Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[Si]([C:20]#[N:21])(C)(C)C.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]=[C:8]2[C:20]#[N:21]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc2c(c1OC)CCCC2=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1OC)CCC=C2C#N
Reaction time: 0.17 h
Yield: 95.8 %

Procedure:
Tetralone 7 (1.7 g, 8.25 mmol) was added as a slurry in freshly distilled toluene (25 mL) to a dried flask with magnetic stirring. TMSCN (1.42 mL, 10.7 mmol) was added dropwise. After stirring for 10 min, BF3.OEt2 (1.57 mL, 12.38 mmol) was added with a syringe. The reaction was stirred at room temperature for 3 h, until no starting material remained. The reaction was quenched by pouring over 30 mL ice water and stirring vigorously. To this aqueous mixture were added 20 mL of Et2O, and the layers were separated. The aqueous layer was extracted twice more with Et2O and once with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure to afford a tan solid (1.7 g, 7.9 mmol, 96%) that was recrystallized from MeOH to yield fine, colorless needles; mp 138-140° C. (lit.36 mp 137-139° C.). 1H NMR: (300 MHz, CDCl3): δ 7.18 (d, 1H, J=8 Hz, ArH); 6.80 (d, 1H, J=8 Hz, ArH); 6.75 (t, 1H, J=4.6 Hz, ArCH2CH2CH); 3.88 (s, 3H, ArOCH3); 3.76 (s, 3H, ArOCH3); 2.87 (t, 2H, J=8 Hz, ArCH2); 2.44 (m, 2H, ArCH2CH2). EIMS (M+)=215.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[OH:25])[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[C:28]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[OH:25])[C:9]2=[O:27])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)c(O)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)c(O)c1
Yield: 27.5 %

Procedure:
To a solution of 1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one (27.9 g, 63.8 mmol) in dichloromethane (200 mL) were added trifluoroacetic acid (2 mL) and triethylsilane (1.5 mL) at ambient temperature. The reaction mixture was refluxed for 15 h. The mixture was concentrated in vacuo to dryness. The residue was purified by flash chromatograph using 25% ethyl acetate in hexane to afford 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxyphenyl)-1,3-dihydro-2H-indol-2-one (7.40 g, 27%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.40-7.18 (m, 11H), 7.13-7.06 (m, 2H), 6.97 (s, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.67-6.64 (m, 1H), 6.57-6.52 (m, 1H), 6.41 (dd, J=8.4, 2.4 Hz, 1H), 5.11 (s, 1H), 3.77 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][CH2:18][OH:19])[CH:8]=[C:9](C(C)(C)C)[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][CH2:18][OH:19])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(CCCO)cc(C(C)(C)C)c1O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(CCCO)ccc1O
Temperature: 40 °C
Reaction time: 6 h
Yield: 64.4 %

Procedure:
3-(3',5'-Di-tert-butyl-4'-hydroxyphenyl)-1-propanol (100 g, 0.38 mol) was dissolved in 500 ml of trifluoracetic acid. The solution was stirred at 40° C. for six hours, then poured into an ice-water mixture. The mixture was extracted with methylene chloride. The methylene chloride layer was washed with aqueous sodium carbonate and evaporated. A solution of sodium hydroxide (25 g) in 400 ml of methanol was added to the residue. The mixture was stirred at room temperature for 30 minutes, neutralized with 1N hydrochloric acid and extracted with methylene chloride. The methylene chloride layer was washed with aqueous sodium carbonate and water, dried with anhydrous sodium sulfate, and evaporated. The residue was vacuum distilled to give 51 g (64%) of the product.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[N:18][CH:17]=[CH:16][N:15]=3)[CH2:10][CH2:9]2)=[C:5]([CH3:27])[NH:4][N:3]=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1>[C:28]1([S:34]([N:4]2[C:5]([CH3:27])=[C:6]([CH2:7][N:8]3[CH2:13][CH2:12][N:11]([C:14]4[C:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=5)=[N:18][CH:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)[C:2]([CH3:1])=[N:3]2)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1n[nH]c(C)c1CN1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1nn(S(=O)(=O)c2ccccc2)c(C)c1CN1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Temperature: 120 °C
Reaction time: 4 h
Yield: 68.1 %

