Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([C:6]([OH:13])=NC(O)=[N:9]2)=[N:4][CH:3]=1.[OH-:14].[Na+].Cl>O>[NH2:9][C:10]1[C:5]([C:6]([OH:13])=[O:14])=[N:4][CH:3]=[C:2]([CH3:1])[N:11]=1
Reactant: [OH-]
Reactant: Cc1cnc2c(O)nc(O)nc2n1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cnc(C(=O)O)c(N)n1
Temperature: 150 °C

Procedure:
7-Methyl-pteridine-2,4-diol (prepared by the procedure of ‘Synthesis of 2,6-Disubstituted pyrazines and Related Derivates’, Sharefkin, D. M. J. Am. Chem. Soc., 1959, 345) (4 g, 22.5 mmol) is suspended in a solution of NaOH (2.17 g, 53 mmol) in H2O (20 ml), in an autoclave, and the mixture is heated to 150° C. for 3 days. The reaction mixture is cooled to room temperature and the pH is adjusted to 2.5 by the slow addition of 6M HCl (98 ml). The resulting suspension is cooled in a fridge for 1.5 hours, and the solid is then collected by filtration, washed with cold H2O, and MeOH, and dried in vacuo to yield 3-amino-5-methyl-pyrazin-2-carboxylic acid as a beige solid. [M+H]+ 154
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[C:22]1(O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][O:19][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: Oc1ccccc1
Reactant: CC(C)(C)CN(CCO)c1ccc(C#N)c(C(F)(F)F)c1
Product: CC(C)(C)CN(CCOc1ccccc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1C from 4-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and phenol: 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=9.0 Hz, 1H), 7.31-7.23 (m, 2H), 7.11 (d, J=2.2 Hz, 1H), 6.69 (app. t, J=7.3 Hz, 1H), 6.91 (dd, J=8.9, 2.4 Hz, 1H), 6.83 (d, J=8.2 Hz, 2H), 4.11 (t, J=5.7 Hz, 2H), 3.93 (t, J=5.7 Hz, 2H), 3.40 (s, 2H), 1.01 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([CH3:11])=[CH2:10])[CH:8]=1.[N-:18]=[N+:19]=[N-:20].[Na+].O.CCOC(C)=O>CN(C=O)C>[N:18]([CH2:2][C:3]1[CH:4]=[C:5]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([CH3:11])=[CH2:10])[CH:8]=1)=[N+:19]=[N-:20]
Reactant: C=C(C)c1cc(CCl)cc(N(C)S(C)(=O)=O)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)c1cc(CN=[N+]=[N-])cc(N(C)S(C)(=O)=O)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of crude N-(3-(chloromethyl)-5-(prop-1-en-2-yl)phenyl)-N-methylmethanesulfonamide and 91.2 mg (1.40 mmol) of NaN3 in 4 mL of DMF was stirred at 70° C. for about 3 h. Water and EtOAc were added, and the organic layer was washed with water (2×) and then brine. The aqueous layer was extracted with EtOAc, and the combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography provided 88.4 mg of N-(3-(azidomethyl)-5-(prop-1-en-2-yl)phenyl)-N-methylmethanesulfonamide as a mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7](=[CH2:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:14]([OH:17])(=[S:16])[CH3:15]>>[C:14]([S:16][CH2:11][CH:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9])(=[O:17])[CH3:15]
Reactant: C=C(Cc1ccc(Cl)cc1)C(=O)O
Reactant: CC(O)=S
Product: CC(=O)SCC(Cc1ccc(Cl)cc1)C(=O)O
Yield: 47 %

Procedure:
By working in a way similar to that described in example 8 and by using 2-(4-chlorobenzyl)-propenoic acid (6.7 g; 0.034 moles), prepared as described in example 13, and thioacetic acid (3.64 ml; 0.051 moles), a crude was obtained which chromatographed on silica gel (eluent ligroin:ethyl acetate=1:1) afforded 3-acetylthio-2-(4-chlorobenzyl)-propionic acid (4.36 g; 47% yield) as oil.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:20]=1.Cl.N1C=CC=CC=1>C(OC(O)C)C>[CH3:15][N:13]([CH3:14])[CH:10]1[CH2:11][CH2:12][N:8]([C:6]([C:5]2[CH:16]=[CH:17][C:2]([NH:1][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:3][CH:4]=2)=[O:7])[CH2:9]1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Reactant: CN(C)C1CCN(C(=O)c2ccc(N)cc2)C1
