Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:23][CH2:22][N:5]2[C:6]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:7]=3[C:8]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)=[N+:9]([O-])[CH2:10][CH:4]2[CH2:3]1.P(Cl)(Cl)[Cl:25].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:23][CH2:22][N:5]2[C:6]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:7]=3[C:8]([C:12]3[O:13][C:14]([Cl:25])=[CH:15][CH:16]=3)=[N:9][CH2:10][CH:4]2[CH2:3]1
Reactant: ClP(Cl)Cl
Reactant: Cc1ccc2c(c1)C(c1ccco1)=[N+]([O-])CC1CN(C)CCN21
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)C(c1ccc(Cl)o1)=NCC1CN(C)CCN21

Procedure:
9.3 g of 1,2,3,4,4a,5-hexahydro-3,9-dimethyl-7-(2-furyl)-pyrazino[1,2-a][1,4]benzodiazepine 6-oxide (prepared analogously to Example 5) are heated under reflux in 150 ml of chloroform with 17 ml of phosphorus trichloride for 1 hour. The reaction mixture is then treated with aqueous sodium hydroxide solution and worked up. The resulting crude product is separated into its components by chromatography on aluminium oxide of activity level II, using methylene chloride/chloroform. 1.7 g of the less polar 1,2,3,4,4a,5-hexahydro-3,9-dimethyl-7-(5-chloro-2-furyl)-pyrazino[1,2-a][1,4]benzodiazepine are thereby initially obtained in the first fraction, and the product is isolated as an oil (IR: 1,615 cm-1C=N) (b). 5 g of the more highly polar 1,2,3,4,4a,5-hexahydro-3,9-dimethyl-7-(2-furyl)-pyrazino[1,2-a][1,4]benzodiazepine (a) are then obtained.
Reaction SMILES: [CH3:1][NH2:2].O.C(O[C:7]([C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([Br:16])[N:10]=1)=[O:8])C>CO>[NH2:15][C:14]1[C:9]([C:7]([NH:2][CH3:1])=[O:8])=[N:10][C:11]([Br:16])=[CH:12][CH:13]=1
Reactant: CN
Reactant: CCOC(=O)c1nc(Br)ccc1N
Solvent: O
Solvent: CO
Product: CNC(=O)c1nc(Br)ccc1N
Temperature: 100 °C

Procedure:
A 10M solution of Methylamine in H2O (30.0 mL, 386 mmol) was added to a stainless steel reactor containing 3-amino-6-bromopyridine-2-carboxylic acid ethyl ester (Compound 6E, 7.614 g, 31.07 mmol) in MeOH (20.0 mL). The reactor was sealed and heated to 100° C. for 16 hours. The cooled reaction mixture was transferred to a round bottom flask and concentrated in vacuo forming a yellow precipitate which was collected by filtration. Further precipitate formed in the filtrate which was also collected. The combined precipitates were dried in vacuo to afford the title compound as 6.18 g of a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.80 (br. s., 1H), 7.27 (d, J=8.6 Hz, 1H), 6.91 (d, J=8.6 Hz, 1H), 6.02 (br. s., 2H), 2.97 (d, J=5.1 Hz, 3H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].CC(C)([O-])C.[K+].Cl[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25].O>CS(C)=O>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][N:5]([C:6]1[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:10][CH:11]=1)[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: CN(C)CCCl
Reactant: CS(=O)(=O)Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)CCN(c1cccc([N+](=O)[O-])c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 g (23.1 mmol) of 3-methylsulphonylamino-nitrobenzene are dissolved in 50 ml of DMSO and combined with 6.5 g (58 mmol) of potassium tert. butoxide while cooling with ice. The solution thus obtained is added dropwise to a solution of 5 g (34.7 mmol) of 2-chloro-N,N-dimethyl-ethylamine in 30 ml of DMSO. The mixture is stirred for 2 hours at ambient temperature and then heated for 6 hours to 100° C. After cooling to ambient temperature 400 ml of water are added. The mixture is extracted with ethyl acetate. Water and 1 N hydrochloric acid are added to the combined organic phases until an acid reaction is obtained. The aqueous phase is washed with ethyl acetate. Then the aqueous phase is made alkaline with sodium carbonate and the product is extracted with ethyl acetate. Drying the combined organic phases over magnesium sulphate and eliminating the solvents in vacuo yields the product as a red oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:15](=[O:16])[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=3)([CH3:17])[NH:13][C:12]2=[O:25])[CH:5]=1.[C:27]([NH:37][CH2:38][C:39]#[CH:40])([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].N(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.[Cu]I.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>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:15](=[O:16])[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:40]#[C:39][CH2:38][NH:37][C:27]([O:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:28])[CH:19]=3)([CH3:17])[NH:13][C:12]2=[O:25])[CH:5]=1
Reactant: COC(=O)c1cccc(CN2C(=O)NC(C)(c3cccc(Br)c3)C2=O)c1
Reactant: C#CCNC(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CN2C(=O)NC(C)(c3cccc(C#CCNC(=O)OCc4ccccc4)c3)C2=O)c1
Temperature: 100 °C

