Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].Cl[C:3]1[N:8]=[C:7]([Cl:9])[CH:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1>C(OC)(C)(C)C>[NH2:1][C:3]1[N:8]=[C:7]([Cl:9])[CH:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1
Reactant: FC(F)(F)Oc1cc(Cl)nc(Cl)n1
Reactant: N
Solvent: COC(C)(C)C
Product: Nc1nc(Cl)cc(OC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.3 g (0.25 mol) of gaseous ammonia were passed over the course of 45 minutes into a stirred mixture of 23.3 g (0.1 mol) of 2,4-dichloro-6-trifluoromethoxypyrimidine and 150 ml of methyl tert.-butyl ether at −50 to −45° C. The mixture was stirred at −50° C. for 30 minutes, at −30° C. for 1 hour and at 25° C. for 1 hour. The precipitate was filtered off with suction, washed with water and dried, resulting in 5.4 g (33.1% of theory) of 4-amino-2,4-dichloropyrimidine of melting point 270-272° C. as by-product. The filtrate was washed with water, dried and concentrated under reduced pressure, and the residue was chromatographed with 5:1 petroleum ether/ether, the initial fractions yielding 3 g (12.8% of theory) of starting material as a colorless oil, and subsequent fractions containing 9 g (42% of theory) of the title compound as colorless crystals of melting point 55-56° C. Conversion was 48.3%.
Reaction SMILES: Br.C([O:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[C:11]([O:20]C)[C:12]([F:19])=[C:13]([F:18])[CH:14]=2)[N:9]([CH2:22][CH3:23])[CH:8]=1)=[O:6])C.O>CC(O)=O>[CH2:22]([N:9]1[C:10]2[C:15](=[CH:14][C:13]([F:18])=[C:12]([F:19])[C:11]=2[OH:20])[C:16](=[O:17])[C:7]([C:5]([OH:6])=[O:4])=[CH:8]1)[CH3:23]
Reactant: CCOC(=O)c1cn(CC)c2c(OC)c(F)c(F)cc2c1=O
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(O)c21
Temperature: 110 °C
Reaction time: 24 h
Yield: 78.9 %

Procedure:
48% aq. HBr (35 ml) was added to a solution of 1-ethyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (9.34 g; prepared according to EP 241 206) in AcOH (30 ml). The orange solution was stirred at 110° C. for 24 h. It was poured into water (200 ml) and the grey-white precipitate was filtered. The crystals were collected and dried in vacuo to afford 6.37 g (79% yield) of a beige solid. 1H NMR (DMSOd6; δ ppm): 1.43 (3H, t, J=7); 4.85 (2H, q, J=7); 7.76 (1H, dd, J=8 and J=10); 8.91 (1H, s); 12.02 (1H, broad); 14.90 (1H, broad).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22]O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.O1CCOCC1>O1CCOCC1>[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH2:1])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: OCCCCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)OCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 65.2 %

