Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:28][CH2:27]1>CN(C=O)C>[CH2:32]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])[CH2:27][CH2:28]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1n[nH]c2ccccc12
Temperature: 60 °C
Yield: 85.1 %

Procedure:
A stirred solution of 1-H-indazole-3-carboxylic acid (8.11 g, 50.0 mmol) in dry DMF (140 ml) under argon atmosphere was added CDI (8.92 g, 55 mmol) and heated at 60° C. for 2 h. The mixture was cooled to room temperature, dropwise added 4-amino-1-benzylpiperidine (9.51 g, 50.0 mmol) previously dissolved in DMF (20 ml). The mixture was heated at 60° C. for 2 h, cooled to room temperature and the solvent evaporated in vacuo. The residue was added CH2Cl2 (250 ml) and the organic layer washed with H2O (100 ml), 1 N aqueous NaOH (100 ml), H2O (100 ml) and brine (100 ml). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The residue was recrystalilized from EtOH to leave the expected product as a white solid (14.23 g, 85.1%).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:28]=[C:27]([Cl:29])[S:26][C:17]=2[N:18]=[C:19]([C:21]2[O:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[O:25]1[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:28]=[C:27]([Cl:29])[S:26][C:17]=3[N:18]=2)=[CH:22][CH:23]=[N:24]1
Reactant: Clc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Clc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[CH3:45][C:33]1[N:32]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:26][CH:27]=2)[C:40]2[C:35]([C:34]=1[CH3:44])=[CH:36][C:37]([C:41](=[O:42])[NH:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)=[CH:38][CH:39]=2
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc([N+](=O)[O-])cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-nitrobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].C(O)C.[C:22](OC)(=[O:25])[C:23]#[CH:24]>>[C:11]([C:10]1[CH:24]=[CH:23][C:22](=[O:25])[N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[NH:3][C:2]=12)(=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#CC(=O)OC
Reactant: O=C(Cc1nc2ccccc2[nH]1)c1ccccc1
Solvent: CCO
Product: O=C(c1ccccc1)c1ccc(=O)n2c1[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.6 %

Procedure:
200 mg (0.733 mmol) of the compound of Example II are dissolved in 5 mL ethanol 70 mg (0.833 mmol) sodium bicarbonate and 70 mg (0.833 mmol) methyl propiolate are added at room temperature and the mixture is stirred for 24 h at room temperature. The solvent is evaporated under vacuum and the crude is stirred with ethyl acetate, filtered and dried to yield 77.3 mg (37% of th.) 4-benzoylpyrido[1,2-a]-benzimidazol-1(5H)-one.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[F:15][C:16]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([F:27])[C:17]=1C(O)=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:11]([O:10][C:6](=[O:5])[C:17]1[C:16]([F:15])=[CH:24][C:23]([O:25][CH3:26])=[CH:22][C:21]=1[F:27])([CH3:12])([CH3:13])[CH3:14]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: COc1cc(F)c(C(=O)O)c(F)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(F)c(C(=O)OC(C)(C)C)c(F)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
N,N-dimethylformamide di-tert-butyl acetal (75 ml, 0.31 mol) in toluene (60 ml) was added dropwise over 1.5 hours to 2,6-difluoro-4-methoxy-benzoic acid (15 g, 80 mmol)(Mol. Cryst. Liq. Cryst. 1989, 172) in toluene (120 ml) at 80° C. under a nitrogen atmosphere. The mixture was stirred at 80° C. for 30 minutes and then cooled to room temperature. Ethyl acetate (100 ml) was added and the organic solution was washed with saturated sodium hydrogen carbonate solution (2×150 ml), brine (150 ml), dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using diethyl ether in pentane as eluant (10:90) to give the title compound as an oil (17.91 g).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:12]([CH3:11])(=[O:14])=[O:13])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCc1cc(Br)ccc1N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCc1cc(Br)ccc1NS(C)(=O)=O
Reaction time: 15 h
Yield: 79.6 %

