Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH3:2][Si:3](Cl)([Cl:5])[Cl:4].II.BrC(Br)C.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>C(OCC)C>[CH3:2][Si:3]([Cl:5])([Cl:4])[CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(CCl)cc1
Reactant: C[Si](Cl)(Cl)Cl
Agent: CC(Br)Br
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: COc1ccc(C[Si](C)(Cl)Cl)cc1
Reaction time: 4 h
Yield: 65.2 %

Procedure:
In a 1-liter three-neck flask equipped with a stirrer, reflux condenser, dropping funnel, and thermometer were placed 23.3 g (1.00 mol) of magnesium powder, 82.6 g (0.640 mol) of methyltrichlorosilane, and 200 ml of diethyl ether. The magnesium was activated with iodine and dibromoethane. The flask was cooled to 10° C. to 0° C. A mixture of 50.0 g (0.319 mol) of p-methoxybenzyl chloride and 300 ml of diethyl ether was added dropwise with stirring from the dropping funnel over 4 hours at 10° C. to 0° C. After aging at room temperature for 1 hour, excess magnesium and magnesium chloride were removed by suction filtration. The filtrate was distilled to give 48.8 g (0.208 mol) of the desired product in a yield of 65%.
Reaction SMILES: [CH:1]([N:14]1[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=[CH:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(C)C(S(O)(=O)=O)=CC=C[CH:28]=1>C(O)CC>[CH:1]([N:14]1[C:18]([C:19]([O:21][CH2:22][CH2:23][CH3:28])=[O:20])=[CH:17][N:16]=[CH:15]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: COC(=O)c1cncn1C(c1ccccc1)c1ccccc1
Solvent: CCCO
Product: CCCOC(=O)c1cncn1C(c1ccccc1)c1ccccc1

Procedure:
The compound was prepared by transesterification of 2.9 g (0.01 mol) of 1-benzhydryl-5-methoxycarbonyl-imidazole of Example 8. To this end it was refluxed for some time in 100 cc of propanol and in the presence of catalytic amounts of toluene sulfonic acid. The colorless crystals obtained had a melting point of 81° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[O:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:22]=2[O:21][CH2:20][CH2:19]1>>[O:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([N:28]3[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]4([CH2:16][CH3:17])[C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[NH:8][C:7]4=[O:15])[CH2:30][CH2:29]3)[C:22]=2[O:21][CH2:20][CH2:19]1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Product: CCC1(CCCCN2CCN(c3cccc4c3OCCO4)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)-piperazine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.[OH-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1N
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2cnccc2NC(=O)OC(C)(C)C)cc1
Reaction time: 0.75 h
Yield: 60.7 %

Procedure:
A solution of N4-(tert-butyloxycarbonyl)-3,4-pyridine-diamine (500 mg, 2.40 mmol) and pyridine (0.213 mL, 2.63 mmol) in methylene chloride (12 mL) was treated with p-anisoyl chloride (408 mg, 2.40 mmol). After 0.75 hr, the mixture was poured into a mixture of ethyl acetate and 1 N aqueous sodium hydroxide. The organic layer was washed with saturated sodium chloride, dried (magnesium sulfate), and filtered. Concentration in vacuo and recrystallization of the residue, followed by flash chromatography (silica gel, hexanes/ethyl acetate) yielded 500 mg (60%) of the title compound.
Reaction SMILES: [CH3:1][O:2][P:3]([NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)([O:5][CH3:6])=[O:4].[Li+].[OH-].Cl>O1CCOCC1>[CH3:1][O:2][P:3]([NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)([O:5][CH3:6])=[O:4]
Reactant: COC(=O)c1ccc(NP(=O)(OC)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COP(=O)(Nc1ccc(C(=O)O)cc1)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 4-[(dimethoxyphosphoryl)amino]benzoate (1.50 g, 5.79 mmol) was made 0.25 M in dioxane and to this stirring solution was added 3M aq LiOH. The resulting solution was stirred at ambient temperature for 16 h. The reaction mixture was then neutralized to pH=7 with 1N aq HCl and concentrated in vacuo to afford the requisite product. MS: cal'd 243 (MH+), exp 243 (MH+)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[CH:12][C:11]2[C:14](=[C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:28])[O:15][CH:16]([CH2:17][CH3:18])[C:10]=2[CH:9]=1>C(O)(C)C>[CH2:17]([CH:16]1[C:10]2[CH:9]=[C:8]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:13]=[CH:12][C:11]=2[C:14](=[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:28])[O:15]1)[CH3:18]
Reactant: CCC1OC(=C2C(=O)Nc3ccccc32)c2cnc(Cl)cc21
Reactant: C1COCCN1
Solvent: CC(C)O
Product: CCC1OC(=C2C(=O)Nc3ccccc32)c2cnc(N3CCOCC3)cc21
Temperature: 25 °C
Yield: 54.1 %

