Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1Cl)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[SH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[S:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnccc1Cl
Reactant: COC(=O)CCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnccc1SCCC(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
To a stirred solution of 4-chloro-pyridine-3-carboxylic acid ethyl ester (4.30 g, 23.2 mmol) in dry tetrahydrofuran (45 ml) is added potassium tert-butoxide (3.12 g, 27.9 mmol) portion wise at 0° C., followed by the addition of methyl 3-mercaptopropanoate (3.35 g, 27.9 mmol). The reaction mixture is stirred at RT for 2 h. After completion of the reaction, the solvent is distilled off and the residue is diluted with water (30 ml). The aqueous layer is extracted with EtOAc (3×40 ml). The combined organic layers are washed with water (40 ml), brine (40 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 30% EtOAc/hexane) to get 4-(2-methoxycarbonyl-ethylsulfanyl)-pyridine-3-carboxylic acid ethyl ester (3.0 g, 11.2 mmol, 48%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=1.C([Li])(C)(C)C.[I:17]I.O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:17])[C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=1
Reactant: II
Reactant: COCOc1ccc(F)nc1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cnc(F)cc1I
Temperature: 25 °C
Yield: 52.8 %

Procedure:
Cool a solution of 2-fluoro-5-methoxymethoxy-pyridine (4.1 g, 26.1 mmol) in THF (60 mL) to −75° C. Add tert-butyllithium (1.7 M in pentane, 30.4 mL, 51.7 mmol) over a period of 30 min. Stir the mixture for an additional half an hour. Add iodine (9.8 g, 38.6 mmol, dissolved in 60 mL of THF). Stir for 1 h after the addition is complete. Allow the temperature to raise to RT over 1 h while stirring. Treat the mixture with water. Extract the solution with ethyl acetate three times. Wash the organic layer with aqueous saturated sodium chloride. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo to a brown solid. Triturate the brown solid with hexane. Filter to afford the title compound (3.9 g, 53%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 3.53 (s, 3H), 5.23 (s, 2H), 7.39 (d, J=4.0 Hz, 1H), 7.96 (d, J=1.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:21][C:22]2[CH:26]=[C:25]([O:27][CH:28]([CH3:30])[CH3:29])[NH:24][N:23]=2)=[N:4][C:5]([NH:10][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:12][OH:13])=[C:6]([CH:9]=1)[C:7]#[N:8].[OH-:31].[K+].OO>CO>[F:1][C:2]1[C:3]([NH:21][C:22]2[CH:26]=[C:25]([O:27][CH:28]([CH3:30])[CH3:29])[NH:24][N:23]=2)=[N:4][C:5]([NH:10][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:12][OH:13])=[C:6]([CH:9]=1)[C:7]([NH2:8])=[O:31]
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(C#N)cc2F)n[nH]1
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: CO
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(C(N)=O)cc2F)n[nH]1
Temperature: 65 °C
Yield: 85.6 %

Procedure:
(R)-5-Fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)-6-(5-isopropoxy-1H-pyrazol -3-ylamino)nicotinonitrile (Example 11; 0.06 g, 0.1 mmol) was placed in MeOH (5 ml) at 25° C. A 25% aqueous solution (0.2 ml) of KOH (0.05 g, 0.7 mmol) was then added, followed by the addition of 0.05 ml of 30% H2O2. The resulting dark red solution was heated to 65° C. for 1 h, cooled to 25° C., and concentrated. The resulting residue was dissolved in EtOAc (50 ml), washed with water (30 ml), dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM-MeOH=30:1) to give the title compound (0.037 g, 60%). 1H NMR (400 MHz, CD3OD) δ 7.75 (d, J=11.9 Hz, 1H), 7.43-7.39 (m, 2H), 7.06-7.02 (m, 2H), 5.37 (br s, 1H), 5.10-5.02 (m, 1H), 4.60-4.54 (m, 1H), 3.90-3.86 (m, 1H), 3.79-3.74 (m, 1H), 1.32 (d, J=6.0 Hz, 6H). MS: Calcd.: 432. Found: [M+H]+ 433.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]=O)=[CH:7][CH:6]=1.CSC.B.CO>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH3:12])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(NC=O)cc1
Agent: B
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: CNc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of methyl(4-formylaminophenyl)acetate (4.31 g) in THF (20.0 mL) at 0° C. was slowly added borane dimethylsulfide (8.61 mL, 90.8 mmol). The reaction mixture was stirred at room temperature overnight and then cooled to 0° C. MeOH (15 mL) was added cautiously and the resulting mixture was stirred for 3 h. The mixture was then concentrated under reduced pressure to give the title compound (4.0 g, 73% yield, 2 steps) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl>>[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][N:4]1[CH:5]=[N:6][C:2]([NH2:1])=[N:3]1
Reactant: ClCc1cccc(Cl)c1
Reactant: Nc1nc[nH]n1
Product: Nc1ncn(Cc2cccc(Cl)c2)n1