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc(Nc3nc(-c4ccccc4)nc4ccccc34)cc2)C1
Temperature: 135 °C
Yield: 17.1 %

Procedure:
A mixture of 1-(4-aminobenzoyl)-3-dimethylamino-pyrrolidine (46 mg, 0.2 mmol), 4-chloro-2-phenylquinazoline (48 mg, 0.2 mmol) and pyridine hydrochloride (23 mg, 0.2 mmol) in ethoxyethanol is heated to 135° C. overnight, cooled to room temperature and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, methanol and water and purified by reverse-phase semi-preparative HPLC1 to give the title product as a white powder (15 mg), identified by HPLC and mass spectral analyses. Retention Time, 2.69 min.; MS [438.2 m/e (M+H)]. 1Semi-preparative HPLC Conditions: A=0.02% TFA in water, B=0.02% TFA in acetonitrile, 10-95% B in 8 min., 34 mL/min, 50° C., 215 nm detection, Waters Xterra™ 20×50 mm column.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6](=O)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH2:15][CH2:16][CH2:17][N:18]3[C:23](=[O:36])[CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:29]=2[CH3:35])[CH:10]=[N:9]1)#[N:2].N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C[Si]([N:54]=[N+:55]=[N-:56])(C)C>C(Cl)Cl>[CH3:35][C:29]1[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:28]=1[O:27][CH2:26][CH2:25][CH2:24][C:23]([N:18]1[C:19]2[C:14](=[C:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[N:5]([CH2:4][CH2:3][C:1]#[N:2])[N:56]=[N:55][N:54]=4)[CH:12]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:16][CH2:17]1)=[O:36]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(CC(=O)NCCC#N)c4)cccc32)c1C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5nnnn5CCC#N)c4)cccc32)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of N-(2-cyanoethyl)-2-(4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)-1H-pyrazol-1-yl)acetamide (20 mg, 0.04 mmol) and pyridine (19 μL, 0.24 mmol) in DCM (0.4 mL) under argon was added PCl5 (13 mg, 0.06 mmol) in one portion, and the resulting mixture was heated to reflux for 3 h. The reaction was cooled to room temperature and trimethylsilyl azide (18 mg, 0.16 mmol) was added. The resulting mixture was stirred at room temperature overnight and carefully quenched with saturated aqueous NaHCO3. The resulting mixture was stirred vigorously for 15 min. The organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (17 mg, 81% yield) as white foam. LCMS, [M+H]+=525.2. 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.47 (s, 1H), 7.30-7.16 (m, 2H), 7.10 (d, J=8.7 Hz, 1H), 7.03 (t, J=7.9 Hz, 1H), 6.76 (d, J=7.5 Hz, 1H), 6.64 (d, J=8.2 Hz, 1H), 5.74 (s, 2H), 4.95 (t, J=6.9 Hz, 2H), 3.93 (s, 2H), 3.78 (t, J=6.8 Hz, 2H), 3.06 (t, J=6.9 Hz, 2H), 2.74 (t, J=7.1 Hz, 2H), 2.52 (s, 2H), 2.24-2.11 (m, 5H), 1.96-1.78 (m, 5H).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:10]([CH3:19])[C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[CH2:7][N:6]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO.O>[CH2:20]([N:6]1[CH2:7][C@@H:8]([N:10]([CH3:19])[C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:16])[Cl:17])=[O:12])[CH2:9][C@H:5]1[C:3]([OH:4])=[O:2])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(=O)OCC(Cl)(Cl)Cl)CN1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)OCC(Cl)(Cl)Cl)[C@H]1C[C@@H](C(=O)O)N(Cc2ccccc2)C1
