Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH2:16][CH:15]1[CH:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=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.[H-].[Na+].[CH3:28]I>CN(C)C=O>[CH:1]([N:14]1[CH2:17][CH2:16][CH:15]1[CH:18]([NH:25][CH3:28])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2.50 g of 1-benzhydryl-2-(α-aminobenzyl)azetidine in 25 ml. of N,N-dimethylformamide, add 365 mg. of a 55% dispension of sodium hydride. Stir the mixture under a nitrogen atmosphere and when frothing subsides, warm and maintain the stirred mixture at 40° for twenty minutes. Cool the mixture to -25° C. and add 1.20 g. of methyl iodide. Remove the reaction mixture from the cooling bath and allow it to warm to room temperature. After ca. 15 minutes at room temperature, pour the contents of the reaction flask into a stirred mixture of 100 ml. of water and 25 ml. of ether. Separate the layers and re-extract the aqueous phase with ether. Combine all ether extracts, wash successively with water and brine, dry over anhydrous sodium sulfate, and strip off solvent in vacuo. Crystallize the residual solid from ether to obtain the analytically pure title compound containing 1/4 mole of water-of-crystallization and having m.p. 111°-113°.
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[C@H:4]1[C@@H:9]([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:8][O:7][C@@H:6]([CH3:20])[O:5]1.[H-].[Na+].[C:23]1([CH:29](Br)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.C(OCC)(=O)C>[C:23]1([CH:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:1]/[N:2]=[CH:3]/[C@H:4]2[C@@H:9]([CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:8][O:7][C@@H:6]([CH3:20])[O:5]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1/C=N/O
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1/C=N/OC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of (2R,4R,5S)-(E)-4-hydroxyiminomethyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (100 mg) in N,N-dimethylformamide (5 ml) was added sodium hydride (14 mg 60% in oil) at 5° C. After being stirred at the same temperature for 30 minutes, to the solution was added diphenylmethyl bromide (86.6 mg) and the mixture was stirred in an ice bath for additional 2 hours. The solution was diluted with ethyl acetate and washed successively with water and brine, dried over magnesium sulfate. The solvent was evaporated in vacuo and the crude residue was purified with preparative TLC with a mixture of n-hexane and ethyl acetate (4:1) as an eluent to give (2R,4R,5S)-(E)-4-diphenylmethoxyiminomethyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane
Reaction SMILES: N1(C2C=CC(O[CH:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=CC=2)C=CN=C1.CO.[CH3:21][O:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH:33]=O)=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:21][O:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][N:13]2[CH2:14][CH2:15][CH2:16][CH2:11][CH2:12]2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C=O)c2ccccc12
Reactant: c1cn(-c2ccc(OC3CCCNC3)cc2)cn1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN2CCCCC2)c2ccccc12
Reaction time: 8 h
Yield: 16.8 %

Procedure:
To a mixture of 3-[4-(imidazol-1-yl)phenoxy]piperidine (308 mg, 1.26 mmol), methanol (6.0 mL) was added 4-methoxy-1-naphthaldehyde (1.25 eq, 298 mg), followed by borane pyridine complex (0.196 mL, 1.25 eq.). The resulting mixture was stirred overnight. The methanol was evaporated, and the residue diluted with ethyl acetate, washed with water and brine. Evaporation of the solvent in vacuo gave a crude product. Flash column chromatography on silical gel with 1-2% methanol in methylene chloride afforded 3-[4-(imidazol-1-yl)phenoxy]-]-1-[(4-methoxynaphth-1-yl)methyl]piperidine (54 mg), 1H NMR(CDCl3) 8.30 (m, 2), 7.70 (s, 1), 7.50 (m, 2), 7.30 (s, 1), 7.20 (m, 4), 6.90 (m, 2), 6.70 (d, 2), 4.30 (m, 1), 4.00 (s, 3), 3.90 (AB q , 2), 3.10 (m, 1), 2.80 (m, 1), 2.10-2.30 (m, 3), 1.80 (m, 1), 1.40-1.70 (m, 2) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH2:3]1.[N+:14]([O-])([OH:16])=[O:15]>[N+](C1C=CC=CC=1)([O-])=O>[CH3:1][C:2]1([CH3:13])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:12][C:4]=2[CH2:3]1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)Cc2ccccc2B(O)O1
Solvent: O=[N+]([O-])c1ccccc1
Product: CC1(C)Cc2ccc([N+](=O)[O-])cc2B(O)O1
Temperature: -45 °C
Reaction time: 0.75 h
Yield: 45 %

