Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][C:20](=S)[N:19]([CH:24]([C:26]([O:28]CC)=O)[CH3:25])[C:18]=3[CH:31]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:33][NH2:34]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([CH3:12])([O:13][C:14]2[CH:31]=[C:18]3[C:17](=[CH:16][CH:15]=2)[O:22][CH2:21][C:20]2[N:19]3[CH:24]([CH3:25])[C:26](=[O:28])[NH:33][N:34]=2)[CH2:11]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(C)N1C(=S)COc2ccc(OC3(C)CN(C(=O)OC(C)(C)C)C3)cc21
Solvent: O
Solvent: CCO
Product: CC1C(=O)NN=C2COc3ccc(OC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.095 g, 0.211 mmol) in EtOH (5 mL) was added hydrazine hydrate (0.105 g, 2.109 mmol) and the mixture was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by preparative TLC (eluting with 30% EtOAc in petroleum ether) to give 3-methyl-3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (0.064 g, 75%) as a white solid. LC/MS (Table 1, Method 2) Rt=1.143 min.; MS m/z: 403 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][CH:5]=1)=[O:3].C1(C)C(S([O-])(=O)=[O:19])=CC=CC=1.C([N+](CC)(CC)CC)C>[Pt].CO>[OH:10][C:7]1[CH:6]=[CH:5][C:4]([C:2]([CH:1]=[O:19])=[O:3])=[CH:9][CH:8]=1
Reactant: Cc1ccccc1S(=O)(=O)[O-]
Reactant: COc1ccc(C(C)=O)cc1
Agent: [Pt]
Agent: CC[N+](CC)(CC)CC
Solvent: CO
Product: O=CC(=O)c1ccc(O)cc1

Procedure:
In a standard undivided cell having a platinum anode and a glossy carbon cathode (33 cm2 each) there is charged 200 g methanol (65° C.), 11.3 g of 4-methoxyacetophenone (4-MAP), and 11.5 g tetraethylammonium toluene sulfonate. This electrolysis is conducted at a current density of about 30 mA/cm2 until a current passage of 50.9 Ah is charged (633% of theoretical value). According to an iodometrical determination, a current efficiency of 50% is obtained. About 150 g methanol is distilled off and the remaining solution is neutralized with aqueous NaHCO3 and extracted with ethyl acetate. The extract is dried and the solvent is removed by evaporation. The remaining oil is separated by column chromatography (silica gel, MTBE/cyclohexane =1/4). The acetal product is 6.4 g of 2,2-dimethoxy-1-[4-methoxyphenyl]-ethanale (41% based on 4-MAP). Subsequent hydrolysis at 62° C. yields 4hydroxyphenyl glyoxal (HPGO).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][CH:11]=1>O.C(O)(=O)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][C:14](=[O:21])[C:15](=[N:1][OH:3])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(=O)CCc1cccc(Cl)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)CCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (12.6 g) in water (25 ml) was added to a stirred solution of the product from step (i) (42.2 g) in acetic acid (50 ml) at <30° C. The reaction mixture was stirred at room temperature for 30 min. Water (75 ml) was added and the mixture was stirred for 2 hours and extracted with diethyl ether. The combined extracts were washed with water and saturated aqueous sodium bicarbonate solution. The organic layer was collected, dried (MgSO4) and solvent evaporated under reduced pressure to give the subtitle product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH2:30]([S:37]CC1C=CC=CC=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Na]>CN(C)C=O>[CH2:30]([S:37][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reactant: c1ccc(CSCc2ccccc2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSCc4ccccc4)cc2)CCO3)cc1
Yield: 149.2 %

