Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C@@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:8]([C:18]([O:20][CH3:21])=[O:19])[CH2:7]1>CN(C)C=O>[N:1]([C@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:8]([C:18]([O:20][CH3:21])=[O:19])[CH2:7]1)=[N+:2]=[N-:3]
Reactant: COC(=O)[C@@H]1C[C@H](Br)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 100.5 %

Procedure:
A dispersion of sodium azide (0.90 g, 13.84 mmol) and 1-(tert-butyl)-2-methyl (2S,4S)-4-bromotetrahydro-1H-1,2-pyrroledicarboxylate (4) (1.0 g, 3.24 mmol) in anhydrous dimethylformamide (32 mL) was heated for 64 h under an atmosphere of nitrogen. The mixture was cooled to room temperature, poured into ice-cold water and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with hexane-ethyl acetate (3:1 to 1:1, v/v) to give the title azide (5) (0.88 g, 93%) as a pale yellow oil:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:3]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>C1(C)C(C)=CC=CC=1>[CH:19]([NH:22][C:2]1[N:7]=[C:6]([NH:9][CH:10]([CH3:17])[CH3:11])[N:5]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][C:10]2([CH3:18])[CH3:17])[N:3]=1)([CH3:21])[CH3:20]
Reactant: CC(C)N
Reactant: CC1(C)CCCC(C)(C)N1c1nc(Cl)nc(Cl)n1
Solvent: Cc1ccccc1C
Product: CC(C)Nc1nc(NC(C)C)nc(N2C(C)(C)CCCC2(C)C)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
43.4 g of 2,4-dichloro-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine are heated in an autoclave to 160° for 8 hours with 39.0 g of isopropylamine in 200 ml of xylene. After cooling to room temperature, the autoclave contents are washed three times, each with 100 ml of water, and the yellowish xylene solution is dried over sodium sulfate, stirred for 10 minutes with 5 g of Tonsil Optimum (bleaching earth), filtered and evaporated. The 2,4-bis-isopropylamino-6-(2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine obtained is a slightly yellowish resin which could not be crystallized.
Reaction SMILES: [Cl:1][C:2]1[C:3]([SH:10])=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][C:17]=1Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([S:10][C:17]2[CH:16]=[CH:15][C:14]([C:19]([F:22])([F:21])[F:20])=[CH:13][C:12]=2[Cl:11])=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Reactant: Nc1cc(Cl)c(S)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Cl)c(Sc2ccc(C(F)(F)F)cc2Cl)cc1F
Reaction time: 2 h
Yield: 66 %

Procedure:
5.00 Grams of 5-chloro-2-fluoro-4-mercaptoaniline, 12.2 g of 3,4-dichlorobenzotrifluoride and 4.31 g of potassium carbonate were dissolved in 30 ml of dimethylformamide, and the resulting solution was stirred for 2 hours at a temperature of from 100° to 110° C. in an oil bath. Thereafter, the reaction solution was poured into water and extracted with three 200-ml portions of diethyl ether. The extract obtained was washed with water, dried, filtered and concentrated. The residue obtained was subjected to chromatography on silica gel to obtain 6.57 g of 5-chloro-2-fluoro-4-[2-chloro-4-(trifluoromethyl)phenylthio]aniline.
Reaction SMILES: CC(OC(C)=O)=O.[N+:8]1([O-])[C:9](=[CH:13][CH:14]=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17])C(O)=O.[OH-].[Na+].OC1C=CC(C(O)=O)=CN=1.C(Cl)[Cl:34]>CCN(CC)CC>[Cl:34][C:9]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:19][N:8]=1
Reactant: ClCCl
Reactant: O=C(O)c1ccc(C(=O)O)[n+]([O-])c1
Agent: O=C(O)c1ccc(O)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(Cl)nc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 54.2 %

