Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([CH2:8][O:9]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[Cl:20][C:21]1[CH:22]=[CH:23][C:24](O)=[C:25]([CH:28]=1)[CH:26]=[O:27].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:9][CH2:8][C:3]2([C:1]#[N:2])[CH2:4][CH2:5][CH2:6][CH2:7]2)=[C:25]([CH:26]=[O:27])[CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C#N)CCCC2)cc1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC1(COc2ccc(Cl)cc2C=O)CCCC1
Temperature: 100 °C

Procedure:
To a solution of the crude toluene-4-sulfonic acid 1-cyano-cyclopentylmethyl ester in DMF (70 mL) was added 5-chloro-2-hydroxy-benzaldehyde (12.48 g, 80 mmol) and K2CO3 (13.25 g, 96 mmol). After heated at 100° C. for 3 h, the reaction mixture was poured into water. The solution was diluted with EtOAc (200 mL), washed with water, dried and concentrated to give the title compound as a yellow oil (17.4 g). The oil was used for next step reaction directly without further purification.
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH3:6])[CH3:3].[Mg].[CH3:8][CH:9]([Mg]Br)[CH2:10][CH2:11][CH3:12].[P:15]([O-])(OCCCC)(OCCCC)=[O:16].S(=O)(=O)(O)O>O1CCCC1.C(OCC)C>[CH3:3][CH:2]([PH:15](=[O:16])[CH:9]([CH2:10][CH2:11][CH3:12])[CH3:8])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOP(=O)([O-])OCCCC
Reactant: CCCC(C)[Mg]Br
Reactant: CCCC(C)Br
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC(C)[PH](=O)C(C)CCC
Temperature: 10 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
A Grignard solution prepared from 2-bromopentane (227.3 g, 1.5 moles) and magnesium (39.6 g) in tetrahydrofuran (500 cm3) was estimated by a standard procedure and found to contain 1.05 moles of 2-pentyl magnesium bromide. The solution was diluted with diethyl ether (250 cm3) and cooled to 10° C. in an atmosphere of nitrogen. A solution of dibutyl phosphate (67.9 g, 0.35 moles) in diethyl ether (500 cm3) was added with stirring during 1 hr. whilst the temperature was maintained at 10°-15° C. The solution was then boiled under reflux for ten min. to complete the reaction. The solution was cooled to 10° C. and 25% aqueous sulphuric acid (500 cm3) was added with stirring during 1 hr. The organic layer was separated and successively extracted with water (two 300 cm3 amounts), 10% aqueous sodium bicarbonate (300 cm3), and water (two 300 cm3 amounts). It was then dried (magnesium sulphate) and filtered and distilled yielding di-2-pentylphosphine oxide (35.0 g ), b.p. 110° C. at a pressure of 0.8 mm of mercury. All of this compound was stirred in nitrogen atmosphere with phosphorus trichloride (10 cm3) at 22° C. After 1 hr. it was found by gas chromatography that about 20% remained unreacted; a second addition of phosphorus trichloride (10 cm3) was made and stirring was continued for a further 2 hr. when reaction had reached about 95% completion. The solution was distilled yielding volatile phosphorus compounds and finally chloro di-2-pentylphosphine (27.5 g), b.p. 72°-74° C. under a pressure of 1.5 mm of mercury.
Reaction SMILES: CN(C=O)C.Br[CH2:7][CH2:8][Cl:9].C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([Br:24])[C:18]=1[OH:25]>C(OCC)(=O)C>[Br:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([Br:24])[C:18]=1[O:25][CH2:7][CH2:8][Cl:9]