Procedure:
A solution of morpholine (200 mg, 2.29 mmol) in 4 mL of isopropanol is treated with 3-(6-Chloro-1-ethyl-1H-furo[3,4-c]pyridin-3-ylidene)-1,3-dihydro-indol-2-one (100 mg, 0.31 mmol) in one portion and the reaction mixture is heated to reflux for 72 h. The reaction mixture is cooled to room temperature and the solid which precipitated from solution is collected by filtration and dried to give the title compound as a yellow solid (61 mg, 54%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.[Br:10][C:11]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>C(Cl)Cl.O>[Br:10][C:11]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:14]
Reactant: Cc1cccc(C(=O)Cl)c1Br
Reactant: NCCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C(=O)NCCc2ccccc2)c1Br
Reaction time: 8 h

Procedure:
To a solution of 2-phenethylamine (0.28 mL, 2.195 mmol) in DCM (2.0 mL) was added 2-bromo-3-methylbenzoyl chloride (0.15 mL, 0.998 mmol) dropwise via syringe at ambient temperature. Mixture was allowed to stir overnight, then diluted with water (30 mL) and extracted with DCM (30 mL). The organic extract was washed with 1N HCl (2×25 mL) and 1N NaOH (2×25 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give 2-bromo-3-methyl-N-phenethylbenzamide as a white solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]CC)=O)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][NH2:27]>C(O)C>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([NH:26][NH2:27])=[O:23])[CH2:16][CH2:15]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
Synthesized according to General Procedure C: 6{23} (5.68 g, 17.4 mmol, 1 equiv.), anhydrous hydrazine (1.6 mL, 52.2 mmol, 3 equiv.), ethanol (35.2 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{23} (3.60 g, 64%) as a light yellow solid. 1H-NMR (500 MHz, CDCl3): δ 8.13 (br s, 1H), 7.41 (dd, 4H, J=1.5, 8.5 Hz), 7.28-7.25 (m, 4H), 7.20-7.16 (m, 2H), 4.23 (s, 1H), 3.82 (br s, 2H), 3.08 (s, 2H), 2.54 (br s, 4H), 2.40 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.5, 142.2, 128.5, 127.8, 127.0, 76.0, 60.5, 53.9, 51.8.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][N+:21]([O-])=O)[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CCO.[Ni]>[CH2:1]([O:3][C:4]([C:6]1([CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][NH2:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(C[N+](=O)[O-])c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1(C(CN)c2ccccc2)CCN(Cc2ccccc2)CC1
Yield: 98.9 %

Procedure:
A solution of rac-1-benzyl-4-(2-nitro-1-phenyl-ethyl)-piperidine-4-carboxylic acid ethyl ester (3.18 g, 8 mmol) in dry EtOH (240 mL) was hydrogenated in the presence of Ra—Ni (3 g) at 60 bar at 55° C. for 3 h. After cooling and decompression of the reaction vessel, the mixture was filtered over celite and the filtrate evaporated to leave the title compound (2.9 g, 99%) as a clear oil. MS: m/e=367.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13]>>[CH3:15][O:14][C:12](=[O:13])[C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[F:9])=[O:16]
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1ccc(Cl)cc1F
Product: COC(=O)C(=O)Nc1ccc(Cl)cc1F

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 4-chloro-2-fluoroaniline and methyl chlorooxoacetate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([O:17]C)=[C:10]([O:19]C)[CH:9]=1)=[O:7]>Br.C(O)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([OH:17])=[C:10]([OH:19])[CH:9]=1)=[O:7]
Reactant: COc1cc(C(=O)c2cccs2)cc([N+](=O)[O-])c1OC
Agent: Br
Solvent: CC(=O)O
Product: O=C(c1cc(O)c(O)c([N+](=O)[O-])c1)c1cccs1