Procedure:
36.6 g of Ac2O, 60 g of Et3N and 600 g of CH2Cl2 were placed in a flask and heated at 40° C. 36.6 of isocinchomeronic acid-N-oxide was added in portions. After a further 1.5 hours, NaOH (10 percent) was added while strongly stirring until the final pH reached 13. The phases were separated. The CH2Cl2 -solution was dried with solid NaOH and was kept for the next batch. The aqueous solution was acidified with concentrated HCl (final pH was about 2). The product obtained hereby was sucked off, washed and dried. The yield was 54.2 percent of 2-chlor-5-pyridine carboxylic acid (6-chloronicotinic acid) and 37.7 percent of 2-hydroxy-5-pyridine carboxylic acid (6-hydroxynicotinic acid).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25](O)=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([F:22])=[C:17]([CH:23]=[CH2:24])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[N:35]1[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:25]([NH:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][C:34]=2[N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:51])[O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:36]2)=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([F:22])=[C:17]([CH:23]=[CH2:24])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1cc2nc(C(=O)O)c(NC(=O)OCc3ccccc3)cc2cc1F
Reactant: Nc1cnccc1N1CCC[C@H](NC(=O)OCc2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=Cc1cc2nc(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OCc4ccccc4)C3)c(NC(=O)OCc3ccccc3)cc2cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-6-fluoro-7-vinylquinoline-2-carboxylic acid (153.2 mg, 0.4182 mmol), benzyl [(3S)-1-(3-aminopyridin-4-yl)piperidin-3-yl]carbamate (151.1 mg, 0.4629 mmol) and HATU (485.8 mg, 1.278 mmol), DMF (4.0 mL) was added, followed by DIPEA (570.1 mg, 4.411 mmol). The reaction mixture was stirred at room temperature for 15 h, then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-10% MeOH in DCM) to give the sub-title compound (242.7 mg, 86%). LCMS calc. for C38H36FN6O5(M+H)+: m/z=675.3. found 675.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[F:9].C([N-]C(C)C)(C)C.[Li+].B(OC)(OC)[O:19]C.C(OO)(=O)C>O1CCCC1.O>[Br:1][C:2]1[C:3]([F:9])=[C:4]([OH:19])[C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Fc1cc(Cl)ccc1Br
Reactant: COB(OC)OC
Agent: CC(=O)OO
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1c(Cl)ccc(Br)c1F
Temperature: -20 °C
Yield: 63 %

Procedure:
A solution of 1-bromo-4-chloro-2-fluorobenzene (20.4 g, 0.100 mol) in tetrahydrofuran (THF; 50 mL) was slowly added to lithium diisopropylamide (LDA; 0.125 mol) in THF (600 mL) at −50° C. After addition, the solution was warmed to −20° C. and then cooled to −50° C. A solution of trimethyl borate (13.5 g, 0.130 mol) in THF (20 mL) was added slowly and the temperature was warmed to −20° C. The mixture was then cooled to −70° C. and a solution of peracetic acid (32% in acetic acid, 0.150 mol) was slowly added and the mixture was warmed to ambient temperature. Water (250 mL) was added and the solution was extracted with ethyl acetate (2×200 mL). The combined organic phases were dried and concentrated. The black oil was purified by column chromatography (20% ethyl acetate in hexanes) to give 3-bromo-6-chloro-2-fluorophenol (14.1 g, 0.063 mol) 1H NMR (CDCl3): δ 7.05 (m, 2H), 5.5 (br s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:22])([F:23])[F:24])=[O:25])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccc2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1C(F)(F)F)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 4-(2-trifluoromethylbenzoyl)piperidine-1-carboxylic acid tert-butyl ester (0.812 g, 2.27 mmol) in dichloromethane (60 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at ambient temperature overnight., then washed with saturated NaHCO3. The organic phase was separated, dried over MgSO4 and concentrated. The title compound was obtained in 55% yield (0.319 g) and used for next step reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(#N)C>[N:30]1([C:2]2[N:10]=[C:9]([Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: C1COCCN1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(Cl)c2ncn(C3CCCCO3)c2n1
Solvent: CC#N
Product: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Yield: 91.3 %