Procedure:
5.03 g of phenylalanine and 22.8 g of 4-phenyl-1-butanol were added to 17 mL of 1,4-dioxane, 17 mL of 4N—HCl/1,4-dioxane was added thereto, and the reaction solution was stirred at room temperature for 4 days. The reaction solution was filtered and the filtrate was added with 450 mL of diethyl ether, and stirred at room temperature for 1.5 hours. The deposit was taken by filtration, washed with 50 mL of diethyl ether, and then dried under vacuum, thereby to give 5.90 g of Compound 16.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[C:49]([CH3:56])=[C:50]([CH:53]=[CH:54][CH:55]=1)[CH2:51][NH2:52]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:52][CH2:51][C:50]4[CH:53]=[CH:54][CH:55]=[C:48]([F:47])[C:49]=4[CH3:56])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: Cc1c(F)cccc1CN
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2cccc(F)c2C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with N-(3-fluoro-2-methyl-benzyl)-amine (Alfa) to give the title compound. LC-MS (ES+) 786 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[NH:28][N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]([F:50])([F:49])[F:48].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[N:28]([CH2:46][C:47]([F:50])([F:49])[F:48])[N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(n[nH]c3=O)CO4)cc2)CCC1
Reactant: FC(F)(F)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nn(CC(F)(F)F)c3=O)CO4)cc2)CCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a solution of tert-butyl(1-(4-(1-oxo-8-phenyl-2,4-dihydro-1H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (98 mg, 0.19 mmol) in dry DMF (2 ml) was added potassium carbonate (79 mg, 0.57 mmol) and 2-bromo-1,1,1-trifluoroethane (94 mg, 0.57 mmol) under nitrogen. The resulting mixture was stirred for 1 hour at 80° C. Water was added and the mixture was extracted with EtOAc (3×). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 27% EtOAc in cyclohexane) to give the title compound (45 mg, 40%). 1H NMR (500 MHz, CDCl3): 8.47 (1H, s), 7.26-7.20 (7H,m), 7.14-7.12 (2H, m), 5.25 (2H, s), 4.96 (1H, br s), 4.38 (2H, q), 2.55-2.25 (4H, m), 2.10-2.03 (1H, m), 1.86-1.78 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:10]([CH2:25][CH2:26][CH3:27])[CH:11]1[CH2:20][C:19]2[C:14](=[C:15]([C:21]([NH2:23])=O)[CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=O)[CH2:8][CH3:9]>C1COCC1>[NH2:23][CH2:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][CH2:12][CH:11]([N:10]([CH2:25][CH2:26][CH3:27])[CH2:7][CH2:8][CH3:9])[CH2:20]2
Reactant: CCCN(CCC)C1Cc2cccc(C(N)=O)c2NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCN(CCC)C1CNc2c(CN)cccc2C1
Yield: 59 %

Procedure:
Lithium aluminum hydride (1.5 g) was added to a stirred solution of 3-(dipropylamino)-1,2,3,4-tetrahydro-2-oxo-8-quinolinecarboxamide (0.75 g) in THF (125 mL) and the solution was refluxed for 2 days. The solution was cooled and excess hydride was destroyed by addition of methanol (20 mL) and the solvents were removed under reduced pressure. The residue was partitioned between ethyl acetate (400 mL) and water (15 mL). The ethyl acetate was decanted from the inorganic solids and the solvent removed under reduced pressure. The residual oil was dissolved in chloroform and chromatographed on silica gel. Elution of the column with 5% methanol:chloroform gave 0.40 g of 1,2,3,4-tetrahydro-8-(aminomethyl)-N,N-dipropyl-3-quinolinamine.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][CH2:11][NH:12][C:13](=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]#[C:10][CH2:11][NH:12][C:13](=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCC#CCNC(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC#CCNC(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{4-[6,6-bis-(4-fluoro-phenyl)-hexanoylamino]-but-2-ynyl}-carbamic acid tert-butyl ester (1.6 g, 3.4 mmol) was dissolved in dry CH2Cl2 (50 ml) followed by addition of TFA (20 ml). The resulting solution was stirred at room temperature for 2 hrs. The solution was concentrated under reduced pressure. The resulting residue was dissolved in water (20 ml) and pH of the solution was adjusted to 10. The water phase was extracted with CH2Cl2 (100 ml), and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the desired product in almost quantitative yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[CH:25]=[O:26]>>[CH:25]([C:24]1[CH:23]=[CH:22][C:21]([C:2]2[CH:17]=[CH:16][CH:15]=[C:4]([CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)=[CH:20][C:19]=1[CH3:18])=[O:26]
Reactant: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Reactant: Cc1cc(B(O)O)ccc1C=O
Product: Cc1cc(-c2cccc(CN(C)C(=O)OC(C)(C)C)c2)ccc1C=O
Yield: 84.2 %

