Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:3]=1.C(N(CC)CC)C.[O:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[C:34](Cl)=[O:35]>C(Cl)Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:2]([NH2:1])=[N:3][C:4]([N:16]3[CH2:21][CH2:20][N:19]([C:34]([CH:30]4[O:29][CH2:33][CH2:32][CH2:31]4)=[O:35])[CH2:18][CH2:17]3)=[N:5][C:6]2=[CH:7][C:8]=1[O:14][CH3:15]
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(Cl)C1CCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: -5 °C
Reaction time: 2 h
Yield: 154.9 %

Procedure:
37.6 g 4-amino-2-(1-piperazinyl)-6,7-dimethoxyquinazoline and 15.8 g triethylamine are suspended in 400 ml methylene chloride. The suspension is cooled to -5° C. This suspension is stirred while 21.0 g tetrahydrofuran-2-carboxylic acid chloride are added drop by drop. The suspension is continued to be stirred for two hours at 0° C., thereafter the solvent is distilled off under vacuum. 200 ml methanol and 200 ml acetone are added to the residue. The resulting suspension is kept under reflux for 0.5 hours while stirring. Thereafter, it is cooled to 0° C. The product is isolated by filtration. 78 g of moist terazosin base are obtained.
Reaction SMILES: CN(C)CCN(C)C.C([Li])(CC)C.[CH:14]1[C:30]2[C:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[O:25][C:21]=3[CH:20]=[CH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1.[B:31](OC)([O:34]C)[O:32]C>O1CCCC1.C1(C)C=CC=CC=1.CCCCCC.CCCCCC.C1CCCCC1>[CH:14]1[C:30]2[C:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[O:25][C:21]=3[C:20]([B:31]([OH:34])[OH:32])=[CH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COB(OC)OC
Reactant: c1ccc2c(c1)ccc1oc3ccccc3c12
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: OB(O)c1cc2ccccc2c2c1oc1ccccc12
Temperature: -80 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
After the air in a 500 mL three-neck flask was replaced with nitrogen, 5.8 g (50 mmol) of tetramethylethylenediamine (TMEDA) and 180 mL of tetrahydrofuran (THF) were placed into the flask, and this solution was cooled to −80° C. Then, 50 mL (50 mmol) of sec-butyl lithium (a 1.0 mol/L solution of cyclohexane and n-hexane) was dripped into this solution with a syringe. After that, this solution was stirred at the same temperature for 30 minutes. Then, 10 g (45 mmol) of benzo[b]naphtho[1,2-d]furan dissolved in 70 mL of THF was added dropwise to this solution with a dropping funnel. After that, this solution was stirred at the same temperature for 2 hours. Then, 11 mL (100 mmol) of trimethyl borate was added to this solution, and the mixture was stirred for 2 days while its temperature was returned to room temperature. After that, the aqueous layer of this mixture was subjected to extraction with ethyl acetate, and the obtained solution of the extract and the organic layer were combined and washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine. The organic layer was dried over magnesium sulfate, and after that, this mixture was gravity-filtered. The obtained filtrate was concentrated to give a white solid. Toluene/hexane was added to the obtained solid, the mixture was irradiated with ultrasonic waves, and a solid was collected by suction filtration, so that 9.2 g of a white powder of the object of the synthesis was obtained in 78% yield. The above-described synthesis scheme is illustrated in the following scheme (B-3).
Reaction SMILES: [O:1]([C:8]1[C:9]([C:14]([NH:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[ClH:34]>>[ClH:34].[NH2:19][CH2:18][CH2:17][NH:16][C:14]([C:9]1[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ncccc1Oc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: NCCNC(=O)c1ncccc1Oc1ccccc1

Procedure:
8.7 g of t-butyl [2-(3-phenoxypyridine-2-carboxamido)ethyl]carbamate were reacted with trifluoroacetic acid in an analogous manner to that described in Example 3, paragraph 2. The residue was converted into the hydrochloride which was recrystallized twice from ethanol/ether, whereby there was obtained N-(2-aminoethyl)-3-phenoxypyridine-2-carboxamide hydrochloride as white crystals, m.p. 180°-186°.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[OH:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:19][CH:20]=1.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37](/[C:40](/[CH3:44])=[CH:41]/[CH2:42]O)=[CH:36][CH:35]=2)=[CH:30][CH:29]=1>C1COCC1>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:42]/[CH:41]=[C:40](/[C:37]2[CH:38]=[CH:39][C:34]([C:31]3[CH:30]=[CH:29][C:28]([Br:27])=[CH:33][CH:32]=3)=[CH:35][CH:36]=2)\[CH3:44])[CH:16]=1)[CH3:26]
Reactant: C/C(=C\CO)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(OC/C=C(\C)c2ccc(-c3ccc(Br)cc3)cc2)c1
Reaction time: 16 h
Yield: 51.6 %

