Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH:8]=O.[NH2:10][C:11]1[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:13][CH:14]=[C:15]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:15]2[CH:16]=[C:11]([NH:10][CH2:8][CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][C:2]3=[O:1])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:13][CH:14]=2)=[CH:19][CH:20]=1
Reactant: O=CCN1CCCC1=O
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN1CCCC1=O
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
(2-Oxopyrrolidin-1-yl)acetaldehyde (2.00 g, 15.7 mmol) and ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (2.00 g, 7.32 mmol) were combined in 1:1 dichloroethane/acetic acid (10 mL) and cooled under nitrogen to 0-5° C. Sodium trisacetoxyborohydride (3.10 g, 14.6 mmol) was added and the reaction was stirred for 15 min. Two additional portions of aldehyde (1.0 g, 7.8 mmol) plus sodium triacetoxyborohydride (1.65 g, 7.8 mmol) separated by 15 min. increments were made. The reaction mixture was evaporated in vacuo, dissolved in CH2Cl2, and treated with aqueous K2CO3 (5% w/v). After separating the layers, the aqueous phase was back-extracted twice with CH2Cl2. The combined organic phases were dried over MgSO4, filtered, evaporated in vacuo and purified on silica gel eluting with 0-3% MeOH in EtOAc to provide an oil: 1H NMR (CDCl3) δ 7.89 (1H, d, J=1.4 Hz), 7.83 (1H, br t, J˜6 Hz), 7.15 (2H, dd, J˜9, 6 Hz), 6.98 (2H, t, J˜9 Hz), 6.92 (1H, s), 4.42 (2H, q, J=7 Hz), 3.92 (2H, s), 3.49 (2H, m), 3.41 (2H, t, J=7 Hz), 3.35 (2H, q, J=6 Hz), 2.36 (2H, t, J=8 Hz), 1.99 (2H, m), 1.42 (3H, t, J=7 Hz); ES+ MS: 386 (M+H+).
Reaction SMILES: CO[C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[C:11](#[N:13])[CH3:12]>>[CH:5]1([C:3](=[O:4])[CH2:12][C:11]#[N:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CC#N
Reactant: COC(=O)C1CCCCC1
Product: N#CCC(=O)C1CCCCC1

Procedure:
The title compound was prepared in analogy to example 105 step A from cyclohexanecarboxylic acid methyl ester and acetonitrile. Yellow liquid. MS (ESI): 150.2 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1OCc1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1ccccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 65.2 %

Procedure:
A mixture of 2-benzyloxyphenylboronic acid (20.2 g, 88.6 mmol), methyl 2-bromo-5-nitrobenzoate (25.4 g, 97.5 mmol), cesium carbonate (57.7 g, 177 mmol) and bis(triphenylphosphine)palladium(II) dichloride (1.16 g, 1.65 mmol) was suspended in anhydrous N,N-dimethylformamide (300 mL), and then was stirred under argon atmosphere at 80° C. for 3 days. After cooling down, ethyl acetate (500 mL), diethylether (300 mL) and water (500 mL) were added thereto, and then separated. The aqueous layer was extracted with a mixture of ethyl acetate (200 mL) and diethylether (200 mL). The combined organic layer was washed with water (500 mL, twice) and saturated brine (300 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (21.0 g) as a pale yellow oil. (Yield 65%)
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[ClH:8].[CH2:9](O)[CH3:10]>>[ClH:8].[NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([O:5][CH2:9][CH3:10])=[O:4]
Reactant: CC(C)(N)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(C)(C)N