Procedure:
6-Chloro-9-(tetrahydro-2H-pyran-2-yl)-2-(tributylstannyl)-9H-purine (3.3 g, 6.25 mmol) was dissolved in acetonitrile (30 ml) followed by the addition of morpholine (2.2 ml, 25 mmol) and the resulting mixture was heated to reflux for 1 hour. The reaction mixture was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic layer was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1 to 8:2) to give the title compound (3.3 g, 91%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:23])[CH2:9][CH2:10][C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=O)[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].C(O)=O.CCCCC>C(Cl)Cl.[Zn]>[CH3:1][C:2](=[O:3])[C@@H:4]1[C@:8]2([CH3:23])[C@H:7]([C@H:12]3[C@H:11]([CH2:10][CH2:9]2)[C@:21]2([CH3:22])[C@@H:15]([CH:16]=[CH:17][CH2:19][CH2:20]2)[CH2:14][CH2:13]3)[CH2:6][CH2:5]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Zn]
Solvent: ClCCl
Solvent: O=CO
Solvent: CCCCC
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C=CCC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.5 %

Procedure:
A mixture of 250 mg of progesterone, 7.5 g of zinc dust, 18.75 ml of methylene chloride and 6.25 ml of 90% formic acid was shaken at room temperature for 18 hours, whereupon it was worked up by the procedure described in Example 36. Concentration of a solution of the crude product in methylene chloride with intermittent addition of pentane gave 99.18 mg of 5β-pregn-3-en-20-one, mp 135°-136.5°, 139.5° C., nmr (CDCl3,δ) 5.5 (2, broadened dd; 3--H, 3--H, 4--H), 2.12 (3, S; 21--H) 0.96 (3, S; 19--H), 0.77 (trace, S; 19--H of 5α-isomer?) and 0.61 (3, S; 18--H) ppm.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[P:12](=[S:20])([NH2:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].C(N(CC)CC)C>O>[C:4]1(=[O:6])[N:19]([P:12](=[S:20])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOP(N)(=S)OCC
Solvent: O
Solvent: CCN(CC)CC
Product: CCOP(=S)(OCC)N1C(=O)c2ccccc2C1=O
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
A mixture of the 74.06 g (0.5 mole) phthalic anhydride, 33.84 g (0.2 mole) O,O-diethyl phosphoramidothioate and 50.60 g (0.5 mole) triethylamine was heated at 55° C. for 3.5 hours. Eighty three mls of water were added to the stirred mixture and the system was stirred for 10 minutes and then cooled to 25° C. over a one hour period. The solid was filtered, washed with 150 ml water to give the desired compound, O,O-diethyl phthalimidophosphonothioate, purity by GLC. The yield was calculated to be 76% from the phosphoramidothioate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:21][CH2:22][CH2:23][NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:27])=[O:26]>C(N(C(C)C)C(C)C)C>[OH:21][CH2:22][CH2:23][NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:14][CH2:13]1)(=[O:27])=[O:26]
Reactant: O=S(=O)(CCCCCCCl)NCCO
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)NCCO
Yield: 91.5 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (573.6 mg, 2.00 mmol) and N-(2-hydroxyethyl)-6-chlorohexanesulfonamide (487.5 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(2-hydroxyethyl)-6-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (904.4 mg) as a pale yellow oil (yield: 91.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:28])[CH:15]([CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16](=O)[CH3:17])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:19]=[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:8]([C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:16]=1[CH3:17])=[O:28])[CH3:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc([N+](=O)[O-])cc2)c1C
Temperature: 2.5 °C