Procedure:
A solution of 3,3-dimethyl-3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol (0.82 g, 4.7 mmol) in nitrobenzene (2.5 mL) was added dropwise to fuming nitric acid (10 mL) maintained at −45° C. The reaction was stirred for 45 minutes at this temperature, and then poured onto wet ice (400 mL). This mixture was allowed to stand for 90 minutes, gradually warming to room temperature. The resultant aqueous suspension was extracted with dichloromethane (3×50 mL). The combined organic portions were washed with water (2×50 mL) until the aqueous portion showed a pH of 7. The dichloromethane solution was then dried over sodium sulfate and concentrated to dryness. The resulting oil was triturated with heptane to produce 3,3-Dimethyl-7-nitro-3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (s, 6H) 3.02 (s, 2H) 7.47 (d, J=8.4 Hz, 1H) 8.25 (dd, J=8.3, 2.6 Hz, 1H) 8.47 (d, J=2.5 Hz, 1H) 8.85 (s, 1H). Amount obtained: 468 mg, 45% yield.
Reaction SMILES: [F:1][C:2]1([F:38])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[CH:25][CH:24]=5)[C:20]([CH2:36][CH3:37])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.FC(F)(F)C(O)=O>ClCCl>[F:38][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:35]=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=5)[C:20]([CH2:36][CH3:37])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: CCc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(C(=O)O)cc1
Reaction time: 3 h

Procedure:
Crude tert-butyl 4-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-3-ethylpyridin-2-yl)benzoate (from step a) was taken up in 1 mL of dichloromethane and 1 mL of trifluoroacetic acid (TFA) and allowed to stir for 3 hours. The crude product was then evaporated to dryness, re-dissolved in 1 mL of N,N-dimethylformamide and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% TFA to yield 4-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-3-ethylpyridin-2-yl)benzoic acid. ESI-MS m/z calc. 466.1. found 467.3 (M+1)+. Retention time 1.94 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[CH:18]([CH3:22])[C:19]([NH2:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:18]([CH3:22])[C:19]([NH2:21])=[O:20])=[CH:9][CH:10]=1
Reactant: Oc1ccc(Cc2ccc(Cl)cc2Cl)cc1
Reactant: CC(Br)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Cc2ccc(Cl)cc2Cl)cc1)C(N)=O

Procedure:
A solution of 25.3 g of 4-(2,4-dichlorobenzyl)-phenol and 15.2 g of α-bromopropionic acid amide in 100 ml of dimethyl formamide was stirred for 2 hours at 100° C together with 16 g of potassium carbonate. After cooling, the reaction mixture was poured into 1 liter of water. A viscous oil precipitated which was absorbed in methylene chloride and washed with water. After drying over sodium sulfate, the solvent was distilled off under reduced pressure. The remaining colorless crystals were recrystallized from methanol. Yield: 25.8 g; melting point 148° - 149° C. ##STR5##
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:17][CH2:18][CH2:19][CH3:20])=[CH:6][C:7]2[S:11][C:10]([C:12]([O:14]C)=[O:13])=[CH:9][C:8]=2[CH:16]=1)[CH3:2].[OH-].[K+].O.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:5]([O:17][CH2:18][CH2:19][CH3:20])=[CH:6][C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8]=2[CH:16]=1)[CH3:2]
Reactant: CCCOc1cc2sc(C(=O)OC)cc2cc1OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCOc1cc2sc(C(=O)O)cc2cc1OCC
Yield: 36 %

