49 g, 2.2 mmol) in dimethylacetamide (20 ml) at 0° C. under a nitrogen atmosphere was added sodium hydride (0.11 g, 2.8 mmol). After stirring at 0° C. for 20 min. and then at room temperature for 30 min., a solution of 2-chloro-3-trifluoromethylpyridine (0.60 g, 3.3 mmol) in dimethylacetamide (5 ml) was added. The resulting mixture was heated to reflux for about 3 h 20 min. After cooling, copper bronze (0.45 g, 7.1 mg-atom) was added and heating was continued for 9 h 20 min. The reaction mixture was filtered through a pad of celite and the filtrate was diluted with dichloromethane (200 ml), washed consecutively with water (3×200 ml) and brine (100 ml), dried (magnesium sulfate) and concentrated to dryness. Purification by column chromatography (silica gel, 150 g; n-hexane/ethyl acetate (2/1)) followed by recrystallization from a mixture of isopropyl ether and n-hexane yielded 37 mg (5%) of the titled compound as white solids.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH3:14].[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27](O)=O)=[CH:25][C:24]([CH:30]([F:32])[F:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27]3[O:12][C:11](=[O:13])[C:10]4[C:2](=[C:3]([CH3:14])[CH:4]=[C:5]5[CH:6]=[N:7][NH:8][C:9]5=4)[N:1]=3)=[CH:25][C:24]([CH:30]([F:32])[F:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc2cn[nH]c2c(C(=O)O)c1N
Reactant: O=C(O)c1cc(C(F)F)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(C(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 540 mg (2.82 mmol) of 6-amino-5-methyl-1H-indazole-7-carboxylic acid in 20 mL of anhydrous acetonitrile is added 771 mg (2.82 mmol) of 2-(3-chloro-pyridin-2-yl)-5-difluoromethyl-2H-pyrazole-3-carboxylic acid followed by 1.02 mL (12.7 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 766 μL (9.9 mmol) of methanesulfonyl chloride is added dropwise. The mixture is stirred at 50° C. for 16 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated, washed with cold water and dried. The pale yellowish product obtained is engaged in the next step; LC/MS:429/431 (M+H)+.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C[Si]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(C)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=O)=[CH:24][CH:23]=1>C1COCC1>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:26][CH:27]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)C[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccc(O)cc1)c1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
A solution of lithium hexamethyldisilazide (23.1 mL, 1 M in THF) was added to a stirred solution of ethyl (trimethylsilyl)acetate (2.53 mL, 13.9 mmol) in THF (15 mL) in 10 minutes at −78° C. The reaction mixture was further stirred at this temperature for 20 minutes. A solution of (4-fluoro-phenyl)-(4-hydroxy-phenyl)-methanone (2 g, 9.2 mmol) in THF (30 mL) was slowly added to the reaction mixture. The reaction mixture was brought to 0° C. over 5 hours. The reaction mixture was quenched with saturated NH4Cl solution, extracted into EtOAc and washed with dilute NH4Cl solution. The organic layer was dried over magnesium sulfate. The solvent was removed under vacuum, and the resulting product was flash chromatographed on silica gel, giving M2.1 as an oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.[CH2:19]([NH:21][C:22]([C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][N:25]=1)=[O:23])[CH3:20].O>C(=O)([O-])[O-].[K+].[K+].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>[CH2:19]([NH:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)=[CH:26][N:25]=1)=[O:23])[CH3:20]
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: CCNC(=O)c1ccc(Br)cn1
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: O
Product: CCNC(=O)c1ccc(-c2cnc3[nH]ccc3c2)cn1
Temperature: 80 °C
Yield: 108.2 %

