Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[H-].[Na+].O1CCCC1.Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH3:23]>CCCCCC.O>[CH2:20]([O:19][CH2:18][CH2:17][O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:21][CH2:22][CH3:23]
Reactant: OCCc1cccs1
Reactant: CCCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCCOCCOCCc1cccs1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 33.8 %

Procedure:
6.1 g of 2-thiopheneethanol was cooled to 0° C., and to this, a suspension formed by adding 2.8 g of sodium hydride (60% in oil) to 50 ml of tetrahydrofuran was added dropwise. The solution was stirred at 0° C. for 20 minutes under a nitrogen atmosphere, and to this, 8.2 g of 1-(2-bromo-ethoxy)-butane was added dropwise. Thereafter, the solution was heated to 90° C. and stirred for 9 hours. 100 ml of water and 100 ml of hexane were added to the reaction solution to separate the organic layer. The organic layer was washed with 300 ml of water and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated by a rotary evaporator and purified by a column chromatography (filler: silica gel, eluent: hexane/dichloromethane) to obtain 3.5 g of 2-[2-(2-butoxy-ethoxy)ethyl]-thiophene.
Reaction SMILES: Cl([O-])=O.[Na+].[OH2:5].P([O-])(O)(O)=O.[Na+].[Br:12][C:13]1[N:14]=[C:15]([CH3:20])[NH:16][C:17]=1[CH:18]=[O:19].CC(=CC)C>O.C1COCC1.C(O)(C)(C)C>[Br:12][C:13]1[N:14]=[C:15]([CH3:20])[NH:16][C:17]=1[C:18]([OH:5])=[O:19]
Reactant: Cc1nc(Br)c(C=O)[nH]1
Reactant: O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: Cc1nc(Br)c(C(=O)O)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.6 %

Procedure:
A solution of sodium chlorite (1.6 g, 17.8 mmol) and sodium dihydrogen phosphate monohydrate (1.5 g, 10.6 mmol) in water (3.9 mL) was added to a stirred solution of 4-bromo-2-methyl-1H-imidazole-5-carbaldehyde (0.334 g, 1.8 mmol), 2-methyl-2-butene (11 mL of a 2M solution in THF, 22.0 mmol), and tert-butanol (1.3 mL) in THF (5.5 mL). The reaction mixture was stirred at RT for 6 h. The aqueous phase was separated and extracted with EtOAc (4×10 mL). The combined extracts were dried (Na2SO4), filtered, concentrated and the residue was triturated with diethyl ether to provide the title compound (0.316 g, 87%) as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.91 (br. s., 1H), 2.27 (s, 3H). ES-LCMS: m/z 205.2, 207.3 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:10]=1[CH2:11][NH:12][C:13]1[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=[C:15]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[N:14]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1.CO>[OH:8][C:9]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:10]=1[CH2:11][NH:12][C:13]1[C:18]([C:19]([NH2:21])=[O:20])=[CH:17][N:16]=[C:15]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:25][CH:24]=2)[N:14]=1
Reactant: NC(=O)c1cnc(Nc2ccc(N3CCOCC3)cc2)nc1NCc1c(F)cccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1cnc(Nc2ccc(N3CCOCC3)cc2)nc1NCc1c(O)cccc1F
Reaction time: 6 h
Yield: 48.6 %

Procedure:
A 20 ml portion of THF-methanol (2:1) mixed solution of 290 mg of 4-[(2-benzyloxy-6-fluorobenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide synthesized in the same manner as in Production Example 13 was mixed with 50 mg of 10% palladium-carbon, followed by stirring for 1 hour in a hydrogen atmosphere. The reaction mixture was filtered and then mixed with 100 mg of 10% palladium-carbon, followed by stirring for 6 hours in a hydrogen atmosphere. After filtration of the reaction mixture and subsequent evaporation of the solvent, the resulting residue was purified by a silica gel column chromatography (chloroform-methanol). By recrystallizing the resulting crude crystals (THF-methanol), 117 mg of 4-[(2-hydroxy-6-fluorobenzyl)amino]-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide was obtained as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[F:20][C:21]([F:32])([F:31])C1C=CC=C2C=1NC=C2>>[F:20][C:21]([F:32])([F:31])[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2
Reactant: FC(F)(F)c1cccc2cc[nH]c12
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: CC1(C)OB(c2cc3cccc(C(F)(F)F)c3[nH]2)OC1(C)C