Procedure:
A solution of 0.45 g. of methyl 5-ethoxy-6-propyloxybenzothiophene-2-carboxylate and 0.34 g. of potassium hydroxide in ethanol was heated to reflux for two hours. The solution was poured into water, acidified with hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was extracted with 1N sodium hydroxide. The alkaline solution was acidified with hydrochloric acid and was then extracted with ethyl acetate. The organic extract was dried over sodium sulfate and evaporated in vacuo to provide the desired title product, m.p. 192°-194° C., in an overall molar yield of 36% from 5-ethoxy-6-hydroxybenzothiophene-2-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH2:5]2.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:28]([O:30][CH:31]([O:35][CH2:36][CH3:37])[CH:32](Cl)[CH3:33])[CH3:29]>CN(C=O)C.O>[C:16]1([CH2:15][CH2:14][CH2:13][N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:33][CH2:32][CH:31]([O:35][CH2:36][CH3:37])[O:30][CH2:28][CH3:29])[CH:3]=3)[C:8]2=[O:12])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1c2ccc(O)cc2CCN1CCCc1ccccc1
Reactant: CCOC(OCC)C(C)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CCOc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O)OCC

Procedure:
A solution of 6-hydroxy-2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline (7.55 g, 26.87 mmol), Cs2CO3 (18 g, 53.74 mmol) and chloropropionaldehyde diethyl acetal (5.4 mL, 32.2 mmol) in DMF (100 mL) is stirred for 48 hours. After this time the reaction is diluted with H2O (400 mL) and the resulting mixture extracted with EtOAc (2×200 mL). The combined organic phases are washed with saturated NaCl solution (2×400 mL), dried over MgSO4 and concentrated in vacuo. The residue is chromatographed (silica gel, 1:9 EtOAc/hexane ) to give 2-(3-phenylpropyl)-6-(3,3-diethoxypropyloxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline which is hydrolyzed with 6N HCl in tetrahydrofuran at room temperature to yield β-[2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yloxy]-propionaldehyde.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.C(N(CC)CC)C.[C:23](=[S:25])=[S:24].Cl>CS(C)=O>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:23]([SH:25])=[S:24]
Reactant: S=C=S
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)S
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
(3S)-3-Hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (2.02 g) is dissolved in dimethylsulfoxide (10 ml), and thereto are added triethylamine (1.67 ml) and CS2 (0.72 ml), and the mixture is stirred at room temperature for 3 hours. The reaction mixture is poured onto ice-water and is neutralized with 10% HCl. The precipitated crystals are collected by filtration, washed with water and then recrystallized from methanol to give the title compound (1.46 g, 60%) as colorless needles, m.p. 225°-227° C. IR νmaxNujol (cm-1): 3480, 3340; Mass m/e: 278 (M+), 244 (M+ --H2S); [α]D20 +170.0° (c=1.0, methanol).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6]=12.Br[CH2:18][C:19]#[CH:20].C([Li])CCC>O1CCCC1>[CH3:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]([CH2:20][C:19]#[CH:18])[C:6]=12
Reactant: Cc1scc2c1Nc1ccccc1NC2=O
Reactant: C#CCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCN1c2ccccc2NC(=O)c2csc(C)c21
Yield: 50 %

Procedure:
Prepared analogously to Example la) from 4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 3-bromo-prop-1-yne in the presence of butyllithium and tetrahydrofuran in a yield of 50% of theory. The crude crystalline product was used for subsequent reactions without being further purified by chromatography.
Reaction SMILES: Cl.CN([CH2:5][C:6]1[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=1)C.[NH2:14][C:15]1[C:16]([CH3:25])=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2>C(O)CO>[NH2:14][C:15]1[C:16]([CH3:25])=[CH:17][C:18]([CH2:5][C:6]2[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=2)=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: Cc1ccc2cccnc2c1N
Reactant: CN(C)Cc1c[nH]c(=O)[nH]c1=O
Agent: Cl
Solvent: OCCO
Product: Cc1cc(Cc2c[nH]c(=O)[nH]c2=O)c2cccnc2c1N
Yield: 77.7 %