Procedure:
A mixture of hydantoin 2 (830 mg, 2 mmol), N-Cbz-propargylamine (460 mg, 2.43 mmol; prepared according to the literature by Yasuda et al., patent application 2003, US 2003/0004353), CuI (20 mg, 0.1 mol), PdCl2(PPh3)2 (70 mg, 0.1 mmol) and iPr2NH (850 μL, 6 mmol) in DMF (5 mL) was heated for 15 min at 100° C. (Smith Microwave Synthesizer). The reaction mixture was diluted with EtOAc, washed with 1 M HCl (2×), NaHCO3 (1×), water (3×) and brine (1×), then dried over MgSO4, filtered and concentrated under vacuum. The crude material was subjected to silica gel chromatography (30→50% EtOAc/hexanes) to yield the desired material as a colorless film (598 mg, 57%). 1H NMR (400 MHz, CDCl3) δ 7.89 (m, 2H), 7.21-7.46 (m, 12H), 6.71 (bs, 1H), 4.62 (s, 2H), 4.12 (m, 2H), 3.81 (s, 3H), 1.72 (s, 3H). MS (ES+): 526 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[ClH:14].[N:15]([O-])=O.[Na+]>O>[ClH:14].[NH:1]([C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[NH2:15]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 0 °C
Yield: 93 %

Procedure:
To an ice cooled solution of 2-amino-5-nitrobenzoic acid (50.0 g, 274.5 mmol) in water (350 mL) was added conc. HCl (404 mL). The reaction mixture was stirred until the salt had precipitated out. A solution of sodium nitrite (29.0 g, 411.8 mmol) in water (300 mL) was slowly added at 0° C. with stirring for 15 min. This reaction mixture was slowly added to ice-cold sulfurous acid (2.5 L) followed by stirring at RT for 12 h. The reaction mixture was again cooled to 0° C. and conc. HCl was added unitl solid separates out. The solid was filtered, washed with cold HCl and vacuum dried to afford the title compound as a yellow colored solid 60 g (93%), which was used without further purification. Rf=0.10 (10% MeOH in DCM).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[C:26][CH2:27][NH:28][C:29](=[O:31])[O-:30])=[N:4][CH:5]=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:11]([Cl:24])[CH:10]=1>CN(C)C=O.[Cu]I>[Cl:24][C:11]1[CH:10]=[C:9]([NH:8][C:7]2[C:2]3[NH:1][C:26]([CH2:27][NH:28][C:29](=[O:30])[O:31][C:17]([CH3:22])([CH3:18])[CH3:16])=[CH:25][C:3]=3[N:4]=[CH:5][N:6]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1
Reactant: Nc1c(C#CCNC(=O)[O-])ncnc1Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2[nH]1
Temperature: 80 °C
Reaction time: 12 h
Yield: 148.5 %