Procedure:
In a manner similar to that of Example 1(e), by reacting 1.1 g (3.5 mmol) of tert-butyl (3-bromo-benzyl)-N-methylcarbamate obtained in Example 79(b) with 750 mg (4.6 mmol) of 3-methyl-4-formylbenzene-boronic acid, and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (7/3), 1 g (87%) of the expected product is obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([C:5]1([CH2:16][I:17])[CH2:10][O:9][C:8]2([CH2:15]CCC[CH2:11]2)[O:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(C)=O>[C:1]([C:5]1([CH2:16][I:17])[CH2:10][O:9][C:8]([CH3:15])([CH3:11])[O:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1(CI)COC2(CCCCC2)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)OCC(CI)(C(C)(C)C)CO1

Procedure:
A mixture of 3-t-butyl-3-iodomethyl-(1,5-dioxaspiro[5,5]undecane) (3.5 g.), p-toluenesulphonic acid (0.5 g.) and acetone (200 ml.) was refluxed for 36 hours. The mixture was cooled and sodium hydrogen carbonate (2.0 g.) was added. The solvent was removed in vacuo and the resulting oil was poured into water. The aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and then evaporated in vacuo. 5-t-Butyl-2,2-dimethyl-5-iodomethyl-1,3-dioxane was obtained as a colourless oil (2.3 g.) and was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH2:10][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO>[OH:18][NH:17][C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)[C:2]=1[OH:1])=[NH:5]
Reactant: NO
Reactant: N#Cc1cccc(Cc2c[nH]cn2)c1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(NO)c1cccc(Cc2c[nH]cn2)c1O
Yield: 45.9 %

Procedure:
3 g (0.015 mole) of 2-hydroxy-3-(1H-imidazol-4-ylmethyl-)benzonitrile (prepared in example 1.1 above) are dissolved in 100 ml of methanol and 1.15 g (0.0165 mole) of hydroxylamine hydrochloride and 1.84 g of sodium acetate are added thereto. The resulting mixture is then heated at the reflux temperature for 20 hours. The methanol is evaporated under reduced pressure and the residue is taken up in 100 ml of water. The resulting aqueous solution is neutralized to pH 7 by addition of an aqueous sodium bicarbonate solution. The white precipitate thus formed is filtered off, dried under vacuum and recrystallized from methanol. 1.6 g of N,2-dihydroxy-3-(1H-imidazol-4-ylmethyl)-benzenecarboximidamide, identical to the product obtained in example 2.5 above, are obtained. Yield 46%.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)#[N:2].CO.[ClH:17].CO[CH:20](OC)[CH2:21][NH2:22]>CCOCC>[ClH:17].[NH:2]1[CH:20]=[CH:21][N:22]=[C:1]1[CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(CCC#N)cc1
Reactant: COC(CN)OC
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1ccc(CCc2ncc[nH]2)cc1

Procedure:
Nitrile 23-3 (400 mg, 2.11 mmol) was dissolved in 10 mL Et2O at 0° MeOH (289 μL, 4.2 mmol) was added, the mixture was saturated with anhydrous HCl. Once the white ppt. formed, the solvent was evaporated and replaced with MeOH (5 mL), cooled to 0°, and aminoacetaldehyde dimethylacetal (250 μL, 2.3 mmol) was added. The reaction was heated to reflux for 3 days then concentrated, diluted in 10 mL 6N HCl and concentrated again providing 23-4 as a solid.
Reaction SMILES: [OH:1][C:2]1([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[O:6][C:5](=[O:7])[C:4]([C:8]2[CH:16]=[C:15]([O:17][CH3:18])[C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)=[C:3]1[CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1.O[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>ClCCl>[CH3:18][O:17][C:15]1[C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=[C:8]([C:4]2[C:5](=[O:7])[O:6][C:2]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)([O:1][CH2:41][CH2:42][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[C:3]=2[CH2:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)[CH:16]=1
Reactant: COc1ccc(C2(O)OC(=O)C(c3cc(OC)c4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Reactant: OCCN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(C2(OCCN3CCOCC3)OC(=O)C(c3cc(OC)c4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Reaction time: 24 h