Procedure:
A stirred suspension of 2-amino-2-methylpropanoic acid (165 g) in ethanol at 0° C. was saturated with hydrogen chloride gas. The mixture was heated at reflux for 4 hours and the solvent was evaporated under reduced pressure to give ethyl 2-amino-2-methylpropanoate hydrochloride as a white solid. Sodium carbonate (100 g) was slowly added to a suspension of the solid in water followed by 40% aqueous formaldehyde solution (150 g) and the suspension was stirred for 3 hours. The mixture was extracted with ether, the organic solution was washed with water, dried (magnesium sulphate) and solvent evaporated under reduced pressure to give ethyl 2-(N-methyleneamino)-2-methylpropanoate (137.8 g) in equilibrium with its trimer 1,3,5-tri(1-ethoxycarbonyl-1-methylethyl)hexahydrotriazine as a colourless oil, IR (liquid film) 2980(s), 1725(vs), 1250(s), 1140(vs).
Reaction SMILES: N#N.[N:3]([C@H:6]1[C@H:10](O)[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[N+:4]=[N-:5].CCN(S(F)(F)[F:25])CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[N:3]([C@H:6]1[C@H:10]([F:25])[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[N+:4]=[N-:5]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N=[N+]=[N-])C1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)[C@H](N=[N+]=[N-])C1
Temperature: -60 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of trans-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (J. Med. Chem. 2010, 53, 6730-6746) (288 mg, 1.26 mmol) in CH2Cl2 (1.1 mL) was added dropwise a solution of DAST (0.345 mL, 2.61 mmol) in CH2Cl2 (1.1 mL) at −78° C. After being stirred for 2 h at −60° C., the reaction mixture was warmed to 0° C., poured into aq. 10% Na2CO3, and extracted with CH2Cl2. The organic layer was separated, washed with water, dried over MgSO4, and concentrated under reduced pressure. The residue was purified with FC (Hept/EA, 9.5:0.5→7:3) to afford trans-tert-butyl 3-azido-4-fluoropyrrolidine-1-carboxylate as a yellow oil. TLC: rf (Hept/EA, 7:3)=0.53.
Reaction SMILES: [C:1]12([OH:13])[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.O1CCCC1.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28]>O>[C:26]([O:13][C:1]12[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2)(=[O:30])[C:27]([CH3:29])=[CH2:28]
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Reactant: C=C(C)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC12CC3CC(O)(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10 mmol of 1,3,5-adamantanetriol, 10 mmol of triethylamine, and 40 ml of tetrahydrofuran were mixed, and 10 mmol of methacrylic acid chloride was added dropwise to the mixture for about 30 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 24 hours. After the reaction had been completed, to the reaction mixture was added water, followed by purification by column chromatography to give 1-methacryloyloxy-3,5-dihydroxyadamantane.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:22]([NH:24][CH2:25][C@@H:26]([C:48]([OH:50])=[O:49])[CH2:27][C:28]1([C:33]([NH:35][C@H:36]([C:45]([OH:47])=[O:46])[CH2:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:23])[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=O)C1C=CC=CC=1.C(O)C.O>[Pd].CC(C)=O>[C:48]([C@H:26]([CH2:25][NH:24][C:22](=[O:23])[C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:27][C:28]1([C:33]([NH:35][C@H:36]([C:45]([OH:47])=[O:46])[CH2:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)([OH:50])=[O:49]
Reactant: CS(=O)(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)NC[C@H](CC1(C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)CCCC1)C(=O)O
Agent: [Pd]
Solvent: CCO
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)(=O)N[C@@H](CCCCN)C(=O)NC[C@H](CC1(C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)CCCC1)C(=O)O

Procedure:
A solution of (S,S,S)-N-(1-[3-(N6-benzyloxycarbonyl-N2-mesyllysylamino)-2-carboxypropyl]-1-cyclopentylcarbonyl)tyrosine (see Preparation 9) (371 g) in a 9:1 ethanol/water mixture (2.225 l) was hydrogenated at 414 kPa (60 psi) and room temperature over a 10% palladium-on-carbon catalyst (37.0 g) for 4 hours. The catalyst was filtered off and the filtrate evaporated to leave the crude product as a foam. This material was stirred with acetone (3.13 l) for 24 hours to give the title compound as a white amorphous solid (283 g). Found: C,52.97; H,7.02; N,8.97. C26H40N4O9S requires: C,53.41; H,6.90; N,9.58%.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.[H][H]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:12])[CH2:3]1
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Reactant: [H][H]
Solvent: Cc1ccccc1
Product: CC1CC(C)(C)c2cccc(N)c21
Reaction time: 1 h

Procedure:
Into a reaction vessel were charged 31.7 parts by weight of (3R)-1,1,3-trimethyl-4-aminoindane (optical purity of 67.0% ee) and 0.36 parts by weight of 5% palladium-alumina, thereby obtaining a mixture. The reaction vessel was sealed and the gas in the reaction vessel was replaced with nitrogen. While the mixture was stirred, into the reaction vessel was charged hydrogen until the internal pressure of hydrogen in the reaction vessel reached 0.5 MPa, and the mixture was stirred at an internal temperature of 60° C. After 1 hour, the gas in the reaction vessel was replaced with nitrogen, and the mixture was stirred at an internal temperature of 155° C. and an internal pressure of 0.1 MPa for 7 hours, thereby obtaining a reaction mixture. The obtained reaction mixture was cooled and filtered. The obtained solid was washed with 45 parts by weight of toluene. The washing liquid recovered after washing and the filtrate obtained by filtration were combined to obtain a solution of 73.4 parts by weight of 1,1,3-trimethyl-4-aminoindane in toluene. The obtained 1,1,3-trimethyl-4-aminoindane had an optical purity of 4.5% ee and a recovery rate of 98.7%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:17]=1>C(#N)C.C(OCC)(=O)C>[CH2:7]([O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(O)c2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OCc2ccccc2)c2ccccc2c1
Yield: 98.1 %

