Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[C:8]3[S:22][C:21]([Cl:23])=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30]([O:32][C:33](Cl)=[O:34])[CH3:31]>O1CCOCC1>[CH2:30]([O:32][C:33]([NH:1][CH2:2][C:3]1[N:7]2[C:8]3[S:22][C:21]([Cl:23])=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1)=[O:34])[CH3:31]
Reactant: NCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)NCc1nnc2n1-c1sc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 3 h

Procedure:
0.6 g of 9-aminomethyl-2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine are dissolved in 15 ml of absolute dioxane. 1.5 g of potassium carbonate are suspended in the solution and 0.18 g of chloroformic acid ethyl ester added with stirring. After 3 hours, the solid material is filtered off from the solution. The residue obtained after evaporation of the filtrate is recrystallized from ethyl acetate containing active carbon, to yield 9-ethoxycarbonylaminomethyl-2-chloro-4-(o-chlorophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine.
Reaction SMILES: C[SH:2].C[O-].[Na+].[Na].C12(C)C(C)(C)C(CC1)C[CH2+:8]2[CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:17]([O:19][CH3:20])=O>CO>[CH3:8][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:17]([O:19][CH3:20])=[S:2]
Reactant: CS
Reactant: COC(=O)CCCCCCC(C(=O)OC)[CH2+]1CC2CCC1(C)C2(C)C
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)CCCCCCC(C)C(=S)OC
Yield: 58 %

Procedure:
Methyl mercaptan (excess) is passed into a rapidly stirred solution of sodium methoxide (13.5 g., 0.25 mole) in dry methanol (200 ml.) at 0° C. to generate sodium methylmercaptide. The resulting solution is treated with dimethyl 2-bormoazelate (55.0 g., 0.186 mole), then stirred and heated at reflux under nitrogen for 5 hours. The reaction solution is concentrated in vacuo, diluted with ether and filtered. The filtrate is washed with water (until the washings are neutral), dried over sodium sulfate and distilled providing the title compound as a colorless liquid (28.4 g., 58%), bp 0.2 mm 128°-138° C.; pmr (CDCl3) δ 2.10 (s, 3H), 2.31 (t,2H), 3.20 (t,H), 3,63 (s,3H) and 3.71 (s, 3H).
Reaction SMILES: [Cl-].[Cl-].[CH2:3]([Ta+2:8]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:4]([CH3:7])([CH3:6])[CH3:5].[CH2:19]([Li])[C:20]([CH3:23])([CH3:22])[CH3:21]>CCCCC>[CH2:14]([Ta:8]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: [Li]CC(C)(C)C
Reactant: CC(C)(C)C[Ta+2](CC(C)(C)C)CC(C)(C)C
Agent: [Cl-]
Solvent: CCCCC
Product: CC(C)(C)C=[Ta](CC(C)(C)C)(CC(C)(C)C)CC(C)(C)C
Reaction time: 24 h

Procedure:
a solution of 0.5 g of trineopentyltantalum dichloride and 0.17 g of neopentyllithium in 4 ml of pentane was allowed to stand at room temperature for 24 hr in a glass vessel wrapped in foil. (In later experiments it was found that the foil wrapping was unnecessary.) The lithium chloride that had precipitated was separated by filtration, and the filtrate was allowed to stand for another 24 hr at room temperature. No more solid precipitated during this time. Volatile materials were removed under reduced pressure to give trineopentyl(neopentylidene)tantalum, (C5H11)3Ta=C5H10, as an orange crystalline solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1)[CH3:21]
Reactant: CNC
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(CN(C)C)cc2s1

Procedure:
The title compound (24 mg) was prepared starting from 40 mg of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine and excess dimethylamine. MS (m/z, ES+): 288.1 (M+1, 20%), 243.1 (M-(CH3)2N, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C@H:8]2[C@@H:17]([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[O:10][CH2:9]2)=[CH:5][CH:4]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH2:30]Cl)[CH:25]=1>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C@H:8]2[C@@H:17]([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:30][C:26]4[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[CH:28][N:27]=4)[CH:15]=3)[O:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccnc(CCl)c1
Reactant: COc1ccc(O[C@@H]2COc3ccc(O)cc3[C@@H]2O)cc1
Product: COc1ccc(O[C@@H]2COc3ccc(OCc4cc(OC)ccn4)cc3[C@@H]2O)cc1

