Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]([NH2:12])=[CH:5][CH:4]=1.Cl[C:14]1[S:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:18]=1.[I-].[K+].C(=O)(O)[O-].[Na+]>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:12]=[C:14]1[S:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:18]1[C:8]2=[O:10]
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: COC(=O)c1cnc(Cl)s1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Product: COC(=O)c1cn2c(=O)c3cc(OC)ccc3nc2s1
Yield: 33.3 %

Procedure:
An intimate mixture of 1.49 g of 5-methoxyanthranilic acid, 1.58 g of methyl 2-chlorothiazole-5-carboxylate and 0.075 g of powdered potassium iodide was stirred and heated in an oil bath at 160°-165° for 80 minutes. The resultant dark solid was treated with 75 ml of a saturated solution of sodium bicarbonate and extracted with three portions of chloroform. The combined, dried (over magnesium sulfate) extract was concentrated in vacuo to a tan solid (1.59 g). Crystallization from methylene chloride-ether gave 0.86 g of methyl 7-methoxy-5-oxo-5H-thiazolo[2,3-b]quinazoline-2-carboxylate, having a melting point of 186°-192° C. This methyl ester was hydrolyzed by stirring for 16 hours at room temperature with 30 ml of 1 N sodium hydroxide and 30 ml of methanol. After filtration, the filtrate was acidified with acetic acid to pH5 and concentrated in vacuo. Water was added and the solid was removed by filtration. Since the base treatment also opens the lactam, this solid was refluxed for 1 hour in 75 ml of acetic acid. After concentration to 25 ml, the product crystallized on cooling and was filtered to give 0.53 of pure 7-methoxy-5-oxo-5H-thiazolo[2,3-b]quinazoline-2-carboxylic acid having a melting point of 247°-247.5° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[N:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH2:2][CH3:3].Br[CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=2)[C:14]1=O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:24][O:23][C:18]1[CH:17]=[CH:16][C:15]2[C:14]3[N:11]=[C:8]4[N:9]([C:13]=3[CH2:22][CH2:21][C:20]=2[CH:19]=1)[N:10]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=[CH:7]4
Reactant: COc1ccc2c(c1)CCC(Br)C2=O
Reactant: CCCOc1ccc(N)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccc2nc3c(n2n1)CCc1cc(OC)ccc1-3
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A stirred mixture of 6-propoxypyridazin-3-amine (120 mg, 0.78 mmol), 2-bromo-6-methoxy-3,4-dihydronaphthalen-1 (2H)-one (200 mg, 0.78 mmol) in ethanol was heated under reflux for 0.5 hours. The mixture was cooled and sodium bicarbonate (66 mg, 0.78 mmol) added. The mixture was stirred at room temperature for 3 days and evaporated. The residue was extracted with chloroform and the extract washed with saturated, aqueous, sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel. Elution with 1-2% methanol in dichloromethane afforded Compound 121 (30 mg) as a white solid. 1H n.m.r. (CDCl3) δ 1.05, t, J=7.4 Hz, 3H; 1.74-1.94, m, 2H; 3.14, s, 4H; 3.82, s, 3H; 4.28, t, J=6.8 Hz, 2H; 6.60, d, J=9.9 Hz, 1H; 6.78-6.89, m, 2H; 7.77, d, J=9.6 Hz, 1H; 7.87, d, J=7.9 Hz, 1H.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([CH2:18][CH2:19][C:20]#[N:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])([O-])=O>CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([CH2:18][CH2:19][C:20]#[N:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]
Reactant: N#CCCN(c1ccccc1F)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: N#CCCN(c1ccccc1N)c1ccccc1F
Reaction time: 3 h
Yield: 108.2 %

Procedure:
N-(2-Nitrophenyl)-N-(2-cyanoethyl)-2-fluoroaniline (6.37 g) was dissolved in methanol (60 ml), 10% palladium carbon (0.60 g) was added, the mixture was stirred for 3 hours under hydrogen atmosphere. Palladium carbon was removed by filtration, the filtrate was concentrated under reduced pressure, to thereby obtain 6.17 g of the titled compound (Yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O[N:14]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[OH-].[NH4+]>ClCCl>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: O=C(O)c1ccc(F)c(Cl)c1Cl
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(F)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 81.5 %