Procedure:
A solution of N-(4-chloromethylphenyl)-7-(4-methyl-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15g) and sodium benzyl sulfide (0.055g) in dimethylformamide (10ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give N-(4-(benzylthiomethyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 86) (0.17g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:26]([CH:34]1[CH2:38][CH2:37][CH2:36][NH:35]1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: c1ccc(CCC2CCCN2)cc1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2CCc2ccccc2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-phenethylpyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.99 minutes; C29H28Cl2N4O2 (535.47); mass spectrum: (M−H)−=535/537 (chlorine isotope).
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].[Br:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[CH:8]=[O:9].[NH4+].[Cl-]>C1COCC1>[Br:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[CH:8]([OH:9])[CH2:2][CH3:1]
Reactant: CC[Mg+]
Reactant: O=Cc1c(F)cccc1Br
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1c(F)cccc1Br
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of EtMgBr (35 mL, 35 mmol) in THF (1 M) is added dropwise to a solution of 2-bromo-6-fluoro-benzaldehyde (7 g, 34.5 mmol) in THF at −78° C. The mixture is stirred for 1 hour at −78° C. Saturated NH4Cl is added dropwise to the mixture which is subsequently warmed to room temperature and stirred for 1 hour. The organic layer is separated, extracted with THF (3×100 mL). The combined organic layers are washed with brine, dried and solvent is removed in vacuo. The crude product is purified by flash chromatography (5% EtOAc/hexanes) to obtain 1-(2-bromo-6-fluoro-phenyl)-propan-1-ol.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Cl[CH2:11][C:12]([OH:14])=[O:13].[OH-].[Na+].Cl>O>[C:12]([CH2:11][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])([OH:14])=[O:13]
Reactant: OCc1ccccc1O
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1ccccc1CO
Temperature: 25 °C

Procedure:
A mixture of 2-hydroxybenzyl alcohol (0.5 mol), α-chloroacetic acid (0.5 mol) and solid sodium hydroxide (1.0 mol) in water (1L) is heated at reflux for 6 h. After this time the solution is cooled to ambient temperature and acidified to pH 4 with a 10% solution of hydrogen chloride in water. The product crystalizes from the acidified solution and is isolated and dried by filtration to give 2-Carboxymethoxybenzylalcohol which is used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C:14](=[O:17])[CH2:15][CH3:16])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2.N1C=CC=CC=1.[C:24](Cl)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[Cl:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([NH:13][C:14](=[O:17])[CH2:15][CH3:16])[C:2]([NH:1][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:11]2
Reactant: CCCCCC(=O)Cl
Reactant: CCC(=O)Nc1nc2ccc(Cl)cc2nc1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCC(=O)Nc1nc2cc(Cl)ccc2nc1NC(=O)CC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of 50 parts of 3-amino-6-chloro-2-propionamidoquinoxaline in 1000 parts of pyridine was cooled to 5° in an ice bath. A solution of 96 parts of hexanoyl chloride in 88 parts of tetrahydrofuran was added as quickly as possible with good cooling to prevent the temperature from rising above 25°. The reaction mixture was stirred for 10 minutes and then poured into 2500 parts of ice water. The yellow gum which separated was removed by filtration and washed with water and then dissolved in 2700 parts of methylene chloride. The methylene chloride solution was washed in succession with 1000 parts each of water, 5% aqueous hydrochloric acid, water, 10% aqueous sodium carbonate, and water. The methylene chloride solution was dried (MgSO4) and evaporated. The residue was recrystallized from 1:4 ethyl acetate-benzene, the solid filtered off, and washed with ether to yield 8 parts of 6-chloro-3-hexanamido-2-propionamidoquinoxaline, m.p. 158°-160°, as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].Br[C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>[Fe](Cl)(Cl)Cl.[N+](C)([O-])=O>[CH3:14][C:9]1[CH:10]=[CH:11][C:12]([C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)=[CH:13][C:8]=1[C:3]1[CH:4]=[C:5]([C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: BrC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccccc1-c1ccccc1C
Agent: Cl[Fe](Cl)Cl
Solvent: C[N+](=O)[O-]
Product: Cc1ccc(C23CC4CC(CC(C4)C2)C3)cc1-c1cc(C23CC4CC(CC(C4)C2)C3)ccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
A 100 ml four-neck flask provided with a thermometer, stirrer, reflux tube, and nitrogen-introducing tube was charged with 2,2′-dimethylbiphenyl 14.7 g (80.55 mmol), 1-bromo-adamantane 34.7 g (161.1 mmol), and nitromethane 200 ml and the mixture stirred under a nitrogen flow at room temperature. Iron (III) chloride 1.31 g (8.07 mmol) was added and the result stirred at room temperature until dissolving. An oil bath was heated to 60° C., then the stirring was continued at that temperature for 4 hours. The reaction solution was filtered and rinsed away with a small amount of methanol. The filtered material was stirred in 30 ml of methanol for 30 minutes, then filtered. The obtained residue was dried at 60° C. under reduced pressure to obtain 2,2′-dimethyl-5,5′-bis(1-adamantyl)biphenyl white powder 17.5 g.
Reaction SMILES: [CH2:1]([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[N:38]1([C:46](=O)[CH2:47]Cl)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:46][CH2:47][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(CCl)N1CCCCCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCCCCCC3)cc2)c1
Yield: 83.2 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-azocan-1-yl-2-chloroethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.0 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH:5]=[CH:6][CH:7]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(-c2cccc3[nH]ccc23)c1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To the suspension of 4-(3-bromo-phenyl)-1H-indole (1.48 g, 5.44 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (66 mL) was added pyridinium tribromide (90% purity from Aldrich, 5.80 g, 16.3 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (26 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (1.02 g, 65%) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]1[CH2:39][O:38][CH2:37][CH2:36][O:35]1)(=O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:39][O:38][CH2:37][CH2:36][O:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: O=S(=O)(OCC1COCCO1)C(F)(F)F
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(CC2COCCO2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
346 mg (purity 93%, 0.86 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in the presence of 0.95 ml (0.95 mmol, 1.1 eq.) of bis(trimethylsilyl)lithium amide (1M in THF) and 430 mg (purity 90%, 1.55 mmol, 1.8 eq.) of 1,4-dioxan-2-ylmethyl trifluoromethanesulphonate (racemate) were reacted according to General Method 7B. Yield: 133 mg (33% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]([NH:8][C:9]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13]C)=O)=[O:7])[CH3:2].CCOCC.CC[O-].[Na+].[Na]>C(O)C>[OH:7][C:6]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:23])=[C:11]([OH:13])[C:10]2[C:9](=[C:18]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:16][CH:15]=2)[N:8]=1
Reactant: CCOC(=O)CC(=O)Nc1c(C(=O)OC)cccc1C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1c(O)nc2c(C(F)(F)F)cccc2c1O
Yield: 94.8 %

