Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>O1OCCCC1>[C:4]([C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1Br
Reactant: C1CNCCN1
Agent: C1CCOOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccccc1N1CCNCC1
Temperature: 25 °C
Yield: 25.5 %

Procedure:
To a solution of methyl 2-bromobenzoate (1.63 g, 17.8 mmol) in 1,6-dioxane (100 ml) at room temperature was added piperazine (15.3 g, 178 mmol) and K2CO3 (4.92 g 35 mmol). The resulting mixture was heated to reflux for 7 days after which the reaction mixture was cooled to room temperature. The solvent and the excess piperazine were removed in vacuo along with heating with a hot water bath. The residue was dissolved in iN NaOH solution, extracted with CH2Cl2 (6×30 ml), and dried over Na2SO4. The solvent was removed in vacuo to obtain 1-(2-carbomethoxyphenyl)-piperazine as a yellow oil (1.0 g, 26%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C1N2CN3CN(C2)CN1C3.[C:20](O)(=[O:22])C.O>>[OH:9][C:3]1[C:4]([CH3:8])=[CH:5][C:6]([CH:20]=[O:22])=[CH:7][C:2]=1[CH3:1]
Reactant: CC(=O)O
Reactant: Cc1cccc(C)c1O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: Cc1cc(C=O)cc(C)c1O
Temperature: 100 °C

Procedure:
2,6-Dimethylphenol (0.34 g/mL) and hexamethylenetetramine (2 eq.) are dissolved in 2:1 acetic acid/water mixture. The whole is heated at 100° C. for 4 hours. The reaction mixture is cooled to room temperature and poured into a water/ice mixture. The precipitate is drained.
Reaction SMILES: O[C:2]1[C:7]([I:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O>>[Cl:13][C:2]1[C:7]([I:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc(Cl)c(I)c1
Temperature: 140 °C
Yield: 83.3 %

Procedure:
2-Hydroxy-3-iodo-5-nitropyridine (2.55 g, 9.5 mmol), phosphorous pentachloride (2.60 g, 12 mmol) and phosphorous oxychloride (2 mL) were combined in a flask under nitrogen and heated to 140° C. for 45 mins. The cooled reaction mixture was poured over ice to give a solid which was partitioned between CH2Cl2 and water. The organic layer was separated, washed with brine, dried (MgSO4), filtered, and the solvent was removed in vacuo to give compound 765B (2.25 g, 83%) as a yellow solid. HPLC: 98.5% at 2.75 min(YMC S5 ODS column) eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 nm.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C2C(=CC=CC=2)C=CC=1O.C1(=O)C2C(=CC=CC=2)C(=O)C=C1.C1(O)C2C(=CC=CC=2)C(O)=CC=1>>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1cccc2ccccc12
Agent: O=C1C=CC(=O)c2ccccc21
Agent: Oc1ccc(O)c2ccccc12
Agent: Oc1ccc2ccccc2c1
Product: c1ccc2ccccc2c1

Procedure:
The peroxygenase oxidised naphthalene yielding multiple products 1-naphthol, 2-naphthol, 1,4-naphthoquinone, naphthalene-1,4-diol and some unidentified products.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19].Cl>C(OCC)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:17](=[O:20])[CH:18]=[CH2:19]
Reactant: Cc1cccc(C)c1N
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2,6-dimethylaniline (8.68 g, 0.0718 mole) and triethylamine (15.3 ml) in ethyl ether (250 ml) was cooled to +5° C. A solution of acryloyl chloride (6.47 g, 0.0716 mole) in ethyl ether (25 ml) was added dropwise with stirring over a 20 minute period. The solution was allowed to warm to room temperature and stirred for 72 hours. 10 Percent hydrochloric acid (150 ml) was added and the layers separated. The acid layer was extracted with ethyl acetate (150 ml), combined, washed with water (150 ml), dried over sodium sulfate, filtered and the solvents evaporated. The solid was taken up in hot ethyl acetate and recrystallized from hexane to yield the title compound, m.p. ca. 143.5°-145.0° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.[OH-:23].[Na+].C(Cl)(Cl)Cl.Cl>CC(C)=O.O>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:14]([CH3:9])([CH3:13])[C:5]([OH:4])=[O:23])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(O)ccc23)c(F)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(C)(Oc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1)C(=O)O
Yield: 72.5 %