Procedure:
Potassium carbonate (19.2 g) and benzyl bromide (19.0 g) were added to a solution of ethyl 4-hydroxy-2-naphthoate (20 g) in acetonitrile (200 ml) and the mixture was heated to reflux for 2 hours. After being cooled, the reaction solution was diluted with ethyl acetate and insoluble materials were filtered through Celite. The filtrate was concentrated in vacuo and the resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=100/1) to give ethyl 4-(benzyloxy)-2-naphthoate (27.8 g) as a pale yellow oil.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.O=[CH:12][C@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14].Cl>O1CCOCC1.C1C=CC=CC=1>[CH2:4]1[CH2:5][CH2:6][C:1]2([O:14][C@@H:13]([C@H:15]3[O:16][C@@H:21]4[O:22][C:1]5([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[O:20][C@H:19]4[C@H:17]3[OH:18])[CH2:12][O:7]2)[CH2:2][CH2:3]1
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C1CCCCC1
Agent: Cl
Solvent: c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O[C@@H]1[C@@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1[C@H]1COC2(CCCCC2)O1
Temperature: 65 °C
Reaction time: 7 h
Yield: 92.6 %

Procedure:
To a mixed solution of 150 ml of cyclohexanone and 120 ml of dichloromethane were added 10.0 g of D-mannose, 200 mg of cupric acetate monohydrate and 1 ml of a 2 mole/l solution of hydrogen chloride in dioxane, and the mixture was stirred for 7 hours under reflux in a warm-water bath at 65° C. The refluxing solvent was continuously dried with 20 g of molecular sieves 3A which was placed between the reaction vessel and the cooling tube. After the conclusion of the reaction, the reaction solution was diluted with benzene, washed with aqueous sodium hydrogen-carbonate and water, and dried over anhydrous magnesium sulfate. When the solvent and cyclohexanone were distilled off under reduced pressure, there was obtained 17.5 g (92.6%) of 2,3:5,6-di-O-cyclohexylidene-α-D-mannofuranose as a residue. The compound, when recrystallized from hexane, showed a melting point of 122° to 124° C.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:9][C@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11]>ClCCl>[CH2:4]1[CH2:5][CH2:6][C:1]2([O:11][C@@H:10]([C@H:12]3[O:13][C@@H:18]4[O:19][C:1]5([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[O:17][C@H:16]4[C@H:14]3[OH:15])[CH2:9][O:7]2)[CH2:2][CH2:3]1
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C1CCCCC1
Solvent: ClCCl
Product: O[C@@H]1[C@@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1[C@H]1COC2(CCCCC2)O1
Reaction time: 9 h
Yield: 95 %

Procedure:
To a mixed solution of 150 ml of cyclohexanone and 120 ml of dichloromethane were added 10.0 g of D-mannose and 125 mg of anhydrous cupric chloride, and the mixture was stirred for 9 hours under reflux in a warm-water bath at 63° to 65° C. The refluxing solvent was continuously dried with 20 g of molecular sieves 3A which was placed between the reaction vessel and cooling tube. The reaction solution was diluted with benzene, washed with aqueous sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. When the solvent and cyclohexanone were distilled off under reduced pressure, there was obtained 17.9 g (95%) of 2,3:5,6-di-O-cyclohexylidene-α-D-mannofuranose (purity of not less than 95%) as a residue. The compound, when recrystallized from n-hexane, showed a melting point of 122° to 124° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:12])=O.[BH4-].[Na+].[OH-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: Nc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)Nc1ccc(F)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of 22.2 g (0.2 m) 4-fluoroaniline, and 17.6 ml (0.24 m) acetone in 120 ml (2 m) glacial acetic acid in the three neck 500 ml round bottom flask was stirred mechanically and cooled to approximately 10° C. in an ice bath. To this solution 9.4 g (0.25 m) sodium borohydride was added in parts while keeping the temperature below 20° C. It was allowed to stir at 20° C. for 30 minutes and one hour at room temperature. The mixture was poured into 500 ml ice water. The aqueous solution was made alkaline by dropwise addition of 120 ml 50% aqueous sodium hydroxide solution below 25° C. The product was extracted with hexane, (2×100 ml) which was washed with saturated sodium chloride solution, dried on anhydrous magnesium sulfate and evaporated to give a clear liquid. The product was distilled to give a clear colorless liquid product, 21.8 g B.P. 40°/0.5 mm. Yield 71%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[CH3:28][NH:29][CH3:30]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:29]([CH3:30])[CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Product: CC(=O)c1ccc(S(=O)(=O)N(C)C)cc1