Procedure:
p-Nitroaniline (5 mmol, 0.7 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.25 g), and tosic acid were combined in ethanol, then heated under reflux. The reaction mixture was cooled on ice (0-5° C.), and the precipitate filtered from the reaction mixture. 1H-NMR analysis confirmed that the precipitate was the named product, (CDCl3, ppm); 1.38 t (3H), 2.45 s (3H), 4.20 q (2H), 6.80 s (1H), 6.97-7.35 bm (7H), 8.25 d (2H).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17]O.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C=O>CCCCCC>[O:22]1[CH2:23][CH2:24][N:19]([CH2:17][NH:10][C:8](=[S:9])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: NC(=S)C(c1ccccc1)c1ccccn1
Reactant: CO
Agent: C=O
Solvent: CCCCCC
Product: S=C(NCN1CCOCC1)C(c1ccccc1)c1ccccn1

Procedure:
2-Phenyl-2-(2-pyridyl)thioacetamide (1.14 g.) is suspended in 20 ml. of methanol. To the suspension is added 0.49 ml. of morpholine and 0.45 ml. of formalin. The mixture is heated on a steam bath until all of the materials are dissolved. The solution is then cooled and hexane is added. Concentrating to dryness and recrystallizing the residue from isopropanol gives N-morpholinomethyl-2-phenyl-2-(2-pyridyl)thioacetamide, m.p. 128°-130°C.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=[C:2]1[C:14]([O:16]C)=O.CO.[NH3:20].C(OCC)C>CN(C=O)C>[NH:1]1[C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=[C:2]1[C:14]([NH2:20])=[O:16]
Reactant: N
Reactant: COC(=O)c1cc2c([nH]1)-c1ccncc1CC2
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CO
Product: NC(=O)c1cc2c([nH]1)-c1ccncc1CC2
Yield: 50 %

Procedure:
A solution of methyl 4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-2-carboxylate L1 (0.44 mmol) in DMF (5 mL), MeOH (5 ml) and 30% aq NH3 (10 mL) was heated at 80° C. in a close vessel for 8 h. The solvent was evaporated, the residue was dissolved with DCM and washed with water. The organic layer was dried (Na2SO4) and concentrated to provide, after trituration with diethylether, the title compound (50% yield). ESI (+) MS: m/z 214 (MH+). 1H NMR: 2.69 (m, 2H), 2.84 (m, 2H), 6.72 (d, J=2.19, 1H), 7.08 (bs, 1H), 7.74 (d, J=5.12, 1H), 8.33-8.44 (2m, 2H), 12.01 (s, 1H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][OH:16].[F:23][C:24]1[C:29]([F:30])=[C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:27]=[CH:26][C:25]=1[C:36]1[N:41]=[CH:40][C:39](O)=[CH:38][N:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:23][C:24]1[C:29]([F:30])=[C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:27]=[CH:26][C:25]=1[C:36]1[N:37]=[CH:38][C:39]([O:16][CH2:15][C@H:14]([F:13])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:40][N:41]=1
Reactant: CCCCCc1ccc(-c2ncc(O)cn2)c(F)c1F
Reactant: CCCCCC[C@@H](F)CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCC[C@@H](F)COc1cnc(-c2ccc(CCCCC)c(F)c2F)nc1
Yield: 55.3 %

Procedure:
--DEAD (470 mg, 2.70 mmol) in THF (3 ml) was added dropwise via syringe to a stirring solution of (R)-(+)-2-fluorooctanol (396 mg, 2.70 mmol), the hydroxypyrimidine 33 (750 mg, 2.70 mmol) and triphenylphosphine (707 mg, 2.70 mmol) in THF (10 ml) under nitrogen at ambient temperature for 15 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (3 to 5% ethyl acetate-light petroleum) to give the 2-fluorooctyloxypyrimidine 34 (610 mg, 55%) (from MeOH), m.p. 74.7° C.; [α]D25 -3.6° (c 2.7 in CHCl3); νmax /cm-1 (KBr) 2950, 2920, 1575, 1545, 1460, 1440, 1280, 1210, 1130, 1080 and 995; δ 0.90 (6H, overlapping t, Me), 1.26-1.93 (16H, m), 2.70 (2H, t, ArCH2), 4.22 (2H, dd, 3JHF 22 and Jvic 4, OCH2), 4.87 (1H, d of sext, 2JHF 49 and J4, CHF), 7.02 (1H ddd, J7.5, 7 and 2, 5'-H), 7.6 (1H, ddd, J7.5, 7 and 2, 6'-H) and 8.55 (2H, s, 4- and 6-H); m/z 408 (M+), 365, 351, 291, 278, 250 and 221.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH2:18])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][CH:21]([C:25]([OH:27])=O)[C:22](O)=[O:23].[F:28][C:29]([F:38])([F:37])[C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][C@H:12]([NH:18][C:22](=[O:23])[CH:21]([C:25](=[O:27])[NH:33][C:32]1[CH:34]=[CH:35][CH:36]=[C:30]([C:29]([F:28])([F:37])[F:38])[CH:31]=1)[CH3:20])[C@@H:13]([OH:17])[C:14]#[C:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(C(=O)O)C(=O)O
Reactant: CC#C[C@H](O)[C@@H](N)CNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)C(C)C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.2 %