Procedure:
5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (37, 0.424 g, 1.74 mmol), 5-bromo-pyridine-2-carboxylic acid ethylamide (36, 0.159 g, 0.694 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.016 g, 0.014 mmol) were mixed in 1.00 M potassium carbonate in water (4.2 mL, 4.2 mmol). The reaction mixture was heated at 80° C. overnight. The two layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The crude material was purified by silica gel flash chromatography. The appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (38, 200 mg). MS (ESI) [M+H+]+=267.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+].[CH2:15]([SH:17])[CH3:16]>CC(C)=O.O>[Cl:1][C:2]1[N:3]=[C:4]([S:17][CH2:15][CH3:16])[C:5]2[N:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CCS
Reactant: Clc1nc(Cl)c2ncccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCSc1nc(Cl)nc2cccnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A suspension of 15 gm (0.075 mol) of 2,4-dichloropyrido[3,2-d]pyrimidine in 100 ml of acetone at -40°C was admixed with a solution of 3.2 gm (0.08 mol) of sodium hydroxide and 4.9 gm (5.8 ml) of ethylmercaptan in 25 ml of water, and the mixture was stirred for two hours at room temperature. Thereafter, 200 ml of water were added to the reaction mixture, and the precipitate formed thereby was collected and recrystallized from petroleum ether, yielding 11.0 gm (65% of theory) of 2-chloro-4-ethylmercapto-pyrido[3,2-d]pyrimidine, m.p. 101°-103°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=2)[N:7]=1)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[S:39])[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2c(Cl)cccc2c1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2c(Cl)cccc2c1=S
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Ethyl-8-chloro-4-oxo-1-[4-(1H-pyrazol-1-yl)benzyl]-1,4-dihydrocinnoline-3-carboxylate (627 mg, 1.53 mmol) was dissolved in toluene (7 mL), treated with Lawesson's Reagent (434 mg, 1.074 mmol, 0.7 equiv) and placed into an oil bath preheated at 105° C. for 5 minutes. The mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by silica gel gradient chromatography (100:0 to 60:40; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][C:14]([OH:16])=[O:15].[S:17]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:22]([C:19]1[CH:20]=[CH:21][S:17][CH:18]=1)(=[O:24])=[O:23])[CH:7]=[C:6]2[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: COc1ccc2[nH]cc(CCC(=O)O)c2c1
Product: COc1ccc2c(c1)c(CCC(=O)O)cn2S(=O)(=O)c1ccsc1

Procedure:
3-[5-Methoxy-1-(thiophene-3-sulfonyl)-1H-indol-3-yl]-propionic acid 99 was prepared from 3-(5-methoxy-1H-indol-3-yl)-propionic acid 96 and 3-thienyl-sulfonyl chloride using the same protocol as described in step 8, Example 4. (M−1, 364.4)
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19](CC)CC)[CH3:18].C(Cl)(=O)OCC.C(N)C>O.O1CCCC1>[CH2:17]([NH:19][C:14](=[O:16])[CH2:13][CH2:12][C:8]1[CH:9]=[N:10][O:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:18]
Reactant: CCN(CC)CC
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)CCc1cnoc1-c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a mixture of 3-(5-phenyl-4-isoxazolyl)propionic acid (1.00 g), triethylamine (1.0 ml) and tetrahydrofuran (50 ml) was added ethyl chlorocarbonate (0.5 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ethylamine solution (10 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give N-ethyl-3-(5-phenyl-4-isoxazolyl)propionamide (0.93 g, yield 83%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 75–76° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([O:12][CH3:13])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[Br:15]Br.O>C(Cl)(Cl)Cl>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([O:12][CH3:13])=[O:11])[CH:9]=1)=[O:3]
Reactant: COS(=O)c1cc(C(C)=O)ccc1C
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: O
Product: COS(=O)c1cc(C(=O)CBr)ccc1C
Temperature: 40 °C
Yield: 89.4 %

Procedure:
In 200 ml of chloroform was dissolved 21.2 g of methyl 5-acetyl-2-methylbenzenesulfinate and then 16.8 g of bromine was added dropwise to the solution with stirring at 40° C. After the reaction was over, the reaction mixture was added to 500 ml of water and the chloroform layer formed was recovered, washed with a saturated aqueous sodium hydrogencarbonate solution, and dried with anhydrous magnesium sulfate. Then, the solvent was distilled off and the crude crystals formed were recrystallized from ethanol to provide 26 g of methyl 5-bromoacetyl-2-methylbenzenesulfinate having a melting point of 123°-125° C.
Reaction SMILES: [CH2:1]([OH:7])[C@H:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH3:8][C:9]([CH3:11])=O>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>[CH3:8][C:9]1([CH3:11])[O:6][C@H:2]([CH2:3][CH2:4][OH:5])[CH2:1][O:7]1
Reactant: OCC[C@@H](O)CO
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)OC[C@@H](CCO)O1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 72.3 %