Procedure:
4-Bromo-2-ethyl-aniline (2 mL, 14 mmol) dissolved in anhydrous pyridine (35 mL) at room temperature was treated with methylsulfonyl chloride (1.3 mL, 16.8 mmol). The reaction was stirred at that temperature for 15 hours before it was diluted with EtOAc. The mixture was washed with H2O, brine and dried over MgSO4. The solvent was removed in vacuo and the residue was purified with flash chromatography (SiO2, 5-30% EtOAc in hexanes) to afford the desired product (3.1 g, 81% yield). 1H NMR (300 MHz, CDCl3): δ 1.25 (t, J=7.5 Hz, 3 H), 2.61-2.68 (m, 2 H), 3.02 (s, 3 H), 6.36 (s, 1 H), 7.36-7.39 (m, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[C:19]([O:22][CH2:23][C:24](Cl)=[O:25])(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([O:22][CH2:23][C:24]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5])=[O:25])(=[O:21])[CH3:20]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CNc1cccc(N)c1C(N)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNc1cccc(NC(=O)COC(C)=O)c1C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-(methylamino)benzamide (3.6 g) in methylene chloride (100 ml) is added pyridine (4.8 ml), and thereto is added dropwise acetoxyacetyl chloride (3.2 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are washed with water and ether and then are recrystallized from ethanol to give the title compound (4.2 g) having the following physical properties.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6](=O)[CH3:7])(=[O:4])=[O:3].O.[NH2:10][NH2:11]>C(O)C>[CH3:1][S:2]([CH2:5][C:6](=[N:10][NH2:11])[CH3:7])(=[O:4])=[O:3]
Reactant: CC(=O)CS(C)(=O)=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(CS(C)(=O)=O)=NN
Temperature: 0 °C
Reaction time: 23.5 h

Procedure:
To a 200 ml volume four-necked flask, 1-methylsulfonyl-2-propanone (7-2-1) (10.21 g) and ethanol (50 ml) were added under a nitrogen atmosphere and cooled to 0° C. Hydrazine monohydrate (14-b) (3.9 ml) was added dropwise. After stirring at room temperature for 23.5 hours, the mixture was concentrated under reduced pressure to give 10.69 g of (1-methylsulfonyl-2-propylidene)hydrazine (5-2-2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1F>C(#N)C>[F:7][C:8]1[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([F:15])[C:13]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: C1CNCCN1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)c(N2CCNCC2)c(F)c1
Yield: 96.4 %

Procedure:
A solution of piperazine (24 g, 0.28 mol) and 3,4,5-trifluoronitrobenzene (13 mL, 0.11 mol) in acetonitrile (200 mL) was stirred at 60° C. The progress of reaction was monitored by TLC. On completion, acetonitrile was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL) and resulting solution was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1:9 methanol:chloroform) to provide title compound (25.8 g, 92%) as orange solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].Cl[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1>C1COCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)=[O:5])=[N:15][CH:16]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: CC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)cn1)c1ccc(F)cc1
Yield: 8.5 %

Procedure:
Sodium hydride (Aldrich, 60% in oil, 13.03 g) was suspended in anhydrous THF (250 ml). 4-Fluoroacetophenone (15 g, 108.6 mmol) in anhydrous THF (100 ml) was added dropwise and the mixture heated to reflux for 1 h under nitrogen. The solution was cooled to 0° and 2,5 dichloropyridine (16.07 g) in anhydrous THF (75 ml) was added dropwise. The mixture was then heated to reflux overnight before being recooled to 0° and quenched with water dropwise (CAUTION! Hydrogen gas evolved, exothermic). The resulting reaction mixture was washed with brine and the organic phase dried and concentrated to give a mobile brown oil which was adsorbed onto silica gel and purified by Biotage chromatography with cyclohexane:ethyl acetate (40:1) as eluant. Combination and concentration of appropriate fractions gave the title compound as a yellow solid (2.31 g, 8.5%) which exists as a mixture of keto:enol forms, 1:2. NMR (CDCl3) δ 4.44 (2H, s, keto CH2); 6.0 (apparent 2H, s, enol CH═); 7.05-7.15 (10H, m); 7.26 (1H, d, J 9 Hz); 7.6-7.65 (apparent 3H, 2x dd, J 9 & 2 Hz); 7.8 (4H, dd, J 9 & 5 Hz); 8.35 (apparent 2H, J 3 Hz, N═CH); 8.52 (1H, J 3 Hz, N═CH) Tlc SiO2 cyclohexane:ethyl acetate (3:1) Rf 0.56 detection uv254.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12].[NH2:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([CH3:28])[N:21]=1>O1CCOCC1>[F:18][C:2]([F:1])([F:17])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]([NH:19][C:20]1[N:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([CH3:28])[N:21]=1)=[O:16])(=[O:13])=[O:12]
Reactant: O=C=NS(=O)(=O)c1ccccc1C=CC(F)(F)F
Reactant: COc1nc(C)nc(N)n1
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C=CC(F)(F)F)n1
Temperature: 20 °C