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-trifluoromethyl-1H-indole.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][NH:5][C:4](=[O:7])[CH2:3]1.[ClH:9].[OH2:10]>>[ClH:9].[NH2:5][CH2:6][C:2]([CH3:8])([CH3:1])[CH2:3][C:4]([OH:10])=[O:7]
Reactant: CC1(C)CNC(=O)C1
Reactant: O
Agent: Cl
Product: CC(C)(CN)CC(=O)O
Temperature: 120 °C

Procedure:
4,4-Dimethyl-2-pyrrolidinone (2.52 g, 22.3 mmol) was added to a mixture of concentrated HCl (50 mL) and water (50 mL) and the resulting mixture was refluxed at 120° C. for 20 hours. After it was cooled to room temperature, the mixture was washed twice with dichloromethane. The aqueous layer was evaporated to give 4-amino-3,3-dimethyl-butyric acid hydrochloride compound 55-B (3.4 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([O:20][CH2:21][CH3:22])(=[O:19])[C@H:16]([CH3:18])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[CH2:21]([O:20][C:15](=[O:19])[C@@H:16]([CH3:18])[O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:22]
Reactant: CCOC(=O)[C@H](C)O
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)Oc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 4-hydroxy-3-nitrobenzoate (5.0 g) and ethyl L-lactate (2.9 ml) in tetrahydrofuran (120 ml) was added triphenylphosphine (10 g), and the mixture was stirred at room temperature for 10 minutes. To the mixture was added under ice-cooling diisopropyl azodicarboxylate (20 ml), and the mixture was stirred at 60° C. for 4 hours. The reaction solution was cooled to room temperature, and water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the title compound (9.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 4-trifluoromethoxybenzenesulfonyl chloride (344 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12d as a solid (313 mg, 78.8%). HPLC: 98% (Rt=12.22 min).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[C:3]=1[C:12]#[N:13].[CH3:14][N:15]=[C:16]=[O:17]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.O1CCCC1>[CH3:14][NH:15][C:16]([NH:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH2:8][CH3:9])[CH2:10][CH3:11])[C:3]=1[C:12]#[N:13])=[O:17]
Reactant: CCN(CC)c1nsc(N)c1C#N
Reactant: CN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: CCN(CC)c1nsc(NC(=O)NC)c1C#N

Procedure:
A mixture of 9.8 g of 5-amino-4-cyano-3-(diethylamino)isothiazole, 20 drops of dibutyltin diacetate, and about 15 ml of methyl isocyanate in 50 ml of dry tetrahydrofuran was heated under reflux for 21 hours, at which time thin-layer chromatographic analysis indicated reaction to be complete. The solution was concentrated under reduced pressure and the residue was recrystallized from ethanol to give 11.7 g of white 1-methyl-3-(4-cyano-3-(diethylamino)-5-isothiazolyl)urea, m.p. 182°-183°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:5]2.C([O-])(=O)C.[K+].[Br:32]Br.O>C(O)(=O)C>[Br:32][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:8]2
Reactant: BrBr
Reactant: CCCCC(=O)c1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
To an ice-cooled mixture of 1-[2-(6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (1.59 g, 4.62 mmol) in glacial acetic acid (50 mL) was added potassium acetate (4.54 g, 46.2 mmol). The mixture was stirred at room temperature for 15 minutes and then chilled again in an ice bath. Bromine (0.27 mL, 5.3 mmol) in acetic acid (6 mL) was added dropwise. The mixture was stirred at room temperature for 15 minutes. It was poured into excess water and filtered. The precipitate was dissolved in ethyl acetate, with some warming, and dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to dryness to afford 1-[2-(5-bromo-6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone as a yellow solid (1.85 g), mp 171-172° C. Mass spectrum (+APCl, [M+H]+) m/z 423. 1HNMR (400 MHz, DMSO-d6): δ10.95 (s, 1H), 8.4 (d, 1H, J=1.7 Hz), 8.15 (d, 1H, J=9.0 Hz), 8.05-8.1 (m, 2H), 7.95 (dd, 1H, J=8.8 Hz and 2.0 Hz), 7.7-7.75 (m, 1H), 7.35-7.45 (m, 3H), 2.75 (t, 2H, J=7.3 Hz), 1.5-1.6 (m, 2H), 1.1-1.2 (m, 2H), and 0.7 ppm (t, 3H, J=7.3 Hz). Elemental Analysis for C23H19BrO3. 0.25 H2O: Calculated: C, 64.57; H, 4.59; N, 0.00. Found: C, 64.19; H, 4.26; N, 0.05.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][C:6]([OH:10])([C:8]#[N:9])[CH2:5][C:4]([CH3:12])([CH3:11])[NH:3]1.S(=O)(=O)(O)O.[C:19](O)(=O)[CH3:20]>>[CH2:19]([CH:20]1[NH:9][CH2:8][C:6]2([CH2:5][C:4]([CH3:12])([CH3:11])[NH:3][C:2]([CH3:13])([CH3:1])[CH2:7]2)[O:10]1)[CH2:2][CH2:7][CH2:6][CH2:5][CH:4]([CH3:12])[CH3:11]
Reactant: CC(=O)O
Reactant: CC1(C)CC(O)(C#N)CC(C)(C)N1
Agent: O=S(=O)(O)O
Product: CC(C)CCCCCC1NCC2(CC(C)(C)NC(C)(C)C2)O1