Procedure:
2 g of 3,4-dimethoxy-5-nitrophenyl 2-thienyl ketone are stirred at 100° for 8 hours in a mixture of 20 ml of 30-33 percent hydrobromic acid in glacial acetic acid and 20 ml of 48 percent aqueous hydrobromic acid. The reaction mixture is subsequently evaporated to dryness. The residue is taken up in ethyl acetate, washed with water, dried over sodium sulfate and filtered, and the filtrate is evaporated. After recrystallization from ethyl acetate/hexane there is obtained 3,4-dihydroxy-5-nitrophenyl 2-thienyl ketone of m.p. 155°-157°.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21](O)=[O:22].FC1C=CC(C2(C3C=CC(F)=CC=3)CCCN(CC(O)=O)C2=O)=CC=1.[F:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2([C:61]3[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=3)[CH2:60][CH2:59][NH:58][CH2:57]2)=[CH:52][CH:51]=1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[F:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2([C:61]3[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=3)[CH2:60][CH2:59][N:58]([C:21](=[O:22])[CH2:20][N:3]3[CH2:4][CH2:5][CH2:6][C:7]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2]3=[O:1])[CH2:57]2)=[CH:52][CH:51]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Fc1ccc(C2(c3ccc(F)cc3)CCNC2)cc1
Agent: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid from Example 68E for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 3,3-bis(4-fluorophenyl)pyrrolidine from Example 203A for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.30 (d, J=4.4, 8H), 7.25-7.21 (m, 2H), 7.17-7.10 (m, 4H), 6.98-6.88 (m, 4H), 4.14-4.07 (m, 4H), 3.67-3.45 (m, 4H), 2.70-2.60 (m, 2H), 2.55 (t, J=6.7, 1H), 2.45 (t, J=6.8, 1H), 1.90-1.78 (m, 2H); MS (DCI) m/z 551.2 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[C@@:5]([OH:33])([CH3:32])[CH2:6][N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[F:31])=[CH:20][CH:19]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])C.[CH2:35]([OH:39])[CH:36]([CH3:38])[CH3:37].Cl.O1CCOCC1>>[CH2:35]([O:39][C:4](=[O:3])[C@@:5]([OH:33])([CH3:32])[CH2:6][N:7]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[F:31])=[CH:22][CH:23]=1)[NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([OH:16])[CH:12]=1)=[O:10])[CH:36]([CH3:38])[CH3:37]
Reactant: CCOC(=O)[C@](C)(O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(O)no1
Reactant: CC(C)CO
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)COC(=O)[C@](C)(O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
(R)-3-[N-(5′-Chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-hydroxy-isoxazole-5-carbonyl)-hydrazino]-2-hydroxy-2-methyl-propionic acid ethyl ester (100 mg, 0.2 mmol) was dissolved in isobutyl alcohol (6 mL, 60 mmol), followed by the addition of 4 M HCl in dioxane (1 mL, 4 mmol). The resulting mixture was stirred at room temperature for 8 hours, then evaporated under reduced pressure and purified by preparative HPLC. The clean fractions were combined and lyophilized to yield the title compound (52 mg, 100% purity). MS m/z [M+H]+ calc'd for C25H27ClFN3O6, 520.16; found 520.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1.[CH2:13]([O:15][C:16](=[O:20])/[CH:17]=[CH:18]\I)[CH3:14]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH:18]=[CH:17][C:16]([O:15][CH2:13][CH3:14])=[O:20])=[CH:6][CH:5]=1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Reactant: CCOC(=O)/C=C\I
Product: CCOC(=O)C=CC#Cc1ccc(C(=O)OC)cc1