Procedure:
A mixture of tert-butyl (3-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-yl]prop-2-ynylcarbamate (720 mg) and copper(I) iodide (55.2 mg) in N,N-dimethylformamide (7.0 mL) was stirred at 80° C. for 12 hrs. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, eluent, ethyl acetate→methanol:ethyl acetate=1:9) to give the title compound (604 mg) as pale-yellow powder crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH:21](N)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>CC(O)=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[CH:7]3)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Nc1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cccc3cnccc23)C1
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
To a solution of 5-amino-isoquinoline (47 g, 0.320 mol) in CH3COOH (1800 mL) was added 3-amino-piperidine-1-carboxylic acid tert-butyl ester (69.6 g, 0.376 mol) and Na2SO4 (267 g, 1.88 mol) at room temperature. The mixture was stirred at room temperate for 0.5 hour. Then to the mixture was added NaBH(OAc)3 (84.6 g, 0.376 mol) little by little. The mixture was stirred at room temperature for 18 hours. The mixture was adjusted to pH 8 by the addition of K2CO3 and extracted with EtOAc(2 L×3). (The combined layers were dried over Na2SO4, filtered and then concentrated in vacuo to afford crude product, which was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=5:1) to give 3-(isoquinolin-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (55 g, 53%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:25][CH2:26][CH3:27])=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8]CC1C=CC=CC=1)=[O:7])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]2)[CH2:25][CH2:26][CH3:27])=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: [H][H]
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCc2ccccc2)c(OCC)c1)c1ccccc1N1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: CCCC(NC(=O)Cc1ccc(C(=O)O)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
0.25 g (0.47 mmol) of benzyl 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate was hydrogenated in 10 ml of ethanol with 0.12 g of 10% palladium-on-charcoal at 50 and a pressure of 5 bar of hydrogen. After 5 hours the catalyst was filtered off through diatomaceous earth, and the filtrate was evaporated in vacuo. The evaporation residue was crystallized from petroleum ether/ethanol.
Reaction SMILES: [C:1]1([CH3:36])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:13][CH:12]([NH:27]C(OC(C)(C)C)=O)[C:11]2=[O:35])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1>Cl.O1CCOCC1>[C:1]1([CH3:36])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([CH2:22][CH:23]=[C:24]([CH3:25])[CH3:26])[CH2:13][CH:12]([NH2:27])[C:11]2=[O:35])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)=CCN1CC(NC(=O)OC(C)(C)C)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)=CCN1CC(N)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(3-methyl-2-butenyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (780 mg) was suspended in 4N HCl-dioxane (10 ml), the suspension was stirred for one hour at 50° C. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, washed with diethyl ether, alkalified with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, to thereby obtain 493 mg of the titled compound (Yield: 79.4%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[CH2:9].C(N(CC)CC)C.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:22]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[CH2:9])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=C(c1ccccc1O)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(c1ccccc1OC(c1ccccc1)(c1ccccc1)c1ccccc1)n1ccnc1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
To a suspension of 1-[1-(2-hydroxyphenyl)vinyl]imidazole (500 mg) and triethylamine (407 mg) in dry methylene chloride (5 ml) is added trityl chloride (1.12 g) under stirring at room temperature, and the mixture is stirred at room temperature for 1 hour. To the mixture ice water is added and extracted with methylene chloride. The methylene chloride extract is dried on anhydrous sodium sulfate, and then concentrated. The residue is chromatographed on a column of silica gel, and eluted with methylene chloride-methanol (3-5%). The eluate is concentrated and the residue is crystallized from isopropyl ether and a small amount of petroleum ether to give 1-[1-(2-trityloxyphenyl)vinyl]imidazole (525 mg). mp. 149°-144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][NH:20][C:19](=[O:23])[N:18]=3)=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].Cl.Cl[CH2:30][C:31]1[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][N:20]([CH2:30][C:31]4[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=4)[C:19](=[O:23])[N:18]=3)=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:24]([F:25])([F:26])[F:27]
Reactant: Cn1cc(CCl)cn1
Reactant: O=c1nc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cn2)cc[nH]1
Agent: Cl
Product: Cn1cc(Cn2ccc(OCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cn3)nc2=O)cn1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 4-{[(5-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-2-pyridinyl)methyl]oxy}-2(1H)-pyrimidinone and 4-(Chloromethyl)-1-methyl-1H-pyrazole hydrochloride. LC-MS (ESI): m/z 492 [M+H]+; 3.79 min (ret time).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Sn](C)(C)C)[N:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[C:3]=1[Cl:17].Br[C:19]1[C:27]([F:28])=[CH:26][C:22]2=[N:23][O:24][N:25]=[C:21]2[CH:20]=1.C(OCC)(=O)C.[Na+].[Cl-]>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>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:19]2[C:27]([F:28])=[CH:26][C:22]3=[N:23][O:24][N:25]=[C:21]3[CH:20]=2)[N:5]=[C:4]([C:13]([O:15][CH3:16])=[O:14])[C:3]=1[Cl:17]
Reactant: COC(=O)c1nc([Sn](C)(C)C)c(F)c(N)c1Cl
Reactant: Fc1cc2nonc2cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2cc3nonc3cc2F)c(F)c(N)c1Cl
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 18.8 %