Procedure:
A solution of 2,3-dichloro-4-fluorobenzoic acid (0.200 g, 0.92 mmol) in dichloromethane (˜4 ml) was treated with 1-hydroxybenzotriazole (0.162 g, 1.2 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.230 g, 1.2 mmol), and triethylamine (0.56 ml, 4.0 mmol) under argon at room temperature. The mixture was stirred at room temperature for 40 minutes then treated with) 32% aqueous ammonium hydroxide (0.088 ml) and stirred overnight at room temperature. The mixture was diluted with dichloromethane and washed sequentially with water and then with saturated aqueous sodium hydrogen carbonate. The organic layer was separated and dried over sodium sulphate then concentrated to give 2,3-dichloro-4-fluorobenzamide (0.156 g) as a white solid that was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:4]([CH3:6])([CH3:5])[CH:3]1[CH2:7][OH:8].[H-].[Na+].[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]([F:26])=[C:17]([CH:25]=1)[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[O:19]>CN(C=O)C.O.CCOC(C)=O>[Cl:12][C:13]1[C:14]([O:8][CH2:7][CH:3]2[C:4]([CH3:6])([CH3:5])[C:2]2([CH3:9])[CH3:1])=[CH:15][C:16]([F:26])=[C:17]([CH:25]=1)[C:18]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])=[O:19]
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CC1(C)C(CO)C1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(COc2cc(F)c(C(=O)NS(C)(=O)=O)cc2Cl)C1(C)C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
To a stirred solution of (2,2,3,3-tetramethylcyclopropyl)methanol (80 mg, 0.62 mmol) in dry DMF (10 mL) at 0° C. was added NaH (25 mg, 0.62 mmol). After being stirred for 30 min, 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (54 mg, 0.21 mmol) was added. After being stirred at room temperature for 18 h, the mixture was diluted with water (10 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (20 ml×2). The combined organic layers was dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford 5-chloro-2-fluoro-N-(methylsulfonyl)-4-((2,2,3,3-tetramethylcyclopropyl)-methoxy)benzamide (20 mg, 25% yield) as a white solid. LCMS (ESI) Method A: RT=5.11 min, m/z: 268 [M−109]+. 1H NMR (500 MHz, DMSO-d6): δ 7.35 (d, J=9.0 Hz 1H), 7.03 (d, J=7.0 Hz, 1H), 6.04 (brs, 1H), 3.99 (d, J=7.5 Hz, 2H), 2.80 (s, 3H), 1.06 (s, 6H), 0.99 (s, 6H), 0.65 (t, J=7.5 Hz, 1H); 13C NMR (125 MHz, MeOH-d4): δ 159.4 (d, J=3.5 Hz), 133.9 (d, J=2.1 Hz), 114.1, 104.2, 103.9, 71.4, 41.7, 32.5, 24.2, 23.7, 17.4.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=[O:2].[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([CH2:28]C#N)=[CH:24][CH:23]=1>>[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([C:28]2[O:2][N:1]=[C:4]3[CH:9]=[CH:8][C:7]([C:10]4[N:14]([C:15]5[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=5)[N:13]=[CH:12][CH:11]=4)=[CH:6][C:5]=23)=[CH:24][CH:23]=1
Reactant: Cc1ccc(-n2nccc2-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: Cc1ccc(CC#N)cc1
Product: Cc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(C)cc4)cc23)cc1