Procedure:
From the damp 4-acetylbenzenesulfonyl chloride from 200 g. of sodium 4-acetylbenzenesulfonate, and 1 1. of 20% aqueous dimethylamine, following the procedure of c) above, there is obtained 4-acetyl-N,N-dimethylbenzenesulfonamide; m.p. 97°-99° C. after crystallization from aqueous ethanol.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([Cl:10])=[CH:8][N:9]=1)(=[O:3])[CH3:2].CN(C=O)C.[H-].[Na+].[CH3:18][O:19][CH2:20][CH2:21]Br>C(OCC)(=O)C>[Cl:10][C:7]1[S:6][C:5](=[N:4][C:1](=[O:3])[CH3:2])[N:9]([CH2:21][CH2:20][O:19][CH3:18])[CH:8]=1
Reactant: CC(=O)Nc1ncc(Cl)s1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCn1cc(Cl)sc1=NC(C)=O
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
A flask was charged with 2-acetamido-5-chlorothiazole (Lancaster, 19.3 g, 110 mmol) in 200 mL of 2:1 THE/DMF. To the solution was added sodium hydride (60% dispersion in mineral oil, 5.44 g, 142 mmol). The mixture was stinred at room temperature for 15 minutes and then 2-bromoethyl methyl ether (18.3 g, 131 mmol) was added. The mixture was warmed to 85° C. and stirred overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on SiO2 using a gradient of 0% to 100% ethyl acetate:hexane to provide 10.3 g (42%) of the title compound as the more polar regioisomer: 1H NMR (300 MHz, CDCl3) δ 2.28 (s, 3 H) 3.35 (s, 3 H) 3.65-3.71 (m, 2 H) 4.28-4.36 (m, 2 H) 7.00 (s, 1 H); MS (ESI+) m/z 235 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][C:3]=1[O:18][CH3:19].C([O-])([O-])=O.[K+].[K+].Cl[C:27]1[N:32]=[C:31]([Cl:33])[C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1>O1CCOCC1>[Cl:33][C:31]1[C:30]([C:34]([F:36])([F:35])[F:37])=[CH:29][N:28]=[C:27]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][C:3]=2[O:18][CH3:19])[N:32]=1
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1N
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(C(=O)OCc2ccccc2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 130 °C
Reaction time: 1.67 h

Procedure:
Benzyl 4-amino-3-methoxybenzoate (1.92 g, 6.8 mmol) and K2CO3 (2.38 g, 17 mmol) are suspended in 4 mL dioxane and then combined with 2,4-dichloro-5-trifluoromethylpyrimidine (1.48 mL, 6.8 mmol). The suspension is then refluxed with stirring in the oil bath (approx. 130° C.) for 100 min. After the reaction has ended the reaction mixture is filtered, the filtrate is concentrated by rotary evaporation and purified by normal phase column chromatography. The product-containing fractions of A-3a (HPLC-MS: tRet.=1.94 min; MS (M−H)+=436) are combined and concentrated by rotary evaporation.
Reaction SMILES: [Li+].CCC[CH2-].[Cl:6][C:7]1[N:8]=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:10]2[S:15][CH:14]=[CH:13][C:11]=2[N:12]=1.[I:22]I>C1COCC1>[Cl:6][C:7]1[N:8]=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:10]2[S:15][C:14]([I:22])=[CH:13][C:11]=2[N:12]=1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: II
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
N-Butyllithium (9.4 mL, 22.48 mmol, 2.5 M in hexane solution) was added to a mixture of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine (3.0 g, 11.74 mmol) in 60 mL of THF at −78° C. The reaction mixture was allowed to warm to −40° C. and stirred for 30 min. A solution of iodine (6.0 g, 23.48 mmol) in 10 mL of THF was added dropwise. After the addition was completed. The reaction mixture was brought to room temperature and stirred for 2 h. The mixture was quenched by diluting with dichloromethane (300 mL) and extracting with H2O (2×100 mL). The organic layer was washed with Na2S2O3 (2×100 mL), H2O (2×100 mL), dried over MgSO4, filtered and evaporated to afford 2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine (3.4 g, 75%).
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:16])=[CH:7][C:8](S(O)(=O)=O)=[CH:9]2)=[CH:4][CH:3]=1.C1(=O)OC(=O)CC1>>[CH:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[OH:16])[CH:11]=1
Reactant: Nc1ccc2c(O)cc(S(=O)(=O)O)cc2c1
Agent: O=C1CCC(=O)O1
Product: Oc1cccc2ccccc12

