Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][C:12](OCC)=[O:13].[H-].C([Al+]CC(C)C)C(C)C.[NH4+].[Cl-].Cl>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[CH2:11][CH:12]=[O:13]
Reactant: CCOC(=O)CC1=Cc2ccccc2CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: O=CCC1=Cc2ccccc2CC1
Temperature: -60 °C
Reaction time: 2 h

Procedure:
A solution, cooled to -60° C., of 18.60 g (0.086 mol) of the ester obtained in Step 1 in 360 ml of CH2Cl2 is treated, dropwise, with a molar solution of diisobutylaluminium hydride in CH2Cl2 (170 ml). After stirring for 2 hours at -60° C., the mixture is hydrolysed, at that temperature, by successive addition of NH4Cl 10% (35 ml) and 1N HCl (42 ml). The temperature of the mixture is increased to 20° C. over a period of 1 hour and the precipitate formed is then suctioned off and washed with CH2Cl2. The filtrate is washed with water and then with saturated NaCl solution, dried and evaporated. The oily residue obtained is chromatographed on silica, eluting with a mixture of cyclohexane/EtOAc=95/5. The expected compound is isolated in the form of a colourless oil and is used as such for the following reaction.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[O:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=O)C.CC(C[AlH]CC(C)C)C>CCOCC>[CH3:11][C:9]1[O:8][C:7]([C:12]([F:15])([F:13])[F:14])=[C:6]([CH2:4][OH:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(C)oc1C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Product: Cc1cc(CO)c(C(F)(F)F)o1
Reaction time: 0.17 h
Yield: 58.5 %

Procedure:
To a solution of 5-methyl-2-trifluoromethyl-furan-3-carboxylic acid ethyl ester (0.83 g, 3.7 mmol) in Et2O at 0° C., was added DIBAL-H (1.0 M in THF, 1.5 mL). After 10 min, the ice bath was removed and additional DIBAL-H was added (1.0 M in THF, 14.5 mL). After 2 h, the reaction was quenched with a saturated solution of sodium potassium tartrate (aq.) and allowed to stir overnight. After 18 h, EtOAc was added and the organic layer separated and dried provide the title compound (0.39 g, 58%). 1H NMR (CDCl3): 6.19 (s, 1H), 4.62 (s, 2H), 2.36-2.28 (m, 3H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:17]3[CH:18]=[CH:19][S:20][C:16]=3[C:15]3[CH:14]=[CH:13][C:12]([C:21]([OH:23])=O)=[CH:11][C:10]=3[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26].CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:24][S:25]([NH:28][C:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[S:20][CH:19]=[CH:18][C:17]=3[C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:9][C:10]=2[CH:11]=1)=[O:23])(=[O:27])=[O:26]
Reactant: O=C(O)c1ccc2c(c1)nc(Nc1ccccc1)c1ccsc12
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)c1ccc2c(c1)nc(Nc1ccccc1)c1ccsc12
Reaction time: 5 h
Yield: 80.6 %

Procedure:
4-(phenylamino)thieno[3,2-c]quinoline-7-carboxylic acid (6 mg) was reacted with methyl sulfonamide (120 mg), EDCI (80 mg) and DMAP (20 mg) in anhydrous DMF (0.5 ml). After 5 hours, water was added and the solution subjected to preparative HPLC. Genevac evaporation provided N-(methylsulfonyl)-4-(phenylamino)thieno[3,2-c]quinoline-7-carboxamide as a solid (6 mg, 81% yield). LCMS (ES): 95% pure, m/z 398 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[Cl:13]N1C(=O)CCC1=O>CC(O)=O>[Cl:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2[nH]nc(Cl)c2c1
Temperature: 50 °C
Yield: 43.4 %

Procedure:
5-Nitroindazole (5 g, 30.7 mmol) was suspended in glacial AcOH (150 mL) and the mixture heated to 50° C. N-Chlorosuccinimide (4.9 g, 36.8 mmol) was added and the mixture heated at relux (solution forms) for 1 hour. The reaction mixture was concentrated and partitioned between EtOAc and brine. The organic phase was washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated to a yellow solid. Recrystallisation from EtOH provided the title compound as a pale yellow solid (2.63 g, 43%); 1H NMR (400 MHz, DMSO) δ 7.73 (1H, d), 8.21 (1H, dd), 8.51 (1H, d), 13.97 (1H, brs); MS (ES−) m/e=196.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][C:9](=[S:16])[S:10][CH2:11][CH2:12][C:13](O)=[O:14])=[C:6]([F:17])[C:5]([F:18])=[C:4]([F:19])[C:3]=1[F:20].OS(O)(=O)=O>C(OC(=O)C)(=O)C>[F:1][C:2]1[C:7]([N:8]2[C:13](=[O:14])[CH2:12][CH2:11][S:10][C:9]2=[S:16])=[C:6]([F:17])[C:5]([F:18])=[C:4]([F:19])[C:3]=1[F:20]
Reactant: O=C(O)CCSC(=S)Nc1c(F)c(F)c(F)c(F)c1F
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CCSC(=S)N1c1c(F)c(F)c(F)c(F)c1F