Reactant: Oc1c(Br)cc(F)cc1Br
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc(Br)c(OCCCl)c(Br)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
DMF (50 mL), 1-bromo-2-chloroethane (1.0 mL, 12 mmol), and potassium carbonate (1.7 g, 12 mmol) were added to 2,6-dibromo-4-fluorophenol (3.0 g, 11 mmol), and stirred at 50° C. overnight. Ethyl acetate was used as an extraction solvent, and after washing with water and saturated brine, and the resultant was dried over magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel column chromatography to thus obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:36]=[CH:35][C:18]([CH2:19][NH:20][O:21][C@H:22]4[C@H:27]([O:28][CH3:29])[C@H:26]([O:30][CH3:31])[C@@H:25]([O:32][CH3:33])[C@H:24]([CH3:34])[O:23]4)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:39](N(C(C)C)CC)(C)C.CI>O1CCCC1.O>[CH3:39][N:20]([CH2:19][C:18]1[CH:35]=[CH:36][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:37])[F:38])=[CH:5][CH:6]=3)[N:11]=2)=[CH:16][CH:17]=1)[O:21][C@H:22]1[C@H:27]([O:28][CH3:29])[C@H:26]([O:30][CH3:31])[C@@H:25]([O:32][CH3:33])[C@H:24]([CH3:34])[O:23]1
Reactant: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ONCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)[C@@H]1OC
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON(C)Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)[C@@H]1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of N-{4-[1-(4-trifluoromethoxyphenyl)-1 H-[1 ,2,4]triazol-3-yl]-benzyl}O-((2S ,3R,4R,5S ,6S)-3 ,4 ,5-trimethoxy-6-methyl-tetrahydropyran-2-yl)-hydroxylamine. (3; 205 mg, 0.38 mmol) in tetrahydrofuran (THF; 10 mL) was added diisopropylethylamine (DIEA; 300 μL, 1.7 mmol) followed by methyl iodide (250 μL, 4.0 mmol). This solution was heated to reflux. After 1 h, due to apparent precipitation of quaternized DIEA, anhydrous potassium carbonate (K2CO3) was added to the mixture along with methyl iodide (200 μL, 3.2 mmol), and the suspension was allowed to stir at reflux an additional 21 h. The mixture was then cooled to room temperature, diluted with H2O and extracted with EtOAc (2×). The organic fractions were combined, washed with brine, dried with anhydrous Na2SO4 and evaporated at room temperature under vacuum. The resulting crude material was purified by silica gel chromatography (eluting with 60% EtOAc in Hexane). The title product (131 mg, 63%) was isolated as a pale yellow solid: mp 93-100° C.; 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J=4.1 Hz, 1H), 8.16 (d, J=8.3 Hz, 2H), 7.88-7.75 (m, 2H), 7.52 (t, J=10.7 Hz, 2H), 7.39 (t, J=9.5 Hz, 2H), 4.37 (d, J=13.2 Hz, 2H), 3.98-2.89 (m, 15H), 1.25 (dd, J=24.7, 6.2 Hz, 3H); ESIMS m/z 553 (M+H).
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[CH:4][N:3]=1.C(=O)(O)O.[NH2:28][C:29]([NH2:31])=[NH:30].O>CN(C)C(=O)C>[NH2:30][C:29]1[N:31]=[C:8]([NH2:9])[C:7]2[C:2](=[N:3][CH:4]=[C:5]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:22])([F:21])[F:23])[CH:11]=3)[N:6]=2)[N:28]=1
Reactant: N=C(N)N
Reactant: N#Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cnc1N
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nc(N)c2nc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cnc2n1