Procedure:
Prepared in analogy to example 3a) starting with 3-amino-1,2,4-triazole and 3-chloro benzyl chloride. The title compound was obtained as a colorless solid (Yield=9%). MS ISP (m/e): 211.0 & 209.0 (43 & 100) [M+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].[H][H]>C(O)C.[Pd]>[NH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([OH:12])=[C:4]([CH3:11])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)cc(C)c1O
Yield: 86 %

Procedure:
A solution of 1 g (6 mmole) of 2,6-dimethyl-4-nitrophenol in 20 ml of ethanol is placed under 1.5 bar of hydrogen in the presence, of 10% Pd/C for 1 hour. The Pd/C is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure. The evaporation residue crystallizes spontaneously, it is washed twice with 50 ml of heptane and dried overnight under vacuum. A cream coloured solid is obtained with a yield of 86%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:21])[N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>ClCCl>[CH3:20][O:19][CH2:18][CH2:17][N:15]([CH3:16])[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:21].[ClH:22]
Reactant: COCCN(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Product: COCCN(C)C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To piperazine-1,4-dicarboxylic acid tert-butyl ester 4-nitro-phenyl ester (500 mg, 1.42 mmol) in anhydrous THF (5 mL) was added N-(2-methoxy-ethyl)methylamine (2 eq., 254 mg). The reaction mixture was refluxed overnight, then evaporated in vacuo and purified by chromatography to give 4-[(2-methoxyethyl)-methyl-carbamoyl]piperazine-1-carboxylic acid tert-butyl ester as a clear oil (304 mg, 71%). To 4-[(2-methoxyethyl)-methyl-carbamoyl]piperazine-1-carboxylic acid tert-butyl ester (304 mg, 1.01 mmol) in dichloromethane (3 mL) was added HCl (2M solution in ether), the reaction mixture stirred at rt overnight and then evaporated in vacuo to give piperazine-1-carboxylic acid (2-methoxy-ethyl)-methyl-amide as HCl salt (330 mg).
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[CH3:15][NH:16][C:17]([C:19]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH:20]1[C:22](N)=O)=O.[H-].[OH-].[Na+].[ClH:34]>C1C=CC=CC=1.O.C(O)C.CCOCC>[ClH:34].[CH3:15][N:16]1[CH2:22][CH:20]2[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([CH2:21]2)[CH2:17]1
Reactant: CNC(=O)C1(c2ccccc2)CC1C(N)=O
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CN1CC2CC2(c2ccccc2)C1