Procedure:
The title compound, yellow solid (35 mg, 27%), MS (ISP) m/z=366.2 [(M+H)+], mp 190° C., was prepared in accordance with the general method of example 1 from 5-(4-nitro-phenyl)-1-p-tolyl-1H-pyrazole (intermediate E) (100 mg, 353 μmol) and commercially available 2-(p-tolyl)-acetonitrile.
Reaction SMILES: CC([CH2:5][N:6]([CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([C:27](=[O:29])[CH3:28])[C@@H:22]([CH3:30])[CH2:21][C@H:20]3[NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=2)[CH:14]=[N:13]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O.[ClH:46].CCOCC>ClCCl>[ClH:46].[C:27]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([C:15]3[CH:14]=[N:13][N:12]([CH2:11][CH2:10][NH:6][CH3:5])[CH:16]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=2)[CH2:21][C@@H:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(CC(C)(C)C)C(=O)[O-])c3)cc2[C@H](Nc2ccc(C)cn2)C[C@@H]1C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CNCCn1cc(-c2ccc3c(c2)[C@H](Nc2ccc(C)cn2)C[C@H](C)N3C(C)=O)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A solution of 1,1-dimethylethyl[2-(4-{(2S,4R)-1-acetyl-2-methyl-4-[(5-methyl-2-pyridinyl)amino]-1,2,3,4-tetrahydro-6-quinolinyl}-1H-pyrazol-1-yl)ethyl]methylcarbamate (for a preparation see intermediate 77) (40 mg, 0.077 mmol) in dichloromethane (DCM) (4 mL) was treated with trifluoroacetic acid (1 mL, 12.98 mmol) and the resulting mixture was stirred at room temperature for 3 h then concentrated in vacuo. The residue was loaded onto a 2 g SCX cartridge and eluted with MeOH (45 mL) followed by 2M NH3 in MeOH (45 mL). The ammonia fractions were combined and concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and the solution was treated with HCl (1M in Et2O, 0.09 mmol, 0.09 ml) then was concentrated in vacuo. Trituration of the residue with Et2O gave (2S,4R)-1-acetyl-2-methyl-6-{-1-[2-(methylamino)ethyl]-1H-pyrazol-4-yl}-N-(5-methyl-2-pyridinyl)-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (39 mg, 0.073 mmol, 94%) as a beige solid.
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:10]2=[C:11]([CH3:15])[C:12]([OH:14])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.CCN(C(C)C)C(C)C.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>C(Cl)Cl>[CH2:32]([NH:34][C:35](=[O:36])[O:14][C:12]1[C:11]([CH3:15])=[C:10]2[N:9]([CH:13]=1)[N:8]=[CH:7][N:6]=[C:5]2[O:4][C:3]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:2]=1[F:1])[CH3:33]
Reactant: Cc1c(O)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Oc1cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
To a mixture of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol (25 mg, 0.082 mmol, Compound F of Example 1), DIEA (0.017 mL, 0.1 mmol) in CH2Cl2 (5 mL) was added ethyl isocyanate (0.078 mL, 0.1 mL) and stirred at room temperature for 2 h. The reaction was quenched with water (5 mL). The organic layer was separated, dried and concentrated in vacuo. The mixture was purified by flash chromatography (1-5% Methanol/CH2Cl2) to give the title compound (12.5 mg, 32%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11]COC.[C:15]1(OB(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC.C(O)C.C(OCC)(=O)C>[OH:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COCOc1ccc([N+](=O)[O-])cc1Br
Reactant: OB(O)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(O)c(-c2ccccc2)c1
Temperature: 80 °C

Procedure:
5.3 g (0.02 mole) of 2-bromo-1-methoxymethoxy-4-nitrobenzene from step B and 2.80 g (0.023 mole) of phenylboric acid were dissolved in 70 mL of 1,2-dimethoxyethane under argon. Then, 0.5 g (0.0005 mole) of tetrakis-(triphenylphosphine)palladium and 13 mL of 2 N potassium carbonate solution were added, and the reaction mixture was heated to 80° C. At the end of the reaction, the reaction mixture was poured into 100 mL of ethyl acetate and the organic phase was extracted with dilute sodium hydroxide solution and then dried with magnesium sulfate. The solvent was distilled off in a rotary evaporator, and the residue was purified on silica gel using petroleum ether/ethyl acetate (9:1). The product thus obtained was heated to 50° C. in a mixture of 40 mL of ethanol and 15 mL of a 2.9 M ethanolic hydrochloric acid solution. After neutralization with NaOH, the solvent was distilled off in a rotary evaporator, and the residue was purified by vacuum distillation. This gave 3.5 g (82% of the theoretical) of 2-hydroxy-5-nitrobiphenyl.
Reaction SMILES: [C:1]1([C@H:7]([NH:32][C:33]([O:35][C@@H:36]2[CH:41]3[CH2:42][CH2:43][N:38]([CH2:39][CH2:40]3)[CH2:37]2)=[O:34])[C:8]2[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=2)[O:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1CC=CCC=1>C(O)C.[Pd]>[N:38]12[CH2:39][CH2:40][CH:41]([CH2:42][CH2:43]1)[C@@H:36]([O:35][C:33](=[O:34])[NH:32][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]1[CH:31]=[CH:30][CH:29]=[C:10]([O:11][CH2:12][CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[CH:9]=1)[CH2:37]2
Reactant: O=C(N[C@@H](c1ccccc1)c1cccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)c1)O[C@H]1CN2CCC1CC2
Agent: [Pd]
Agent: CC1=CCC=CC1
Solvent: CCO
Product: O=C(N[C@@H](c1ccccc1)c1cccc(OCC2CCNCC2)c1)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 103.3 %

