Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C2OC(C(OCC)=O)(C)CC=2C=CC=1.ClC1C=CC(O)=C(C=1)C=O.ClC(C)C(OCC)=O.[Cl:35][C:36]1[CH:37]=[CH:38][C:39]2[O:43][C:42]([C:45]([O:47][CH2:48][CH3:49])=[O:46])([CH3:44])[CH:41](O)[C:40]=2[CH:51]=1.O1C2C=CC=CC=2C=C1.S(Cl)(Cl)=O.[H][H]>CN(C)C=O.C(Cl)Cl.[Pd].C(O)C.N1C=CC=CC=1>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]2[O:43][C:42]([C:45]([O:47][CH2:48][CH3:49])=[O:46])([CH3:44])[CH2:41][C:40]=2[CH:51]=1
Reactant: CCOC(=O)C1(C)Oc2ccc(Cl)cc2C1O
Reactant: [H][H]
Agent: [Pd]
Agent: CCOC(=O)C(C)Cl
Agent: CCOC(=O)C1(C)Cc2cccc(N)c2O1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)Cc2cc(Cl)ccc2O1

Procedure:
Schema 7 illustrates the synthesis of an amino substituted 2,3-dihydro-2-alkoxycarbonyl-2-alkylbenzofuran, for example, 7-amino-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran by the cyclization of 5-chloro-2-hydroxybenzaldehyde with an alkyl 2-chloropropionate, for example, ethyl 2-chloropropionate, under basic conditions in N,N-dimethylformamide at 60°-70° C., affording the corresponding 5-chloro-2-ethoxycarbonyl-2,3-dihydro-3-hydroxy-2-methylbenzofuran (XXVII). The so-prepared benzofuran is chlorinated with thionyl chloride in the presence of pyridine in methylene chloride at 0°-10° C., then dechlorinated by treatment with hydrogen in the presence of 10% palladium on carbon in ethanol, yielding the corresponding 3-unsubstituted intermediate 5-chloro-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran (XXX). The 3-unsubstituted benzofuran is in turn nitrated with 90% nitric acid and concentrated sulfuric acid at 10°-16° C., affording 5-chloro-2-ethoxycarbonyl-2,3-dihydro-2-methyl-7-nitrobenzofuran (XXXI), which is then hydrogenated in the presence of 10% palladium on carbon in ethanol, affording the free amine intermediate 7-amino-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran ((XXXII). The so-prepared intermediate is optionally halogenated with, for example, N-bromosuccinimide in N,N-dimethylformamide, affording the corresponding 7-amino-4-bromo-2-ethoxycarbonyl-2,3-dihydro-2-methylbenzofuran (XXXIII) intermediate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[CH:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[CH:13][N:14]=[C:10]3[CH2:9][N+:8]([O-:32])=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+]([O-])C2
Temperature: 0 °C

Procedure:
A stirred mixture is 1.0 g. of 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine (Ia) in absolute ethanol in an ice bath is treated with 1.0 g. of m-chloroperbenzoic acid. The mixture is allowed to stand in the ice bath for about 8 hours at room temperature at about 24° C. for approximately 18 hours. It is then concentrated in vacuo, the residue thus obtained is suspended in aqueous, cold, dilute potassium carbonate solution and extracted with methylene chloride. The extract is washed with water, dried and concentrated in vacuo. The residue thus obtained is chromatographed on 100 g. of silica gel to give 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine-5-oxide
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]([CH3:13])[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1.C(N(CC)CC)C>S(Cl)(Cl)=O>[CH3:23][N:24]1[CH2:25][CH2:26][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][N:37]([C:20]([C:17]5[CH:18]=[CH:19][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[N:9]([CH3:13])[CH:10]=[CH:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:15][CH:16]=5)=[O:22])[C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:28][CH2:29]1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: Cc1cc(-c2nccn2C)ccc1-c1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1cc(-c2nccn2C)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1
Reaction time: 72 h
Yield: 40.7 %

