Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([NH:11][S:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[S:8][C:7]=2[CH:21]=1.CC(C)([O-])C.[K+].[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:32]Br>C1COCC1.CCOC(C)=O>[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[F:37])[CH2:32][N:11]([C:9]1[S:8][C:7]2[CH:21]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH:10]=1)[S:12]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: Fc1ccc(CBr)cc1F
Reactant: COc1ccc2cc(NS(=O)(=O)c3cccnc3)sc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2cc(N(Cc3ccc(F)c(F)c3)S(=O)(=O)c3cccnc3)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of compound 141-F (0.488 g; 1.52 mmol) in THF (15 mL) was added 1M potassium tert-butoxide (2.28 mL; 2.28 mmol) and the reaction mixture was stirred at ambient temperature for 30 min. 3,4-Difluorobenzyl bromide (0.409 g; 1.97 mmol), dissolved in THF (1.0 mL), was added drop-wise, and the reaction was stirred at ambient temperature for 18 h. The reaction was diluted with EtOAc, washed with 2N HCl, water, brine, dried over Na2SO4, filtered, the solvent evaporated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2) eluting with a heptane-EtOAc gradient to afford an oily semi-solid, which was further purified by reverse-phase semi-prep HPLC (Gemini, C-18 column; 100×30 mm I.D.; 5μ) eluting with a 55% to 75% MeCN—H2O gradient to afford compound 141-G as a white solid (0.447 g, 66%). 1H-NMR (DMSO-d6): δ 3.76 (s, 3H), 4.89 (s, 2H), 6.93-6.96 (m, 1H), 7.11 (s, 1H), 7.19-7.20 (m, 1H), 7.34-7.43 (m, 3H), 7.60-7.62 (d, 1H), 7.70-7.73 (m, 1H), 8.21-8.24 (m, 1H), 8.93-8.96 (m, 2H); MS: m/z 447.0 (MH+).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C(F)=NC(F)=NC=1[F:15].N1C=CC=CC=1>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]([F:15])=[O:12])([CH3:7])([CH3:6])[CH3:5]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)F
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To an oven-dried, septaed 10 mL round-bottom flask, cooled under an argon atmosphere, and charged with N-BOC-glycine, 24a, (175.2 mg, 1.00 mmol) was added 2.5 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15° C. and to the flask was added cyanuric fluoride (450 μL, 5 mmol). The reaction was stirred at −15° C. for 15 minutes then anhydrous pyridine (81 μL, 1.0 mmol) was added. Stirring was maintained at −15° C. for 90 minutes, with reaction progress indicated by the gradual formation of a precipitate. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The product crystallized upon storage at 0° C., affording 145.6 mg of 25a as white crystals. FTIR (neat) 1859 cm−1.
Reaction SMILES: [C:1]([O:5]CC)(=O)[C:2]#[CH:3].[NH2:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[CH3:19]>>[CH3:19][N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[CH2:12][CH2:11][C:10]1[CH:20]=[CH:21][CH:22]=[CH:23][C:9]=1[NH:8][C:1](=[O:5])[C:2]#[C:3][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:10]=1
Reactant: CN1CCCCC1CCc1ccccc1N
Reactant: C#CC(=O)OCC
Product: CN1CCCCC1CCc1ccccc1NC(=O)C#Cc1ccccc1

Procedure:
Reaction of ethyl propiolate with 2-(o-aminophenethyl)-1-methylpiperidine according to the procedure of Example 115 affords 2'-[2-(1-methyl-2-piperidyl)ethyl]phenylpropiolanilide, m.p. 104.5° - 106.5° C. (corr.), from ethyl acetate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C@@H:10]12[C:19](=O)[O:18][C:16](=[O:17])[C@@H:11]1[CH2:12][CH:13]=[CH:14][CH2:15]2.[BH4-].[Na+].Cl>O.CC(O)C>[OH:18][CH2:19][CH:10]1[CH:11]([C:16]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:17])[CH2:12][CH:13]=[CH:14][CH2:15]1
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Reactant: NCCN1CCCCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=C(NCCN1CCCCC1)C1CC=CCC1CO
Temperature: 140 °C
Reaction time: 6 h