Procedure:
To a solution of 4-(3,5-dimethyl-1H-pyrazol-4-ylmethyl)-3′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.160 g, 0.4 mmol, 1 eq) add benzenesulfonyl chloride (56 μL, 0.4 mmol) followed by pyridine (1 mL). Heat to 120° C. with stirring for 4 hr. Add water and extract 3 times with ethyl acetate (20 mL), dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 25:75 to 75:25 ethyl acetate:DCM). Lyophilize from a 50% acetonitrile/water solution to give the title compound as a white solid (138 mg, 68%). MS (ES): m/z=507.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(CON)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added tert-butyl 3-[(aminooxy)methyl]piperidine-1-carboxylate 152 (0.312 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 153 (0.37 g, 84%) as a white foam.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>CCOCC>[F:1][C:2]([F:16])([F:17])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][C:2]([F:1])([F:16])[F:17])[CH2:11][CH2:12]1
Reactant: FC(F)(F)Oc1ccccc1N1CCNCC1
Solvent: CCOCC
Product: FC(F)(F)Oc1ccccc1NCCN1CCN(c2ccccc2OC(F)(F)F)CC1
Temperature: 120 °C
Yield: 41 %

Procedure:
The title compound was obtained following the procedure described for example 54, but using 1-(2-trifluoromethoxyphenyl)piperazine in place of 1-(4-nitro-2-methoxyphenyl)piperazine. The reaction mixture was heated at 120° C. for 8 h. The residue obtained by usual work-up and extraction with Et2O was purified by flash chromatography (petroleum ether-EtOAc gradient from 90:10 to 80:20) to afford the title compound. Yield: 41%.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][CH:8]([C:16]([NH:18][S:19]([C:22]2C=C[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])=[O:17])[C:9](N(CC)CC)=[O:10])=[CH:5][CH:4]=1)#[N:2].C(/S(N)(=O)=[O:43])=C\C1C=CC=CC=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]([C:16](=[O:17])[NH:18][S:19](/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:20])=[O:21])[C:9]([OH:10])=[O:43])=[CH:32][CH:33]=1)#[N:2]
Reactant: CCN(CC)C(=O)C(Cc1ccc(C#N)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: NS(=O)(=O)/C=C/c1ccccc1
Product: N#Cc1ccc(CC(C(=O)O)C(=O)NS(=O)(=O)/C=C/c2ccccc2)cc1
Yield: 176.7 %

Procedure:
In the same manner as in Example 152 (3), the object compound was obtained using the compound (1.57 g) obtained in Example 111 (2) and trans-β-styrenesulfonamide (1.25 g). This was subjected to hydrolysis in the same manner as in Example 1 (3) to give the title compound (2.30 g) as a white powder.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br[CH2:25][C:26]([NH2:28])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([O:23][CH2:25][C:26]([NH2:28])=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(OCC(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
To a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol 490 (80 mg, 0.26 mmol) in DMF (3 mL) was added 2-bromoacetamide (53 mg, 0.39 mmol) and cesium carbonate (109 mg, 0.33 mmol). The reaction mixture stirred at RT for 16 h before being diluted with water. The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic extracts, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM) to yield 428 as a white solid (61 mg, 64%). LCMS: RT=6.70 min, [M+H]+=369; 1H NMR (400 MHz, d6-DMSO) 8.28 (1H, d, J=9.8 Hz), 7.85 (1H, s), 7.82 (1H, s), 7.51 (1H, s), 7.35 (1H, s), 6.76 (1H, dd, J=9.8, 2.7 Hz), 6.54 (1H, d, J=2.7 Hz), 5.85 (1H, sept, J=6.6 Hz), 4.49-4.39 (6H, m), 1.43 (6H, d, J=6.6 Hz).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]#[N:9])[CH2:3]1.C([N-]C(C)C)(C)C.[Li+].[C:18](=O)([O:22]CC)[O:19][CH2:20][CH3:21].Cl>C1COCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4]([C:8]#[N:9])([C:18]([O:19][CH2:20][CH3:21])=[O:22])[CH2:3]1
Reactant: CCOC(=O)OCC
Reactant: CC1CCCC(C#N)C1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C#N)CCCC(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 17 g of 3-methylcyclohexanecarbonitrile in 140 ml of THF has added to it, at -78°, a lithium diisopropylamide solution (prepared from 140 ml of THF, 16 g of diisopropylamine and 100 ml of 1.6-molar butyllithium solution in hexane), followed, after 2 hours, by 25 g of diethyl carbonate, and stirring is continued for one hour. After heating to room temperature and pouring onto 300 ml of ice-water the mixture is neutralized with dilute hydrochloric acid. Customary working up and distillation gives ethyl 3-methyl-1-cyanocyclohexanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1.CCN=C=NCCCN(C)C.[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:13])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1
Reactant: OCc1ccccc1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)OCc2ccccc2)C1
Reaction time: 16 h

Procedure:
2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetic acid was mixed with EDCI and benzyl alcohol and the reaction mixture was stirred for 16 h to obtain benzyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([CH2:13][OH:14])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2S[CH2:5][CH2:4]1.[S:16]([O-:21])(O[O-])(=O)=[O:17].[K+].[K+].[OH-].[Na+]>O>[CH3:15][N:2]([CH3:1])[C:3]1([CH2:13][OH:14])[C:8]2[CH:7]=[CH:12][CH:11]=[CH:10][C:9]=2[S:16](=[O:21])(=[O:17])[CH2:5][CH2:4]1
Reactant: O=S(=O)([O-])O[O-]
Reactant: CN(C)C1(CO)CCSc2ccccc21
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)C1(CO)CCS(=O)(=O)c2ccccc21
Yield: 50.1 %