Procedure:
Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (353 mg, 1.4 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (0.4 mL, 1.4 mmol), ethyl 3-hydroxyphenylacetate (120 mg, 0.7 mmol) and (E)-3-(4′-bromo-biphenyl-4-yl)-but-2-en-1-ol (200 mg, 0.7 mmol) in dry THF (10 ml), the mixture stirred for 16 h, filtered and concentrated in vacuo. The crude product was then purified by column chromatography on silica (eluent: 20% ethyl acetate in heptane) to give 168 mg (44%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[CH3:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[CH3:18]>>[OH:4][C:3]([C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([CH3:11])[CH:13]=1)([C:5]([F:8])([F:7])[F:6])[C:2]([F:10])([F:9])[F:1]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Cc1ccccc1C
Product: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1C

Procedure:
This compound was prepared from o-xylene and hexafluoroacetone: bp 101°-102°/20.0 mm Hg; ND25 1.4334; lit. (1) bp 200-200.5°/760 mm Hg.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][NH:6][CH2:5][C:4]2([CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:15]=[C:16]([CH2:20][CH2:21][OH:22])[CH:17]=[CH:18][CH:19]=3)[CH2:9][CH2:8]2)[O:3]1.[CH3:24][C:25]1[S:26][CH:27]=[C:28]([C:30](O)=[O:31])[N:29]=1.CO.C(N(CC)CC)C>ClCCl>[OH:22][CH2:21][CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:10]1[CH2:11][CH2:12][C:4]2([O:3][C:2]([CH3:23])([CH3:1])[CH2:7][N:6]([C:30]([C:28]3[N:29]=[C:25]([CH3:24])[S:26][CH:27]=3)=[O:31])[CH2:5]2)[CH2:8][CH2:9]1
Reactant: CC1(C)CNCC2(CCN(Cc3cccc(CCO)c3)CC2)O1
Reactant: Cc1nc(C(=O)O)cs1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CC(C)(C)OC3(CCN(Cc4cccc(CCO)c4)CC3)C2)cs1
Reaction time: 18 h

Procedure:
The subtitled compound was prepared using a similar method to that described in Example 22 step (a) using 2-(3-((2,2-dimethyl-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenyl)ethanol (0.2 g) (Example 271, step e) and 2-methylthiazole-4-carboxylic acid (0.09 g). The reaction mixture was stirred for 18 h, and the elution solvent for the chromatography was 2% methanol in dichloromethane with 1% triethylamine. Yield 0.16 g
Reaction SMILES: C(O[K])(C)(C)C.F[C:8]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1.Cl>C1COCC1>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:8]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:21]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Reactant: Nc1cccnc1
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(C(F)(F)F)cc1Nc1cccnc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
tert-Butoxy potassium was added to a mixture of 2-fluoro-4-(trifluoromethyl)benzonitrile, 3-pyridine amine and THF, followed by stirring at room temperature for 7 hours. After neutralizing the reaction liquid by adding 1 M hydrochloric acid thereto and subsequent extraction with chloroform, the solvent was evaporated under a reduced pressure. The residue was purified by column chromatography to obtain 2-(pyridine-3-ylamino)-4-(trifluoromethyl)benzonitrile.
Reaction SMILES: [C-]#N.[Na+].Br[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[CH3:15][NH:16]CCNC.[OH-].[NH4+]>[Cu]I.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH3:12])[C:15]#[N:16]
Reactant: COc1ccc(Br)cc1OC
Reactant: CNCCNC
Agent: [Cu]I
Agent: [C-]#N
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C#N)cc1OC
Temperature: 110 °C
Reaction time: 24 h