Procedure:
The compound [(2S,3S)-2-amino-3-hydroxy-hex-4-ynyl]-carbamic acid benzyl ester (173 mg, 0.46 mmol, prepared as described in WO PCT 0250019) was dissolved in 5 mL of 1:1 CH2Cl2/DMF. The resultant solution was charged sequentially with 2-methyl-malonic acid (54 mg, 0.46 mmol), meta-trifluoromethylaniline (0.06 mL, 0.46 mmol), N,N-diisopropylethylamine (0.8 mL, 4.6 mmol) and HATU (434 mg, 1.1 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide {(2S,3S)-3-hydroxy-2-[2-(3-trifluoromethyl-phenylcarbamoyl)-propionylamino]-hex-4-ynyl}-carbamic acid benzyl ester (40 mg, 17% yield). MS found: (M+Na)+=528.4.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([O:23][C:24](=[O:39])[C@@H:25]([NH2:38])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:29][CH:28]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24](=[O:39])[CH:25]([NH:38][C:12](=[O:14])[CH:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:31][CH:32]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Yield: 23.1 %

Procedure:
A solution of the product from Example Z (2(S)-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid) (0.20 g, 0.78 mmol) and 2(S)-amino-3-(4-tert-butoxy-phenyl)-propionic acid tert-butyl ester (Bachem, 0.284 g, 0.86 mmol) were coupled according to the procedure described in Example 3. The residue was purified by chromatography (silica gel, 1:1 ethyl acetate/hexane) to give the title compound as a white solid (0.096 g, 29%), mp=87-90° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].O.O.[Sn](Cl)Cl.[C:19]([OH:24])(=[O:23])[C:20]([CH3:22])=O>Cl.O>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][N:10]=[C:20]([CH3:22])[C:19]([OH:24])=[O:23]
Reactant: CC(=O)C(=O)O
Reactant: O=N[O-]
Reactant: Nc1ccc(F)cc1F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CC(=NNc1ccc(F)cc1F)C(=O)O
Temperature: -10 °C
Reaction time: 1 h
Yield: 943.2 %

Procedure:
Under a dry nitrogen atmosphere, a stirred solution of 25.8 g (0.20 mol) of 2,4-difluoroaniline in 235 ml of concentrated hydrochloric acid was cooled to -10° C. While maintaining this temperature, a solution of 13.8 g (0.20 mol) of sodium nitrite in 80 mol of water was added dropwise. After complete addition, the mixture was stirred at -10° C. for one hour. A solution of 101.5 g (0.450 mol) of tin (II) chloride dihydrate in 115 ml of concentrated hydrochloric acid was added dropwise to the cold reaction mixture. The resultant mixture was stirred for two hours, allowing the reaction temperature to rise to room temperature. Water (200 ml) was added to the mixture followed by the dropwise addition of 17.6 g (0.020 mol) of pyruvic acid in 200 ml of water. The resultant suspension was stirred vigorously for 45 minutes, and was filtered. The filter cake was dried to yield 40.4 g of 2-(2,4-difluorophenylhydrazono)propionic acid as a solid.