Procedure:
N-(2-Aminoethyl)piperidine (2.11 g) was added to cis-4-cyclohexene-1,2-dicarboxylic anhydride (2.50 g) and stirred for 6 hours at 140° C. The reaction mixture was suspended into a mixed solution of 2-propanol (125 ml) and water (21 ml) and then sodium borohydride (3.12 g) was added thereto at room temperature. After being stirred for 68 hours at room temperature, the reaction mixture was acidified with dilute hydrochloric acid and then concentrated. The residue was adjusted to pH 9 with saturated sodium hydrogencarbonate aqueous solution and 1N sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate anhydride, and concentrated, thereby yielding a crude (3.34 g) containing the entitled compound as brown syrup.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2([C:18]([O:20]CC)=[O:19])[CH2:12][CH:11]2[C:13]([O:15]CC)=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2([C:18]([OH:20])=[O:19])[CH2:12][CH:11]2[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C1CC1(C(=O)OCC)c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC1(C(=O)O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
14.2 g of diethyl 1-(3-nitrophenyl)-1,2-cyclopropanedicarboxylate are dissolved in 150 ml of methanol and to this solution are added 100 ml of 1N sodium hydroxide solution. The mixture is stirred overnight and the solvent is then removed from the dark brown solution. The reaction mixture is extracted twice with ether after cooling to 0° C. and adding 50 ml of 2N hydrochloric acid. The ethereal phases are washed repeatedly with a small amount of water, dried over magnesium sulfate, filtered and concentrated. The crystals so obtained are recrystallised from boiling ethyl acetate by adding petroleum ether. The title compound (d) is obtained in the form of pale beige-coloured crystals with m.p. 167°-170° C. and Rf=0.2 on thin-layer silica gel plates in the system methylene chloride/methanol/glacial acetic acid (40:5:1:).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:3]([OH:20])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1cccc([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(CC1CCCC1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.2 %

Procedure:
A solution of 3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid methyl ester (0.55 g, 2.0 mmol) in tetrahydrofuran/water (10 mL, 3:1) was treated with lithium hydroxide (185 mg, 4.40 mmol). The reaction was stirred at 25° C. for 48 h. The tetrahydrofuran was then removed in vacuo. The residue was diluted with water (25 mL) and extracted with ether (1×20 mL). The aqueous layer was acidified to pH=2 with a 3N aqueous hydrochloric acid solution. The product was extracted into methylene chloride (3×25 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (2×25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid (0.48 g, 91.9%) as a tan solid: mp 95-99° C.; EI-HRMS m/e calcd for C14H17NO4 (M+) 263.1157, found 263.1156.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[N:14]=[C:13]3[C:9]([N:10]=[CH:11][N:12]3[CH:15]([CH3:17])[CH3:16])=[C:8](Cl)[N:7]=2)[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>CC(O)C>[S:1]1[CH:5]=[C:4]([C:6]2[N:14]=[C:13]3[C:9]([N:10]=[CH:11][N:12]3[CH:15]([CH3:17])[CH3:16])=[C:8]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:7]=2)[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2
Reactant: CC(C)n1cnc2c(Cl)nc(-c3csc4ccccc34)nc21
Reactant: NCCc1ccc(O)cc1
Solvent: CC(C)O
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(-c3csc4ccccc34)nc21
Temperature: 85 °C