Procedure:
182 g of 2,2,6,6-tetramethyl-4-hydroxy-4-cyanopiperidine, 284 g of isononyl-aldehyde and 200 g of concentrated sulfuric acid are stirred for 25 hours at 60° C. in 600 g of glacial acetic acid in a 2 liter apparatus with agitator. After cooling the main portion of the solvent is distilled off under reduced pressure. The residue is stirred with 500 ml of acetone and suction-filtered, thus yielding 292 g=69% of th. of the sulfuric acid salt of the intended compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[K]>CC(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: [K]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C=O)cc1
Temperature: 0 °C
Yield: 75.4 %

Procedure:
p-Hydroxybenzaldehyde (122 g, 1 mole), ethyl bromoacetate (167 g, 1 mole), potassium carborate (138 g, 1 mole) and acetone (500 ml) were united, stirred and refluxed for 3 hours. The reaction mixture was poured into crushed ice (2 kg). The solid that separates was removed by filtrations, washed with water, dried and recrystallized from ethanol to give 157 g of product, m.p. 41°-42° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])#[N:2]>C1COCC1>[NH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][CH2:3][CH2:1][NH2:2]
Reactant: N#CCCCOCCOCCOCCCC#N
Solvent: C1CCOC1
Product: NCCCCOCCOCCOCCCCN

Procedure:
A stirred solution of 50 mL dry THF containing 0.42 g (10.4 mmol) fresh LAH was heated to gentle reflux under argon for 15 minutes. 0.5 g (2 mmol) 17 in 15 mL dry THF was added dropwise over 20 minutes, maintaining a gentle reflux. The unreacted LAH was quenched with ethanol, and the mixture was treated with dropwise addition of saturated sodium sulfate under efficient stirring until a white precipitate formed. The mixture was filtered, and the precipitate was washed 6×30 mL with THF. The organic extracts were combined and the solvent was removed by rotary evaporation to yield an oil. ESI-MS: predicted, 248.1; observed, 249.1 (M+H+)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[F:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=2)=O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[CH:27][CH:28]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc(Cc2ccccc2N2CCN(c3ccncc3)CC2)cc1
Reaction time: 18 h
Yield: 2 %