Procedure:
An oven dried screw cap test tube was charged with NaCN (107 mg, 2.184 mmol), dried KI (60 mg, 0.361 mmol, 20 mol %) and CuI (34 mg, 0.210 mmol, 10 mol %), evacuated and backfilled with argon three times. 1-Bromo-3,4-dimethoxybenzene (260 μL, 1.807 mmol), N,N′-dimethylethylenediamine (195 μL, 1.832 mmol) and anhydrous toluene (1.2 mL) were added under argon. The tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 24 h. The resulting yellow suspension was cooled to room temperature, 2 mL of ethyl acetate, 1 mL of ammonium hydroxide (30%) and 1 mL of water were added. The mixture was stirred at 25° C. for 10 min, then the organic layer was washed with 1 mL of water and dried over MgSO4. The GC analysis showed complete conversion of starting material with formation of the title product (confirmed by GC-MS).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[C:4]([CH3:16])[C:3]=1[CH3:17].[CH3:18][C@@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:16][C:4]1[C:3]([CH3:17])=[C:2]([N:23]2[CH2:22][CH2:21][NH:20][C@H:19]([CH3:18])[CH2:24]2)[N:7]=[N:6][C:5]=1[C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: C[C@@H]1CNCCN1
Reactant: Cc1c(Cl)nnc(C(=O)c2cccnc2)c1C
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)c2cccnc2)nnc(N2CCN[C@H](C)C2)c1C
Yield: 89.6 %

Procedure:
(6-Chloro-4,5-dimethyl-pyridazin-3-yl)-pyridin-3-yl-methanone (1.2 g, 4.84 mmol) and (R)-2-methyl-piperazine (485 mg, 4.84 mmol) are added to a microwave vial followed by NMP (17 mL) and triethylamine (2.01 mL, 14.49 mmol). The vial is sealed and irradiated in the microwave at 170° C. for 30 min. The crude material is directly purified via flash chromatography on silica gel (0-20% methanol in CH2Cl2). The resulting oil is co-evaporated with CH2Cl2 and heptane to afford the title compound as a powder (1350 mg, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(#N)C.[C:12](O)(=[O:14])[CH3:13]>C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:12](=[O:14])[CH3:13]
Reactant: Nc1ccccc1Br
Reactant: CC(=O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccccc1Br
Yield: 75 %

Procedure:
2-Bromo-1-acetylaminobenzene was synthesized in the usual manner from 2-bromoaniline. That is, 150 ml of acetonitrile was added to 25.0 g of 2-bromoaniline, then 15.1 ml of glacial acetic acid was added thereto, and the reaction mixture was heated under reflux for 2 hours. After bringing its temperature to room temperature, 300 ml of ethyl acetate was added thereto, and after the resulting mixture was washed with water twice, the solvent was distilled off, and recrystallization of the crude crystals from a hexane/ethyl acetate solvent mixture was carried out, to obtain 23.2 g (yield: 75%) of 2-bromo-1-acetylaminobenzene.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[N:11][CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([CH2:8][CH2:7][C:6]([OH:19])=[O:5])=[CH:10][N:11]=1
Reactant: CC(C)(C)OC(=O)CCc1cncc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCc1cncc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 251 %

Procedure:
To a solution of 800 mg of 3-isoquinolin-4-yl-propionic acid tert.-butyl ester in 6.2 mL of DCM was added 6.2 mL of TFA. The reaction mixture was stirred for 2 h at rt and evaporated to dryness to yield 1.57 g of 3-isoquinolin-4-yl-propionic acid as the trifluoroacetic acid salt as a brown solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[CH:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.CC(C)=[O:20].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O>[O-2].[O-2].[O-2].[Cr+6].O>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([C:14]([OH:20])=[O:15])[CH:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cnn(-c2cccc(C(F)(F)F)c2)c1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cnn(-c2cccc(C(F)(F)F)c2)c1
Reaction time: 0.33 h
Yield: 89 %

Procedure:
Into a 500 ml. Erlenmeyer flask, fitted with a thermometer and a magnetic stirrer, containing a solution of 8.3 g. (0.0346 M.) of 1-(m-trifluoromethylphenyl)pyrazole-4-carboxaldehyde in 300 ml. of acetone is slowly added 20.0 ml. of Jones reagent (prepared by dissolving 26.7 g. of chromium trioxide in 23.0 ml. of concentrated sulfuric acid and then diluting to 100 ml. with water), the addition of the Jones reagent being effected while the solution is cooled by an ice water bath. Upon completion of the addition of the Jones reagent, the reaction mixture is stirred, under cooling, for 15 minutes and then for an additional 20 minutes at room temperature, after which time it is quenched with a large volume of water and allowed to stand at room temperature for about 3 hours. The resultant precipitated solids are then filtered and washed successively with water and petroleum ether. The solvent is then removed under vacuum to yield 1-(m-trifluoromethylphenyl)pyrazole-4-carboxylic acid, m.p. 145°-148° C. (Yield: 89%).
Reaction SMILES: [C:1]([PH:4](=[O:6])[O-:5])(=O)[CH3:2].[Na+:7].[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12].C1(C)C=CC=CC=1>C(O)C>[CH3:2][C:1]1([P:4]([O-:6])[O-:5])[NH:12][CH2:11][CH2:10][CH2:9][NH:8]1.[Na+:7].[Na+:7]
Reactant: CC(=O)[PH](=O)[O-]
Reactant: NCCCN
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(P([O-])[O-])NCCCN1