Procedure:
Methyl 4-amino-3-chloro-5-fluoro-6-(trimethylstannyl)picolinate (320 mg, 0.86 mmol) and 5-bromo-6-fluorobenzo[c][1,2,5]oxadiazole (170 mg, 0.78 mmol) were combined in 5 mL dry N,N-dimethylformamide, deaerated with a stream of nitrogen for 15 min. Bis(triphenylphosphine)palladium(II) chloride (55 mg, 0.078 mmol) and cuprous iodide (15 mg, 0.078 mmol) were added and the mixture was heated to 70° C. for 4 h. The mixture was shaken with 20 mL ethyl acetate, 10 mL saturated NaCl, dried (Na2SO4) and the residue was chromatographed on silica with a 5-30% ethyl acetate-hexane gradient to give 50 mg of the title compound as a white solid (50 mg, 19%): mp 180-182° C.; 1H NMR (400 MHz, CDCl3) δ 8.16 (dd, J=6.2, 0.5 Hz, 1H), 7.54 (dd, J=8.7, 0.5 Hz, 1H), 5.07 (s, 2H), 4.00 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −105.64, −105.72, −137.68, −137.76; ESIMS m/z 341 ([M+H]+), 339 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31](=O)[C:32](O)=[O:33])([O-:23])=[O:22].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[C:11]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=[CH:13][CH:14]=[C:9]([N:8]2[C:32](=[O:33])[C:31]([CH2:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N+:21]([O-:23])=[O:22])=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[N:4][C:3]2=3)[CH:10]=1
Reactant: Nc1cccnc1Nc1cccc(-c2ccccc2)c1
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1c(Cc2ccccc2[N+](=O)[O-])nc2cccnc2n1-c1cccc(-c2ccccc2)c1
Yield: 43 %

Procedure:
A mixture of 3-amino-2-(3-biphenylylamino)pyridine (196 mg) and 3-(2-nitrophenyl)pyruvic acid (188 mg) in ethanol (5 ml) was stirred under reflux for 1 hour. The mixture was cooled and then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from methanol to give 4-(3-biphenylyl)-2-(2-nitrobenzyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (140 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([OH:12])[C:9]([OH:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>ClCCl.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([O:12][C:21](=[O:22])[NH:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)[C@H](O)c1ccccc1Cl
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)O[C@@H](C(=O)O)c1ccccc1Cl
Reaction time: 16 h
Yield: 88.2 %

Procedure:
1 g (5 mmol) of (R)-(2-chlorophenyl)hydroxyacetic acid are dissolved in 10 ml of dichloromethane, and 0.77 g (5 mmol) of 4-chlorophenyl isocyanate and 50 mg of dibutyltin dilaurate are added successively, and the mixture is stirred for 16 hours. Conventional work-up gives 1.5 g of (R)-(2-chlorophenyl)(4-chlorophenylcarbamoyloxy)acetic acid.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:20]=[C:19]([CH:21]=[CH:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=3)[C:18]([O:32][CH3:33])=[C:17]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:16]=2)=[CH:13][CH:12]=[C:11]([CH3:38])[N:10]=1)C1C=CC=CC=1>CCOC(C)=O.CO.[OH-].[OH-].[Pd+2]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][C:19]2[CH:20]=[C:15]([C:14]3[C:9](=[O:8])[NH:10][C:11]([CH3:38])=[CH:12][CH:13]=3)[CH:16]=[C:17]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:18]=2[O:32][CH3:33])=[CH:24][CH:25]=1
Reactant: COc1c(C=Cc2ccc([N+](=O)[O-])cc2)cc(-c2ccc(C)nc2OCc2ccccc2)cc1C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1c(CCc2ccc(N)cc2)cc(-c2ccc(C)[nH]c2=O)cc1C(C)(C)C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
step 5—A mixture of 68 (180 mg, 0.354 mmol) and Pd(OH)2 (20 wt % on C, 75 mg, 0.107 mmol) in EtOAc (10 mL) and MeOH (10 mL) was stirred under an atmosphere of hydrogen for 2 h before the catalyst was filtered, and the filtrate was concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (75 to 100% EtOAc) to afford 68 mg (49%) of 3-{3-[2-(4-amino-phenyl)-ethyl]-5-tert-butyl-4-methoxy-phenyl}-6-methyl-1H-pyridin-2-one (70) as a foam.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH2:58][C:59]1[C:68]([N:69]2[CH2:74][CH2:73][O:72][CH2:71][CH2:70]2)=[CH:67][C:66]2[C:61](=[CH:62][C:63]([F:78])=[C:64](B(O)O)[CH:65]=2)[N:60]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[NH2:58][C:59]1[C:68]([N:69]2[CH2:70][CH2:71][O:72][CH2:73][CH2:74]2)=[CH:67][C:66]2[C:61](=[CH:62][C:63]([F:78])=[C:64]([C:2]3[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=3[C:9]([N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[O:10])[CH:65]=2)[N:60]=1
Reactant: Nc1nc2cc(F)c(B(O)O)cc2cc1N1CCOCC1
Reactant: Cc1cccc(C(=O)N2CCCC2)c1Br
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(C(=O)N2CCCC2)c1-c1cc2cc(N3CCOCC3)c(N)nc2cc1F
Temperature: 140 °C