Procedure:
In an aqueous solvent, 23.9 parts of 7-amino-4-hydroxynaphthalene-2-sulfonic acid was condensed with 10.0 parts of succinic anhydride according to a normal method to obtain a naphthol derivative.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:16])=[CH:7][C:8](S(O)(=O)=O)=[CH:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C1C=CC=CC=1>>[CH:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[OH:16])[CH:11]=1
Reactant: Nc1ccc2c(O)cc(S(=O)(=O)O)cc2c1
Solvent: O=C(Cl)c1ccccc1
Product: Oc1cccc2ccccc12

Procedure:
In an aqueous solvent, 23.9 parts of 7-amino-4-hydroxynaphthalene-2-sulfonic acid was condensed with 14.1 parts of benzoyl chloride according to a normal method to obtain a naphthol derivative.
Reaction SMILES: CSC.B.[CH2:5]1[CH2:15][C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.C1([C@@H]2[C@@H](C3C=CC=CC=3)ON(C)B2)C=CC=CC=1>C1COCC1>[C@H:13]1([OH:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:15]1
Reactant: O=C1CCCc2ccccc21
Agent: B
Agent: CN1B[C@H](c2ccccc2)[C@@H](c2ccccc2)O1
Solvent: CSC
Solvent: C1CCOC1
Product: O[C@@H]1CCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Borane dimethylsulfide complex (2M in THF, 7.0 mL, 0.014 moles) was added over 45 minutes at ambient temperature to a solution of α-tetralone (2.92 g, 0.02 moles) and the title compound of Example 1 (247 mg, 0.001 moles) in THF (80 mL). The reaction mixture was stirred for 15 minutes (at which time thin layer chromatography indicated complete consumption of α-tetralone) and then cooled to 0° C. and quenched with methanol 27 mL). The quenched solution was allowed to warm to ambient temperature, with stirring, for 16 hours. The solvents were removed in vacuo and the residue was redissolved with methylene chloride (50 mL) and pH4 phosphate buffer (50 mL). The phases were separated and the organic phase was washed with water (50 mL), treated with MgSO4 and filtered. The solvent was removed in vacuo to afford 2.93 (99%) of -(R)-(+)-1,2,3,4-tetrahydro-1-naphthol as a white solid. HPLC with a chiral support demonstrated that the product had a 94% e.e.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[C:14]([C:16]([CH3:24])([CH3:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[C:12]([C:25]([CH3:33])([CH3:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2O)=[C:4]([N+:35]([O-])=O)[CH:3]=1.[N+](C1C=CC=CC=1N=NC1C=C(C(C)(C)C2C=CC=CC=2)C=C(C(C)(C)C2C=CC=CC=2)C=1O)([O-])=[O:39].CC(C1C=C(C(C)(C)C2C=CC=CC=2)C=CC=1O)(C)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][N:9]([C:10]3[CH:11]=[C:12]([C:25]([CH3:33])([CH3:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=4[OH:39])[CH:13]=[C:14]([C:16]([CH3:23])([CH3:24])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:35]=[C:4]2[CH:3]=1
Reactant: CC(C)(c1ccccc1)c1cc(N=Nc2ccc(Cl)cc2[N+](=O)[O-])c(O)c(C(C)(C)c2ccccc2)c1
Reactant: CC(C)(c1ccccc1)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)c2ccccc2)c1
Agent: CC(C)(c1ccccc1)c1ccc(O)c(C(C)(C)c2ccccc2)c1
Product: CC(C)(c1ccccc1)c1cc(-n2nc3ccc(Cl)cc3n2)cc(C(C)(C)c2ccccc2O)c1
Yield: 70 %

Procedure:
When, using the general procedure of Example 3, the amount of 4-chloro-2-nitro-2'-hydroxy-3',5'-di-(α,α-dimethylbenzyl)azobenzene was substituted for 2-nitro-2'-hydroxy-3',5'-di-(α,α-dimethylbenzyl)azobenzene, the above-named compound was prepared in a yield of 70.0% as light tan crystals melting at 160°-161° C. (Compound 2)