Procedure:
5.6 g of 2-(3,3,3-trifluoro-1-propen-1-yl)phenylsulfonyl isocyanate and 2.5 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine are stirred in absolute dioxan for 3 hours at 70°-80° C. After it has been cooled to 20° C., the reaction mixture is filtered and the clear solution so obtained is concentrated to a quarter of its volume. Then 50 ml of ether are added and 5.0 g of N-[2-(3,3,3-trifluoro-1-propen-1-yl)phenylsulfonyl]-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea crystallise from the solution. Melting point: 154°-155° C.
Reaction SMILES: Cl.C([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][O:14][C:13]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=3[C:11](=[O:22])[C:10]=2[CH:23]=1)(=O)C>CO>[NH2:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][O:14][C:13]3[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=3[C:11](=[O:22])[C:10]=2[CH:23]=1
Reactant: COc1ccc2c(c1)C(=O)c1cc(NC(C)=O)ccc1CO2
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)C(=O)c1cc(N)ccc1CO2
Yield: 74 %

Procedure:
In a mixed solvent of concentrated hydrochloric acid (15 ml) and methanol (15 ml), 9-acetamido-2-methoxy-6,11-dihydrodibenz[b,e]oxepin-11-one obtained in Reference Example 10 (0.93 g, 3.1 mmol) was heated under reflux for one hour. After the reaction was completed, substantially the same procedure as in Reference Example 5 was repeated to give 9-amino-2-methoxy-6,11-dihydrodibenz[b,e]oxepin-11-one (yield: 74%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][N:10]=1)=O)[CH3:2].[NH:19]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=1)[NH2:20]>>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][N:10]=2)[N:19]([C:21]2[CH:26]=[N:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:20]=1)=[O:18])[CH3:2]
Reactant: COc1ccc(NN)cn1
Reactant: CCOC(=O)C(=O)CC(=O)c1cc(SC)ccn1
Product: CCOC(=O)c1cc(-c2cc(SC)ccn2)n(-c2ccc(OC)nc2)n1
Yield: 16.3 %

Procedure:
The general procedure of Referential Example 3-2) was repeated through use of 4-(4-methylthio-2-pyridyl)-2,4-dioxobutanoic acid ethyl ester (1.62 g) and the 5-hydrazino-2-methoxypyridine (0.843 g) prepared in Referential Example 2, to thereby give the title compound as a solid (0.366 g, 16%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:18]2[C:19]([C:25]([C:27]3[CH:28]=[N:29][C:30](F)=[CH:31][CH:32]=3)=[O:26])=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)[CH2:15][O:16][CH3:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C-:34]#[N:35].[K+]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:18]2[C:19]([C:25]([C:27]3[CH:28]=[N:29][C:30]([C:34]#[N:35])=[CH:31][CH:32]=3)=[O:26])=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)[CH2:15][O:16][CH3:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccc(F)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccc(C#N)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4-tert-Butyl —N-[5-chloro-2-(6-fluoro-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-benzenesulfonamide (444 mg, 0.899 mmol) was dissolved in DMF (5 mL). KCN (300 mg, 4.6 mmol) was then added and the reaction mixture was heated to 60° C. for 2 hours. Additional KCN (110 mg, 1.7 mmol) was then added and the reaction was stirred for another 2 hours. The solvent was removed under reduced pressure and the resulting brown oil purified by column (1:4 EtOAc/hexanes) to give 172 mg (0.345 mmol, 38% yield). MS calc'd for C24H24ClN4O4S (MH+): 499.1, found 499.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[N:32]1([CH2:38][C:39]([NH:41][CH:42]([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:35]4[CH2:34][CH2:33][N:32]([CH2:38][C:39]([NH:41][CH:42]([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:36]4)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: CC(C)NC(=O)CN1CCNCC1
Product: CC(C)NC(=O)CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-piperazinyl-N-isopropylacetamide as in General Procedure 10 to give the title compound. LCMS: m/z=615.03 (M+H+); retention time=0.58 minutes.
Reaction SMILES: [CH3:1][C:2]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[Cl:16][C:17]1[CH:22]=[C:21]([N+]([O-])=O)[CH:20]=[CH:19][N:18]=1>>[CH3:1][C:2]1[C:12]([O:13][C:21]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:16])[CH:22]=2)=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CCOC(=O)c1cccc(O)c1C
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cccc(Oc2ccnc(Cl)c2)c1C
Yield: 90 %