Procedure:
10 g of 4-dimethylamino-4-hydroxymethyl-2,3-dihydro-4H-1-benzothiopyran obtained in Example 6 were suspended in 100 ml of water, to which 50 ml of an aqueous solution of 20 g of potassium peroxomonosulfate was added while stirring under ice cooling. After allowing to react for 1 hour, 3N NaOH solution was added thereto for neutralizing the mixture, followed by extraction with ether. After the ether phase was dried with anhydrous magnesium sulfate, the solvent was condensed to obtain 5.73 g of the title compound as colorless crystals. ##STR34## Melting point: 137°-138° C. IR(KBr) cm-1 : 1290, 1130, 760
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[N:10]([CH3:20])[CH2:11][CH2:12][NH:13]C(=O)C(F)(F)F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O>[CH2:1]([O:8][C:9](=[O:21])[N:10]([CH2:11][CH2:12][NH2:13])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCNC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CCN)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
To a solution of compound Y (103.0 g, 340.7 mmol) in MeOH (1200 mL) was added a solution of LiOH (16.4 g, 681.4 mmol) in water (120 mL). The reaction mixture was stirred at room temperature for 3 h. Solvents were evaporated to ¾ of initial volume followed by dilution with water (400 mL). Solution was extracted with EtOAc (2×300 mL). The organic layer was washed with brine (200 mL), dried over MgSO4 and evaporated in vacuo. The resultant residue was dissolved in ether (300 mL) and treated with 2 N HCl/ether (200 mL). The formed precipitate was filtered, washed with ether and dried in vacuo to provide hydrochloric salt of compound Z (54.5 g, 261.2 mmol) as white solid. LC-MS [M+H] 209.5 (C11H16N2O2+H, calc: 209.3).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]1)=O)[CH3:2].[BH4-].[Na+].C(O)(=O)C.N#N>C1COCC1>[CH2:1]([NH:3][CH2:4][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCNC(=O)[C@H]1CC[C@H](C(=O)OC)CC1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCNC[C@H]1CC[C@H](C(=O)OC)CC1
Temperature: 25 °C

Procedure:
A stirred suspension of methyl trans-4-[(ethylamino)carbonyl]cyclohexanecarboxylate (Intermediate 5, 430 mg, 2.01 mmol) and NaBH4 in THF (10 mL) was treated with acetic acid (1.6 mL) and heated at reflux for 16 h an atmosphere of N2. The reaction was cooled to room temperature, quenched with H2O (1 mL) and diluted with 1N NaOH (15 mL). The mixture was extracted with EtOAc (3×40 mL) and the combined extracts were washed with brine (40 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford methyl trans-4-[(ethylamino)methyl]cyclohexanecarboxylate as a clear oil. LCMS=200.2 (M+)+. 1H NMR (CDCl3, 500 MHz): δ 3.67 (s, 3H), 2.67-2.64 (q, J=7.1 Hz, 2H), 2.49-2.46 (m, 2H), 2.28-2.24 (m, 1H), 2.16-1.86 (m, 4H), 1.49-1.41 (m, 2H), 1.12 (t, J=5.5 Hz, 3H), 1.03 (m, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[N:25]4[C:19]([CH2:20][NH:21][CH2:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=54)=[N:18][N:17]=3)[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[N:25]4[C:19]([CH2:20][N:21]([C:38](=[O:40])[CH3:39])[CH2:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=54)=[N:18][N:17]=3)[CH2:12][CH2:11]2)=[N:2]1
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](c4nsc5ccccc54)CC3)n1-2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3nsc4ccccc43)CC2)C1
Reaction time: 20 h

Procedure:
To a solution of trans-1-(4-benzo[d]isothiazol-3-yl-cyclohexyl)-8-chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (35 mg, 0.080 mmol) and triethylamine (0.022 ml, 0.16 mmol) in dichloromethane (0.8 ml) was added acetyl chloride (0.011 ml, 0.16 mmol) at room temperature. Stirring for 20 h was followed by partitioning between water (20 ml) and ethyl acetate (25 ml). The layers were separated. The organic layer was washed with two 25 ml-portions of water. The organic layer was concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (26 mg, 68%) as white solid. MS m/e: 478 ([M+H]+)
Reaction SMILES: [C:1]([S:14]([N:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH-].[K+:32].C(O)(C)C>O>[C:1]([S:14]([N:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][K:32])=[O:27])[CH2:18][CH2:19][CH3:20])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: [K+]
Reactant: CCCN(CCCCCC(=O)OCC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCN(CCCCCC(=O)O[K])S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 61.3 %