Procedure:
Sodium acetylphosphinate (2.6 g, 0.02 mol) and 1,3-diaminopropane (1.7 ml, 1.5 g, 0.02 mol) were stirred together in ethanol (60 ml) for 21/2 days, giving a cloudy pale yellow solution. This was evaporated inder reduced pressure, giving a sticky hydroscopic yellow solid, which contains ethanol by nmr. The solid was dissolved in ethanol, toluene added and re-evaporated to dryness, giving a yellow foam, mp 144°-6°, decomp (3.2 g, 86%). NMR was consistent with the desired structure.
Reaction SMILES: [N: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]([NH:13][C@H:14]([C:19]([OH:21])=O)[CH2:15][C:16](=[O:18])[NH2:17])=[O:12].[NH2:22][C@@H:23]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@H:24]([OH:43])[CH2:25][N:26]1[C@H:35]([C:36]([NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][C@H:33]2[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:27]1.ON1C(=O)C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[C:39]([NH:38][C:36]([C@@H:35]1[CH2:34][C@H:33]2[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:27][N:26]1[CH2:25][C@@H:24]([OH:43])[C@@H:23]([NH:22][C:19](=[O:21])[C@H:14]([CH2:15][C:16](=[O:18])[NH2:17])[NH:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12])[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=c1c2ccccc2nnn1O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Temperature: 20 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
A solution of 287 mg of N-(2-quinolylcarbonyl)-L-asparagine and 401 mg of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide in 3 ml of tetrahydrofuran was cooled to -10° C. and 163 mg of 3-hydroxy-1,2,3-benzotriazin-4(3H)-one and 220 mg of dicyclohexylcarbodiimide were added. The mixture was stirred at -10° C. for 2 hours and at 20° C. for 16 hours, then diluted with ethyl acetate and filtered. The filtrate was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and then evaporated. The residue was chromatographed on silica gel using 4% (by volume) methanol in dichloromethane for the elution to give 537 mg of N-tert.butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid: MS: m/e 671 [M+H]+.
Reaction SMILES: [S-2:1].[Na+:2].[Na+].[C:4]([Cl:13])(=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>O.[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC>[S-2:1].[Na+:2].[Na+:2].[C:4]([O-:12])(=[S:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Na+:2].[Cl-:13].[Na+:2]
Reactant: CCCCCCCC(=O)Cl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCC([O-])=S
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
A 16 weight percent aqueous solution of sodium sulfide was prepared by dissolving sodium sulfide (101 grams, 1.29 moles) in the form of hydrated flakes (168 grams, 60%) into 463 grams of water in a 5-liter round-bottomed flask. A dropping funnel was charged with octanoyl chloride (210.5 grams, 1.294 moles). The temperature of the sodium sulfide solution in the 5-liter flask measured 23° C. The addition of the octanoyl chloride to the 5-liter flask was begun with stirring of the contents of the 5-liter flask with a mechanical stirrer, immediately after the addition of 0.21 grams of a concentrated aqueous solution of methyltrioctylammonium chloride to the 5-liter flask. The addition of the octanoyl chloride was completed in 3 minutes with external cooling of the 5-liter flask using an ice-water bath. The contents of the 5-liter flask reached a maximum temperature of 59° C. The contents of the 5-liter flask were then cooled to ambient temperature and stirring was stopped, yielding a clear, slightly viscous, one-phase aqueous solution of sodium thiooctanoate and sodium chloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:14][C:15]2[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([N+:25]([O-:27])=[O:26])=[C:4]([CH3:28])[N:3]=1.[NH3:29]>C1COCC1>[NH2:29][C:2]1[N:7]=[C:6]([N:8]([CH2:14][C:15]2[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([N+:25]([O-:27])=[O:26])=[C:4]([CH3:28])[N:3]=1
Reactant: N
Reactant: COC(=O)CN(Cc1ncc(C)c(OC)c1C)c1nc(Cl)nc(C)c1[N+](=O)[O-]
Solvent: C1CCOC1
Product: COC(=O)CN(Cc1ncc(C)c(OC)c1C)c1nc(N)nc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-[(2-chloro-6-methyl-5-nitro-pyrimidin-4-yl)-[(4-methoxy-3,5-dimethyl-pyridin-2-yl)methyl]amino]acetate (Intermediate 28)(465 mg, 1.13 mmol) was stirred in THF (50 mL) and ammonia (28% in water, 10 mL) was added and the mixture stirred at room temperature overnight. The mixtures were concentrated in vacuo and water (200 mL) was added and extracted with DCM (3×100 mL) and concentration in vacuo yielded Intermediate 27 an orange solid (437 mg, 99%); 1H NMR spectrum (400 MHz, DMSO-d6) δ 2.21 (9H, m), 3.63 (3H, d), 3.73 (3H, s), 4.39 (2H, d), 4.98 (2H, d), 7.90 (2H, s), 8.14 (1H, s); Mass spectrum: (M+H)+ 391.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH2:21][N+:22]([O-:24])=O)[CH2:16][C:17](OC)=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Al].C1(C)C=CC=CC=1.Cl>O1CCCC1.O>[OH:24][N:22]1[CH2:21][CH:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)[CH2:16][C:17]1=[O:18]
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc(OC)c(OC2CCCC2)c1
Agent: Cl
Agent: [Al]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C2CC(=O)N(O)C2)cc1OC1CCCC1