Procedure:
2'-Methyl-4'-(1-methylimidazol-2-yl)biphenyl-4-carboxylic acid (D90, 310 mg, 1.06 mmol) was heated at reflux in thionyl chloride (10 ml) for 30 minutes, cooled, evaporated in vacuo and the orange residue redissolved in dry THF (10 ml). 1'-Methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8, 260 mg, 1.06 mmol) and triethylamine (0.15 ml, 1.06 mmol) were added and the mixture stirred for 72 hours. The mixture was evaporated in vacuo, the residue partitioned between H2O and CHCl3 (4 times) and the organics combined, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by flash silica-gel chromatography with 2% MeOH/CHCl3 as eluant to yield the title compound as a pale yellow gum (224 mg, 41%) which was converted to the hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([O:11][CH3:12])=[C:5]([F:13])[C:3]=1N.N([O-])=O.[Na+].[I-:18].[K+]>Cl.O>[F:1][C:2]1[C:3]([I:18])=[C:5]([F:13])[C:6]([O:11][CH3:12])=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: [I-]
Reactant: COc1cc(OC)c(F)c(N)c1F
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(OC)c(F)c(I)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
To a stirred slurry of 2,6-difluoro-3,5-dimethoxyaniline (1.00 g, 5.29 mmol) in 6.0 M hydrogen chloride in water (9.00 mL, 54.0 mmol), a solution of sodium nitrite (0.383 g, 5.55 mmol) in water (2 mL) was added dropwise over 15 minutes at 0° C. After another 15 minutes, the resulting orange-red slurry was added to a solution of potassium iodide (3.50 g, 21.1 mmol) in water (5 mL) in small portions at 0° C. After addition, the reaction mixture was allowed to warm to room temperature and then it was stirred for 1 hour. Solid precipitated which was filtered out. The solid was washed with water and dried under vacuum to give the desired product (1.15 g, 70%). 1H NMR (400 MHz, CDCl3): δ 6.68 (t, J=8.0 Hz, 1H), 3.88 (s, 6H) ppm.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:12]([OH:14])=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH3:20].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C.CN(C)C=O>[C:12]([C:6](=[N:5][O:4][CH:1]1[CH2:3][CH2:2]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:14])[NH2:20]
Reactant: CCOC(=O)C(=NOC1CC1)C(=O)O
Reactant: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOC1CC1)C(N)=O
Temperature: 25 °C

Procedure:
An activated acid, prepared from ethyl hydrogen α-(cyclopropyloxyimino)malonate (syn isomer)(19.78 g), phosphorus oxychloride (11.9 ml) and N,N-dimethylformamide (9.91 ml) by a conventional manner, was added to a saturated ammonia solution in tetrahydrofuran at -30° C. The mixture was gently warmed to ambient temperature. The mixture was poured into a mixture of ethyl acetate (1 l) and ice-water (1 l) and adjusted to pH 7 with saturated aqueous solution of sodium bicarbonate. The organic layer was separated washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography on silica gel (200 g) using chloroform as an eluent to give ethyl 2-carbamoyl-2-(cyclopropyloxyimino)acetate (syn isomer) as a crystal (10.51 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH3:15])([CH3:14])[CH2:9][CH2:8][C:7]2([CH3:17])[CH3:16])(=O)[CH3:2].[Cl-].[OH:19][NH3+:20].Cl>N1C=CC=CC=1>[N:20](=[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH3:15])([CH3:14])[CH2:9][CH2:8][C:7]2([CH3:17])[CH3:16])[CH3:2])[OH:19]
Reactant: [NH3+]O
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Cl-]
Solvent: c1ccncc1
Product: CC(=NO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 100.3 %

Procedure:
15 g (65 millimoles) of 6-acetyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene and 6.5 g (91 millimoles) of hydroxylammonium chloride in 100 ml of pyridine were heated for 1 hour at 80° C. After cooling, the mixture was poured onto water and acidified with 2N hydrochloric acid. The precipitated crystals were filtered off under suction, washed with water and dried. 16 g of 6-[1-hydroximinoethyl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene were obtained in this manner. 5 g (20 millimoles) thereof and 5 g (20 millimoles) of terephthalic monomethyl ester chloride were combined and were stirred for 6 hours at 120° C. After cooling, the solidified material was dissolved with about 60 ml of methanol. The supernatant methanol phase was decanted and the solid residue was recrystallized twice from chloroform/methanol. 2.5 g of the title compound of melting point 207°-208° C. were obtained in this manner.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[C:3]3[N:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:14][CH2:15]1
Reactant: C1COCCN1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Product: Clc1ccc2ncnc(N3CCOCC3)c2n1
Yield: 71 %