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a solution of (2S,4S)-1-benzyl-4-[methyl-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester (6.4 mmol) in 18 mL of THF and 12 mL of methanol was added a solution of NaOH (12.8 mmol) in 10 mL water, and the reaction mixture was stirred overnight. The solution was diluted with 40 mL of water and extracted with 20 mL of EA. The aqueous layer was separated and acidified with 2N HCl to PH=5-6. Then the solution was extracted with EA (3×40 mL). The combined organic layers were washed by brine (20 mL), dried over Na2SO4, and concentrated to give 2.6 g of title product in 91% yield. MS m/e=410.4 [M+H]+.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[O:27]>C(OCC)C.O>[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[OH:27]
Reactant: Brc1ccncc1
Reactant: COC1CCCCC1=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: COC1CCCCC1(O)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
A stirred solution of 2.5M n-butyllithium in hexane (30.8ml, 0.77mol) at -78° C. was mixed with diethyl ether (310ml) and a solution of 4-bromopyridine (60.9g, 0.39mol) in diethyl ether (1200 ml) was added dropwise over 3 hours. Stirring was continued for 2 hours and a solution of 2-methoxycyclohexanone (54.3g, 0.42mol) in diethyl ether (total volume 100ml) was added dropwise over 1 hour. The stirred solution was allowed to warm to room temperature and stirring was continued overnight. Water (250ml) was then added to the reaction mixture, keeping the temperature below 20° C. and the mixture stirred for a further 30 minutes. The organic layer was separated and the aqueous layer was extracted with diethyl ether (3×50ml). The combined organic layers were extracted with hydrochloric acid (2N, 2×250ml+100ml) and the combined acidic extracts brought to pH 11 with 5N aqueous sodium hydroxide and extracted with ethyl acetate (3×250ml). The combined ethyl acetate extracts were dried (MgSO4) and evaporated in vacuo. The residue was recrystallized from petroleum ether (60°-80° C.) to give (±)-2-methoxy-l-(pyrid-4-yl)cyclohexanol (32.0g, 0.15mol) as a mixture of cis and trans isomers, m.p. 98°-101° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][O:9][C:10]1[N:15]=[C:14]([C:16]([NH:18][O:19][CH3:20])=[O:17])[CH:13]=[C:12]([N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]([C:30]3[NH:31][C:32]([CH3:37])=[C:33]([Cl:36])[C:34]=3[Cl:35])=[O:29])[CH2:23][CH2:22]2)[N:11]=1>CN(C=O)C>[Cl:35][C:34]1[C:33]([Cl:36])=[C:32]([CH3:37])[NH:31][C:30]=1[C:28]([NH:27][CH:24]1[CH2:23][CH2:22][N:21]([C:12]2[N:11]=[C:10]([O:9][CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[N:15]=[C:14]([C:16]([NH:18][O:19][CH3:20])=[O:17])[CH:13]=2)[CH2:26][CH2:25]1)=[O:29]
Reactant: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(OCCN)n1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(OCCNS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30.1 %

Procedure:
Methane sulfonyl chloride (0.032 ml, 0.412 mmol) was added dropwise to a solution of 2-(2-aminoethoxy)-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-N-methoxypyrimidine-4-carboxamide (Example 319, 0.20 g, 0.412 mmol), TEA (0.11 ml, 0.824 mmol) and DMF (3 ml) at 0° C. The reaction was stirred for 15 minutes at 0° C. then quenched with water. The aqueous phase was extracted with EtOAc, washed with saturated sodium bicarbonate solution, water and brine. It was dried over magnesium sulfate and concentrated to give brown solid, which was purified by reverse phase HPLC (30% to 35% acetonitrile in water, 0.1% TFA) affording the title compound (70 mg).