Procedure:
A solution containing 13.0 g (0.039 mol) methyl 3-(3-cyclopentyloxy-4-methoxyphenyl)-4-nitrobutanoate prepared above in 400 ml tetrahydrofuran containing 4 ml water was gradually added to 3.8 g aluminium foil treated before with a solution of mercuric chloride (1 g) in water. The temperature was held at 15°-20° C. by cooling. The mixture was stirred overnight at ambient temperature after which toluene and 200 ml 6N hydrochloric acid were added. The organic phase was separated and washed with 0.8M sodium hydrogen carbonate solution and evaporated to dryness in vacuo. The residue was crystallized from a mixture of dichloromethane-ether. Yield 1.7 g (15 mp 126°-130° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[CH2:7][C:8]([C:18]1([Cl:21])[CH2:20][CH2:19]1)([OH:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1>CN(C)C=O>[F:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:8]([C:18]2([Cl:21])[CH2:19][CH2:20]2)([OH:17])[CH2:7][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:15][CH:14]=1
Reactant: c1nc[nH]n1
Reactant: OC(CCl)(Cc1ccc(F)cc1)C1(Cl)CC1
Solvent: CN(C)C=O
Product: OC(Cc1ccc(F)cc1)(Cn1cncn1)C1(Cl)CC1
Temperature: 80 °C
Yield: 36.7 %

Procedure:
65 g (0.94 mol) of 1,2,4-triazole and 71 g (0.63 mol) of potassium tert.-butylate are taken in 160 ml of absolute dimethylformamide under a nitrogen atmosphere and are heated to 80° C. A solution of 70.6 g (0.26 mol) of 1-chloro-2-(1-chlorocyclopropyl)-3-(4-fluorophenyl)-propan-2-ol in 90 ml of absolute dimethylformamide is added dropwise at this temperature, with stirring. The mixture is subsequently stirred at 100° C. for 6 hours and is then concentrated by stripping off the diluent under reduced pressure. The residue is taken up in ethyl acetate, the mixture is washed with water and, after drying over sodium sulphate, the solvent is stripped off under reduced pressure. The product which remains is chromatographed over a silica gel column with chloroform as the mobile phase. 28.2 g (39% of theory) of 1-(4-fluorophenyl)-2-(1-chloro-cyclopropyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol are obtained in this manner in the form of a solid substance of melting point 111° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(C)c(I)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C)c(C#C[Si](C)(C)C)c1
Temperature: 50 °C

Procedure:
A mixture of methyl 3-iodo-4-methylbenzoate (2.0 g, 7 mmol), trimethylsilylacetylene (1.2 ml, 8 mmol), Pd(PPh3)4 (0.42 g, 0.3 mmol), CuI (0.137 g, 0.7 mmol) and diisopropylethylamine (2.5 ml, 11.4 mmol) in THF (20 ml) was heated at 50° C. for 12 hrs under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and filtered through a Celite® bed. The clear filtrate was concentrated and the residue purified by flash chromatography on silica gel (elution with 2% ethyl acetate in n-hexane) to provide methyl 4-methyl-3-[(trimethylsilyl)ethynyl]benzoate.