Procedure:
To a mixture of 4-(2-fluoro-4-nitrophenoxy)quinolin-7-ol (5 g, 16.7 mmol) and NaOH (6.7 g, 166.7 mmol) in acetone (67 mL) was added chloroform (21.9 g, 183.3 mmol) dropwise at room temperature. After the mixture turned brown color, the reaction was heated to reflux for 1 hour. Water (10 mL) was then added to the reaction mixture, and the resulted solution was adjusted to pH 3˜4 with 1 N HCl solution. The resulted mixture was concentrated in vacuo, and then extracted with EtOAc (30 mL). The organic phase was separated, concentrated in vacuo, and treated with 95% EtOH (10 mL). The resulted solid was collected by filtration, dried in vacuo overnight to afford the title compound as a brown solid (2.34 g, 36.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)C(C)C)(C)C.CS(C)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:25])([F:26])[F:24])(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
Sulfur trioxide pyridine complex (1.12 mg, 7.0 mmol) was added to a solution of 3-[5-methyl-3-(2-trifluoromethylphenylsulfonyloxy)phenoxy]propanol (700 mg, 1.8 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.7 mL, 5.5 mmol), and dimethylsulfoxide (0.4 mL, 5.6 mmol) in CH2Cl2 (20 mL). The reaction mixture was stirred at a ambient temperature for 1 hour and then quenched with 10% citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), then the dichloromethane solution was washed with 10% citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (CH2Cl2) to give the title compound as a colorless oil (595 mg, 85%). 1H-NMR (300 MHz, CDCl3) δ9.84 (s, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.80 (t, J=7.6 Hz, 1H), 7.70 (t, J=7.3 Hz, 1H), 6.62 (s, 1H), 6.51 (s, 1H), 6.45 (s, 1H), 4.21 (t, J=6.0 Hz, 2H), 2.87 (t, J=6.0 Hz, 2H), 2.25 (s, 3H).
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:4][NH:3][CH2:2]1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[CH2:18]([O:17][C:15]([CH:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH2:2][N:3]([C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([F:20])=[CH:22][CH:23]=2)[CH2:4]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)C1CNCCc2c1[nH]c1ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate (0.46 g, 1.8 mmol) in DCM (6 mL) was added 4-fluorobenzoyl chloride (0.26 mL, 1.2 equiv) and TEA (0.38 mL, 1.5 equiv) and the mixture was stirred for 1 hour at 20° C. Evaporation of solvent gave a crude product, which was purified by column chromatography on silica gel eluting with MeOH-DCM (1:9) to afford 3-(4-fluorobenzoyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester; (543 mg, 80%) MS (ES): 381 (MH+).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:16][C:17]1[C:18]([NH2:24])=[N:19][CH:20]=[C:21]([Br:23])[CH:22]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)C.[H-].[Na+]>CS(C)=O.O>[Br:23][C:21]1[CH:20]=[N:19][C:18]2[NH:24][C:4](=[O:3])[CH2:5][N:6]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)[CH2:16][C:17]=2[CH:22]=1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1)Cc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN2CC(=O)Nc3ncc(Br)cc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A solution of [(2-amino-5-bromo-pyridin-3-ylmethyl)-(4-methoxy-benzyl)amino]acetic acid ethyl ester (13.0 g, 31.9 mmol) in DMSO (200 mL) was treated with NaH (60% dispersion in mineral oil, 1.30 g, 32.5 mmol). After stirring at room temperature overnight, the mixture was diluted with H2O (500 mL) and a precipitate formed. The solid was isolated by filtration, washed with H2O, and dried under vacuum at 50° C. for 6.5 h to give the title compound (7.16 g, 62%) as a tan powder: MS (ESI) m/e 362 (M+H)+.
Reaction SMILES: [N:1]1([CH2:5][C:6]([CH3:16])([CH3:15])[O:7][C:8]2[CH:9]=[CH:10][C:11](Cl)=[N:12][CH:13]=2)[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C[Si]([N-:46][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1.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]>[N:1]1([CH2:5][C:6]([CH3:16])([CH3:15])[O:7][C:8]2[CH:9]=[CH:10][C:11]([NH2:46])=[N:12][CH:13]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(CN1CCC1)Oc1ccc(Cl)nc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(CN1CCC1)Oc1ccc(N)nc1
Temperature: 75 °C