Procedure:
To a stirred solution of 30 ml of sodium bis(2-methoxyethoxy)aluminum hydride (70% benzene solution) is added dropwise a solution of 5.5 g of N-methyl-1-phenyl-1,2-cyclopropanedicarboxamide (U.S. Pat. No. 3,166,571-Ex. 1) in 400 ml of benzene over a one hour period at room temperature under nitrogen. The mixture is heated at reflux under nitrogen for 90 minutes. The excess hydride reagent is decomposed by the cautious addition of 25 ml of 10 N sodium hydroxide and then diluted to 200 ml with water. The benzene phase is separated and the aqueous phase is extracted with chloroform. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure giving a liquid. The liquid is dissolved in ethanol and acidified with 15 ml of 2.3 N ethanolic hydrogen chloride. The addition of ether causes the formation of a solid which is recrystallized from isopropyl alcohol-hexane giving white crystals, m.p. 158°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:11]1[C:20]([CH:21]=[O:22])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][C:11]1[C:20]([CH:21]=[O:22])=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1cc2ccccc2nc1Cl
Product: O=Cc1cc2ccccc2nc1Oc1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared according to preparation 65 starting from 3,4-dichlorophenol and 2-chloro-3-quinoline carboxaldehyde (Aldrich Chemical Co.); δH (CDCl3, 400 MHz) 7.19 (1H, m), 7.50 (3H, m), 7.74 (2H, m), 7.91 (1H, dd), 8.75 (1H, s), 10.59 (1H, s); MS rn/z318, 320 (MH+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)O1.Br[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([F:29])[C:26]=1[CH:27]=[O:28].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>CN(C=O)C.C(OCC)(=O)C>[F:29][C:25]1[CH:24]=[N:23][CH:22]=[C:21]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)[C:26]=1[CH:27]=[O:28]
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Reactant: O=Cc1c(F)cncc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1c(F)cncc1-c1ccc2c(c1)COC2=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-isobenzofuran-1-one (210 mg, 0.809 mmol) in DMF (4 mL) was added 3-bromo-5-fluoro-pyridine-4-carbaldehyde (150 mg, 0.735 mmol) and 2M aqueous sodium carbonate (0.735 mL, 1.471 mmol). The reaction mixture was flushed and evacuated with N2 twice followed by the addition of PdCl2(dppf).CH2Cl2 adduct (30.0 mg, 0.037 mmol). The reaction mixture was stirred at 100° C. for 1 hour. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with water twice. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to afford 3-fluoro-5-(1-oxo-1,3-dihydro-isobenzofuran-5-yl)-pyridine-4-carbaldehyde, which was taken into the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][C:3]=1[O:11][CH3:12].[CH2:13]([S:15]([NH:18][C@@H:19]([CH:23]([CH3:25])[CH3:24])[C:20](O)=[O:21])(=[O:17])=[O:16])[CH3:14].F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:20](=[O:21])[C@@H:19]([NH:18][S:15]([CH2:13][CH3:14])(=[O:17])=[O:16])[CH:23]([CH3:25])[CH3:24])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(CCN)ccc1O
Reactant: CCS(=O)(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(O)c(OC)c1)C(C)C

Procedure:
1.7 g of 2-(4-hydroxy-3-methoxy-phenyl)-ethylamine and 2.1 g of (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid are stirred at room temperature for 2 hours together with 4.6 g of (benzotriazol-1-yl)-tris(dimethylamino)phosphonium hexafluorophosphate and 4.5 ml of diisopropylethylamine in 40 ml of dimethylformamide. The reaction mixture is then introduced into 600 ml of water. Extraction is carried out twice using 400 ml of ethyl acetate each time. The organic phases are washed twice using 300 ml of water each time and once with 200 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, yielding (S)-2-(ethylsulfonylamino)3-methyl-butyric acid N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-amide in the form of a brown oil, which can be purified by chromatography on silica gel with ethyl acetate.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH2:8]([NH:9][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.4 %

Procedure:
To a solution of 2-phenylethylamine (3.0 g, 24.8 mmol) in DMF (30 ml) was added ethyl bromoacetate (3.0 ml, 27.3 mmol) at 5° C. Then triethylamine (4.15 ml, 29.8 mmol) was added thereto at the same temperature. After stirring the resulting mixture at room temperature for 18 hours, the reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (methylene chloride:MeOH, 20:1) to give ethyl phenethylaminoacetate (1.87 g, 37%) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH2:16])[CH2:13][C@H:12]1[C:17]1[O:18][CH:19]=[CH:20][N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](O)=[O:34]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH:16][C:33]([C:24]2[CH:25]=[CH:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]=2[OH:22])=[O:34])[CH2:13][C@H:12]1[C:17]1[O:18][CH:19]=[CH:20][N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1
Reactant: O=C(O)c1ccc2ccccc2c1O
Product: O=C(N[C@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1)c1ccc2ccccc2c1O