Procedure:
Under a nitrogen atmosphere, a stirred solution of 1.0 gram (0.003 mole) of 2-amino-3-cyano-5-[3,5-di(trifluoromethyl)phenyl]pyrazine and 1.3 grams (0.007 mole) of guanidine carbonate in 10 mL of N,N-dimethylacetamide is heated at about 150° C. for 40 hours. After this time, the reaction mixture is poured into 50 mL of water. The resultant solid is collected by filtration and is then slurried in 25 mL of diethyl ether. The solid is again collected by filtration and is then recrystallized from ethanol, yielding 2,4-diamino-6-[3,5-di(trifluoromethyl)phenyl]pteridine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]([CH2:11][CH2:12][CH2:13][CH3:14])[C:7](=[NH:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:18]=1[C:19](O)=[O:20].CCN(CC)CC.CCCP(=O)=O>C1COCC1>[CH2:11]([N:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6]/[C:7]/1=[N:15]\[C:19](=[O:20])[C:18]1[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:17]=1[F:16])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCn1ccc(C(C)(C)C)cc1=N
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Agent: CCCP(=O)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCn1ccc(C(C)(C)C)c/c1=N\C(=O)c1cc(C(F)(F)F)ccc1F
Yield: 44.2 %

Procedure:
A mixture of Example 92A (315 mg, 1.3 mmol), 2-fluoro-5-(trifluoromethyl)benzoic acid (324 mg, 1.56 mmol), Et3N (543 μL, 3.89 mmol) and propylphosphonic anhydride (927 μL, 1.56 mmol) in THF (15 mL) was stirred at room temperature for 12 hours. The reaction mixture was quenched with NaHCO3 and extracted twice with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 10-100% EtOAc/hexanes gradient) to afford 228 mg (44%) of the title compound. MS (DCI/NH3) m/z 397 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][N:14]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:23])[CH3:15].[Cl:24][Si](C)(C)C>C(OCC)C.C(O)C.O>[ClH:24].[CH3:15][N:14]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[OH:23])[CH3:13]
Reactant: Brc1cccnc1
Reactant: C[Si](C)(C)Cl
Reactant: CN(C)CC1CCCCC1=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CN(C)CC1CCCCC1(O)c1cccnc1
Product: Cl
Temperature: -30 °C
Reaction time: 1 h

Procedure:
224 ml n-butyllithium solution (2.5 mol/l in hexane) were added dropwise to a solution of 54 ml 3-bromopyridine in 750 ml analytical grade diethyl ether in the course of 30 minutes at a temperature of −35 to −40° C. After a further 20 minutes at this temperature, 86.9 g 2-dimethylaminomethylcyclohexanone, dissolved in 90 ml analytical grade diethyl ether, were added dropwise in the course of 30 minutes, with continued cooling, and the mixture was stirred again for 60 minutes with gentle warming to −30° C. 150 ml water were then added with warming of the reaction mixture to 0° C., the phases were separated, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over magnesium sulfate and filtered and the filtrate was concentrated. The crude product obtained (139 g) was dissolved in 700 ml absolute ethanol, and 142 ml chlorotrimethylsilane and 20.2 ml water were added in succession and the mixture was stirred in an ice-bath for 12 hours. The solid which had precipitated out was filtered off with suction, washed with a little absolute ethanol and dried at 90° C. in vacuo (approx. 50 mbar) for two hours. 63.9 g 2-dimethylaminomethyl-1-pyridin-3-yl-cyclohexanol hydrochloride were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[CH2:10][CH:11]2[C:20](=[O:21])[NH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]2)=[CH:4][CH:3]=1.[CH3:23][N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26]>>[O:21]=[C:20]1[NH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]1[CH2:10][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][C:25](=[O:26])[N:24]([CH3:23])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:3][CH:4]=1)=[O:22]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(CC1Nc2ccccc2NC1=O)Nc1ccc(O)cc1
Product: CN(C(=O)Oc1ccc(NC(=O)CC2Nc3ccccc3NC2=O)cc1)c1ccccc1

Procedure:
The title product was prepared from N-(4-hydroxyphenyl)-2-(3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl)acetamide and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (20%, yellow solid). HPLC-MS: m/z=431.2 (M+1); Rt: 3.55 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O.CN>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([NH:24][CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
A solution of (R)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1' carbonyldiimidazole (2.69 g, 0.0166 mole), and dry tetrahydrofuran (100 ml) was stirred at room temperature for 1.75 hours with a stream of nitrogen bubbling through it. A solution of methylamine in tetrahydrofuran (33 ml of a 3.03 M solution, 0.996 mole) was added and the reaction mixture was stirred at room temperature overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was triturated in water, collected by filtration, rinsed twice with water, twice with 5% potassium hydroxide solution, and twice again with water. The solid was dissolved in hot isopropyl alcohol, charcoaled, and filtered while hot. Water was added to the cloud point, and upon cooling, solid precipitated. The solid was collected by filtration and dried under high vacuum at 50° C. overnight to give 3.21 g (62%) of title compound, mp 217°-218° C.
Reaction SMILES: Cl.[CH3:2][NH2:3].C(=O)([O-])[O-].[K+].[K+].I[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=2)=[CH:17][C:16]=1[C:32]1[CH:41]=[CH:40][C:39]2[C:38]([CH3:43])([CH3:42])[CH2:37][CH2:36][C:35]([CH3:45])([CH3:44])[C:34]=2[CH:33]=1>C(O)C>[CH3:2][NH:3][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=2)=[CH:17][C:16]=1[C:32]1[CH:41]=[CH:40][C:39]2[C:38]([CH3:43])([CH3:42])[CH2:37][CH2:36][C:35]([CH3:45])([CH3:44])[C:34]=2[CH:33]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCI)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(OCCCNC)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 76.3 %