Procedure:
By the method of Example 13, the title product of Example 20 (494 mg, 3 mmol) and freshly prepared 4-methoxy-2-picolyl chloride (903 mg, 3 mmol) were converted to present title product, purified by chromatography on silica gel using 51:25:4 toluene:ethyl acetate:isopropanol as eluant and recrystallization from toluene, 564 mg; m.p. 80°-82° C.; tlc Rf 0.3 (19:1 CH2Cl2 :isopropanol); exact mass calculated: 409.1531; found: 409.1530.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[O:5][C:6]1[N:7]=[C:8]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:9]([C:14]([NH2:16])=[O:15])=[N:10][C:11]=1[CH2:12][CH3:13].C(N(C(C)C)CC)(C)C.[C:43](Cl)(=[O:46])[CH:44]=[CH2:45]>C(Cl)(Cl)Cl>[C:43]([NH:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[O:5][C:6]1[N:7]=[C:8]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[C:9]([C:14]([NH2:16])=[O:15])=[N:10][C:11]=1[CH2:12][CH3:13])(=[O:46])[CH:44]=[CH2:45]
Reactant: C=CC(=O)Cl
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCN(C)CC4)cc3)c(C(N)=O)nc2CC)c1
Reaction time: 1 h

Procedure:
To a mixture of 5-(3-aminophenoxy)-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (2 g), diisopropylethylamine (1.53 mL), and chloroform (100 mL) was added acryloyl chloride (508 μL) under ice-cooling, followed by stirring for 1 hour. Acryloyl chloride (363 μL) was added thereto, followed by stirring for 1 hour. The mixture was subject to liquid separation by the addition of chloroform and a saturated aqueous sodium hydrogen carbonate solution, and the organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=1:0:0-200:10:1). Ethyl acetate was added thereto, the solid was collected by filtration and then dried under reduced pressure to obtain 5-[3-(acryloylamino)phenoxy]-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (1.6 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:26](=[O:27])[C:25]3[CH:24]=[CH:23][C:22]([N:19]4[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]4)=[CH:30][CH:29]=3)[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-c2cccnc2Cl)n1
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2ccc(C(=O)Nc3nccc(-c4cccnc4Cl)n3)cc2)CC1
Temperature: 50 °C
Reaction time: 17 h