Procedure:
2-(benzo[b]thiophen-3-yl)-6-chloro-9-isopropyl-9H-purine (2.2 g, 0.0067 mol) was suspended in anhydrous 2-propanol (70 mL) in a pressure tube. Tyramine (1.01 g, 0.0074 mol) was added. The tube was sealed and heated at 85° C. for 16 hr. Additional tyramine (0.50 g, 0.0037 mol) was added and the mixture was heated at 85° C. for 48 hr. The reaction was concentrated. Aqueous sodium bicarbonate solution was added to the residue, which was extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with 50 to 85% EtOAc in hexane to afford a solid. The solid was triturated with methanol to provide the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([C:4]1([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:16])[CH:2]=[CH2:3].C1(=O)C=CC(=[O:27])C=C1.O.Cl(O)(=O)(=O)=O>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:17]([C:4]1([CH2:1][C:2](=[O:27])[CH3:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:16])[CH2:18][CH2:19][CH3:20]
Reactant: O=C1C=CC(=O)C=C1
Reactant: C=CCC1(CCCC)CCc2cc(OC)ccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC#N
Product: CCCCC1(CC(C)=O)CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-allyl-2-butyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone (931 mg, 3.4 mmol) in acetonitrile (10 mL) was treated with benzoquinone (553 mg, 5.12 mmol), palladium(II) acetate (155 mg, 0.69 mmol), water (0.50 mL, 28 mmol), and perchloric acid (70%, ˜0.14 mL, 1.6 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was partitioned between CH2Cl2 (200 mL) and water (100 mL) and the aqueous phase was back-extracted with CH2Cl2 (2×75 mL). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue (1.17 g) was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40S (4×7 cm) silica gel column, eluting with 10:1 to 5:1 hexane-EtOAc. The product-containing fractions were evaporated under vacuum to afford 2-butyl-6-methoxy-2-(2-oxopropyl)-3,4-dihydro-1(2H)-naphthalenone as an oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[N:17]3)[CH:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl.O>[N:16]1([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C@H:6]3[CH2:5][CH2:4][C@H:3]([CH2:2][NH:1][C:25](=[O:27])[CH3:26])[CH2:8][CH2:7]3)[N:15]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: NC[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
TEA (52 μL, 0.37 mmol) was added, under nitrogen atmosphere, to a solution of trans-(4-aminomethyl-cyclohexyl)-(4-benzotriazol-1-yl-pyrimidin-2-yl)-amine (60 mg, 0.185 mmol) in DCM (3 mL). The mixture was cooled to −78° C. and acetyl chloride (13.2 μL, 0.185 mmol) was added. The reaction mixture was stirred at RT overnight; it was then poured in water and extracted 3 times with a mixture of isopropanol and chloroform. The combined organic extracts were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude residue was purified via preparative TLC to give 10 mg of trans-N-[4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclohexylmethyl]-acetamide. 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (1 H, d, J=8.19 Hz), 8.41 (1 H, d, J=5.14 Hz), 8.12 (1 H, d, J=8.19 Hz), 7.57-7.67 (1 H, m), 7.42-7.51 (2 H, m), 7.16-7.24 (0.3 H, m), 5.55-5.64 (0.7 H, m), 5.18-5.43 (1 H, m), 3.80-3.93 (1 H, m), 3.11-3.25 (2 H, m), 2.27 (1 H, s), 2.19-2.35 (2 H, m), 2.00 (2 H, s), 1.85-1.95 (2 H, m), 1.50-1.63 (1 H, m), 1.11-1.37 (4 H, m).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:27]=[CH:26][C:6]2[C:7](=[O:25])[CH2:8][CH2:9][CH2:10][N:11]([C:16]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:24])[CH3:23])=[O:17])[C:12](=[O:15])[CH2:13][CH2:14][C:5]=2[CH:4]=1.[CH2:28]([OH:30])[CH3:29]>C(Cl)Cl>[C:22]([NH:21][CH2:20][CH2:19][CH2:18][C:16]([NH:11][CH2:10][CH2:9][CH2:8][C:7]([C:6]1[CH:26]=[CH:27][C:3]([Cl:2])=[CH:4][C:5]=1[CH2:14][CH2:13][C:12]([O:30][CH2:28][CH3:29])=[O:15])=[O:25])=[O:17])(=[O:24])[CH3:23]
Reactant: CCO
Reactant: CC(=O)NCCCC(=O)N1CCCC(=O)c2ccc(Cl)cc2CCC1=O
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(=O)CCCNC(C)=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
1 ml of concentrated hydrochloric acid is added to a solution of 2.66 g (0.007 mol) of N-[3-[(11-chloro-2,3,5,6,7,8-hexahydro-3,8-dioxo-4-benzazecin-4-(1H)-yl)carbonyl]propyl]acetamide in 100 ml of ethanol and 30 ml of methylene chloride and the mixture is stirred at room temperature for 5 days. The solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on aluminum oxide with ethyl acetate/ethanol (19:1) and crystallization from methylene chloride/ether gives ethyl 2-[4-(4-acetamidobutyramido)butyryl]-5-chlorohydrocinnamate as white crystals with melting point 95°.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7]4=[C:8]([C:17](=[O:21])[NH:18][C:19](=[S:20])[N:6]4[C:5]=2[CH:4]=1)[CH:9]=[CH:10][CH:11]=3.[OH-].[K+].[CH3:26]C(C)=O.CI>O>[CH3:26][S:20][C:19]1[N:6]2[C:7]3[C:12]([S:13][C:14]4[CH:15]=[CH:16][C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][C:5]=42)=[CH:11][CH:10]=[CH:9][C:8]=3[C:17](=[O:21])[N:18]=1
Reactant: O=c1[nH]c(=S)n2c3c(cccc13)Sc1ccc(C(F)(F)F)cc1-2
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSc1nc(=O)c2cccc3c2n1-c1cc(C(F)(F)F)ccc1S3
Reaction time: 18 h