Procedure:
The general procedure was used to convert 4-Ethynyl-benzoic acid methyl ester and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (30% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow solid (450 mg, 88% yield). 1H NMR (400 MHz, CDCl3) δ 8.01-7.99 (d, J=8.5, 2H), 7.59-7.57 (d, J=8.5, 2H), 6.37-6.34 (d, J=11.4, 1H), 6.20-6.17 (d, J=11.4, 1H), 4.29-4.23 (q, J=7.1, 2H), 3.91 (s, 3H), 1.34-1.30 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 166.36, 164.60, 131.91, 130.31, 129.52, 129.37, 127.29, 122.25, 99.73, 88.79, 60.55, 52.24, 14.30. Anal. Calcd. for C15H14O4: C, 69.76; H, 5.46; Found C, 69.90; H, 5.55. m.p.: 49.0°-51.0° C.
Reaction SMILES: CO[C:3]1[CH:19]=[C:18]([NH:20][CH3:21])[C:17]([N+:22]([O-])=O)=[CH:16][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][CH3:15])=[O:13])[CH:7]=1.[Br:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1>O1CCOCC1>[CH3:15][NH:14][C:12]([C:8]1[CH:7]=[C:6]([O:5][C:4]2[CH:3]=[CH:19][C:18]3[N:20]([CH3:21])[C:30]([C:29]4[CH:32]=[CH:33][C:26]([Br:25])=[CH:27][CH:28]=4)=[N:22][C:17]=3[CH:16]=2)[CH:11]=[CH:10][N:9]=1)=[O:13]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CNC(=O)c1cc(Oc2cc([N+](=O)[O-])c(NC)cc2OC)ccn1
Solvent: C1COCCO1
Product: CNC(=O)c1cc(Oc2ccc3c(c2)nc(-c2ccc(Br)cc2)n3C)ccn1
Temperature: 100 °C

Procedure:
A mixture of diamine 1 (137 mg, 0.36 mmol) and 4-bromobenzaldehyde (66 mg, 0.50 mmol) in dry dioxane (2 mL) was heated to 100° C. for 16 h. The reaction mixture was allowed to cool to rt and was then concentrated. The resulting residue was purified by reverse phase HPLC to finish 2 as the TFA salt: LCMS m/z 437.1, tR=2.16 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[N:6][C:5]=1Cl.CN.[CH:15]([N:18](C(C)C)CC)(C)C>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[N:6][C:5]=1[NH:18][CH3:15]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Agent: CN
Product: CNc1nc(Cl)ccc1C(=O)OC

Procedure:
A solution of 2,6-dichloro-nicotinic acid methyl ester (1.5 g), methylamine (0.99 ml) (33% by weight in ethanol) and diisopropylethylamine (“Hunig's base”) (1.38 ml) was heated in a microwave for 10 minutes at 120° C. The reaction mixture was partitioned between ethyl acetate and water. The phases were separated and the organic layer was concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:9) to give 6-chloro-2-methylamino-nicotinic acid methyl ester as a white solid (915 mg). 1H-NMR (400 MHz, CDCl3): 8.03 (bs, 1H), 7.99-8.01 (d, 1H), 6.49-6.51 (d, 1H), 3.86 (s, 3H), 3.05-3.06 (d, 3H) ppm.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[NH2:22][C:23]1[CH:35]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[O:36]([C:34]1[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])=[C:23]([NH:22][C:19]([C:16]2[CH:17]=[N:18][C:13]([N:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]3)=[CH:14][CH:15]=2)=[O:21])[CH:35]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(O)c1ccc(N2CCCCC2)nc1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1ccc(N2CCCCC2)nc1
Reaction time: 1 h

Procedure:
1.3 mL of methylene chloride, 1.3 μL of N,N-dimethylformamide and 0.031 mL of oxalyl chloride were added sequentially to 69 mg of 6-(piperidin-1-yl)pyridine-3-carboxylic acid at room temperature, and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 57 mg of tert-butyl 2-amino-4-phenoxybenzoate, 3.7 mL of methylene chloride and 0.22 mL of triethylamine and stirred at room temperature for 2 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane; ethyl acetate=8:1] to obtain tert-butyl 4-phenoxy-2-(6-(piperidin-1-yl)pyridine-3-carboxamido)benzoate.
Reaction SMILES: Cl.[S:2]1([C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[NH:5]1)(=[O:4])=[O:3].[CH2:14]([OH:17])[CH2:15][OH:16]>>[NH2:5][S:2]([C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:6]([O:16][CH2:15][CH2:14][OH:17])=[O:7])(=[O:4])=[O:3]
Reactant: OCCO
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: Cl
Product: NS(=O)(=O)c1ccccc1C(=O)OCCO
Temperature: 41 °C
Reaction time: 65 h