Reaction SMILES: OCC(CO)O.C([O:14][CH2:15][CH:16]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[O:17][CH3:18])C1C=CC=CC=1>[Pd].CO>[Si:21]([O:20][CH2:19][CH:16]([CH2:15][OH:14])[O:17][CH3:18])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: COC(COCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: OCC(O)CO
Solvent: CO
Product: COC(CO)CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of the protected glycerol derivative Compound 41 (5.0 g, 16 mmol) and 10% palladium on activated carbon (wet Degussa type E101 NE/W) (0.43 g) in MeOH (50 mL) was evacuated using an aspirator pump and filled with hydrogen. After 2 hours, TLC analysis showed the reaction to be complete, the mixture was filtered through Celite and the filtrate was evaporated to dryness to give 1-O-t-butyldimethylsilyl-2-O-methyl-rac-glycerol (Compound 42) (99%) as a colourless oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:15]=[CH:14][C:13]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[S:35]([CH3:38])(=[O:37])=[O:36])=[CH:25][C:24]=3[F:39])[C:18]2=[O:40])=[CH:12][C:9]=1[C:10]#[N:11].C[N:42](C=O)C.[OH2:46]>O>[F:7][C:8]1[CH:15]=[CH:14][C:13]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[S:35]([CH3:38])(=[O:37])=[O:36])=[CH:25][C:24]=3[F:39])[C:18]2=[O:40])=[CH:12][C:9]=1[C:10]([NH:42][OH:46])=[NH:11]
Reactant: CN(C)C=O
Reactant: O
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(N2CCCC(Nc3ccc(F)c(C#N)c3)C2=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CS(=O)(=O)c1ccccc1-c1ccc(N2CCCC(Nc3ccc(F)c(C(=N)NO)c3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72 %

Procedure:
A mixture of acetoxyhydroamic acid (27 mg, 2.5eq) and K2CO3 (98 mg, 5eq) in DMF/H2O (3:1, 4 ml) was stirred at room temperature for 20min. To this mixture was added 2-fluoro-5-[1-(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-2-oxo-piperidin-3-ylamino]-benzonitrile (68 mg, 0.141 mmol) prepared as described under Ex. 58a above. The whole was stirred and heated at 110° C. for 18 h. The mixture was diluted with water and extracted 3× with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated. Purification by reverse phase HPLC yielded the title compound (50 mg, 72%) 1H NMR (DMSO-d6) δ 8.11 (1H, d, J=8 Hz), 7.79 (1H, t, J=7,3 Hz), 7.71 (1H, t, J=7,73 Hz), 7.46 (2H, m), 7.37 (1H, d, J=11 Hz), 7.28 (1H, d, J=8 Hz), 7.18 (1H, t, J=9.5 Hz), 6.98 (1H, m), 6,85 (1H, m), 4.29 (1H, m), 3.72 (2H, t, J=6.2 Hz), 2.91 (3H, s), 2.28 (1H, m), 2.08 (2H, m), 1,84 (1H, m). MS 515.3 (M+H)+.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.Cl.Cl.[CH3:14][N:15]([CH3:17])[NH2:16].C(N(CC)C1C=CC=CC=1)C>C1(C)C=CC=CC=1>[CH3:14][N:15]([CH3:17])[N:16]1[C:4](=[O:5])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1]1=[O:6]
Reactant: CN(C)N
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: CN(C)N1C(=O)c2ccccc2C1=O
Yield: 85 %

Procedure:
To the suspension of phthalic anhydride (62.5 mmol) in toluene (500 ml), N,N-dimethyl hydrazine dihydrochloride (50 mmol) and diethyl-phenyl-amine (90 mmol) were added. The reaction mixture was refluxed for 18 hours while removing the formed water via a Dean-Stark trap. Then, toluene was evaporated under reduced pressure and the resulting crude was purified on silica gel chromatography with (1:5) EtOAc:dichloromethane, to give the desired product in 85% yield.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.Br[CH2:18][C@H:19]([CH3:22])[CH2:20][OH:21].O.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>CC(C)=O.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][C@H:19]([CH3:22])[CH2:20][OH:21])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)nsc2c1
Reactant: C[C@H](CO)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)/C=C/C(=O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: C[C@H](CO)CN1CCC(c2nsc3cc(F)ccc23)CC1
Reaction time: 16 h