Procedure:
In a manner similar to that of Example 1c, by reaction of 905 mg (13.4 mmol) of methylamine hydrochloride, 1.85 g (13.4 mmol) of potassium carbonate and 800 mg (1.34 mmol) of ethyl 4′-(3-iodopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (obtained in Example 1b) in 50 ml of ethanol. 511 mg of ethyl 4′-(3-methylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (m.p.=141° C., yield=76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.Cl.[NH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=O.[OH2:31]>>[NH2:14][C:15]1[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[N:7][C:8]2[C:4]([C:5]=1[C:6]([OH:11])=[O:31])=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: NCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: O
Agent: Cl
Product: Nc1c(-c2ccc(-c3ccc(F)cc3)cc2)nc2ccc(F)cc2c1C(=O)O

Procedure:
A basic aqueous solution of 4.13 g of 5-fluoroisatin in water was reacted with 9.3 g of 2-amino-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)-ethanone hydrochloride by the procedure described in example 20, giving 7.13 g of the desired compound as a yellow solid, mp 241°-243° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=C[C:3]=1[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]2([CH3:23])[CH3:22])=[CH2:9].C(N(CCCC)CCCC)CCC.[C]=O.[C:39]([O:42][CH2:43]C)(=[O:41])[CH3:40]>CO.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:20][C:16]1([CH3:21])[CH2:15][CH2:14][C:13]([CH3:22])([CH3:23])[C:12]2[CH:11]=[C:10]([C:8]([C:3]3[CH:2]=[CH:7][CH:6]=[CH:5][C:40]=3[C:39]([O:42][CH3:43])=[O:41])=[CH2:9])[CH:19]=[CH:18][C:17]1=2
Reactant: CCOC(C)=O
Reactant: C=C(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CCCCN(CCCC)CCCC
Solvent: CO
Product: C=C(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccccc1C(=O)OC

Procedure:
A solution of 6-[1-(2-iodophenyl)vinyl]-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (9.5 g, 22 mmol), palladium diacetate (560 mg, 2.5 mmol)-and tributylamine (12 ml, 50 mmol) in methanol (500 ml) is heated for 3 h at 100° C. under a pressure of carbon monoxide (3 bar). After concentration on an evaporator under vacuum at 40° C., the oil obtained is diluted in ethyl acetate and washed three times with water. The product is purified by flash chromatography on a column of silica.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([O:13][CH2:14][C:15](=O)[CH3:16])[CH:11]=[CH:12][C:4]=2[O:3]1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S(=O)(=O)(O)O.[H][H]>CO.[Pt].C(O)(C)C>[CH2:19]([NH:26][CH:15]([CH3:16])[CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:4]2[O:3][C:2]([CH3:18])([CH3:1])[NH:7][C:6](=[O:8])[C:5]=2[CH:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)COc1ccc2c(c1)C(=O)NC(C)(C)O2
Reactant: [H][H]
Agent: [Pt]
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(C)O
Product: CC(COc1ccc2c(c1)C(=O)NC(C)(C)O2)NCc1ccccc1