Procedure:
To a solution of benzyl 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)methyl)phenoxy)methyl)piperidine-1-carboxylate (1.32 g, 2.26 mmol) in ethanol (100 mL) was added palladium on charcoal (0.66 g) and stirred at room temperature for 10 minutes. 1-Methyl-1,4-cyclohexadiene (1.27 mL, 11.3 mmol) was added and the reaction mixture heated to reflux. The reaction mixture was stirred under reflux for 1 hour. The reaction mixture was allowed to cool and the suspension filtered. The filtrate was evaporated at reduced pressure to afford the title compound (1.05 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][C:3]=1[O:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[N:45][CH:46]=1>CN(C)C=O.[Cl-].[NH4+]>[CH3:32][O:31][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:2]=1[O:1][CH2:40][C:41]1[CH:46]=[N:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: COc1cc(Cn2cnc3cc(C4CCN(C(=O)OC(C)(C)C)CC4)ccc32)ccc1O
Reactant: COc1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C5CCN(C(=O)OC(C)(C)C)CC5)ccc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
To a stirred solution of tert-butyl 4-(1-(4-hydroxy-3-methoxybenzyl)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (0.51 g, 1.16 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (0.32 g, 2.32 mmol). The mixture was treated with a solution of 5-(chloromethyl)-2-methoxypyridine (219 mg, 1.39 mmol) in N,N-dimethylformamide (2 mL) added dropwise. The mixture was stirred at room temperature. After 16 h, the mixture was diluted with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (3×10 mL), dried over sodium sulfate, filtered and concentrated to afford 0.53 g (82%) of tert-butyl 4-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate as a light yellow solid.
Reaction SMILES: C(N[C:5](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=3[CH:18]=2)=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])(=O)C.Cl.C([OH:34])C>O>[OH:34][C:5](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:23]([CH3:27])([CH3:28])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=3[CH:18]=2)=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CC(=O)NC(=Cc1ccc(Oc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1)C(=O)O
Reactant: CCO
Agent: Cl
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(Oc3ccc(C=C(O)C(=O)O)cc3)ccc21

Procedure:
1.6 g of (4 mmol) of α-acetamido-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyloxy)cinnamic acid, 25 ml of concentrated hydrochloric acid and 25 ml of ethyl alcohol were introduced into a round-bottomed flask and the mixture was heated at reflux for eight hours. The reaction medium was poured into water and extracted with ethyl acetate, and the organic phase was decanted, washed with water, dried over magnesium sulfate and evaporated. The residue obtained was triturated in a mixture of hexane and ethyl ether (80:20)and the mixture was filtered. 1.06 g (72%) of the expected acid was recovered, having a melting point of 207°-10° C.
Reaction SMILES: [F:1][C:2]1[C:3]([S:41][CH3:42])=[C:4]([C:9]2[C:10]([C:24](=[O:40])[C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:27][CH:26]=3)=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([O:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:13]=[CH:12]3)[CH:5]=[C:6]([F:8])[CH:7]=1.C(CN)O.[Cl-].[NH4+]>B.C1COCC1.C1(C(C2C=CC=CC=2)([C@@H]2CCCN2)O)C=CC=CC=1>[F:1][C:2]1[C:3]([S:41][CH3:42])=[C:4]([C:9]2[C:10]([CH:24]([OH:40])[C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:29][CH:30]=3)=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([O:19][S:20]([CH3:23])(=[O:21])=[O:22])[CH:13]=[CH:12]3)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CSc1c(F)cc(F)cc1-c1ccc2cc(OS(C)(=O)=O)ccc2c1C(=O)c1ccc(OCCN2CCCCC2)cc1
Agent: B
Agent: OC(c1ccccc1)(c1ccccc1)[C@@H]1CCCN1
Agent: [Cl-]
Solvent: NCCO
Solvent: C1CCOC1
Product: CSc1c(F)cc(F)cc1-c1ccc2cc(OS(C)(=O)=O)ccc2c1C(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 45 °C
Yield: 113.7 %