Procedure:
The title compound was synthesized in 71% yield from 4,6-dichloro-pyrido[3,2-d]pyrimidine and morpholine by the procedure of example 65, and was characterized by its mass spectrum as follows: MS (m/z): 251.1 ([M+H]+, 100).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=[O:22])[CH:12]([CH3:21])[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)=[CH:5][CH:4]=1)#[N:2].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CS(O)(=O)=O.FC(F)(F)S(O)(=O)=O>C1(C)C(C)=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:12]([CH3:21])[C:11](=[O:22])[CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C(=O)CC(=O)c1ccc(C#N)cc1)C(=O)c1ccccc1
Reactant: Nc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2)n(-c2ccccc2)c(-c2ccc(C#N)cc2)cc1=O
Yield: 20.1 %

Procedure:
In 400 ml of xylene were dissolved 10.0 g (0.033 mole) of 5-(4-cyanophenyl)-2-methyl-1-phenyl-1,3,5-pentanetrione, 25.0 g (0.26 mole) of aniline and 7.0 g (0.073 mole) of methanesulfonic acid. The solution obtained was heated under reflux for 30 minutes in a reactor fitted with a Dean-Stark apparatus. After cooling, 6.5 g (0.043 mole) of trifluoromethanesulfonic acid was added further to the reaction mixture and the resultant mixture was similarly heated under reflux for 30 minutes. After cooling, solid matter was removed from the reaction mixture, followed by concentration under pressure. The concentrate was extracted with dichloromethane. The organic layer was washed successively with 100 ml of 10% hydrochloric acid, 100 ml of a 10% aqueous solution of sodium hydroxide and water. The organic layer was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was subjected to chromatography on a silica gel column (eluent: ethyl acetate). The resultant crystals were washed with acetone to afford 2.4 g of 6-(4-cyanophenyl)-3-methyl-1,2-diphenyl-4(1H)-pyridinone having a melting point of 229°-233° C.
Reaction SMILES: [CH2:1]([CH:9]1[O:13][C:12]2[CH:14]=[CH:15][C:16](B(O)O)=[CH:17][C:11]=2[O:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[N:26][CH:27]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].O.C(O)C>[CH2:1]([CH:9]1[O:13][C:12]2[CH:14]=[CH:15][C:16]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[N:26][CH:27]=3)=[CH:17][C:11]=2[O:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1Oc2ccc(B(O)O)cc2O1
Reactant: CCCCCCCCOc1ccc(Br)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ccc3c(c2)OC(CCCCCCCC)O3)cn1

Procedure:
5 mmol of 2-octyl-benzo[1,3]dioxole-5-boronic acid and 5 mmol of 5-bromo-2-octyloxypyridine are introduced into a mixture of 30 ml of toluene, 15 ml of ethanol and 15 ml of water. 0.05 mmol of tetrakis(triphenylphosphine)palladium(O) and 12 mmol of sodium carbonate are added, and the mixture is refluxed for 6 hours. The phases are separated, the aqueous phase is extracted with tert-butyl methyl ether, and the combined organic phases are dried by means of Na2SO4. For further purification, the substance is chromatographed on silica gel.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: OB(O)c1ccccc1Cl
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccccc2Cl)s1
Yield: 16.8 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, starting from 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol) and 2-chlorophenylboronic acid (9 mg, 0.06 mmol) giving 3.5 mg (16%) of the title compound. MS (ESI+) calcd for C17H12ClN5O2S2 417.012094, found 417.012204.
Reaction SMILES: [CH:1](/[P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6])=[CH:2]/[CH3:3].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:6][O:5][P:4](/[CH:1]=[CH:2]/[CH2:3][Br:10])(=[O:9])[O:7][CH3:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: C/C=C\P(=O)(OC)OC
Solvent: ClC(Cl)(Cl)Cl
Product: COP(=O)(/C=C/CBr)OC
Temperature: 25 °C
Yield: 53.1 %

Procedure:
To a solution of dimethyl cis-1-propenylphosphonate (6.10 g.) in carbon tetrachloride (60 ml.) was added N-bromosuccinimide (7.97 g.). The reaction mixture was heated to reflux for 2 hours and then cooled to ambient temperature to give precipitates, which were filtered off. The filtrates were concentrated under reduced pressure to give an oily residue, which was subjected to a column chromatography on silica gel and eluted with a mixture of chloroform and ethyl acetate (8:2) to give dimethyl 3-bromo trans-1-propenylphosphonic acid (4.94 g.).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:10]=2)[CH:7]=1.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16]>>[C:11]([C:9]1[N:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)c1nc2ncc(Br)cn2n1
Product: CC(C)(C)c1nc2ncc(C#C[Si](C)(C)C)cn2n1