Procedure:
Hydrogen chloride gas was passed through a mixture of 54.9 g of saccharin and 500 ml of ethylene glycol for 11/2 hours. The mixture, which had warmed to 41° C., was then stirred at ambient temperature for 65 hours. The resulting solution was poured into 2 liters of ice water and the product extracted with ethyl acetate. The extracts were washed with water, dried (MgSO4), and the solvent removed under reduced pressure to give a colorless oil which slowly crystallized. The white solid was triturated with n-butylchloride to give 44.9 g of the title compound, m.p. 84°-86.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1.[CH:18]1([CH2:26][CH2:27]Br)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C(C)C>[CH:18]1([CH2:26][CH2:27][N:15]2[CH2:14][CH2:13][N:12]([C:4]3[C:3]([O:2][CH3:1])=[CH:11][C:7]4[CH2:8][CH2:9][O:10][C:6]=4[CH:5]=3)[CH2:17][CH2:16]2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19]1
Reactant: COc1cc2c(cc1N1CCNCC1)OCC2
Reactant: BrCCC1Cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: COc1cc2c(cc1N1CCN(CCC3Cc4ccccc43)CC1)OCC2
Yield: 70.3 %

Procedure:
2.21 g (8.2 mmol) of 4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine (Preparation 1), 1.72 g (8.2 mmol) of 2-(benzocyclobutan-1-yl)-1-bromoethane and 3.48 g (32.8 mmol) of sodium carbonate in 33 ml of methyl isobutyl ketone are heated at reflux for 14 h. The whole is evaporated to dryness, taken up in 200 ml of ethyl acetate and 100 ml of N sodium hydroxide solution and decanted, and the organic phase is washed with 100 ml of a saturated sodium chloride solution. After drying over MgSO4 and evaporation, the residue obtained is chromatographed on silica (eluant: CH2Cl2 /CH3OH: 98/2) to yield 2.1 g of the expected product. By the addition of a 2% fumaric acid solution in ethanol, 1.7 g of the fumarate of the title compound is obtained. M.p. 193°-194° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)c2cc(F)ccc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)c2cc(F)ccc2c1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
To a mixture of 6-fluoro-4-hydroxy-naphthalene-2-carboxylic acid methyl ester (4.6 g, 21 mmol), potassium carbonate (5.8 g, 42 mmol) and acetone (100 mL) was added benzyl bromide (5.47 g, 32 mmol). After being stirred vigorously at reflux for 4 hours under a nitrogen atmosphere, the resulting mixture was cooled to room temperature, and filtered. The organic solution was concentrated in vacuo to give 4-benzyloxy-6-fluoro-naphthalene-2-carboxylic acid methyl ester (5.85 g, 90%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4]1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][O:2][C:3]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:18][CH:19]=3)=[CH:10][CH:11]=2)[CH2:5][CH2:4]1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OC)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COC1(c2ccc(C#Cc3ccc(CC(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-methoxycyclopropyl)-phenylethynyl]-phenyl }-acetate (Compound 68, 100.0 mg, 0.31 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution) and stirred overnight at room temperature. Work-up afforded 80.0 mg (84%) of the title compound as an orange solid.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]([OH:22])=[O:21])=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:37])[CH3:36])[CH:30]=1.C(OC(=O)C)(=O)C>>[CH3:36][N:35]([CH3:37])[C:31]1[CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=[CH:33][C:32]=1[C:16]1([C:12]2[CH:13]=[CH:14][C:15]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([C:10]=3[CH:11]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20](=[O:22])[O:21]1
Reactant: CCn1c2ccccc2c2cc(C(=O)c3ccccc3C(=O)O)ccc21
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Product: CCn1c2ccccc2c2cc(C3(c4ccc(N(C)C)cc4N(C)C)OC(=O)c4ccccc43)ccc21

Procedure:
A mixture of 3.43 g (0.01 mole) of 2-[(9-ethyl-3-carbazolyl)carbonyl]benzoic acid, 1.80 g (0.011 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and 4.0 ml of acetic anhydride was interacted in a manner similar to that described in Example 1, part C above to yield 3-[2,4-bis(dimethylamino)phenyl]-3-(9-ethyl-3-carbazolyl)phthalide (Formula V: R0 =R1 =R2 =R3 =H; R=CH3 ; R4 =N(CH3)2 ; R8 =CH2CH3) which melted over the range 134°-142° C. A significant infrared absorption maximum appeared at 1753 cm-1 (C=O; s). A toluene solution of this product spotted on silica gel developed a bordeaux-colored image.