Procedure:
A mixture of 8.36 g (0.0406 mole) of 5-[(dimethylamino)methyl]uracil hydrochloride (B. Roth, J. Z. Strelitz, and B. S. Rauckman, J. Med. Chem. 23, 379 (1980) and 6.43 g (0.0406 mole) of 8-amino-7-methylquinoline (R. Long and K. Schofield, J. Chem. Soc. 1953, 2350) in 60 ml of ethylene glycol under nitrogen was heated at 135° for 4 hours. The mixture was cooled and the precipitated solid was collected, washed with ethanol and ether and dried. This crude product was purified by suspension in 550 ml of boiling ethanol and collection of the insoluble product. Yield, 8.90 g of the title compound (78%) m.p. 302°-305° (dec.). Anal. Calcd for C21H20N4 : C, 76.80; H, 6.14; N, 17.06. Found: C, 76.82; H, 6.17; N, 17.04.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=O)[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:19][CH2:18][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[CH2:10][CH2:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1.O>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[S:40])[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:19][CH2:18][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[CH2:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)NC(=O)NC4=O)c(F)c2)C(=O)O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=S)NC[C@H]1CN(c2ccc(N3CCC4(CC3)NC(=O)NC4=O)c(F)c2)C(=O)O1

Procedure:
A stirred suspension of 32 (0.210 g, 0.500 mmol) in dioxane (5.0 mL), under nitrogen was treated with Lawesson's Reagent (0.202 g, 0.500 mmol), refluxed for 4 h and concentrated in vacuo. The residue was chromatographed on silica gel with mixctures of MeOH—NH4OH—CHCl3 containing 1-10% MeOH and 0.1-0.5% NH4OH and the resulting product was crystallized from MeOH—CHCl3—EtOAc to give 0.0491 g of 3: mip 218.5° C.; HR FAB MS theory for C19H22FN5O4S (M+): 435.1376; found 435.1370. Anal. calcd for C19H22FN5O4S. 0.5 H2O: C, 51.34; H, 5.21; N. 15.76. Found: C, 51.69; H, 5.00; N, 15.25.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH:12][C:26](=[O:27])[CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Product: Cc1nc(-c2sc(NC(=O)Cc3ccccc3)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and phenyl-acetyl chloride.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:7]([NH:9][CH2:10][C:11]([O:13]C1C=CC([N+]([O-])=O)=CC=1)=O)=[O:8])(=[O:3])[CH3:2].[NH2:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34]>>[C:1]([S:4][CH2:5][CH:6]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:7]([NH:9][CH2:10][C:11]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])=[O:13])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CC(C)C)C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Product: CC(=O)SCC(CC(C)C)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O

Procedure:
As described in Example 7 of U.S. Pat. No. 4,235,885, this compound can be prepared by reacting (±)-N-[2-[(acetylthio)methyl]-4-methyl-1-oxopentyl]glycine, 4-nitrophenyl ester with (L)-arginine to give (±)-N-[N-[2-[(acetylthio)methyl]-4-methyl-1-oxopentyl]glycyl]-L-arginine. An aqueous chilled solution of this product is then treated with concentrated ammonia to give (±)-N-[N-[2-(mercaptomethyl)-4-methyl-1-oxopentyl]glycyl]-L-arginine; m.p. 132°-146°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(Br)C1C=CC=CC=1>[CH2:5]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2)[C:4]1[CH:9]=[CH:10][CH:11]=[CH:2][CH:3]=1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCCc2cc(OCc3ccccc3)ccc21
Temperature: 40 °C
Reaction time: 3.5 h
Yield: 182.5 %

Procedure:
To a solution of 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one (24.3 g) in acetone (160 mL), benzyl bromide (29.4 mL) and potassium carbonate (31.1 g) were added at room temperature, followed by stirring at 40° C. for 3.5 hours. After filtering off the insoluble matters and concentrating the mixture, the residue was washed with a mixed solvent of tert-butyl methyl ether-hexane (1:4) to thereby give the title compound (34.5 g) having the following physical properties.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[C:12]([OH:14])=[O:13])([O-:8])=[O:7].O.[CH2:20](O)[CH3:21]>>[N+:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[C:12]([O:14][CH2:20][CH3:21])=[O:13])([O-:8])=[O:7]
Reactant: CCO
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 20 °C