Procedure:
A solution of 49.8 g of 2,3-dihydro-2,2-dimethyl-6-(2-oxopropoxy)-4H-1,3-benzoxazin-4-one and 21.4 g of benzylamine in 700 ml of methanol is hydrogenated with the addition of 0.5 g of concentrated sulphuric acid and 3 g of Pt/C-catalyst (5%) until the equivalent amount of hydrogen has been asborbed. Working up analogously to Example (1d) yields 6-(2-benzylaminopropoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one having a melting point of 127°-129° (from isopropanol).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH:10]=[CH2:11])[NH2:6].[OH:14]O>O1CCCC1>[OH:14][CH2:11][CH2:10][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:2]([F:12])([F:13])[F:1]
Reactant: C=Cc1ccc(N)cc1C(F)(F)F
Reactant: OO
Solvent: C1CCOC1
Product: Nc1ccc(CCO)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
In 10 mL of anhydrous tetrahydrofuran, 2.47 g (13.2 mmol) of 3-trifluoromethyl-4-vinylaniline was dissolved, and 2.75 mL (30.0 mmol) of borane-dimethyl sulfide complex was added dropwise thereto in an argon atmosphere, and the mixture solution was stirred at room temperature four hours. To the reaction solution, 5 mL of a 1N sodium hydroxyl aqueous solution and 3 mL of a 30% hydrogen peroxide aqueous solution were added and the mixture solution was stirred at 0° C. for one hour. The reaction solution was concentrated and the residue was partitioned between water and ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The product was purified by a silica gel column (n-hexane:ethyl acetate=2:1) to obtain 1.3 g (48%) of a target product as a pale yellow oil.
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:11][NH:12][C:13](=[S:16])[NH:14][NH2:15].[OH-].[K+]>O1CCCC1>[CH2:2]([C:1]1[N:12]([CH3:11])[C:13]([SH:16])=[N:14][N:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CNC(=S)NN
Reactant: CCCCCCCC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCc1nnc(S)n1C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
5 g (30.74 mmol, 1 eq) of octanoyl chloride and 3.58 g (33.81 mmol, 1.1 eq) of 4-methyl-3-thiosemicarbazide in solution in 350 ml of tetrahydrofuran are stirred for 3 hours at room temperature. The solution is concentrated to dryness. The solid obtained is taken up in 350 ml of a 10% aqueous potassium hydroxide solution 35 g (0.82 mmol, 20 eq). The reaction mixture is stirred overnight under reflux. In the cold state, the reaction medium is acidified. The precipitate obtained is filtered, washed with a minimum of water and then dried. 5.94 g (90%) of the expected compound are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2]1.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]=O>[CH2:15]([O:14][C:12]([CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=1)=[O:13])[CH3:16]
Reactant: Brc1cccnc1
Reactant: CCOC(=O)CCc1c[nH]c2ccccc12
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCOC(=O)CCc1cn(-c2cccnc2)c2ccccc12

Procedure:
A solution of 8.0 g of ethyl 3-(3-indolyl)propionate and 6.3 g of 3-bromopyridine in 100 ml of pyridine is refluxed with 5.0 g of copper oxide and 10 g of anhydrous potassium carbonate for 48 hours. Evaporation and chromatography on 300 g of silica with 1:1 ethyl ether:hexane as eluant yields 3-[2-(ethoxycarbonyl)ethyl]-N-(3-pyridyl)indole as an oil; Rf =0.2, IR (CH2Cl2) 1725 cm-1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:30]([F:33])([F:32])[F:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=1>>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]([C:30]([F:31])([F:32])[F:33])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Reactant: CCOC(=O)C(c1ccc(N)cc1)C(F)(F)F
Product: CCOC(=O)C(c1ccc(Nc2cc(CC)nc(-c3cccc(Cl)c3)n2)cc1)C(F)(F)F
Yield: 98 %

Procedure:
Following General Procedure A1, 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.055 g, 0.22 mmol) was reacted with ethyl 2-(4-aminophenyl)-3,3,3-trifluoropropanoate (0.080 g, 0.33 mmol) to afford the title compound (0.100 g, 100%) as an amber oil. MW=463.88. 1H NMR (CDCl3, 300 MHz) δ 8.44-8.39 (m, 1H), 8.34-8.27 (m, 1H), 7.57-7.46 (m, 4H), 7.44-7.36 (m, 2H), 6.87 (s, 1H), 6.54 (s, 1H), 4.38-4.11 (m, 3H), 2.74 (q, J=7.6 Hz, 2H), 1.40-1.21 (m, 6H); APCI MS m/z 464 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17]>C1C=CC=CC=1.C(Cl)Cl>[CH2:16]([NH:18][C:19]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[O:20])[CH3:17]
Reactant: CCN=C=O
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCNC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1

Procedure:
To a stirred and chilled (15°-20° C.) solution of 0.024 mole of 3-[3-(trifluoromethyl)phenoxy]azetidine in 50 ml of dry benzene was added dropwise 1.99 g (0.028 mole) of ethyl isocyanate. The reaction mixture was stirred at room temperature overnight and was diluted with 50 ml of methylene chloride. The solution was washed with 5% sodium hydroxide (2×50 ml), water (50 ml), saturated sodium chloride (25 ml), dried over sodium hydroxide, and concentrated in vacuo. The residue (9.6 g) was twice recrystallized from ethyl acetate-isopropyl ether to give 5.4 g or a white solid, m.p. 125°-126° C.