Procedure:
A solution of N-(4-pyridyl)piperazine (8.15 g), 4,4′-difluorobenzophenone (13.1 g) and powdered potassium carbonate (9.12 g) was stirred at 95° C. in DMSO (100 ml) overnight. The solution was poured into water (1500 ml) to give a precipitate which was filtered, washed with water and dried. The solid (7.82 g) was stirred in trifluoroacetic acid (25 ml) under argon with triethylsilane (10 ml) for 18 hours. The solution was poured into water (315 ml), taken to pH 12 with sodium hydroxide solution and extracted with dichloromethane (2×300 ml). The combined dichloromethane extracts were washed with water, dried (Na2SO4) and evaporated to give a residue which was purified by chromatography on alumina (ICN Alumina N 32-63) using 0.5% methanol in dichloromethane as eluant. The solid obtained was recrystallised from a mixture of ethyl acetate/isohexane to give 1-(4-fluorobenzylphenyl)-4-(4-pyridyl)piperazine (350 mg) as a solid, m.p. 110-111° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH2:10]2.[CH3:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C@H:28]([OH:36])[CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:22][C:20]=2[N:21]=1.CCN(C(C)C)C(C)C>CCO>[CH2:12]1[C:13]2[C:9](=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:33]3[CH2:34][CH2:35][N:30]([CH2:29][C@@H:28]([OH:36])[CH2:27][O:26][C:23]4[CH:24]=[CH:25][C:19]5[S:18][C:17]([CH3:16])=[N:21][C:20]=5[CH:22]=4)[CH2:31][CH2:32]3)=[CH:15][CH:14]=2)[CH2:10][CH2:11]1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Reactant: BrCCCCOc1ccc2c(c1)CCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCCCOc4ccc5c(c4)CCC5)CC3)ccc2s1
Temperature: 25 °C

Procedure:
A solution of 4-bromo-1-indan-5-yloxybutane (934 mg, 3.46 mmol, crude) in EtOH (10 mL) was treated with (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol as prepared in Example 3A (250 mg, 0.81 mmol) and DIEA (0.57 mL, 3.3 mmol) and refluxed for 14 hours. Upon cooling to RT, the solution was then concentrated under reduced pressure and purified via an Isco™ (100% EtOAc 4 min, 10 min gradient to 25% MeOH/EtOAc, hold 6 min.) to afford (2R)-3-[4-(4-indan-5-yloxybutyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][N:20]=3)[CH2:17][NH:16][CH2:15][CH2:14]4)=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.[CH3:21][C@@:22]1([CH2:29][S:30](Cl)(=[O:32])=[O:31])[C:26](=[O:27])[NH:25][C:24](=[O:28])[NH:23]1>CCOC(C)=O.CCOC(C)=O.CO>[CH:2]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][N:20]=3)[CH2:17][N:16]([S:30]([CH2:29][C@@:22]3([CH3:21])[NH:23][C:24](=[O:28])[NH:25][C:26]3=[O:27])(=[O:31])=[O:32])[CH2:15][CH2:14]4)=[CH:7][CH:6]=2)[CH2:4][CH2:3]1
Reactant: c1cc(C2CC2)ncc1-c1cc2c(cn1)CNCC2
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@]1(CS(=O)(=O)N2CCc3cc(-c4ccc(C5CC5)nc4)ncc3C2)NC(=O)NC1=O
Yield: 6.8 %

Procedure:
The title compound was prepared from 6-(6-cyclopropylpyridin-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine hydrochloride (0.63 mmol) and [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (0.70 mmol) following the general procedure of Example 1. Column chromatography with neat EtOAc and EtOAc-MeOH (9:1) as eluents gave 0.060 g of almost pure product. Recrystallisation from 99% EtOH gave 0.019 g (7.0%) of the title compound as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](F)[CH:3]=1.O.[NH2:10][NH2:11].[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:10][NH2:11])[CH:3]=1
Reactant: NN
Reactant: Fc1cc(Br)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NNc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask was charged with a stir bar, 4-bromo-2-fluoro-pyridine (2.00 g), and hydrazine hydrate (5.5 mL). The resulting mixture was vigorously stirred at room temperature overnight. Then, 4 M aqueous NaOH solution (5 mL) and water (10 mL) were added and the mixture was vigorously stirred for another 10 min. The precipitate was separated by filtration, washed with water, and dried at 50° C. The title compound was isolated as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]3[O:20][C:19]([C:21]([O:23]C)=[O:22])=[CH:18][CH:17]=3)[C:13](=[O:25])[N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:11]([CH3:36])=[C:10]2[C:37]([CH:39]2[CH2:41][CH2:40]2)=[O:38])=[CH:5][CH:4]=1)#[N:2].[OH-].[Li+].Cl.CO>O1CCCC1.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]3[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=3)[C:13](=[O:25])[N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:11]([CH3:36])=[C:10]2[C:37]([CH:39]2[CH2:40][CH2:41]2)=[O:38])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)C3CC3)C2c2ccc(C#N)cc2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)N(Cc2ccc(C(=O)O)o2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of methyl 5-{[6-(4-cyanophenyl)-5-(cyclopropylcarbonyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]methyl}-2-furoate (Example 42) (50 mg, 0.09 mmol) in tetrahydrofuran (1.5 ml) is treated with a solution of lithium hydroxide (2.34 mg, 0.1 mmol) in water (1.5 ml). After three hours stirring at room temperature, additional lithium hydroxide (2.34 mg, 0.1 mmol) is added. The reaction solution is stirred overnight (16 h), then allowed to stand for 48 h. The solution is acidified with 1 N hydrochloric acid (500 μl). After 5 minutes stirring, a precipitate is obtained. Methanol (3 ml) is added, and the crude reaction solution is purified directly by preparative HPLC (RP18 column; eluent: acetonitrile/water 30:70→90:10). The title compound is isolated as a brownish solid.
Reaction SMILES: CS(C)=O.[OH-:5].[Na+].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10](F)[C:9]=1[N+:16]([O-:18])=[O:17].Cl>CCOCC.O>[F:7][C:8]1[C:9]([N+:16]([O-:18])=[O:17])=[C:10]([OH:5])[CH:11]=[C:12]([F:14])[CH:13]=1
Reactant: [OH-]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=[N+]([O-])c1c(O)cc(F)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.6 %