Procedure:
10-Trifluoromethyl-1H-pyrimido[5,4,3-kl]phenothiazine-3-one-1(2H)-thione (53.6 g., 0.152 mol.) was added to a stirred solution of 8.95 g. (0.160 mol.) of potassium hydroxide in 1680 ml. of acetone and 720 ml. of water. After all the solid had dissolved and a clear yellow solution formed, 22.8 g. (10 ml., 0.160 mol.) of methyl iodide was added in one portion. The reaction mixture was stirred at 25° for 18 hours, diluted with 1000 ml. of water and chilled in an ice-bath for several hours. The resulting light yellow solid was collected by filtration and washed with water to give 1-methylmercapto-10-trifluoromethyl-3H-pyrimido[5,4,3-kl]phenothiazine-3-one, m.p. 229°-231° (ethanol).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([NH2:13])[CH:3]=1.[C:14](Cl)(=[O:16])[CH3:15]>N1C=CC=CC=1.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([NH:13][C:14](=[O:16])[CH3:15])[CH:3]=1
Reactant: CCOc1nc(N)cc(N)c1C#N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOc1nc(NC(C)=O)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
To 50 mg (0.28 mmol) of 4,6-diamino-2-ethoxy-nicotinonitrile dissolved in 1 mL of pyridine was added 60 μL (0.84 mmol) of acetyl chloride. The mixture was stirred at ambient temperature for 2 hours then diluted with 7 mL of water. The precipitate was filtered and washed with 5 mL of water. The supernatant was extracted with ethyl acetate (3×5 mL), then the combined ethyl acetate layers were back extracted with brine (1×5 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to a solid. This was combined with the precipitated product, dissolved in methanol/ethyl acetate, and concentrated. Most of the remaining pyridine was removed by coevaporation with toluene under reduced pressure. The product was purified via silica gel chromatography, eluting with 50% ethyl acetate/hexanes to provide 31 mg (50%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.73 (s, 1H), 7.17 (s, 1H), 6.88 (s, 2H), 4.32 (q, 2H, J=7.1 Hz), 2.07 (s, 3H), 1.29 (t, 3H, J=7.1 Hz); MS (ESI) m/e=221 (M+H)+, m/e=219 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[C:5]#[N:6].[N-:11]=[N+:12]=[N-:13].[Na+]>[Br-].[Zn+2].[Br-]>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:13][N:12]=[N:11][N:6]=2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: N#Cc1cc(Br)cc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Product: Brc1cc(Br)cc(-c2nnn[nH]2)c1
Temperature: 120 °C
Yield: 95 %

Procedure:
A round-bottomed flask was charged with 3,5-dibromobenzonitrile (15.65 g, 60.00 mmol), sodium azide (7.80 g, 120.00 mmol) and zinc bromide (27.00 g, 120.00 mmol). After degassed, DMF (100 mL) was added. The reaction mixture was heated to 120° C. and stirred at this temperature until complete. The reaction was cooled to rt and then in an ice-water bath. 300 mL of 1N aqueous HCl was added. The white precipitate formed was collected by suction filtration, washed with water, and dried together with phosphorous pentoxide under vacuum to afford 17.32 g (95%) of product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[CH:2].[C:12]1([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])#[CH:2]
Reactant: C#Cc1cccc(C(=O)Cl)c1
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: ClCCl
Product: C#Cc1cccc(C(=O)N(c2ccccc2)c2ccccc2)c1

Procedure:
Air in a 20 ml Schlenk tube was replaced by Ar gas and 1.02 g (7 mmol) of m-ethynylbenzoic acid and 5 g (42 mmol) of thionyl chloride were added to the tube and the mixture was stirred at 50° C. for 2 hours and then excess thionyl chloride was removed by distillation under reduced pressure to obtain m-ethynylbenzoyl chloride. To the m-ethynylbenzoyl chloride obtained was added a solution having 2.44 g (14.4 mmol) of diphenylamine dissolved in 7 ml of dichloromethane under ice-cooling and then the resultant mixture was stirred at room temperature for one hour. After completion of the stirring, dichloromethane was removed by distillation under reduced pressure and 35 ml of water was added to the resultant residue. The mixture was extracted with 35 ml of ethyl acetate, the extract was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure using an evaporator. The resultant crude reaction product was purified by column chromatography (hexane/AcOEt10/1) using silica gel to obtain 0.7 g of 3-ethynyl-N,N-diphenylbenzamide which is a desired product as pale yellow liquid. (Yield: 35%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2(O)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][C:10](=[O:22])[CH:9]2[CH2:23][C:24]([O:26]C)=[O:25])[CH:7]=1.Br>C1(C)C=CC=CC=1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][C:10](=[O:22])[C:9]=2[CH2:23][C:24]([OH:26])=[O:25])[CH:7]=1
Reactant: COC(=O)CC1C(=O)Nc2ccc(C(F)(F)F)cc2C1(O)c1cc(Cl)ccc1OC
Agent: Br
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(Cl)cc1-c1c(CC(=O)O)c(=O)[nH]c2ccc(C(F)(F)F)cc12
Yield: 78.3 %