Procedure:
(2S,4S)-4-[(1 -hydroxy-naphthalene-2-carbonyl)-amino]-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester was prepared from (2S,4S)-4-amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C26H24N3O5 [(M+H)+] 458, obsd. 458.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH3:23]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:21][CH2:22][CH3:23])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cc(C(=O)OC)c2ccccc21

Procedure:
A solution of 0.16 g (1.00 mmol) of indole-3-carboxylic acid methyl ester, 0.5 g (4 mmol) of K2CO3 and 0.5 g (5 mmol) of 1-bromopropane in 10 ml of DMF was stirred at 50° C. overnight. The mixture was partitioned between EtOAc and water. The aqueous phase was extracted with additional EtOAc. The combined organic phases were washed with water, brine and finally dried over Na2SO4 to give crude 1-propylindole-3-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH:5]=[N:6][OH:7].[Cl:12]N1C(=O)CCC1=O>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([Cl:12])=[N:6][OH:7])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccc(Cl)c(Cl)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 132.7 %

Procedure:
The title compound of Step A (3.7 g) was dissolved in 100 mL of dimethylformamide and 2.6 g of N-chlorosuccinimide was added. The reaction mixture was stirred at about 30° C. for 2 h and then at room temperature overnight. The mixture was diluted with 200 mL of water and extracted with three 100 mL portions of diethyl ether. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give 5.8 g of the title compound of Step B as an oil. 1H NMR (CDCl3): δ 10.41 (s,1H), 7.95 (d,1H,J=2 Hz), 7.69 (dd,1H,J=2, 8 Hz), 7.46 (d,1H,J=8 Hz). The crude oil also contained DMF. The crude material was triturated in hexane and collected by filtration to yield 5.2 g of white solid, still containing DMF, which was used in the next step without additional purification or characterization.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[C:3]=1[CH3:23].[OH:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([C:32]1[CH:40]=[CH:39][C:35]2[O:36][CH2:37][O:38][C:34]=2[CH:33]=1)=[O:31]>>[O:36]1[C:35]2[CH:39]=[CH:40][C:32]([C:30]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:19]3[CH:20]=[CH:21][C:16]([S:13]([N:11]([CH3:12])[C:4]4[C:3]([CH3:23])=[CH:2][CH:10]=[CH:9][C:5]=4[C:6]([OH:8])=[O:7])(=[O:15])=[O:14])=[CH:17][CH:18]=3)=[O:31])=[CH:33][C:34]=2[O:38][CH2:37]1
Reactant: O=C(NCCCCO)c1ccc2c(c1)OCO2
Reactant: Cc1ccc(C(=O)O)c(N(C)S(=O)(=O)c2ccc(F)cc2)c1C
Product: Cc1cccc(C(=O)O)c1N(C)S(=O)(=O)c1ccc(OCCCCNC(=O)c2ccc3c(c2)OCO3)cc1
Yield: 60 %