Procedure:
2 ml of concentrated sulfuric acid were added to a solution of 10 g of 3-nitro-4-fluoro-benzoic acid in 50 ml of ethanol and the mixture was refluxed for three hours. 8 ml of concentrated sulfuric acid were added to the mixture which was refluxed for 16 hours and was cooled to 20° C. The mixture was poured into water with stirring and was filtered. The solid product was washed and dried to obtain 10.5 g of ethyl 3-nitro-4-fluoro-benzoate melting at 50° C. The said product was reacted as in Example 1 to obtain 0-(4-ethoxycarbonyl-2-nitro-phenyl)-hydroxylamine melting at 102° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.C(NC(C)C)(C)C.[Li].[Br:21]Br>O1CCCC1>[Br:21][C:11]1[S:12][C:3]2[C:4](=[N:5][CH:6]=[C:7]([C:8]#[N:9])[C:2]=2[Cl:1])[CH:10]=1
Reactant: BrBr
Reactant: N#Cc1cnc2ccsc2c1Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#Cc1cnc2cc(Br)sc2c1Cl
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 17 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol) in tetrahydrofuran (9.0 mL) at −78° C. is slowly added lithium diisopropylamine (0.62 mL, 1.24 mmol, 2M in tetrahydrofuran) over 10 minutes. After 40 minutes, a solution of bromine (198 mg, 1.24 mmol) in 1.5 mL of tetrahydrofuran is added slowly to the solution of the anion. The temperature is maintained at −78° C. for 5 hours then warmed to room temperature for 1 hour. The reaction mixture is poured into ice water, extracted with dichloromethane, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by preparative thin layer chromatography developing with 90% dichloromethane in hexane to provide 48 mg of 2-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile as a pink solid, 1H NMR (DMSO-d6) δ 8.13 (s, 1H), 9.12 (s, 1H); MS 272.8, 274.8, 276.8 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.O1CCCCC1[O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[CH:31]=[CH:32][CH:33]=2)[CH:16]=[C:17]([O:19]C2CCCCO2)[CH:18]=1>C1COCC1.O>[OH:42][C:40]([CH3:43])([CH3:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]=[CH:34][C:30]1[CH:29]=[C:28]([CH:27]=[CH:26][C:15]2[CH:14]=[C:13]([OH:12])[CH:18]=[C:17]([OH:19])[CH:16]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(O)CCCCC=Cc1cccc(C=Cc2cc(OC3CCCCO3)cc(OC3CCCCO3)c2)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)CCCCC=Cc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 25(d), by reacting 0.037 ml of concentrated sulphuric acid with 374 mg (0.72 mmol) of 8-(3-{2-[3,5-bis(tetrahydropyran-2-yloxy)phenyl]vinyl}phenyl)-2-methyloct-7-en-2-ol in 4 ml of THF and 2 ml of water, after purification on a silica column (ethyl acetate 40-heptane 60), a beige powder (m=40 mg; Y=16%) is obtained. m.p.=152-4° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([OH:18])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.Br[CH2:20][CH3:21]>C(#N)C>[O:1]=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O:18][CH2:20][CH3:21])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1
Reactant: COC(=O)N1CC2CCC(=O)CC2CC1C(=O)O
Reactant: CCBr
Solvent: CC#N
Product: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Temperature: 50 °C

Procedure:
In Scheme II, Step A, 6-oxo-2-(Pg)-decahydroisoquinoline-3-carboxylic acid (Pg is as defined hereinabove) is esterified by reaction with a compound of formula R3—Br (where R3 is as herein defined above) to provide the 6-oxo-2-(Pg)-decahydroisoquinoline-3-carboxylate intermediate of compound (1). For example 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid is dissolved in acetonitrile and treated with tiethylamine and bromoethane. The reaction is heated at 50° C. for about 3 hours, cooled and partitioned between 50:50 ethyl acetate/heptane and 1N HCL. The organic phase is isolated and washed 3 times with water, saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide Ethyl 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate, a compound of structure (1). This crude material may then be purified under standard conditions well known in the art. For example, the crude material is dissolved in 10% ethyl acetate/heptane and applied to a plug of silica gel (10 g in 10% ethyl acetate/heptane). The plug is eluted with, 10% ethyl acetate/heptane, 15% ethyl acetate/heptane, and 25% ethyl acetate/heptane. The eluents are combined and concentrated under vacuum to provide the purified compound of structure (1).