Procedure:
A stirred suspension of crude 4-(5-chloro-2-methoxyphenyl)-4-hydroxy-1,2,3,4-tetrahydro-2-oxo-6-(trifluoromethyl)-3-quinolineacetic acid, methyl ester prepared in Step B (2 g, 4.5 mmol) in toluene (25 mL) was treated with a solution of 35% HBr in acetic acid (5 mL). The resultant mixture was heated at 85° C. overnight. The reaction mixture was evaporated to dryness and the residue was partitioned between water and EtOAc. The EtOAc extract was washed with brine and dried (MgSO4) and then evaporated to afford the title compound (1.45 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[CH2:16][CH2:15][N:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:13](=[O:24])[C:12]=2[C:11]([CH3:25])=[CH:10]1.C1C(=O)N([Br:33])C(=O)C1.O>CN(C=O)C>[Br:33][C:10]1[N:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:17]2[CH2:16][CH2:15][N:14]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:13](=[O:24])[C:12]=2[C:11]=1[CH3:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cn(-c2ccc(Cl)cc2Cl)c2c1C(=O)N(N1CCCCC1)CC2
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2c(n(-c3ccc(Cl)cc3Cl)c1Br)CCN(N1CCCCC1)C2=O
Reaction time: 1 h
Yield: 40 %

Procedure:
To as solution of 1-(2,4-dichlorophenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one (0.93 g, 2.46 mmol) in DMF (25 ml) was added NBS (0.48, 2.71 mmol) at 0° C. The reaction mixture was stirred at this temperature for one hour and then water was added. The mixture was extracted with ether (×3). The combined ether extracts were dried (Na2SO4), filtered and concentrated to give 0.45 g (40%) of the title compound after flash chromatography (heptane:EtOAc gradient).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[OH:7].[C:8](Cl)(=[O:10])[CH3:9]>>[OH:7][C@H:3]1[CH2:4][CH2:5][CH2:6][C@@H:2]1[NH:1][C:8](=[O:10])[CH3:9]
Reactant: N[C@H]1CCC[C@@H]1O
Reactant: CC(=O)Cl
Product: CC(=O)N[C@H]1CCC[C@@H]1O

Procedure:
Following the procedure of Example 2A, 74.7 g of (S,S)-(+)-2-aminocyclopentanol were reacted with acetyl chloride to provide 107.9 g of the title intermediate as an oil which crystallized upon cooling. NMR.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:17][CH:16]2[N:18](C(OCC)=O)[CH:13]([CH2:14][CH2:15]2)[CH:12]=1.O.NN.[OH-].[K+].O>C(O)CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:12][CH:13]2[NH:18][CH:16]([CH2:15][CH2:14]2)[CH:17]=1
Reactant: CCOC(=O)N1C2C=C(c3ccc4ccccc4c3)CC1CC2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: C1=C(c2ccc3ccccc3c2)CC2CCC1N2
Temperature: 25 °C

Procedure:
A mixture of 5.0 gm (16.3 mMol) 3-(naphth-2-yl)-8-ethoxycarbonyl-8-azabicyclo[3.2.1]oct-2-ene, 4.07 gm (81.3 mMol) hydrazine hydrate, and 5.49 gm (97.8 mMol) potassium hydroxide in 120 mL ethylene glycol was heated at reflux for 2 hours. The reaction mixture was allowed to cool gradually to room temperature. After 16 hours the reaction mixture was poured into water and extracted well with diethyl ether. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 1N hydrochloric acid and the solution washed with diethyl ether. The aqueous phase was basified and the mixture extracted well with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to provide the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH2:21][CH2:22][C:23]#[N:24].O1CCOCC1>C(O)(C)(C)C>[Cl:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[C:23]([NH2:24])[C:22]([CH2:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH3:11])=[CH:4]2
Reactant: COc1cccc(OC)c1CCC#N
Reactant: Nc1ccc(Cl)cc1C=O
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: COc1cccc(OC)c1Cc1cc2cc(Cl)ccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-chlorobenzaldehyde and 3-(2,6-dimethoxyphenyl)propionitrile. Instead of dioxane, tert-butanol was used from [sic; as]1 the solvent. 1TN: “aus” (from) appears to be a typo for “als” (as).