Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1C=CC=CC=1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=O.[NH2:18][C:19]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.N1CCCC1>CCO.CN(C1C=CN=CC=1)C>[Cl:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:20]2[C:19]=1[N:18]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])[C:8]([NH2:1])=[CH:21]2
Reactant: O=C(CBr)c1ccccc1Cl
Reactant: c1ccncc1
Reactant: Nc1c(Cl)cccc1C=O
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: C1CCNC1
Product: Nc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Temperature: 6070 °C

Procedure:
To pyridine (2.1 ml, 26 mmol) in EtOH (60 ml) was added 2-bromo-1-(2-chlorophenyl)ethanone (6.1 g, 26 mmol) in EtOH (40 ml) dropwise over 10 min. The resulting mixture was heated at 6070° C. for 1 hour and cooled to room temperature. To the mixture were added pyridine (1.25 ml), 2-amino-3-chlorobenzaldehyde (3.72 g, 24.0 mmol) and DMAP (0.05 g, cat.). The mixture was heated at reflux for 48 hrs. The reaction mixture was cooled to room temperature and pyrrolidine (4.60 ml, 55.0 mmol) was added. After heating at reflux overnight, the resulting mixture was concentrated. The residue was partitioned between saturated aqueous NaHCO3 and CH2Cl2. The combined organic layers were dried, concentrated. Flash chromatography of the residue over silica gel, using 3:7 EtOAc-hexane, gave 8-chloro-2-(2-chlorophenyl)-quinolin-3-amine, 1H-NMR (DMSO-d6) δ 7.67 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.50-7.57 (m, 3H), 7.46 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.39 (t, J=8.0 Hz, 1H), 5.32 (br, 2H). Mass Spectrum (ESI) m/e=289.0 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17]C#N)[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:25](=[O:28])(O)[O-:26].[Na+]>O.C(O)(=O)C>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][C:25]([OH:26])=[O:28])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccc2nc(-c3ccccc3)ccc2c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc2nc(-c3ccccc3)ccc2c1

Procedure:
A mixture of 10 g of 2-phenyl-6-quinolineacetonitrile, 19 ml of water, 19 ml of concentrated sulphuric acid and 19 ml of glacial acetic acid is kept under reflux for 2 hours. Thereafter, ice and water are added and the pH is adjusted to 5-6 with solid sodium bicarbonate. The crystals which thereupon precipitate are filtered off and rinsed with water. Recrystallisation from methanol-ether-petroleum ether yields 2-phenyl-6-quinolineacetic acid of melting point 176°-179°C. 2-(p-Chlorophenyl)-6-quinoline-acetic acid and 2-(p-fluorophenyl)-6-quinolineacetic acid are obtained analogously.
Reaction SMILES: [CH3:1][NH2:2].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2([C:14]([S:16]C)=S)[CH2:13][CH2:12][CH2:11][S:10]2)[CH:4]=1.C>C(O)C>[CH3:1][NH:2][C:14]([C:9]1([C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11][S:10]1)=[S:16]
Reactant: CN
Reactant: CSC(=S)C1(c2cccnc2)CCCS1
Solvent: CCO
Product: CNC(=S)C1(c2cccnc2)CCCS1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A 33% (weight/volume) solution of methylamine in ethanol (11 cc) is added dropwise, in the course of 5 minutes, to a solution of methyl 2-(pyrid-3-yl)-tetrahydrothiophen-2-carbodithioate (14.3 g) in ethanol (50 cc), kept at a temperature of about 20° C. The solution is subsequently stirred for 5 hours at the same temperature and then cooled to 0° C. The resulting crystals are filtered off, washed with ethanol (8 cc) and then twice with diisopropyl ether (20 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The product thus obtained (7.2 g) is dissolved in boiling ethanol (35 cc); decolourising charcoal (0.4 g) is added to the solution, which is filtered hot, and the filtrate is then cooled for 1 hour at a temperature of about 5° C. The resulting crystals are filtered off, washed with ethanol (5 cc) and then twice with diisopropyl ether (14 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 40° C. N-Methyl-2-(pyrid-3-yl)-tetrahydrothiophen-2-carbothioamide (5.8 g), melting at 133° C., is thus obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(OCC)(=O)C>[Br-:7].[CH2:12]([O:11][C:9]([CH2:8][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)CBr
Reactant: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C[n+]1ccccc1
Product: [Br-]
Reaction time: 12 h