Procedure:
In a 48 mL sealed pressure vessel, added 4-(2-chloropyridin-3-yl)pyrimidin-2-amine (Step 1, 0.72 g, 3.5 mmol), 4-(4-methylpiperazin-1-yl)benzoyl chloride (1.0 g, 4.2 mmol), chloroform (5.0 mL), and N,N-diisopropylethylamine (0.73 mL, 4.2 mmol). The mixture was stirred at 50° C. for 17 hours, and concentrated to yield N-(4-(2-chloropyridin-3-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)benzamide as a light brown solid. MS (M+H)+=409; Calc'd 408.88 for C21H21ClN6O.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[N+:36]([C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42]O)([O-:38])=[O:37]>O1CCCC1>[C:32]([O:31][C:29]([N:20]([CH2:42][C:41]1[CH:44]=[CH:45][CH:46]=[C:39]([N+:36]([O-:38])=[O:37])[CH:40]=1)[NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(Cc1cccc([N+](=O)[O-])c1)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
To a solution of triphenylphosphine (2.06 g) in tetrahydrofuran (20 ml), a solution of di-t-butyl azodicarboxylate (1.80 g) in tetrahydrofuran (15 ml) was added dropwise under ice cooling and stirred for 15 min. To the reaction mixture, a solution of m-nitrobenzyl alcohol (1.0 g) in tetrahydrofuran (15 ml) was added dropwise and stirred at room temperature for 63 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1) to give 2.25 g of the titled compound (yield, 94%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:21])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].[CH2:22](Br)[C:23]#[CH:24].C1(C)C=CC=CC=1>C1COCC1>[CH2:19]([OH:20])[CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:21][CH2:24][C:23]#[CH:22]
Reactant: OCCOCCOCCOCCOCCOCCO
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CCOCCOCCOCCOCCOCCOCCO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
Sodium hydride, 60% dispersion in mineral oil, (0.86 g, 21.4 mmol) was added in portions to the solution of hexaethylene glycol (5.5 g, 19.4 mmol) in anhydrous THF (40 mL) at 0° C. (FIG. 3). The reaction mixture was stirred at 0° C. for 15 minutes then propargyl bromide, 80% in toluene, (2.4 mL, 21.4 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 3 hours. The formed sodium bromide was removed by filtration and the solvent was evaporated. The crude product was purified on SiO2 column using methanol/dichloromethane gradient 0-100% to yield 3.4 g (54%) of 1 as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.45 (t, J=2.4 Hz, 1H), 2.74 (bs, 1H), 3.61-3.71 (m, 24H), 4.21 (d, J=2.4 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): δ 58.4, 61.7, 69.1, 70.3-70.6, 72.5, 74.5, 79.7; MS ESI (m/z): [M+H]+ calcd. for C15H29O7, 321.38; found 321.4.
Reaction SMILES: CN(C)C(=O)[S:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)=[CH:7][CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C(OCC)C>[CH3:20][O:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([O:21][CH3:22])[CH:16]=1)/[CH:12]=[CH:11]/[C:8]1[CH:7]=[CH:6][C:5]([SH:4])=[CH:10][CH:9]=1
Reactant: COc1cc(/C=C/c2ccc(SC(=O)N(C)C)cc2)cc(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1cc(/C=C/c2ccc(S)cc2)cc(OC)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of (E)-S-4-(3,5-dimethoxystyryl)phenyl dimethylcarbamothioate (50 mg, 0.14 mM) in ethyl ether (10 mL) was added LiAlH4 (6 mg, 0.14 mM) at 0° C. The reaction mixture was stirred at 65° C. for 3 h. The mixture was poured into water (10 mL) and a solution of 1M HCL (10 mL). The crude mixture was purified by column chromatography eluting with hexanes:ethyl acetate (4:1) and gave ARS27.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[NH3:16]>C(Cl)(Cl)Cl>[C:10]1([C:1]2[CH:6]=[CH:5][C:4]([C:7]([NH2:16])=[O:8])=[CH:3][CH:2]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
A mixture of 27 g (0.12 mole) of 4-biphenylcarbonyl chloride and 300 ml of AR chloroform was saturated with anhydrous ammonia while maintaining a temperature of 20°. Following the 20 min. addition the white precipitate was collected, washed with cold water and oven-dried (60°) to give 23.5 g, m.p. shrinks 228°, melts 230°-233°.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5]([CH3:7])=[C:4]([CH3:8])[C:3]=1[CH3:9].C([Li])CCC.Br[CH2:16][CH2:17][Cl:18].O>C(OCC)C>[CH3:1][C:2]1[CH:6]([CH2:16][CH2:17][Cl:18])[C:5]([CH3:7])=[C:4]([CH3:8])[C:3]=1[CH3:9]
Reactant: CC1=C(C)C(C)=C(C)C1
Reactant: ClCCBr
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC1=C(C)C(CCCl)C(C)=C1C
Temperature: 2 °C
Reaction time: 18 h

Procedure:
A 1-liter three-necked flask, provided with a dropping funnel, condenser, mechanical stirrer and nitrogen inlet, was charged with 30.5 g of 1,2,3,4-tetramethylcyclopentadiene (0.25 mol), dissolved in 700 mL of ethoxyethane, and cooled to 2° C. Then 160 mL of n-butyllithium (1.6 M in hexane; 0.26 mol) were added dropwise in two hours, followed by 18 hours of stirring at room temperature with the aid of a mechanical stirrer. Then 36.0 g of 1-bromo-2-chloroethane (0.25 mol) were added all at once. The reaction mixture was stirred at room temperature for 10 days. GC analysis of a sample showed that the conversion of the tetramethylcyclopentadiene was 91%. One hundred ml of water were added to the reaction mixture, followed by separation of the water phase and the organic phase. The organic layer was washed once with 50 mL of saturated aqueous sodium chloride solution, dried with sodium sulphate, filtered and boiled down. The residue (43.9 g) proved to have the following composition according to gas chromatography (GC) analysis: apart from the starting materials, 1-bromo-2-chloroethane (9 wt %) and 1,2,3,4-tetramethylcyclopentadiene (9 wt %). Only non-geminally coupled product (84%) and geminally coupled product (16%) were found to be present.
Reaction SMILES: [OH:1][C:2]1[C:15](CCC)=[C:14](O)[CH:13]=[CH:12][C:3]=1[C:4](C1C=CC=CC=1)=O.[NH2:20]O.Cl.CC([O-])=O.[Na+]>CCOC(C)=O>[O:1]1[C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[CH:4]=[N:20]1
Reactant: CCCc1c(O)ccc(C(=O)c2ccccc2)c1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: c1ccc2oncc2c1