Procedure:
Using the method of Example 3, Step A, ethyl 2-methyl-3-hydroxybenzoate (2.27 g, 12.6 mmol), 60% sodium hydride in mineral oil (505 mg, 12.6 mmol), and 2-chloro-4-nitropyridine (2.00 g, 12.6 mmol) were reacted to provide ethyl 2-methyl-3-(2-chloropyridin-4-yloxy)benzoate (3.31 g, 90% yield) as a clear oil. 1H NMR (CDCl3) δ 8.22 (d, 1H), 7.83 (d, 1H), 7.33 (t, 1H), 7.18 (d, 1H), 6.70-6.72 (m, 2H), 4.39 (quartet, 2H), 2.38 (s, 3H), 1.41 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH:5]2O.O.[NH2:14]N>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][N:14]=[CH:5]2
Reactant: NN
Reactant: O=C1NC(O)c2cc(Br)ccc21
Solvent: O
Product: O=c1[nH]ncc2cc(Br)ccc12
Temperature: 95 °C
Yield: 46.6 %

Procedure:
A mixture of 5-bromo-3-hydroxy-2,3-dihydro-isoindol-1-one (15.75 g, 69.06 mmol) and hydrazine hydrate (70 mL, 1439.2 mmol) was heated at 95° C. for 5 h. The precipitate was filtered, washed with water and the crude material triturated with hot EtOAc to afford the product (7.25 g, 46.6%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]2[NH:11][C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>CN(C=O)C>[N:25]1[CH:26]=[CH:27][C:22]([CH:20]([OH:19])[CH2:21][N:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]2=3)=[CH:23][CH:24]=1
Reactant: CN1Cc2c([nH]c3ncccc23)C(C)(C)C1
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1Cc2c(n(CC(O)c3ccncc3)c3ncccc23)C(C)(C)C1
Reaction time: 12 h
Yield: 9.6 %

Procedure:
6,8,8-Trimethyl-6,7,8,9-tetrahydro-5H-1,6,9-triaza-fluorene (100 mg, 0.465 mmol) was dissolved in DMF (2 mL) and sodium hydride (56 mg, 1.39 mmol) was added portionwise under nitrogen. 4-Oxiranyl-pyridine (113 mg, 0.933 mmol) was added dropwise at RT and stirred for 12 h. After consumption of starting material (by monitoring TLC and LCMS), the reaction mixture was poured in to ice water and extracted with EtOAc (2×25 mL). The combined organic layer was washed with water (5×10 mL), the organic layer was dried over anhydrous sodium sulfate and concentrated, and the crude product purified by reverse phase chromatography to obtain 15 mg of 1-pyridin-4-yl-2-(6,8,8-trimethyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-ethanol. 1HNMR (CDCl3, freebase) δ (ppm): 8.63 (d, 2H), 8.22 (d, 1H), 7.75 (d, 1H), 7.45 (d, 2H), 7.09 (dd, 1H), 5.17 (d, 1H), 4.53 (dd, 1H), 4.47 (d, 1H), 3.71 (d, 1H), 3.44 (d, 1H), 2.5 (s, 3H), 2.49 (d, 1H), 2.44 (d, 1H), 1.47 (s, 3H), 1.32 (s, 3H). Separation by chiral HPLC provided enantiomers 17a and 17b. Optical rotations: Compound 17a, (+)50.54 (c 0.56, Chloroform, 99.31% HPLC purity); Compound 17b, (−)51.38 (c 0.55, Chloroform, 95.62% HPLC purity).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2ccccc2)nc1
Temperature: 90 °C