Procedure:
A mixture of pyridine (3 g, 38 mmol) and ethyl bromoacetate (6.3 g, 38 mmol) in 30 ml of ethyl acetate was stirred for 12 h. The precipitate formed was isolated by filtration and washed with diethyl ether (30 ml), to give, after drying, 7 g of 1-ethoxycarbonylmethylpyridinium bromide 5.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=O)[NH:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[CH2:2]1.[CH3:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[C:26]1(C)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[CH3:26][C:16]1[CH:15]=[CH:14][C:11]2[N:12]3[CH2:1][CH2:2][C:3]4[C:13]3=[C:7]([CH:6]=[CH:5][CH:4]=4)[C:8]([N:23]3[CH2:24][CH2:25][CH:20]([CH3:19])[CH2:21][CH2:22]3)=[N:9][C:10]=2[CH:17]=1
Reactant: CC1CCNCC1
Reactant: O=C1Nc2ccccc2N2CCc3cccc1c32
Reactant: Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: Cc1ccc2c(c1)N=C(N1CCC(C)CC1)c1cccc3c1N2CC3
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 6.26 g (0.0250 mole) of 9-methyl-1,2- , dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one and 1000 ml of toluene was heated under nitrogen until a solution resulted. Then there was added 24.8 g (0.250 mole) of 4-methylpiperidine, followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was heated under reflux for three hours, cooled to room temperature and filtered. The filtrate was stirred with 500 ml of 2N sodium hydroxide solution for 15 minutes and the layers were separated. The aqueous phase was extracted with 250 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to 8.1 g (98%) of product. Recrystallization from ethyl acetate provided the analytical sample, mp 194°-196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:33]=1[NH2:34].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:34][C:33]3[CH:35]=[C:36]([C:39]([F:40])([F:41])[F:42])[CH:37]=[CH:38][C:32]=3[F:31])=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)O)c3c(c2[nH]1)CC(C)(C)O3
Reactant: Nc1cc(C(F)(F)F)ccc1F
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3cc(C(F)(F)F)ccc3F)c3c(c2[nH]1)CC(C)(C)O3
Yield: 9.8 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-35, 0.100 g, 0.268 mmol), thionyl chloride (3.0 mL), 2-fluoro-5-(trifluoromethyl) aniline (0.053 g, 0.296 mmol), THF (10.0 mL) and DIPEA (3 mL). The obtained crude product was purified by column chromatography on neutral alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.014 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 2.25 (s, 3H), 3.15 (s, 2H), 7.32 (m, 4H), 7.54 (m, 3H), 8.98 (s, 1H), 10.25 (s, 1H), 11.50 (s, 1H); MS [M+H]+: 533.37.
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]([CH3:30])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][CH2:18][C:19]2[CH:20]=[N:21][N:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:23]=2)[N:14]=1)[CH3:8])(C)(C)C.[ClH:32].C(O[CH2:37][CH3:38])(=O)C>C(OCC)C>[ClH:32].[CH3:8][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][N:17]([C:20]2[NH:21][N:22]=[C:37]([CH3:38])[CH:19]=2)[CH2:18][C:19]2[CH:20]=[N:21][N:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:23]=2)[N:14]=1)([CH3:30])[C:6]([OH:5])=[O:31]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNCc2cnn(-c3ccccc3)c2)cs1
Agent: Cl
Solvent: CCOCC
Product: Cc1cc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2cnn(-c3ccccc3)c2)[nH]n1