Procedure:
To a degassed solution of 5-(2-azetidin-1-yl-1,1-dimethyl-ethoxy)-2-chloro-pyridin (21.2 g, 88.1 mmol) in anhydrous tetrahydrofuran (314 ml) was added 2-(dicyclohexylphosphino)biphenyl (6.17 g, 17.6 mmol) and tris(dibenzylideneacetone)dipalladium(0) (8.06 g, 8.81 mmol). Then a solution of 1 M lithium bis(trimethylsilyl)amide in THF (264 ml, 264 mmol) was added via addition funnel over 5 minutes. The reaction mixture was stirred under argon atmosphere at 75° C. over-night. The reaction mixture was poured into a saturated solution of aqueous ammonium chloride (400 ml) and extracted with ethyl acetate (350 ml). The organic phase was collected and washed with 50% diluted brine (350 ml). The organic phase was collected and the aqueous phases were back extracted with ethyl acetate (2×200 ml). The combined organics were dried from magnesium sulfate, filtered and stripped. The remainder was purified by Analogix flash column chromatography (80 g column), eluting with 0% to 12% methanol in dichloromethane to provide the desired 5-(2-azetidin-1-yl-1,1-dimethyl-ethoxy)-pyridin-2-ylamine (10.59 g) as a dark brown semi-viscous oil (as well as a less-pure fraction which could be re-purified under similar conditions to provide another 4.01 g of product). LC/MS calc'd for C12H19N3O (m/e) 221.3, obs'd 222 (M+H, ES+).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:14][CH3:15])[CH:6]=1)([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].C(O)(=O)C>C(OC(=O)C)(=O)C>[CH:1]([O:4][C:5]1[C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:14][CH3:15])[CH:6]=1)([CH3:3])[CH3:2]
Reactant: COc1cc(OC(C)C)ccc1C(=O)O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1cc(OC(C)C)c([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1.61 g portion of 4-isopropoxy-2-methoxybenzoic acid was dissolved in 20 ml of acetic anhydride, 0.38 ml of concentrated nitric acid and a small amount of acetic acid were added, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction solution was poured on crushed ice, extracted with chloroform and then dried over anhydrous sodium sulfate. After evaporation of the solvent under a reduced pressure, the resulting residue was dissolved in 5 ml of tetrahydrofuran and 5 ml of 1N sodium hydroxide aqueous solution, followed by stirring for 1 hour. The reaction solution was poured into 1N hydrochloric acid aqueous solution, extracted with chloroform and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1-10:1) to give 0.43 g of 4-isopropoxy-2-methoxy-5-nitrobenzoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](C)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cu]C#N.[CH3:16][N:17]([CH3:20])C=O>>[CH3:2][C:3]1[C:20]2[N:17]=[CH:16][CH:9]=[CH:8][C:7]=2[C:6]([C:11]#[N:10])=[CH:5][CH:4]=1
Reactant: Cc1ccc(Br)c2ncccc12
Reactant: CN(C)C=O
Agent: N#C[Cu]
Product: Cc1ccc(C#N)c2cccnc12
Temperature: 200 °C