Procedure:
The 2,4-dihydroxy-3-propylbenzophenone (2.5 g, 1.0 Eq, 9.8 mmol) was converted to the oxime with NH2OH--HCl (2.7 g, 4.0 Eq, 39 mmol) and NaOAc (3.21 g, 4.0 Eq, 39 mmol) as in Example 7 Step A. The oxime was purified by elution from a silica gel column (180 g E. Merck 40-63μ) with 97:3 Toluene: EtOAc. The product oxime (1.82 g) was further treated as in Example 7 Step A with acetic anhydride (15 ml) and subsequent reflux in pyridine (15 ml). The cooled reaction mixture was poured into 2 N Hcl and EtOAc. The aqueous phase was extracted with EtOAc and washed with sat'd aq NaHCO3, followed by sat'd aq NaCl. The EtOAc extracts were dried over Na2SO4 and reduced i. vac. The residue was taken up in refluxing toluene (50 ml). The product benzisoxazole is obtained as colorless crystals upon cooling to RT.
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[S:11]([NH:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16](O)=[O:17])(=[O:13])=[O:12].S(Cl)([Cl:28])=O>C1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([Cl:28])=[O:17])(=[O:13])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc2ccccc2c1
Solvent: c1ccccc1
Product: O=C(Cl)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 18 h

Procedure:
4 g of (S)-2-(2-naphthylsulonylamino)-3-phenyl-propionic acid are dissolved in 40 ml of anhydrous benzene-anhydrous tetrahydrofuran (3:1), and 3.2 ml of thionyl chloride are added thereto. The mixture is stirred at 40° to 50° C for 18 hours. The reaction mixture is condensed to dryness under reduced pressure, and the residue is recrystallized from a mixture of benzene and n-hexane. 3.2 g of (S)-2-(2-naphthylsulfonylamino)-3-phenyl-propionyl chloride are obtained.
Reaction SMILES: C1(=O)[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]([C:19]([OH:21])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)C(=O)C2=CC=CC=C12.O.NN>CO>[NH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[C:14]([C:19]([OH:21])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: NCc1ccccc1-c1ccccc1C(=O)O
Temperature: 40 °C
Yield: 75.4 %

Procedure:
A suspension of 10.0 g (28 mmol) of 2′-phthalimidomethylbiphenyl-2-carboxylic acid in 450 ml of methanol was treated with 20 ml of hydrazine hydrate and heated at 40° C. for 1.5 h. The reaction mixture was concentrated and the residue was taken up in 250 ml of methylene chloride. After filtering off undissolved 2,3-dihydrophthalazine-1,4-dione, the mother liquor was concentrated and 4.8 g of 2′-aminomethylbiphenyl-2-carboxylic acid were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]#[N:10])=[N:6][CH:7]=1.Br[CH2:12][CH2:13]Br>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:9]#[N:10])[CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: BrCCBr
Reactant: N#CCc1ccc(Br)cn1
Product: N#CC1(c2ccc(Br)cn2)CC1
Yield: 88 %

Procedure:
Alternatively, the title compound was prepared from (5-bromo-pyridin-2-yl)-acetonitrile and 1,2-dibromoethane following a procedure analogous to that described in Step 3 for Intermediate 4. Yield: 88% of theory.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([N:13]2[CH2:18][CH2:17][S:16][CH2:15][CH2:14]2)[CH:5]=[C:4]([CH3:19])[N+:3]=1[O-:20].[OH-].[K+].C(O)CO.[ClH:27]>O>[ClH:27].[CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N:13]2[CH2:14][CH2:15][S:16][CH2:17][CH2:18]2)[CH:5]=[C:4]([CH3:19])[N+:3]=1[O-:20]
Reactant: CCOC(=O)c1c(N2CCSCC2)cc(C)[n+]([O-])c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1cc(N2CCSCC2)c(C(=O)O)c(C)[n+]1[O-]