Procedure:
Dimethylsulfoxide (which will hereinafter be abbreviated as “DMSO”) (50 ml) and 10N NaOH (12 ml, 120 mmol) were added to 1,3,5-trifluoro-2-nitrobenzene (10.0 g, 56.5 mmol). The mixture was stirred at room temperature for 15 hours. Water (100 ml) and ether (200 ml) were added to separate the reaction mixture into layers. The water layer thus obtained was acidified with 1N HCl, followed by extraction with ether (2×200 ml). The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform-ethyl acetate (10:1) eluate fractions, the title compound (7.97 g, 81%) was obtained as a yellow crystalline powder.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH:11]([CH3:15])[C:12]([O-:14])=[O:13])[CH:7]=[CH:8][C:9]=1[OH:10])([O-])=O.COC1C=CC(C(C)C(O)=O)=CC=1.I>>[OH:10][C:9]1[CH:4]=[CH:5][C:6]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1
Reactant: CC(C(=O)[O-])c1ccc(O)c([N+](=O)[O-])c1
Agent: COc1ccc(C(C)C(=O)O)cc1
Agent: I
Product: CC(C(=O)O)c1ccc(O)cc1

Procedure:
Also, the compounds (III) used for this invention, for example, 2-(3-nitro-4-hydroxyphenyl)propionate can be prepared by demethylating 2-(4-methoxyphenyl)propionic acid with hydroiodic acid and the like to obtain 2-(4-hydroxyphenyl)- propionic acid, by esterifying the above compound with an usual method to obtain, for example, methyl 2-(4-hydroxyphenyl)propionate and by nitrating the above compounds. Alternately, 2-(3-nitro-4-hydroxyphenyl)propionate can be prepared by nitrating the above 2-(4-hydroxyphenyl)propionic acid with an usual method and by esterificating the resultant compound. The above reactions can be applied to 4-hydroxyphenylacetate as well. The above reaction scheme is shown as follows: ##STR12## wherein R1 has the same meaning as above
Reaction SMILES: C([N:5]1[CH2:17][CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[C:6]1(C(OCC1C=CC=CC=1)=O)[C:18]([NH2:20])=[O:19])(C)(C)C>Br.C(O)(=O)C>[C:14]([C:6]1([C:18]([NH2:20])=[O:19])[C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH2:16][CH2:17][NH:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)([CH3:15])([CH3:9])[CH3:13]
Reactant: CC(C)(C)N1CCc2c([nH]c3ccccc23)C1(C(N)=O)C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)(C)C1(C(N)=O)NCCc2c1[nH]c1ccccc21
Yield: 155 %

Procedure:
1.62 g of tert.butyl-benzyloxycarbonyl-1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide were dissolved in 10 ml of a 45% solution of hydrogen bromide in acetic acid. After 30 minutes the solution was evaporated and the residue was taken up in water. After filtration the filtrate was washed three times with diethyl ether and then neutralized by the addition of saturated aqueous sodium bicarbonate solution. The product was extracted from the now turbid aqueous layer with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulphate and evaporated to give 0.84 g of tert.butyl 1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxamide as a white crystalline solid of melting point 144° C.