Yield: 69.1 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.6 g, 20 mmol), (R)-(+)-3-bromo-2-methyl-1-propanol (3.0 g, 20 mmol), K2 CO3 (2.7 g, 20 mmol), tetrabutylammonium sulfate (0.058 g), CH3 CN (95 ml) and H2O (19 ml) was stirred and refluxed for 4.5 hours. After standing at ambient temperature for 16 hours, the reaction was poured into H2O, and subsequent extractive workup of the aqueous with EtOAc yielded 6.8 g of a partially solidified oil. The product was purified by flash chromatography on silica gel, eluting the column with CH2Cl2, then 2% MeOH--CH2Cl2 and finally 5% MeOH--CH2Cl2. Concentration of the appropriate fractions yielded 5.2 g of a waxy solid. The solid was dissolved in acetone and fumaric acid (1.9 g, 1.0 eq) was added and the reaction briefly heated at reflux. The resultant fumarate salt precipitated from solution yielding 4.8 g of white solid. The compound was recrystallized from acetonitrile to yield 3.1 g (36%) of the alcohol as a white solid, m.p.=151°-153° C.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:18][C:19]([C@@H:21]([NH:28][C:29]([C@H:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:32][C:33]([O:35]CC)=O)=[O:30])[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[O:20])[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:46][NH2:47]>CO>[CH:1]1([CH2:7][C@H:8]([NH:18][C:19]([C@@H:21]([NH:28][C:29]([C@H:31]([CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:32][C:33]([NH:46][NH2:47])=[O:35])=[O:30])[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[O:20])[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:15])[CH3:16])[CH:12]=[CH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)OCC)Cc1ccccc1)C(C)C
Reactant: NN
Solvent: O
Solvent: CO
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)NN)Cc1ccccc1)C(C)C

Procedure:
100 mg (0.164 mmol) of ethyl (R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyrate were stirred at room temperature for 3 hours in a solution of 30% hydrazine hydrate in methanol. Thereafter, the reaction mixture was evaporated and the residue was chromatographed on silica gel with a 14:1:0.1 mixture of methylene chloride, methanol and ammonia. Crystallization of the crude product from methanol/methylene chloride/ether yielded (R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]-carbamoyl]4-phenylbutyrohydrazide as white crystals, melting point 109°.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:26])[C@@H:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[NH2:21])=[CH:14][N:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.Cl[C:36](Cl)([O:38]C(=O)OC(Cl)(Cl)Cl)Cl.O>ClCCl>[CH3:1][C:2]1([CH3:27])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([N:18]4[C:19](=[O:26])[C@@H:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[NH:21][C:36]4=[O:38])=[CH:14][N:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC1(C)COc2cccc(Oc3ncc(NC(=O)[C@H](N)C(C)(C)C)cn3)c21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)COc2cccc(Oc3ncc(N4C(=O)N[C@H](C(C)(C)C)C4=O)cn3)c21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
N1-{2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}-3-methyl-D-valinamide (Intermediate 78, 9.9 mg) was dissolved in dry dichloromethane (1 ml). The reaction mixture was cooled down in an ice bath. Triethylamine (22.35 μl, 0.160 mmol) was added. The reaction mixture was cooled down at 0° C. Then 0.5 ml of a solution of triphosgene in dry dichloromethane (0.015 mmol) was added dropwise. The reaction mixture was stirred under argon during 20 min at 0° C. Some water (2 ml) was added and the aqueous layer was extracted with dichloromethane 4 times. After drying over sodium sulphate, the solvents were removed under vacuum. The residue obtained was purified by flash chromatography on silica gel (Companion system, 4 g silica cartridge) with cyclohexane/ethylacetate as eluents from 100/0 to 60/40. This afforded the title compound (7.7 mg).