Procedure:
A compound obtained using 2-methyl-2-{[4-(2-{[(1-phenyl-1H-pyrazol-4-yl)methyl]amino}ethyl)-1,3-thiazol-2-yl]thio}propionic acid tert-butyl ester synthesized in Example 451-2, and by an operation similar to that of Example 446 was dissolved in diethyl ether, and reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH:15]=[C:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1.[H][H]>[Pd].CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])=[CH:13][CH:12]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCNc3ncccn3)cc2)S1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(Cc2ccc(OCCNc3ncccn3)cc2)S1

Procedure:
A mixture of 5-[4-(2-(2-pyrimidinylamino)ethoxy)benzylidene]-2,4-thiazolidinedione (3 g) and 10% palladium on charcoal (9 g) in DMF (70 ml) was stirred under a pressure of 200 psi of hydrogen until hydrogen uptake ceased. The mixture was filtered through diatomaceous earth, and the filter pad washed exhaustively with DMF. The combined filtrates were evaporated to dryness and the title compound (m.p. 173° C.) obtained following recrystallization from methanol.
Reaction SMILES: [CH3:1][C:2]1([C:18]([O:20]CC)=[O:19])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.[Li+].[OH-]>C(O)C>[CH2:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH3:1])([C:18]([OH:20])=[O:19])[CH2:3]1)=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1(C)CCCN(C(=O)OCc2ccccc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C(=O)O)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 86 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To 1-benzyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (3.0 g, 10.0 mmol) in ethanol (15 mL) was added LiOH (15.0 mL, 30.1 mmol), and the reaction mixture was stirred at 86° C. for 1 hour. The ethanol was removed, and ether (30 mL) was added. The aqueous layer was separated and acidified with saturated potassium hydrogen sulfate to a pH of about 3 to about 4, extracted with ethyl acetate (50 mL), and washed with brine and dried over sodium sulfate. After removal of the solvent, 1-(benzyloxycarbonyl)-3-methylpiperidine-3-carboxylic acid (2.6 g, 92% yield) was isolated as an oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.[Cl-].[Na+]>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([O:16][CH2:15][C:14]2[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=3)=[N:11][O:12][C:13]=2[CH3:17])=[N:20][CH:21]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1onc(-c2cccc(F)c2)c1CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (3.68 g, 18 mmol) in THF (54 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (4.1 g, 68%) which was obtained as a white solid. To a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.1 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (94 mg, 2.2 mmol) in water (5 mL) and methanol (1 mL) added and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (25%, 3 drops) and methanol (2 drops) added. A gum began to form and the mixture was cooled at 0° C. for 1.5 h and then the aqueous layer decanted off. Trituration with diethylether and hexane afforded the title compound (95%) which was obtained as an off white solid. MS: m/e=327.4 [M−H]−.
Reaction SMILES: C([N:8]([CH3:31])[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:9]([CH2:31][NH:8][C:9]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(N(C)Cc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc(C#Cc2ccc(C3(NCCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 147.5 %

Procedure:
Using General Procedure I; a solution of ethyl 4-{4-[1-(benzyl-methylamino)-cyclopropyl]-phenylethynyl}-benzoate (Compound 115, 65.0 mg, 0.16 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 45.0 mg (75%) of the title compound as a solid.
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-])=O)=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1.[C:17]([O:22][CH2:23][CH3:24])(=[O:21])[C:18]([CH3:20])=O>C(OCC)C.C(O)C.[Cl-].[Zn+2].[Cl-]>[Br:4][C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[N:14]=[C:18]([C:17]([O:22][CH2:23][CH3:24])=[O:21])[CH:20]=[C:11]2[CH3:12].[Br:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:14])=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1
Reactant: CC(=O)c1cc(Br)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(C)=O
Agent: Cl[Sn]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CCO
Product: CC(=O)c1cc(Br)ccc1N
Product: CCOC(=O)c1cc(C)c2cc(Br)ccc2n1
Temperature: 70 °C
Yield: 3 %
Yield: 62 %