Procedure:
35.66 g of the product of Step B were added to 800 ml of anhydrous ether in the presence of sodium ethylate prepared from 2.69 g of sodium and 54 ml of ethanol and the mixture was vacuum filtered. The recovered precipitate was dissolved in water and the pH of the solution was adjusted to 1 by addition of 20% hydrochloric acid to obtain 30.56 g of ethyl 2,4-dihydroxy-8-trifluoromethyl-quinoline-3-carboxylate melting at 190° C which was used as is for the next step.
Reaction SMILES: N1C(C)=CC(C)=CC=1C.Cl[C:11]([O:13][CH3:14])=[O:12].[CH3:15][S:16][C:17](=[NH:43])[CH:18]([C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[CH:34][C:33]=1[F:42])[NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[CH:22][CH:21]=1.Cl>C1(C)C=CC=CC=1>[CH3:14][O:13][C:11](=[O:12])[N:43]=[C:17]([S:16][CH3:15])[C:18]([C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[CH:34][C:33]=1[F:42])=[N:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)Cl
Reactant: COc1cc(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc1OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: Cc1cc(C)nc(C)c1
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1F
Temperature: 80 °C
Reaction time: 18 h

Procedure:
After adding 9.85 ml of collidine and 4.94 ml of methyl chloroformate to a solution of 8.89 g of 2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetimidic acid methyl ester in 300 ml of toluene, the mixture was stirred at 80° C. for 18 hours under a nitrogen atmosphere. After cooling the reaction mixture, dilute hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (4.12 g, isomeric mixture) as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[N:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[S:25][C:15]=3[N:16]=2)=[CH:24][CH:23]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccncc3)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl-4-(3-nitrobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:3][C:4]([OH:6])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>O1CCCC1>[CH3:1][CH:2]([CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:3][C:4]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:6]
Reactant: C1COCCN1
Reactant: CC(C)=CCC/C(C)=C/CCC(C)CC(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CCC(C)CC(=O)N1CCOCC1
Reaction time: 0.33 h
Yield: 62.9 %