Procedure:
To 125 mL dichloromethane was added 5-Hydroxy-3-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(4-methoxy-phenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one 3.25 g (6.06 mmol), giving a suspension. 4-(2-Hydroxyethyl)morpholine 3.24 g (24.76 mmol) was added, and the mixture was purged with anhydrous HCl gas until saturated. After 24 hours at room temperature, the mixture was evaporated in vacuo and the residue was suspended in warm ethyl ether and water. Decant the aqueous phase and wash the ether phase with 1 N NaOH, followed by water and saturated sodium chloride solution. The ether phase was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to a glassy solid, 2.13 g. The product was identified by 1H NMR, MS [M--H]+ =650 Da.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.O>CN1C(=O)CCC1>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[CH:6]=[CH:7][NH:8]3)=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: Oc1cccc2[nH]ccc12
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cccc3[nH]ccc23)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NaH (1.1 equivalents) is added to a solution of 4-hydroxyindole (1.0 equivalent) in NMP. The resulting mixture is stirred for 2 hours at room temperature. 2-Chloro-5-nitropyridine (1.1 equivalents) is added and the solution is heated to 100° C. for 2 hours. The solution is cooled and poured into water. The aqueous layer is extracted with EtOAc three times. The organic layers are combined and concentrated to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[CH2:29][CH2:28][S:27][CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: C1CSCCN1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCSCC2)cn1
Yield: 97 %

Procedure:
As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (450 mg, 1.45 mmol) was converted using thiomorpholine instead of 2,2,2-trifluoroethylamine to the title compound (SiO2, heptane:ethyl acetate=80:20 to 20:80, 560 mg, 97%) which was obtained as a white solid. MS: m/e=396.1 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:25])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:25])[CH2:12][CH2:13]1
Reactant: O=C1Nc2ccccc2CCN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C1Nc2ccccc2CCN1C1CCNCC1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
3-(1-Benzyl-piperidin-4-yl)-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one (100 mg, 0.3 mmol) in methanol (5 mL) was flushed with nitrogen, and treated with palladium on charcoal (10%, 10 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 50 mg (68%) of the desired material. LC/MS: tR=1.07 min, 246.26 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:34])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[C:9]2=[C:10]([Br:34])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccccc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1OC

Procedure:
Prepared in analogy to that of Example 103(a) from 2,3-dibromo-1-(2-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, NBS and BzOOBz in carbontetrachloride. The title compound, ESI MS (m/z): 561 (M+H)+.
Reaction SMILES: [Cl:1]Cl.[CH3:3][C:4]1[CH:8]([CH3:9])[C:7](=[O:10])[NH:6][N:5]=1>ClCCCl>[CH3:3][C:4]1[C:8]([CH3:9])([Cl:1])[C:7](=[O:10])[NH:6][N:5]=1
Reactant: ClCl
Reactant: CC1=NNC(=O)C1C
Solvent: ClCCCl
Product: CC1=NNC(=O)C1(C)Cl