Procedure:
A 2.2 M solution of zinc(II)chloride (9.31 mL, 20.49 mmol) in diethyl ether was added to tin(II)chloride (3.88 g, 20.49 mmol) and activated 4 Å molecular sieve pellets (1.00 g) in ethanol (10 mL) under argon. Then, 1-(5-bromo-2-nitrophenyl)-ethanone (1.00 g, 4.10 mmol) and ethyl pyruvate (499.6 mg, 4.30 mmol) in ethanol (10 mL) were added to the reaction mixture via canula. The mixture was heated at 70° C. in an oil bath for three hours, then allowed to cool to room temperature, and carefully quenched with saturated sodium bicarbonate. Ethyl acetate was added and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:6 ethyl acetate:hexanes to give 39.4 mg (3%) of ethyl 6-bromo-4-methyl-2-quinolinecarboxylate as a solid and 543.1 mg (62%) of 1-(5-bromo-2-aminophenyl)-ethanone as a solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH:16](=O)[CH3:17].[C:19](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:20].[Na+]>C(Cl)Cl>[CH2:19]([N:1]([CH2:2][C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:16][CH3:17])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1CN
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)C[C@@H]1COCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of (R)-tert-butyl 3-(aminomethyl)morpholine-4-carboxylate (commercially available, 250 mg, 1.16 mmol) and DCM (7 ml) at 0° C. was treated with acetaldehyde (0.162 ml, 2.89 mmol). The reaction mixture was stirred at 0° C. for 15 minutes and sodium triacetoxyborohydride (612 mg, 2.89 mmol) was added all at once. The resulting mixture was stirred for 24 h and the mixture was diluted with 20 ml of DCM (20 ml) and washed with saturated aq. sodium bicarbonate (20 ml). The organic phase was dried over sodium sulfate, filtered, and concentrate under pressure to give (R)-tert-butyl 3-((diethylamino)methyl)morpholine-4-carboxylate (INTERMEDIATE 90, STEP 1)
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH3:3].S(C1C=CC(C)=CC=1)(O[CH2:26][C:27]([F:30])([F:29])[F:28])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OC(=O)C)C>[OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:26][C:27]([F:30])([F:29])[F:28])[CH3:3]
Reactant: C[C@H](O)[C@@H](CCc1ccccc1O)n1cnc(C(N)=O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](O)[C@@H](CCc1ccccc1OCC(F)(F)F)n1cnc(C(N)=O)c1
Temperature: 130 °C
Reaction time: 13 h
Yield: 54.5 %

Procedure:
A mixture of 1-[(2S,3R)-2-hydroxy-5-(2-hydroxyphenyl)-3-pentyl]imidazole-4-carboxamide (10 mg), 2,2,2-trifluoroethyl tosylate (27.4 mg) and potassium carbonate (14.9 mg) in N,N-dimethylformamide (1 ml) was stirred at 130° C. for 13 hours. The mixture was taken up in ethylacetate, washed three times with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (10:1) to give a pale brown powder of 1-{(2S,3R)-2-hydroxy-5-[2-(2,2,2-trifluoroethoxy)phenyl]-3-pentyl}imidazole-4-carboxamide (7) (7.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH2:22](I)[CH3:23]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[C:7]2[N:12]([CH2:22][CH3:23])[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[S:8]2)=[CH:4][CH:3]=1
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Reactant: CCI
Agent: [H-]
Agent: [Li+]
Product: CCn1c(=Nc2ccc(Cl)cc2)sc2ncccc2c1=O
Yield: 58.4 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (3.11 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 25 mg of lithium hydride and 584 mg of ethyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 577 mg of 2-[(4-chlorophenyl)imino]-2,3-dihydro-3-ethyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (58%, recrystallized from a mixture of ether and hexane) as a low polarity substance and 61 mg of 2-[N-(4-chlorophenyl)-N-ethylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (6%, recrystallized from ether) as a high polarity substance.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([OH:23])[CH:22]=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:28][CH2:29][CH2:30]Br)(=[O:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:23][CH2:30][CH2:29][O:28][C:25](=[O:27])[CH3:26])[CH:22]=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc3cc(O)cc(c23)C(=O)N1OCc1ccccc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)OCCOc1cc2c3c(cccc3c1)C(=O)N(OCc1ccccc1)C2=O
Yield: 95.5 %