Procedure:
In anhydrous tetrahydrofuran was dissolved 6.9 g of the compound obtained in step (c) above, and 3 g of triethylamine and then 3.3 g of ethyl chlorocarbonate were added to the solution at 0° C. The mixture was stirred for 20 minutes. Into the liquid reaction mixture was dropped 3.1 g of morpholine at 0° C., and the mixture was stirred for 30 minutes. The liquid reaction mixture was extracted with n-hexane, and the extract was washed with water and dried. The solvent was removed by distillation and the residue was purified by column chromatography using silica gel to obtain 5.6 g of the intended compound in the form of an oil.
Reaction SMILES: Br[C:2]1[N:3]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH:13]([CH3:15])[CH3:14])[N:5]=2.[CH3:22][O-:23].[Na+]>CO>[CH3:14][CH:13]([O:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([O:23][CH3:22])[N:3]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:8]([NH2:11])[N:7]=1)[CH3:15]
Reactant: CC(C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(N)nc(OC(C)C)nc2n1C1CCCCO1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
To a stirred suspension of 8-bromo-2-[(1-methylethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (690 mg, 1.937 mmol) in methanol (15 ml) was added sodium methoxide (30% wt/v solution in methanol, 2.4 ml) and the reaction mixture heated at 50° C. for 2 hours. The reaction mixture was then heated to 70° C. and stirred for 2.5 hours. The solvent was evaporated and the residue partioned between saturated aqueous ammonium chloride solution (15 ml) and ethyl acetate (20 mL). The layers were separated, the aqueous phase was extracted with additional ethyl acetate (2×10 mL) and the organic extracts were combined, dried by passage through a hydrophobic frit and evaporated to give the title compound as a yellow solid (573 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=2)[CH2:14][CH2:13][C:12]1=[O:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[C].[Pd].C(O)C>[NH2:21][C:18]1[CH:19]=[C:20]2[C:15]([CH2:14][CH2:13][C:12](=[O:24])[N:11]2[CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN1C(=O)CCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCN1C(=O)CCc2ccc(N)cc21

Procedure:
An ethanol solution of 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-7-nitro-3,4-dihydroquinoline-2(1H)-one and 10% palladium-carbon was stirred at room temperature for 3 hours under an atmosphere of hydrogen (1 atm), the reaction liquid was filtered, and then the filtrate was concentrated under a reduced pressure. By purifying the residue by silica gel column chromatography, 7-amino-1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3,4-dihydroquinolin-2(1H)-one was obtained.
Reaction SMILES: [ClH:1].Cl.C[C@H]1N[C@@H](C)CN([CH2:11][C@@H:12]([C:24]2([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)C1.[CH3:31][C@H:32]1[NH:37][C@@H:36]([CH3:38])[CH2:35][N:34](C(=O)[C@@H](C2(O)CCCCC2)C2C=CC=C(OC(F)(F)F)C=2)[CH2:33]1>CO>[ClH:1].[ClH:1].[CH3:38][C@H:36]1[NH:37][C@@H:32]([CH3:31])[CH2:33][N:34]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][C@@:24]2([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:23])[F:22])[CH:14]=2)[CH3:11])[OH:30])[CH2:35]1
Reactant: C[C@@H]1CN(C(=O)[C@H](c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)C[C@H](C)N1
Reactant: C[C@@H]1CN(C[C@H](c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)C[C@H](C)N1
Agent: Cl
Solvent: CO
Product: CC(c1cccc(OC(F)(F)F)c1)[C@@]1(O)CCCCC1N1C[C@@H](C)N[C@@H](C)C1

Procedure:
In an analogous manner to Example 1, step 2, 1-{(1S)-2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from 1-{(1R)-2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-oxo-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol. MS (ESI) m/z 401; HRMS: calcd for C21H31F3N2O2+H+, 401.24104; found (ESI, [M+H]+), 401.2418. [α]D25=−10° (c=0.01 g/mL, MeOH); CD=+@268 nm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[H][H]>[Ru].O1CCOCC1>[F:9][C:8]([F:10])([F:11])[CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([NH2:1])[CH2:3]1
Reactant: [H][H]
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: [Ru]
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: NC1CCCC(C(F)(F)F)C1
Temperature: 175 °C

Procedure:
A mixture of 200 parts of 3-aminobenzotrifluoride, 4 parts of sodium methoxide, 15 parts of 5% ruthenium on alumina, and 200 parts of dioxane is heated in an autoclave at 175°C. under 5,000 p.s.i. of hydrogen for 4 hours. The reaction mixture is cooled and filtered and the solvent is evaporated in a rotary evaporator. The residue is distilled to give 159 parts of 3-trifluoromethylcyclohexylamine, b.p. 69°-70°/27 mm.