Procedure:
Charge a flask with (S)-α,α-diphenyl-2-pyrrolidinemethanol (253 mg, 1.0 mmol) and purge flask with nitrogen. Dilute with 1M borane in THF (43 mL, 43 mmol) and heat to 45° C. under nitrogen. Dissolve methanesulfonic acid 6-(3,5-difluoro-2-methylsulfanyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (6.5 g, 10.6 mmol) in THF (40 mL) and add to the catalyst solution via syringe pump over 2 hours. After complete addition, add ethanolamine (12.8 mL, 212 mmol) slowly and heat at 45° C. for 3 hours. Cool the reaction to room temperature and pour into saturated aqueous ammonium chloride. Extract with methylene chloride, dry over sodium sulfate, filter and concentrate. Purify over silica gel eluting with 3% methanol in methylene chloride to yield 7.4 g (93%) of the title compound (60:40 mixture of diastereomers). LCMS Rt (0.01% heptafluorobutyric acid:1.0% isopropylalcohol:water is mobile phase A and 0.01% heptafluorobutyric acid:1.0% isopropylalcohol:acetonitrile is mobile phase B; gradient method 25 to 95% B, Purity@254 nm)=2.91 and 2.94 mm (100%); mass spectrum (ion spray): m/z=614.2 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].BrCC(C1C=CC=CC=1)=[O:14].O.CCO>CN(C=O)C>[OH:14][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(CCl)c1ccccc1
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 70 %

Procedure:
A mixture of 2-chloroacetophenone derivatives (or 2-bromoacetophenone derivatives, 0.19 mol), NaOOCH (0.59 mol) in DMF (140 mL), H2O (100 mL) and EtOH (400 mL) was heated under refluxing. After 5-8 hrs, the reaction mixture was cooled to room temperature, then about half of the solvent was removed under vacuum. The residue was diluted with water, and extracted with CH2Cl2. The combined organic layer was washed by H2O, followed by brine;. After drying over Na2SO4, solvents were evaporated under vacuum. The crude product was washed with hexanes, filtration gave the desired 2-hydroxyacetophenone derivatives as a solid in 70˜85% yield, which were used directly for the next step.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[C:19]([N+:26]([O-:28])=[O:27])[CH:18]=2)(=[O:16])=[O:15])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[Na+]>C1COCC1.Cl>[NH2:23][C:21]1[CH:22]=[C:17]([S:14]([NH:13][CH2:12][CH2:11][CH2:10][NH:9][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=2)(=[O:15])=[O:16])[CH:18]=[C:19]([N+:26]([O-:28])=[O:27])[CH:20]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc(S(=O)(=O)NCCCNc2nc(Cl)ncc2Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cc([N+](=O)[O-])cc(S(=O)(=O)NCCCNc2nc(Cl)ncc2Br)c1
Reaction time: 2 h

Procedure:
A solution of 602 mg (1.28 mmol) of N-[3-(5-bromo-2-chloro-pyrimidin-4-ylamino)-propyl]-3,5-dinitro-benzenesulfonamide in 10 ml of THF is mixed at room temperature with 4.2 ml of a 15% solution of Ti(III)Cl in approximately 10% hydrochloric acid. After 2 hours, it is mixed again with 3.0 ml of a 15% solution of Ti(III)Cl in approximately 10% hydrochloric acid, and it is stirred for another 16 hours. The batch is made basic with 2N NaOH solution and filtered. The filter cake is rewashed with THF and water. The THF of the filtrate is drawn off on a rotary evaporator, and the residue is extracted from ethyl acetate. The combined organic phases are filtered through a Whatman filter and concentrated by evaporation. 440 mg (0.95 mmol, corresponding to 74% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([O:32]C)=[O:31])[CH2:8][CH2:7]1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:21][CH:22]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([OH:32])=[O:31])[CH2:8][CH2:7]1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CCCOC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCCOC)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
To a solution of methyl 1-(3-methoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (376 mg) in a mixture of THF-methanol (5-10 ml) was added 1N sodium hydroxide solution (3.0 ml) at room temperature, and the mixture was stirred at 50° C. for 24 hours. After concentration under reduced pressure, 1N hydrochloric acid was added to pH 3-4, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the resulting crystals were collected by filtration. The crystals were washed with diisopropyl ether and hexane to give 1-(3-methoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (346 mg) as yellow crystals.