Procedure:
2-Benzyloxy-5-hydroxy-benzo[de]isoquinoline-1,3-dione (1.0 g, 3.1 mmol), and 2-bromoethyl acetate (1.5 g, 9.0 mmol) were reacted in acetone (50 mL) in presence of potassium carbonate (0.7 g, 5.1 mmol) following the procedure of Example 22 to give 1.2 g of 2-benzyloxy-5-(2-acetoxy-ethoxy)-benzo[de]isoquinoline-1,3-dione. The hydrogenation of 2-benzyloxy-5-(2-acetoxy-ethoxy)-benzo[de]isoquinoline-1,3-dione (1.2 g) in the presence of 10% Pd/C (0.8 g) in ethyl acetate afforded 0.5 g of the title compound, mp 232-235° C.;
Reaction SMILES: Cl[CH:2]1[N:7](Cl)[CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=[N:3]1.[NH2:13][C:14]1[C:30]([O:31][CH3:32])=[CH:29][C:17]2[CH2:18][CH2:19][N:20]([CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[CH2:21][CH2:22][C:16]=2[CH:15]=1.C(N(CC)C(C)C)(C)C.[CH3:42][CH:43]([S:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[NH2:54])(=[O:47])=[O:46])[CH3:44].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C.O>[CH3:32][O:31][C:30]1[C:14]([NH:13][C:2]2[N:7]=[C:6]([NH:54][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=3[S:45]([CH:43]([CH3:44])[CH3:42])(=[O:47])=[O:46])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)=[CH:15][C:16]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[CH2:19][CH2:18][C:17]=2[CH:29]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: FC(F)(F)C1=CN(Cl)C(Cl)N=C1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc2c(cc1Nc1ncc(C(F)(F)F)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)CCN(CC(=O)N(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.4 %

Procedure:
2,3-Dichloro-5-trifluoromethylpyrimidine (892 mg, 4.11 mmol), 2-(7-amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethylacetamide (1.00 g, 3.6 mmol), and N,N-diisopropylethylamine (699 mg, 5.41 mmol) were combined in isopropanol (17 mL) and stirred at room temperature overnight. The reaction was concentrated and the organics were extracted into dichloromethane. The dichloromethane extract was washed with saturated sodium bicarbonate solution, was dried (sodium sulfate), and was concentrated. Reverse phase chromatography (Gilson) employing gradient elution (20-55% acetonitrile: water) afforded (in order of elution): 2-[7-(2-Chloro-5-trifluoromethylpyrimidin-4-ylamino)-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl]-N,N-dimethylacetamide (453 mg, 27%) and 2-[7-(4-Chloro-5-trifluoromethylpyrimidin-2-ylamino)-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl]-N,N-dimethylacetamide (458 mg, 28%). The latter compound (60 mg, 0.10 mmol) was combined with 2-(propane-2-sulfonyl)phenylamine (29 mg, 0.147 mmol) and 10-camphorsulfonic acid (48 mg, 0.207 mmol) in isopropanol (3 mL) to which had been added 0.01 mL water. The mixture was heated at 180° C. in a microwave for three hours. The reaction was permitted to cool and was concentrated. The organics were extracted into dichloromethane which was subsequently washed with saturated sodium bicarbonate solution, was dried (sodium sulfate), and was concentrated. ISCO chromatography (gradient elution: 1 to 5% MeOH:dichloromethane) afforded the title compound as a brown gum (4 mg, 4%). LCMS (m/e) 621 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.46 (s, 1H), 8.53 (d, J=8 Hz, 1H), 8.37 (s, 1H), 8.15 (s, 1H), 7.89 (d, J=8 Hz, 1H), 7.74 (s, 1H), 7.56 (m, 1H), 7.20 (m, 1H), 6.71 (s, 1H), 3.91 (s, 3H), 3.31 (m, 3H), 3.16 (s, 3H), 3.00 (s, 3H), 2.92 (m, 2H), 2.84 (m, 2H), 2.71 (m, 4H), 1.32 (d, J=7 Hz, 6H).