Procedure:
A round bottom flask fitted with an overhead stirrer was charged with C4F9SO2N(C3H7)(CH2)5COOC2H5 (63.0 g; 0.143 mole), KOH (13.1 g; 0.234 mole; pellets) isopropanol (26 mL) and deionized water (21 mL). The ensuing mixture was refluxed overnight, cooled to room temperature, yielding a solution of C4F9SO2N(C3H7)(CH2)5COOK (61.3% solids).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.CCOCC.[C:12]1([Mg]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C1COCC1>[C:12]1([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: Brc1ccsc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1ccc(-c2ccsc2)cc1
Temperature: 0 °C
Yield: 34.1 %

Procedure:
To a mixture of 1.0 mL (10.6 mmol) of 3-bromothiophene, 20 mL of anhydrous ether, 60 mg (0.11 mmol) of 1,3-[Bis(diphenylphosphino)-propane]dichloronickel(II)[NiCl2 (dppp)] under N2 with stirring at 0° C. was slowly added 7.0 mL (14 mmol) of 2.0 M PhMgCl in THF. The reaction was slowly warmed to room temperature. Note that a vigorous exothermic reaction may occur if the Grignard reagent is added too fast or if the reaction is allowed to warm to room temperature to rapidly. After stirring for 3 h, the mixture was warmed to reflux for 2 h, poured into 20 mL of 5% HCl solution, and extracted with 2×20 mL of ether. The combined organic phases were washed with 15 mL of H2O and 15 mL of brine, dried (MgSO4) and concentrated. Crystallization from hexanes provided 0.58 g (34% yield) of 3-phenylthiophene.
Reaction SMILES: C([O:5][C:6](=[O:47])[C:7]([CH2:43][C:44]#[C:45][CH3:46])([S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([NH:27][CH2:28][C@H:29]([OH:42])[C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:31]=3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][C:9]#[C:10][CH3:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:8]([C:7]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([NH:27][CH2:28][C@H:29]([OH:42])[C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:31]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1)(=[O:13])=[O:14])([CH2:43][C:44]#[C:45][CH3:46])[C:6]([OH:47])=[O:5])[C:9]#[C:10][CH3:11]
Reactant: CC#CCC(CC#CC)(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCC(CC#CC)(C(=O)O)S(=O)(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.8 %

Procedure:
To a solution of 2-(2-butynyl)-2-[(4-{4-[((2R)-2-hydroxy-2-[4-hydroxy-3-[(methylsulfonyl)amino)-phenyl)ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]-4-hexynoicacid tert-butyl ester 0.21 g (0.3 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (0.23 ml, 3 mmol), and the mixture was stirred at room temperature for 2 days. It was then evaporated and treated with 10% sodium bicarbonate solution until pH 6. The resulting suspension was filtered and the precipitate washed with water, and dried in vacuo to give 85 mg of a beige solid; m.p. 175-177° C.; MS (ES) m/z 630.6 (M−H−); HRMS (EI) Calcd. for C30H36N3O8S2 (M−H−): 630.1949, Found: 630.1943.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:22])[N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:40][CH2:41][CH3:42]>CN(C=O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:16]([CH:17]([CH2:40][CH2:41][CH3:42])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:22])[N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COCOc1cccc(-c2nc(-c3ccccc3)nc(C)c2CC(=O)OC)c1
Reactant: CCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1cccc(OCOC)c1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
A solution of methyl 2-(4-(3-(methoxymethoxy)phenyl)-6-methyl-2-phenylpyrimidin-5-yl)acetate (79 mg; 0.209 mmol) in dry DMF (1 mL) was cooled to −15° C. (acetone/ice). LHMDS (0.230 mL; 0.230 mmol; 1M in THF) was added dropwise and the mixture was stirred at −15° C. for 15 min followed by the dropwise addition of iodopropane (0.031 mL; 0.313 mmol), after stirring for 2 h at −15° C. the mixture was allowed to warm to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-10%) in heptane to give 65 mg (73%) of the title compound as a colorless oil. ESI/APCI(+): 421 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:25]1[CH:26]=[CH:27][C:28]2[S:32][CH:31]=[CH:30][C:29]=2[CH:33]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:25]2[CH:26]=[CH:27][C:28]3[S:32][CH:31]=[CH:30][C:29]=3[CH:33]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CCOC(=O)C(N)c1ccc2sccc2c1
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccc2sccc2c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(benzothiophen-5-yl)acetate (prepared as described in S. Kukolja et al., J Med. Chem., 1985, 28, 1896-1903), the title compound was prepared as a solid (mp=126.5-127.5° C.). The product was purified by preparative LC 2000 chromatography using 1:1 hexanes/EtOAc as the eluent.