Procedure:
A mixture of (R)-(+)-1,2,4-butanetriol (30 g, 283 mmol), acetone (200 ml, 2724 mmol) and p-toluenesulfonic acid monohydrate (1.4 g, 7.36 mmol) was stirred at room temperature for 16.5 hours. To the reaction mixture, triethylamine was added and the mixture was concentrated. The crude product was purified by silica gel column chromatography (silica gel, elution solvent: heptane/ethyl acetate=1/0→1/1→1/3 gradient). Desired fractions were concentrated to obtain the title compound (29.9 g, 72.3% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1C(O)=O>C1(C)C=CC=CC=1>[N:13]12[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:3][CH:2]1[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]1
Reactant: C=CCN(CC=O)C(=O)OCC
Reactant: O=C(O)C1CCCCN1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC3CCCCN3C2C1

Procedure:
17.1 g (0.1 mol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heated under reflux overnight with 13 g (0.1 mol) of piperidine-2-carboxylic acid in 200 ml of toluene. The mixture is concentrated and the residue is distilled.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[N:7][CH:8]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][C:30]1=[O:35].[H-].[Na+]>C1COCC1>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[N:7]=[CH:8][C:3]([CH2:2][N:29]4[CH2:34][CH2:33][O:32][CH2:31][C:30]4=[O:35])=[CH:4][CH:5]=3)[S:17][C:16]=12
Reactant: O=C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cn4)sc23)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCCN1Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Yield: 33.4 %

Procedure:
To a solution of 102 (350 mg, 0.842 mmol, scheme 26) in THF (10 mL) was added a solution of the anion [made from morpholin-3-one (340 mg, 4 eq., 3.37 mmol) and NaH (81 mg, 4 eq., 3.37 mmol)] in THF (5 mL)) and the mixture was heated to reflux for 8 hours. The mixture was quenched with saturated NH4Cl solution and extracted with DCM. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. The resultant solid was triturated with acetone to give title compound 121 (135 mg, 33% yield) which was used in the next step with no additional purification. MS (m/z)=481.2 (M+H)
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][C:5]2[CH:8]=[C:9]([C:12]3[C:13]([CH:17]=O)=[N:14][NH:15][N:16]=3)[CH:10]=[CH:11][C:4]=2[O:3]1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]2[CH3:33])=[N:25][CH:26]=1.C(O)(=O)C.B.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Na+].[Na+].[Na+]>CN(C=O)C>[F:35][C:20]([F:19])([F:34])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:17][C:13]3[C:12]([C:9]4[CH:10]=[CH:11][C:4]5[O:3][C:2](=[O:1])[NH:7][CH2:6][C:5]=5[CH:8]=4)=[N:16][NH:15][N:14]=3)[CH2:29][C@H:28]2[CH3:33])=[N:25][CH:26]=1
Reactant: O=Cc1n[nH]nc1-c1ccc2c(c1)CNC(=O)O2
Reactant: C[C@@H]1CNCCN1c1ccc(C(F)(F)F)cn1
Agent: B
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C[C@@H]1CN(Cc2n[nH]nc2-c2ccc3c(c2)CNC(=O)O3)CCN1c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-(3,4-dihydro-2-oxo-2H-benzo[e][1,3]oxazin-6-yl)-2H-1,2,3-triazole-4-carbaldehyde (15 mg, 0.06 mmol) and (R)-1-(5-(trifluoromethyl)pyridin-2-yl)-2-methylpiperazine (20 mg, 0.08 mmol) are mixed in DMF (1 ml) followed by addition of acetic acid (AcOH) (30 ul). The mixture is stirred at room temperature for 30 minute and then sodium triacetate boron hydride (42 mg, 0.2 mmol) is added. The resulting suspension is then stirred at room temperature overnight. The reaction is quenched using an aqueous saturated solution of sodium bicarbonate and then extracted with ethyl acetate (10 ml×4). The combined organic phase is concentrated and the resulting crude product is purified by HPLC giving 6-(5-(((R)-4-(5-(trifluoromethyl)pyridin-2-yl)-3-methylpiperazin-1-yl)methyl)-2H-1,2,3-triazol-4-yl)-3,4-dihydrobenzo[e][1,3]oxazin-2-one as a white powder. m/e:474 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:11])[C:9]=1[Cl:10])=[O:4].S(Cl)([Cl:15])(=O)=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][Cl:15])[C:9]=1[Cl:10])=[O:4]
Reactant: COC(=O)c1scc(C)c1Cl
Reactant: O=S(=O)(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1scc(CCl)c1Cl
Temperature: 25 °C
Yield: 52.8 %