Procedure:
A microwave vessel was charged with (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone (0.081 g, 0.301 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.018 g, 0.038 mmol), Pd2(dba)3 (0.018 g, 0.020 mmol), potassium phosphate (0.106 g, 0.502 mmol), 2-amino-7-fluoro-3-morpholinoquinolin-6-ylboronic acid (0.073 g, 0.251 mmol), dioxane (1.6 mL) and water (0.8 mL). The vessel was purged with argon, sealed and heated by microwave radiation at 140° C. for 15 min. The mixture was concentrated, diluted with EtOAc (10 mL) and the suspension was filtered through celite rinsing with EtOAc. The filtrate was washed with saturated brine (5 mL), dried over sodium sulfate and concentrated. The material was purified by column chromatography on silica gel (33 mL) which had been deactivated with Et3N (3.3 mL) eluting with 1.5% MeOH/EtOAc to afford (2-(2-amino-7-fluoro-3-morpholinoquinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 435 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][F:21])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1.CO.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][F:21])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN
Reactant: FCCCOc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Solvent: CO
Product: CNc1nccc(-c2cc3ccc(OCCCF)cc3s2)n1
Yield: 80.2 %

Procedure:
2-[2-(N-Monomethylamino)pyrimidine-4-yl]-6-(3-fluoropropoxy)benzothiophene (1-38, 56 mg, 81%) was prepared in the same manner as in Example 35 as a yellow solid using 2-(2-chloropyrimidine-4-yl)-6-(3-fluoropropoxy)benzothiophene (105c, 70 mg, 0.22 mmol) obtained in Preparation Example 21 and a 2.0 M methylamine methanol solution (NH2Me in MeOH, 0.17 mL, 0.34 mmol).
Reaction SMILES: CO.[CH2:3]([NH:7][C:8]([C@@H:10]1[C@@H:12]([CH2:13][CH2:14][CH2:15][CH3:16])[O:11]1)=[O:9])[CH2:4][CH2:5][CH3:6].[N-:17]=[N+:18]=[N-:19].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>>[CH2:3]([NH:7][C:8](=[O:9])[C@@H:10]([OH:11])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCNC(=O)[C@H]1O[C@@H]1CCCC
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CO
Product: CCCCNC(=O)[C@@H](O)[C@H](CCCC)N=[N+]=[N-]
Yield: 68 %

Procedure:
A suspension of 30 ml of methanol containing 366 mg (1.84 mmol) of (2S-trans)-N-butyl-3-butyloxiranecarboxamide, 239 mg (3.68 mmol) of sodium azide and 228 mg (1.89 mmol) of anhydrous magnesium sulfate was refluxed for 5 hours. After the temperature of the reaction mixture was returned to room temperature, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the concentrate, and the resulting mixture was washed successively with water, and then a saturated NaCl solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 304 mg (Yield: 68%) of the title compound.