Procedure:
The product of Example 2 (0.30 g, 0.92 mmol) was coupled to N-(4-hydroxybutyl)-1,3-benzodioxole-5-carboxamide, prepared according to Example 21, (0.23 g, 0.96 mmol) using the procedure of Example 3 to provide 0.30 g (60% yield) of yellow solid. MP 110° C.; 1H NMR (DMSO-d6): δ 1.66-1.80 (m,CH2, CH2)1.89 (s, CH3), 3.1 (s, CH3), 3.39-3.45 (m, CH2), 4.08 (t, CH2), 6.08 (s, CH2), 6.9 (d, 1 Ar H), 7.04-7.08 (m, 2 Ar H), 7.33-7.45 (m, 5 Ar H), 7.53-7.58 (m, 2 Ar H), 8.39 (t, NH), 12.8 (s, OH). Electrospray Mass Spec: m/z 541.2 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[C:11]=2[CH2:12][CH2:13][CH3:14])=[O:6])[CH2:3][CH2:2]1>C(O)C.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[C:11]([CH2:12][CH2:13][CH3:14])=[C:7]([C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:6])[N:8]=[N:9]2)=[CH:16][CH:17]=1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a solution of N-cyclopropyl-1-(4-nitrophenyl)-5-propyl-1H-1,2,3-triazole-4-carboxamide (1.2 g) obtained in Example 1c) in ethanol (38 ml) was added 10% Pd/C (50% wet) (0.12 g) and the mixture was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column (methanol/ethyl acetate=1/10) to give the title compound as a white powder (0.91 g, 84%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[F:13][CH:14]([F:23])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+]>C(OCC)(=O)C>[F:13][CH:14]([F:23])[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:20][CH:21]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: Nc1ccc(OC(F)F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nc(Nc2ccc(OC(F)F)cc2)c2ccccc2n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A mixture of 4-chloro-2-methyl-quinazoline (450 mg, 2.52 mmol), 4-difluoromethoxy-phenylamine (0.32 ml, 2.52 mmol) and sodium acetate (248.07 mg, 3.02 mmol) in 6 mL of solvent (THF:water=1:1) was stirred at 70° C. for 1 h. The reaction mixture was diluted with 30 mL of ethyl acetate. It was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by chromatography on silica gel with acetate and hexane (1:5) as eluent, yielding 713 mg of title compound (94%). 1H NMR (CDCl3): 7.87-7.76 (m, 5H), 7.51 (t, J=8.4 Hz, 1H)), 7.40 (brs, 1H), 7.19 (d, J=8.7 Hz, 2H), 6.76-6.27 (three single peaks, 1H), 2.71 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.O.Cl.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:17]3[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: O=C1CCNCC1
Reactant: COc1ccc2cc[nH]c2c1
Agent: Cl
Solvent: O
Product: COc1ccc2c(C3=CCNCC3)c[nH]c2c1
Yield: 87.6 %

Procedure:
Beginning with 2.0 gm (14.0 mMol) 6-methoxy-1H-indole and 4.2 gm (27.0 mMol) 4-piperidone hydrochloride monohydrate, 2.8 gm (90%) of the title compound were recovered as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][C:32]1[NH:33][CH:34]=[CH:35][N:36]=1)([CH3:23])[CH3:22]>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:21]([CH3:23])[CH3:22])[CH2:31][C:32]2[NH:36][CH:35]=[CH:34][N:33]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: CC(C)c1ccccc1NCc1ncc[nH]1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2ncc[nH]2)c2ccccc2C(C)C)[C@@H]1O
Yield: 19.9 %

Procedure:
The title compound (140 mg, 20%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (400 mg, 1.42 mmol) and 2-isopropylphenyl-1H-imidazol-2-ylmethylamine (306 mg, 1.42 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:23][C:22]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=1
Reactant: Brc1ncccn1
Reactant: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1cccc(F)c1-c1cccc(-n2cnc(C(=O)c3ncccn3)c2)c1

Procedure:
This compound is prepared by method C using compound 12g and 2-bromopyrimidine
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:4]=1[C:5](NC)=[O:6])=[O:2].C(=O)([O-])[OH:15].[Na+]>Cl>[CH:1]([C:3]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:4]=1[C:5]([OH:15])=[O:6])=[O:2]
Reactant: O=C([O-])O
Reactant: CNC(=O)c1ccc(Cl)cc1C=O
Agent: Cl
Agent: [Na+]
Product: O=Cc1cc(Cl)ccc1C(=O)O

Procedure:
A mixture of 2-formyl-4-chloro-N-methylbenzamide (3.19 g) and 10M hydrochloric acid (30 ml) was heated at reflux for 18 hours. The mixture was cooled and basified with saturated sodium hydrogen carbonate solution. The solution was then washed with ethyl acetate, then acidified with 2M hydrochloric acid. The product was extracted with ethyl acetate and the combined extracts dried with magnesium sulfate. The solution was then filtered and concentrated. This furnished 2-formyl-4-chlorobenzoic acid as a yellow solid (2.22 g, 75%); 1H NMR (400 MHz, CDCl3) δ 6.65 (0.5H, brs), 7.50 (2H, m), 7.65 (1H, m), 7.85 (0.5H, brm), 8.05 (1H, m).