Procedure:
The title compound, a light yellow solid, MS: m/e=273.3 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 42, step 1) and ethynyl-trimethyl-silane.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:12][N:11]([CH3:13])[CH2:10][NH:9][C:8]2=[N:14][N+:15]([O-:17])=[O:16])[CH2:2]1.[H-].[Na+].[CH3:20]I>CN(C=O)C>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:12][N:11]([CH3:13])[CH2:10][N:9]([CH3:20])[C:8]2=[N:14][N+:15]([O-:17])=[O:16])[CH2:2]1
Reactant: CN1CNC(=N[N+](=O)[O-])N(CC2CCOC2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CN(C)C(=N[N+](=O)[O-])N(CC2CCOC2)C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
A mixture comprising 3.00 g of 1-{(tetrahydro-3-furanyl)methyl}-2-(nitroimino)-5-methylhexahydro-1,3,5-triazine, 0.54 g of sodium hydride and 40 ml of DMF was stirred at 50° C. for 30 minutes. Then, 2.08 g of methyl iodide were added thereto, followed by stirring at 70° C. for 2 hours. The reaction fluid was poured into a saturated saline solution and the mixture was extracted with methylene chloride several times. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The crude oily matter thus obtained was purified by column chromatography to obtain 1.43 g of 1-{(tetrahydro-3-furanyl)methyl}-2-(nitroimino)-3,5-dimethylhexahydro-1,3,5-triazine.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH:26]1([CH:30]=O)[CH2:29][CH2:28][CH2:27]1.O>O1CCCC1>[CH:26]1([CH:30]=[C:11]2[CH2:10][CH2:9][C:8]3[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]=3[C:2]2=[O:1])[CH2:29][CH2:28][CH2:27]1
Reactant: O=CC1CCC1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CCC(=CC1CCC1)C2=O
Temperature: 25 °C
Yield: 38 %

Procedure:
A solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (600 mg, 2.9 mmol) in tetrahydrofuran (10 mL) was cooled to ice bath temperature and treated with 1.0 M lithium hexamethyldisilazide in tetrahydrofuran (5 mL). After stirring for twenty minutes, cyclobutanecarboxaldehyde (J. Med. Chem. 1989, 32, 1001-6) (24 mL of 0.5 M solution in tetrahydrofuran) was slowly added and the mixture allowed to warm to room temperature and stir for 3 days. The mixture was poured into water, extracted three times with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by normal phase flash column chromatography on a 50 g silica gel column (5-50% ethyl acetate/hexanes gradient). Pure fractions were pooled and concentrated in vacuo to yield methyl 6-(cyclobutylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (300 mg, 1.1 mmol, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81-2.03 (m, 4H), 2.14-2.27 (m, 2H), 2.71 (t, J=6.58 Hz, 2H), 2.93-3.00 (m, 2H), 3.34-3.44 (m, 1H), 3.88 (s, 3H), 6.91 (d, J=9.13 Hz, 1H), 7.84-7.95 (m, 2H), 8.01 (d, J=8.06 Hz, 1H). ES-MS m/z 271 (M+H).
Reaction SMILES: [F:1][C:2]([S:5]([NH2:8])(=[O:7])=[O:6])([F:4])[F:3].C(N(CC)CC)C.[N+:16]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23])([O-:18])=[O:17]>ClCCl>[F:1][C:2]([F:4])([F:3])[S:5]([NH:8][C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=1)=[O:23])(=[O:7])=[O:6]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NS(=O)(=O)C(F)(F)F)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.5 %