Procedure:
38.2 g (0.129 mol) of ethyl 2,6-dimethyl-4-thiomorpholinylpyridine-3-carboxylate 1-oxide(see Table 1, Example 19), 10.6 g (0.189 mol) of solid potassium hydroxide and 100 ml of ethylene glycol were heated at 170° C. for 5 hours. The mixture was then diluted with water, neutralized with 6 N hydrochloric acid, and the water and ethylene glycol were removed by distillation under reduced pressure. The residue was taken up in ethanol, insolubles were removed by filtration, and the solution was boiled with active charcoal, filtered once more and ethanolic HCl was added. The mixture was evaporated to dryness, and the hydrochloride was recrystallized from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:22]([O:24][CH2:25][CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][CH:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][C:45]2([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:49][CH2:48][NH:47][CH2:46]2)[CH2:39][CH2:38]1)[CH3:23]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([N:47]1[CH2:48][CH2:49][C:45]([CH2:44][CH2:43][N:40]2[CH2:41][CH2:42][CH:37]([NH:36][C:28]3[N:27]([CH2:26][CH2:25][O:24][CH2:22][CH3:23])[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=3)[CH2:38][CH2:39]2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:46]1)=[O:7]
Reactant: COc1ccc(-n2nnnc2S(C)(=O)=O)cc1C(=O)O
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5nnnc5S(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-(5-methylsulfonyltetrazol-1-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[C:5](=[O:11])[C:4]2[C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1>CN(C)C=O>[CH3:1][N:2]1[CH:7]=[C:6]([C:8]([NH:34][C:35]2[NH:39][N:38]=[N:37][N:36]=2)=[O:9])[C:5](=[O:11])[C:4]2[C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:3]1=2
Reactant: Cn1cc(C(=O)O)c(=O)c2c3ccccc3oc(=O)c21
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2nnn[nH]2)c(=O)c2c3ccccc3oc(=O)c21
Yield: 94.6 %

Procedure:
Prepared by the method described for Ex. 17 from 1,5-dihydro-4-methyl-1,5-dioxo-4H-1-benzopyrano[3,4-b]pyridine-2-carboxylic acid (5.42 g, 0.02 mole), 1,1'-carbonyldiimidazole (6.48 g, 0.04 mole) and 5-aminotetrazole monohydrate (2.06 g, 0.02 mole) in dimethylformamide (90 ml). Recrystallization from dimethylformamide gives pale yellow crystals (6.4 g, 95%), m.p. above 300.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-:15].[K+]>C(O)CCC>[CH2:2]([O:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: [OH-]
Agent: [K+]
Solvent: CCCCO
Product: CCCCOCCCCCCCCCCC(=O)O
Temperature: 40 °C
Reaction time: 5 h
Yield: 14.9 %

Procedure:
11-bromoundecanoic acid (2 g, 17.5 mmol) was added to a solution of potassium hydroxide (1.7 g, 30.2 mmol) in 1-butanol (20 mL) and the solution was stirred at 40° C. for 5 hrs. After cooling, the reaction mixture was extracted with ethyl acetate and water at pH=2. The organic phase was then washed with saturated sodium chloride, dried over sodium sulfate, and the solvent was removed under reduced pressure. The product was purified over silica column chromatography in 2-10% ethyl acetate/hexane/0.2% formic acid to yield 11-(1-butoxy)undecanoic acid (336 mg, 17%). mp 29-30.5° C.; 1H NMR (300 MHz, CDCl3) δ0.84-0.96 (t, 3H, J=7.3, CH3), 1.18-1.46 (bm, 14H, methylene envelope), 1.47-1.68 (bm, 6H, CH2CH2OCH2CH2, CH2CH2COOH), 2.31 (t, 2H, CH2COOH), 3.32-3.46 (bm, 4H, CH2OCH2), 11.02 (br, 1H, COOH); 13C NMR (75.4 MHz, CDCl3 δ14.02, 19.43, 24.74, 26.21, 29.11, 29.28, 29.35, 29.56, 29.64, 29.76, 31.85, 34.14, 70.63, 70.94, 179.82; m/z 259 (M+H).