Reaction SMILES: [CH:1]12C[CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([CH:10]([C:14]([OH:16])=[O:15])[C:11]([OH:13])=[O:12])=O.C12C=CC(CC1)CCC2[CH:26]=[O:27].O1CC[CH2:30][CH2:29]1>>[CH:2]12[CH:1]=[CH:6][CH:5]([CH2:4][CH2:3]1)[CH2:30][CH2:29][CH:8]2[C:10]([CH2:26][OH:27])([C:14]([OH:16])=[O:15])[C:11]([OH:13])=[O:12]
Reactant: O=CC1CCC2C=CC1CC2
Reactant: C1CCOC1
Reactant: O=C(O)C(C(=O)O)C(=O)C1CC2C=CC1C2
Product: O=C(O)C(CO)(C(=O)O)C1CCC2C=CC1CC2
Reaction time: 1 h
Yield: 124.5 %

Procedure:
To a solution containing sodium malonate (17.0 g) of Example 7 in dry tetrahydrofuran (100 g), bicyclo[3,2,2]non-8-ene-2-carboxaldehyde (15 g) obtained in Preparation Example 6 is slowly added, and the reaction is carried out at −20° C. in a nitrogen atmosphere for 1 hour, and then at 50° C. for 10 hours. Then, the reaction mixture is worked up as in the procedure of Example 1, to obtain 24 g of the pure title compound (purity: 99%, yield: 90%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[N:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([NH:22][C:13]([C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[N:12]=2)=[O:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NN1CCCCC1
Reactant: O=C(O)c1cccc(C2CCOCC2)n1
Product: O=C(NN1CCCCC1)c1cccc(C2CCOCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (LC/MS): 290.2 [M+H]+.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].[NH2:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1.BrCBr.[H-].[Na+]>O1CCCC1>[Cl:6][C:5]1[N:4]=[C:2]([Cl:3])[N:1]=[C:8]([N:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][O:15][C:14]3[CH:25]=[CH:26][C:11]([N:10]([C:8]4[N:7]=[C:5]([Cl:6])[N:4]=[C:2]([Cl:3])[N:1]=4)[C:8]4[N:7]=[C:5]([Cl:6])[N:4]=[C:2]([Cl:3])[N:1]=4)=[CH:12][CH:13]=3)=[CH:19][CH:20]=2)[C:8]2[N:7]=[C:5]([Cl:6])[N:4]=[C:2]([Cl:3])[N:1]=2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(OCOc2ccc(N)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: BrCBr
Solvent: C1CCOC1
Product: Clc1nc(Cl)nc(N(c2ccc(OCOc3ccc(N(c4nc(Cl)nc(Cl)n4)c4nc(Cl)nc(Cl)n4)cc3)cc2)c2nc(Cl)nc(Cl)n2)n1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 16 %

Procedure:
Cyanuric chloride (11.473 grams, 62.2 mmol) in dry tetrahydrofuran (50 milliliters) was added to a solution of 1,1-bis(4-aminophenoxy)methane (3.58 grams, 15.55 mmol; prepared as described in Part B of Example VIII except that 1,1-dibromomethane was used instead of 1,5-dibromopentane) in dry tetrahydrofuran (175 milliliters) at −10° C. The mixture was stirred for 10 minutes and sodium hydride (3.75 grams, 93.3 mmol) was added dropwise. The mixture was then heated to 60° C. for 16 hours and subsequently filtered on CELITE. The volatiles were removed under reduced pressure and the crude solid was purified on silica gel using a mixture of AcOEt/hexane (3:7, v/v) as eluant to afford pure 1,1-bis[4-[N,N-bis[4,6-dichloro-1,3,5-triazin-2-yl]amino]phenoxy]methane (2.10 grams, 2.55 mmol, 16 percent yield) as a white solid. Chromatography with silica gel is believed to be responsible for the low yield.