Procedure:
A solution of trifiuoromethylsulphonamide (2.1 g, 14.1 mmol) in anhydrous dichloromethane (50 ml), cooled to 0° C. was treated with triethylamine (2.0 ml, 14.1 mmol) followed by a solution of 3-nitrobenzoyl chloride (2.5 g, 13.4 mmol) in anhydrous dichloromethane (50ml) dropwise. After stirring at 0° C. for 1h, the mixture was stirred at ambient temperature for 2 h. The mixture was extracted using 1M NaOH (100 ml), and the aqueous phase was acidified using 5M HCl. The aqueous phase was then extracted using dichloromethane (4×100 ml), followed by ethyl acetate (2×100 ml). The combined organic layers were dried (Na2SO4) and evaporated in vacuo to leave a yellow solid. This was recrystallised from diethyl ether:hexane (1:1) to afford the title compound (1.5 g, 36%) as a pale yellow solid. mp 80°-83° C. 1H NMR (360 MHz, D6 -DMSO) δ 7.73 (1H, dd, J=8.0 and 8.0 Hz), 8.35 (2H, m), 8.56 (1H, brs), 8.68 (1H, m).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:21])[C@H:11]([NH2:20])[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:8].[I-].[K+].[CH3:24][O:25][C:26](=[O:34])[CH2:27][CH2:28][CH2:29][S:30][CH2:31][CH2:32]Cl.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH2:7]([O:9][C:10](=[O:21])[C@H:11]([NH:20][CH2:32][CH2:31][S:30][CH2:29][CH2:28][CH2:27][C:26]([O:25][CH3:24])=[O:34])[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:8]
Reactant: COC(=O)CCCSCCCl
Reactant: CCOC(=O)CCC[C@@H](N)C(=O)OCC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCC[C@@H](NCCSCCCC(=O)OC)C(=O)OCC
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
A mixture of cesium carbonate (2.71 g, 8.32 mmol) and DMF and water (10:1, 20 mL) was stirred at room temperature for 30 min before a solution of (R)-2-aminohexanedioic acid diethyl ester (prepared from D-α-aminoadipic acid according to Huang, et al., Synth. Commun. 1989, 19, 3485-3496, 1.80 g, 8.28 mmol) in DMF and water (10:1, 2 mL) was added via cannula. After 30 min at room temperature, potassium iodide (276 mg, 1.66 mmol) followed by 4-(2-chloroethylsulfanyl)-butyric acid methyl ester (prepared according to PCT 03/007941, 1.63 g, 8.29 mmol) in DMF and water (10:1, 5 mL) were added. After 23 h at room temperature, the reaction mixture was heated at 90° C. After 2.5 h at 90 ° C, the reaction was cooled to room temperature and saturated aqueous NaHCO3 (100 mL) was added. The mixture was extracted with EtOAc (3×75 mL) and the combined extracts were washed with water (2×100 mL) and brine (2×100 mL) then dried (Na2SO4) filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (10%→40% EtOAc/hexane, gradient) two times afforded 893 mg (29%) of (R)-2-[2-(3-methoxycarbonyl-propylsulfanyl)-ethylamino]-hexanedioic acid diethyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].C([Li])CCC.[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].[Cl-].[NH4+]>O1CCCC1>[CH3:7][C:3]1[C:2]([CH2:8][C:14]([O:15][CH2:16][CH3:17])=[O:18])=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)OCC
Reactant: Cc1cccnc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ncccc1C
Temperature: 25 °C
Yield: 35.2 %

Procedure:
To a mixture of 10.72 g of 2,3-lutidine and 150 ml of tetrahydrofuran was added 63 ml of n-butyllithium (1.6 mol/L hexane solution) at room temperature. Into the mixture, a mixture of 11.81 g of diethyl carbonate and 50 ml of anhydrous tetrahydrofuran was added dropwise at −70° C. The mixture was heated up to room temperature. The reaction mixture was added to ice-cooled ammonium chloride aqueous solution, and extracted with tert-butyl methyl ether. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 16.16 g of the resultant residue was subjected to silica gel column chromatography, to obtain 6.31 g of ethyl (3-methyl-2-pyridyl)acetate.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9](Cl)[C:10]#[CH:11].N1NN=C(COC2C=CC(N3C=NN=N3)=NC=2)C=1>>[CH3:8][C:3]1[C:2]([O:1][CH2:11][C:10]#[CH:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: C#CCCl
Reactant: Cc1ncccc1O
Agent: c1cc(-n2cnnn2)ncc1OCc1cn[nH]n1
Product: C#CCOc1cccnc1C

Procedure:
The title compound was synthesized using 3-hydroxy-2-methylpyridine and propargyl chloride in a manner similar to that described in Intermediate 13, Step 2.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[CH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1>O1CCCC1.[Ni]>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH2:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1ccc(F)cc1)c1ccc(F)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: O=C(CCc1ccc(F)cc1)c1ccc(F)cc1

Procedure:
A solution of 59.9 g of 4,4'-difluorobenzylideneacetophenone in 600 ml of tetrahydrofuran is hydrogenated in the presence of 6 g of Raney nickel. After removal of the catalyst, the reaction mixture is concentrated by rotary evaporation, affording the title compound of the formula ##STR8## as a crude product with a refractive index of n20D =1.5478.