Procedure:
A chlorine gas was introduced into a solution of 3,4-dimethyl-2-pyrazolin-5-one in 1,2-dichloroethane, followed by gradual refluxing. After the reaction, the reaction mixture was cooled and filtered. The solvent was then distilled off. The residue in the form of an oil was recrystallized from a 1:1 mixture of benzene and petroleum ether, whereby 3,4-dimethyl-4-chloro-2-pyrazolin-5-one was obtained.
Reaction SMILES: C(Cl)Cl.C=O.[Br:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:15])=[CH2:14])[CH:10]=[CH:9][C:8]=1[F:16].[C:17](=O)([O-])[OH:18].[Na+]>C(OCC)(=O)C>[Br:6][C:7]1[CH:12]=[C:11]([C:13](=[CH2:15])[CH2:14][CH2:17][OH:18])[CH:10]=[CH:9][C:8]=1[F:16]
Reactant: O=C([O-])O
Reactant: C=C(C)c1ccc(F)c(Br)c1
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=C(CCO)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
A molecular sieve 4A (3.14 g) and a boron trifluoride-diethyl ether complex (2.16 mL, 17.5 mmol) were added to methylene chloride (31 mL), and the mixture was stirred at room temperature for 1 hour. Subsequently, paraformaldehyde (0.46 g, 14.6 mmol) and the compound (3.14 g, 14.6 mmol) obtained in Example 91a were added at −5° C., and the mixture was stirred at the same temperature for 18 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→3:1, v/v) to give the title compound (1.24 g; yield, 35%) as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([N+:21]([O-])=O)=[C:12]2[C:24]([C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.C(OCC)(=O)C.[Fe]>[NH2:21][C:13]1[CH:14]=[N:15][C:16]2[C:11]([C:12]=1[C:24]([C:26]1[CH:27]=[CH:28][C:29]([C:30]#[N:31])=[CH:32][CH:33]=1)=[O:25])=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[C:18]([O:19][CH3:20])[CH:17]=2
Reactant: COc1cc2ncc([N+](=O)[O-])c(C(=O)c3ccc(C#N)cc3)c2cc1OCc1ccccc1
Agent: [Fe]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2ncc(N)c(C(=O)c3ccc(C#N)cc3)c2cc1OCc1ccccc1
Temperature: 66 °C
Yield: 70.9 %

Procedure:
4-(6-Benzyloxy-7-methoxy-3-nitroquinoline-4-carbonyl)benzonitrile (8.82 g, 20.07 mmol), iron powder (11.21 g, 200.7 mmol) and 2.0 M hydrochloric acid (22.76 ml) are suspended in methanol (455 ml) (stirrer motor) and heated at 66° C. for 18 h. When the reaction is complete (TLC (HPTLC) monitoring), the solid material is filtered off through kieselguhr with suction and rinsed with tetrahydrofuran (500 ml). The filtrate is evaporated to half its volume in vacuo. Semi-saturated NaCl solution (300 ml) is subsequently added, and the mixture is extracted twice with ethyl acetate (300 ml each time). The combined organic phases are dried over sodium sulfate, filtered with suction and evaporated to dryness in vacuo. The residue obtained is dissolved in ethyl acetate and filtered through a little flash silica gel. The filtrate is evaporated in vacuo, the residue is suspended in ethyl acetate (70 ml) and ethanol (20 ml), subsequently filtered off with suction and dried in a high vacuum, giving 4-(3-amino-6-benzyloxy-7-methoxyquinoline-4-carbonyl)benzonitrile (5.83 g, 14.23 mmol) as a solid having a melting point of 192.6° C. MS: 410.1 (M+H+), TLC (HPTLC): Rf=0.36 (ethyl acetate).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]([C:14]#[N:15])([CH3:13])[CH2:8][CH2:9][C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:18])=O>C1C=CC=CC=1>[C:1]([N:5]=[N:6][C:7]([C:14]#[N:15])([CH3:13])[CH2:8][CH2:9][C:10]([Cl:18])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)N=NC(C)(C#N)CCC(=O)O
Solvent: c1ccccc1
Product: CC(C)(C)N=NC(C)(C#N)CCC(=O)Cl
Reaction time: 4 h
Yield: 98.8 %

Procedure:
Into a 25 ml round bottom flask was weighed 5 grams (0.0237 mole) of 4-t-butylazo-4-cyanovaleric acid and then 15 ml of benzene and 2 ml of thionyl chloride were added. The acid dissolved and the solution was stirred for 4 hours at 25° C. ± 2° C. (protected from the atmosphere by a CaCl2 tube). At the end of the stirring period the benzene and excess thionyl chloride were evaporated under reduced pressure leaving 5.35 grams (98.8% yield) of 4-t-butylazo-4-cyanovaleryl chloride.