Procedure:
To 2-methoxycarbonyl-3-chloro-4-methylthiophene (100 g, 0.53 mol) in dry carbon tetrachloride (1.5 L) were added sulfuryl chloride (65 mL, 0.81 mol) and benzoyl peroxide (2.5 g, 10 mmol). The reaction was heated at reflux for 17 hours, then cooled to ambient temperature and concentrated of all volatiles in vacuo. Purification of the resulting oil by flash chromatography on silica gel afforded 63 g (54% yield) of 2-methoxycarbonyl-3-chloro-4-(chloromethyl)thiophene as a yellow oil which crystallized to fine needles upon standing; NMR (CDCl3) 7.6 (s, 1), 4.6 (s, 2), 3.9 (s, 3) ppm.
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1.[CH2:25]([CH2:32][CH2:33][NH2:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O.[Cl-].[NH4+]>[CH2:25]([CH2:32][CH2:33][NH:34][C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[C:7]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCCCc1ccccc1
Reactant: Cc1cc(C)c(-c2c3nc(C)nc(Cl)c3n3ccccc23)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(-c2c3nc(C)nc(NCCCc4ccccc4)c3n3ccccc23)c(C)c1
Temperature: 110 °C

Procedure:
A mixture of 4-Chloro-2-methyl-10-(2,4,6-trimethylphenyl)pyrimido-[4,5-b]indolizine (15 mg) and N-benzylethylamine (0.04 mL) in DMSO (0.4 mL) is heated to 110° C. for 2 hours. The mixture is allowed to cool, diluted with aqueous ammonium chloride, and extracted twice with 50% ethyl ether in hexane. The combined extracts are washed with saturated brine, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography (10% to 20% ethyl acetate in hexane) gives 22 mg of the title compound (compound 5, Table 1) as a yellow oil: 1H nmr (400 MHz, CDCl3) d 1.17 (t, 3 H), 2.00 (s, 6 H), 2.38 (s, 3 H), 2.70 (s, 3 H), 3.40 (q, 2 H), 4.72 (s, 2 H), 6.68 (t, 1 H), 7.00 (s, 2 H), 7.03 (d, 1 H), 7.13 (d, 1 H), 7.29 (d, 1 H), 7.35 (t, 2 H), 7.41 (d, 2 H), 8.61 (d, 1 H).
Reaction SMILES: Br[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1.[S:12]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH3:11][O:10][C:5]1[CH:4]=[CH:3][C:2]([C:14]2[CH:15]=[CH:16][S:12][CH:13]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COc1ccc(Br)cc1C=O
Reactant: OB(O)c1ccsc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2ccsc2)cc1C=O
Temperature: 80 °C

Procedure:
3 g of 5-bromo-2-anisaldehyde (0.014 mol) are dissolved in 45 ml of 1,2-dimethoxyethane and 2.68 g of 3-thiopheneboronic acid (0.021 mol) are added, followed by addition of aqueous 2N sodium carbonate solution (4.44 g, 0.042 mol) and a catalytic amount of tetrakis(triphenylphosphine)palladium (0.48 g, 4.19 10−4 mol). The reaction mixture is heated at 80° C. for 20 hours with stirring and is then cooled to room temperature and poured into water. The resulting mixture is extracted with ethyl acetate and the organic phase is washed with saturated aqueous sodium chloride solution. The resulting phase is dried over magnesium sulfate and then filtered, and the solvent is evaporated off under reduced pressure. The title product is isolated by chromatography on a column of silica (eluent: 94/6 cyclohexane/ethyl acetate). 2 g of a beige-colored solid are isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([Cl:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])[CH3:2].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:10]([Cl:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: CCOC(=O)CNc1cc(F)c(Cl)cc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Solvent: c1ccncc1
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(Cl)cc1[N+](=O)[O-]
Yield: 56.9 %

Procedure:
1.16-1.47 (3H, m), 4.04 (2H, d, J=5.3 Hz) 4.16-4.45 (2H, m), 6.47 (1H, d, J=11.1 Hz), 8.25-8.67 (2H, m). 2) By using 0.66 g of N-(4-chloro-5-fluoro-2-nitrophenyl)glycine ethyl ester, 162 mg of imidazole and 4 ml of pyridine, 0.44 g (57%) of N-[4-chloro-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine ethyl ester was obtained.