Procedure:
4.0 g 8-Bromo-5-methyl-quinoline and 1.69 g copper (I) cyanide were dissolved in 16 ml dimethylformamide and stirred at 200° C. for thirty minutes under microwave irradiation. The cooled reaction mixture was poured in 50 ml 2N HCL and extracted with 100 ml ethyl acetate. The organic layer was washed with 50 ml 2N HCl and 30 ml brine and then dried over MgSO4. The solvent was removed in vacuo. The resulting residue was purified on silica gel with the eluent n-heptane ethyl acetate=2:1 to obtain 3.0 g 8-Methyl-quinoline-5-carbonitrile.
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:6][CH2:5][CH:4]([C:7]2OC(=O)[S:9][N:8]=2)[CH2:3]1.ClC1C=CC=C(Cl)C=1.[F:22][C:23]([F:32])([F:31])[C:24]#[C:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[F:1][C:2]1([F:13])[CH2:6][CH2:5][CH:4]([C:7]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([C:23]([F:31])([F:32])[F:22])[S:9][N:8]=2)[CH2:3]1
Reactant: O=c1oc(C2CCC(F)(F)C2)ns1
Reactant: CCOC(=O)C#CC(F)(F)F
Solvent: Clc1cccc(Cl)c1
Product: CCOC(=O)c1c(C2CCC(F)(F)C2)nsc1C(F)(F)F
Temperature: 160 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed 5-(3,3-difluorocyclopentyl)-2H-1,3,4-oxathiazol-2-one (300 mg, 1.45 mmol, 1.00 equiv), 1,3-dichlorobenzene (2 mL), ethyl 4,4,4-trifluorobut-2-ynoate (481 mg, 2.90 mmol, 2.00 equiv). The resulting solution was stirred overnight at 160° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/30). This resulted in 200 mg of ethyl 3-(3,3-difluorocyclopentyl)-5-(trifluoromethyl)-1,2-thiazole-4-carboxylate as brown oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:18][CH3:19])[C:4](=[O:17])[CH:5]=[CH:6][C:7]1[S:11][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=1.[BH4-].[Na+].C(OCC)(=O)C.O>O1CCCC1>[CH3:19][O:18][CH:3]([O:2][CH3:1])[CH:4]([OH:17])[CH:5]=[CH:6][C:7]1[S:11][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=1
Reactant: COC(OC)C(=O)C=Cc1ccc(-c2cccs2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(OC)C(O)C=Cc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(4,4-dimethoxy-3-oxo-1-butenyl)-2,2'-bithiophene (50 mg) in tetrahydrofuran (2.5 ml) was added sodium borohydride (10 mg). The reaction mixture was stirred at room temperature for 1 hour. Ethyl acetate and water was added for partition. The organic layer was dried over anhydrous magnesium sulfate, concentrated and separated by silica gel chromatography. Light greenish oily product was obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C@H:12]1[C@@H:17]([NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]3[S:29][CH2:28][C:27](=[O:30])[NH:26][C:25]=3[CH:31]=2)=[O:20])[CH2:16][CH2:15][N:14]([CH2:32][CH2:33][O:34][C:35]2[CH:44]=[N:43][C:42]3[C:37](=[CH:38][C:39]([O:45][CH3:46])=[CH:40][CH:41]=3)[N:36]=2)[CH2:13]1)=O)C>O1CCCC1>[OH:9][CH2:10][C@@H:12]1[C@@H:17]([NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]3[S:29][CH2:28][C:27](=[O:30])[NH:26][C:25]=3[CH:31]=2)=[O:20])[CH2:16][CH2:15][N:14]([CH2:32][CH2:33][O:34][C:35]2[CH:44]=[N:43][C:42]3[C:37](=[CH:38][C:39]([O:45][CH3:46])=[CH:40][CH:41]=3)[N:36]=2)[CH2:13]1
Reactant: CCOC(=O)[C@@H]1CN(CCOc2cnc3ccc(OC)cc3n2)CC[C@@H]1NC(=O)c1ccc2c(c1)NC(=O)CS2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2ncc(OCCN3CC[C@H](NC(=O)c4ccc5c(c4)NC(=O)CS5)[C@@H](CO)C3)nc2c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 14.3 %

Procedure:
Lithium aluminium hydride (1.0M solution in tetrahydrofuran, 80 μL, 0.08 mmol, 1.0 eq) is added dropwise at −10° C. to a stirred solution of (3R,4S)-1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidine-3-carboxylic acid ethyl ester (50 mg, 0.08 mmol, 1.0 eq) in tetrahydrofuran (5 mL). After 30 minutes stirring at −10° C., the reaction mixture is cautiously quenched with ice-water (2 mL). Tetrahydrofuran is evaporated and the crude is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford (3S,4S)-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {3-hydroxymethyl-1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide as a yellow lyophilizated powder (6 mg, 14% yield).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.O.[NH3:26]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH2:26])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: N
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Solvent: O
Solvent: CC(=O)CC(C)C
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN

Procedure:
Using 5 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138), 100 ml of methylisobutylketone, and 200 ml of 28% ammonia water, a reaction similar to that conducted in Example 107 was carried out. The crystal procipitated was filtered out, yielding 0.9 g of N-(trans-4-methylcyclohexyl)-4-(2-aminoethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1>S(=O)(=O)(O)O>[NH2:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(C(=O)O)cn1
Agent: O=S(=O)(O)O
Product: Nc1ncc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
A mixture of concentrated sulfuric acid (7.5 ml) and concentrated nitric acid (7.5 ml) was added dropwise to a solution of 6-aminonicotinic acid (15 g) in concentrated sulfuric acid (30 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hrs and poured into ice water, and the mixture was stirred for 30 min. The precipitated crystals were collected by filtration and washed with water. The obtained crystals were suspended in concentrated sulfuric acid (60 ml), and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was adjusted with sodium hydroxide to pH 4, and the precipitated crystals were collected by filtration to give the title compound (7.26 g, yield 36%) as pale-as yellow crystals. purity 94%. M+H: 184.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:12]([OH:14])=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>C1C=CC=CC=1>[S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)([OH:33])(=[O:32])=[O:31].[CH2:15]([O:13][C:12](=[O:14])[C@@H:3]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: N[C@H](CCc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1
Yield: 83.7 %

Procedure:
A solution of D-Homophenylalanine hydrochloride (1.7 g, 7.93 mmol), benzyl alcohol (7.2 mL, 64.0 mmol) and p-toluenesulfonic acid monohydrate (1.8 g, 9.5 mmol) in benzene (30 mL) was heated at reflux in Dean Stark apparatus during 5 hrs, after which time additional benzene (100 mL) was distilled from reaction mixture. The residue was triturated with diethyl ether, the solid was filtered and dried to give title product (2.93 g).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][N:18]=1)[C:13](O)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH:21]([NH2:23])[CH3:22].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[CH3:22][CH:21]1[CH2:20][NH:19][C:13]([C:12]2[CH:16]=[CH:17][N:18]=[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:11]=2)=[N:23]1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Reactant: CC(N)CN
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CNC(c2ccnc(NC(=O)c3ccccc3)c2)=N1
Temperature: 25 °C
Yield: 29.4 %

Procedure:
To a solution of 2-benzamidoisonicotinic acid (0.50 g, 2.06 mmol) and 1,2-diaminopropane (0.35 mL, 4.12 mmol) in 1,4-dioxane (20 mL) was added phosphorus oxychloride (0.94 mL, 10.30 mmol) dropwise at ambient temperature under nitrogen atmosphere. The resulting solution was refluxed for 15 hours, cooled to ambient temperature and concentrated in vacuo to dryness. The residue was diluted with saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane (4×50 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate followed by 9:1:0.1 ratio of ethyl acetate, methanol and triethyl amine to give N-(4-(4-methyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide as a pale yellow foam (0.17 g, 29%): MS (ES+) m/z 281.5 (M+1).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:26](Cl)=[N:25][CH:24]=[N:23][C:22]=4[NH:21][C:20]3=[O:29])=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:30]([C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])#[CH:31].Cl>>[N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:26]([NH:35][C:34]5[CH:36]=[CH:37][CH:38]=[C:32]([C:30]#[CH:31])[CH:33]=5)=[N:25][CH:24]=[N:23][C:22]=4[NH:21][C:20]3=[O:29])=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C#Cc1cccc(N)c1
Reactant: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(Cl)c21
Agent: Cl
Product: C#Cc1cccc(Nc2ncnc3c2C(=Cc2[nH]c(C(=O)NCCN4CCOCC4)cc2C)C(=O)N3)c1
Yield: 15 %

Procedure:
The title compound (15% yield) was prepared from 5-(4-chloro-6-oxo-6,7-dihydro-pyrrolo[2,3-d]pyrimidin-5-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide and 3-ethynylaniline according to the procedure described for Example 12 without the conversion to HCl salt. MS 498.2 [M++1].