Procedure:
30 g (0.127 mol) of 2,5-dibromopyridine in suspension in 100 ml of toluene, 15.4 g (0.127 mol) of phenylboronic acid, 4.4 g (0.0038 mol) of tetrakis(triphenylphosphine)palladium, 90 ml of a 2M aqueous solution of sodium carbonate and 4 ml of ethanol are introduced in succession into a 500 ml three-necked flask, and the mixture is heated at 90° C. for 22 h.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[CH:10])(=O)=O.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:6][CH2:7][CH2:8][C:9]#[CH:10])[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: C#CCCCOS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C#CCCCN1CCN(C)CC1
Temperature: 80 °C

Procedure:
A mixture of pent-4-ynyl methanesulfonate (887 mg) and N-methyl piperazine (607 μL) was heated to 80° C. for 4.5 h, diluted with 1,2-dichloroethane (5 mL) and heated to 70° C. for 18 h. Saturated aq. NaHCO3 was added (10 mL) and the mixture was extracted with DCM (3×40 mL), dried over Na2SO4, and concentrated to afford 1-methyl-4-(pent-4-ynyl)piperazine (0.23 g).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=O)[CH2:2][CH2:3][CH3:4].B1C2CCCC1CCC2.C(CN)O>O1CCCC1>[CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)COc2ccc(C(=O)OC)cc21
Agent: B1C2CCCC1CCC2
Solvent: NCCO
Solvent: C1CCOC1
Product: CCCCN1CCOc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of methyl 4-butyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (800 mg) and 9-BBN (1.6 g) in tetrahydrofuran (13 mL) was refluxed for 1.5 h. The mixture was cooled to room temperature, ethanolamine (0.4 mL) was added, and the resulting solution was concentrated under reduced pressure. The residue was washed with hexanes, filtered, and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (silica, 25% ethyl acetate/hexanes) afforded 607 mg of the title compound: 1H NMR (300 MHz, DMSO-d6) δ 7.21, 7.16, 6.75, 4.24–4.21, 3.78, 3.34–3.24, 1.55–1.47, 1.38–1.30, 0.95–0.90.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH:7]([NH:15][CH2:16][C:17]1[S:18][CH:19]=[CH:20][C:21]=1[Br:22])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>ClCCl.C(N(CC)C(C)C)(C)C>[C:1]([O:5][C:6](=[O:23])[CH:7]([N:15]([CH2:16][C:17]1[S:18][CH:19]=[CH:20][C:21]=1[Br:22])[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:25]=1[Cl:24])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1)NCc1sccc1Br
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(Cc1ccccc1)N(Cc1sccc1Br)C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a stirred solution of 2-[(3-Bromo-thiophen-2-ylmethyl)-amino]-3-phenyl-propionic acid tert-butyl ester (91.6 mg, 0.231 mmol) in dichloromethane (3.3 ml) and N,N-diisopropylethylamine (44 μl) was added a solution of 2,4-Dichloro-benzoyl chloride (34 μl, 0.243 mmol) in dichloromethane (1.3 ml). The reaction mixture was stirred at room temperature under nitrogen overnight. Then, the mixture was extracted with sodium bicarbonate/dichloromethane. The extract was dried (sodium sulfate) and evaporated under reduced pressure to yield 2-[(3-Bromo-thiophen-2-ylmethyl)-(2,4-dichloro-benzoyl)-amino]-3-phenyl-propionic acid tert-butyl ester with 92% yield. 1H NMR(Varian 400 MHz, CDCl3) δ(ppm) presence of rotomers 8.08 (d, 0.5H, J=8.7 Hz, ArH), 7.56 (d, 0.5H, J=2.0 Hz, ArH), 7.40 (m, 2H, ArH), 7.23 (m, 2.5H, ArH), 6.99 (d, 0.5H, J=5.4 Hz, ArH), 6.92 (m, 2H, ArH), 6.83 (d, 0.5H, J=5.0 Hz, ArH), 6.54 (d, 1H, J=7.1 Hz, ArH), 5.78 (d, 0.5H, J=8.0 Hz, ArH), 5.20 (m, 1H, NCH2), 4.85 (m, 1H, NCH2), 4.16 (m, 1H, CHCH2), 3.10 (m, 2H, CHCH2), 1.47 (s, 9H, tBu).