Procedure:
The carboxylic acid, 3-[[[(pentafluorophenyl)amino]thioxomethyl]thio]propionic acid (500 mg., 1.51 mmol) is dissolved in acetic anhydride (5 ml.) to give a bright yellow solution. A drop of conc. H2SO4 is added and the solution heated on a steam bath for 2-3 minutes. On cooling, crystals separated, which are recrystallized from ethanol to give pure 3-(pentafluorophenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one as bright yellow translucent crystals (320 mg.) m.p. 163.5°-164.5°.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5](C)=[C:6]([CH:18]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12](S(C)=O)=[CH:11][CH:10]=1)=O.O>Cl>[C:6]1([CH2:7][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:18]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: Cc1ccc(F)cc1C(=O)c1ccc(S(C)=O)cc1
Agent: Cl
Solvent: O
Product: c1ccc(Cc2ccccc2)cc1
Reaction time: 2.5 h

Procedure:
The product from Example 3 A, 5-fluoro-2-methyl-4'-methylsulfinylbenzophenone (0.2 mole), is refluxed in concentrated hydrochloric acid (100 ml.) with zinc amalgam (45 gm.) and water (30 ml.). Hydrogen chloride gas is slowly bubbled in during the reaction. After 2 to 3 hours, the gas supply is stopped and the product steam distilled. The oily distillate is extracted into ether (3 × 300 ml.), washed with water (2 × 50 ml.), dried (MgSO4), filtered and collected by evaporating off the solvent. It is then fractionally distilled under reduced pressure to give pure diphenylmethane.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][C:9]([C:12]#[N:13])=[C:10](Br)[N:6]2[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.COCCOC.O>[NH2:1][C:2]1[C:7]2=[CH:8][C:9]([C:12]#[N:13])=[C:10]([C:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1cc2c(N)ncnn2c1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2c(C#N)cc3c(N)ncnn23)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To the solution of 4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (1.00 g, 4.20 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.95 g, 6.30 mmol) in DMF (50 mL) and DME (6.9 mL), was added sodium carbonate in water (2M, 6.3 mL). The mixture was degassed for 15 min. Dichloro[bis(diphenylphosphino)ferrocene]palladium(II) CH2Cl2 adduct (307 mg, 0.42 mmol) was added. The mixture was stirred at 80° C. under nitrogen overnight then cooled to rt. The mixture was filtered through Celite®, washing with EtOAc (100 mL) then 20% MeOH/DCM (100 mL). The filtrate was concentrated to dryness. ISCO® purification (20% EtOAc/hexane then EtOAc) afforded title compound (1.0 g, 69.4%). 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 2H), 7.97 (s, 1H), 7.34 (s, 1H), 6.38 (t, 1H), 4.02 (d, 2H), 3.58 (t, 2H), 2.62 (t, 2H), 1.41 (s, 9H); LC-MS m/z [M+H]+ 341.2, RT 3.16 min.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:37](Cl)(=[O:40])[O:38][CH3:39]>C(Cl)Cl>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][N:22]([C:37]([O:38][CH3:39])=[O:40])[CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:10]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (45.6 mg, 0.113 mmol) and triethylamine (0.039 mL, 0.283 mmol) in DCM (0.75 mL) was added methyl carbonochloridate (0.013 mL, 0.170 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr, warmed to 23° C., and concentrated via rotary evaporation. The resulting crude material was partitioned between EtOAc and H2O. The organic phase was washed with brine, dried over Na2SO4, filtered, rinsed with EtOAc, and concentrated via rotary evaporation. The crude material was dissolved in toluene (0.5 mL) and purified via medium pressure chromatography using a 2% to 80% gradient eluant of EtOAc in heptane on a 12 g silica gel column (Single Step™) to give the title compound (48.7 mg, 93%) as a white foam. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17-1.19 (m, 6H), 1.80-1.94 (m, 2H), 2.06 (ddd, J=9.5, 5.9, 3.2 Hz, 2H), 2.64 (t, J=5.9 Hz, 2H), 2.82-2.94 (m, 2H), 3.19-3.31 (m, 2H), 3.64 (s, 3H), 3.64-3.69 (m, 2H), 4.07-4.17 (m, 1H), 4.35 (br s, 2H), 4.51 (tt, J=8.1, 3.9 Hz, 1H), 5.53 (d, J=8.3 Hz, 1H), 7.01 (dddd, J=9.3, 8.1, 3.2, 1.5 Hz, 1H), 7.26-7.35 (m, 2H); ESI-MS m/z [M+H]+ 461.9.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[O:21][CH3:22])[C:4]=2[N:5]=[CH:6][N:7]=1.CO.Cl.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:35]=[C:36]([CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[N:37]([CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])[CH:38]=2)=[CH:30][C:29]=1[C:50]([F:53])([F:52])[F:51]>>[CH3:42][N:41]([CH3:43])[CH2:40][CH2:39][N:37]1[CH:38]=[C:34]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[C:29]([C:50]([F:52])([F:51])[F:53])[CH:30]=2)[N:35]=[C:36]1[CH:44]1[CH2:45][CH2:46][N:47]([C:2]2[C:3]3[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=4[O:21][CH3:22])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:48][CH2:49]1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Reactant: COc1ccc(CN2C(=O)Cc3c(Cl)ncnc32)c(OC)c1
Agent: Cl
Solvent: CO
Product: COc1ccc(CN2C(=O)Cc3c(N4CCC(c5nc(-c6ccc(F)c(C(F)(F)F)c6)cn5CCN(C)C)CC4)ncnc32)c(OC)c1
Yield: 60 %

Procedure:
Combine a mixture of 4-chloro-7-(2,4-dimethoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (1.10 equiv; 868.3 mmol; 277.63 g) in methanol (62.44 mol; 2.53 L) at RT, a solution of 2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine dihydrochloride (1.00 equiv; 789.35 mmol; 361.0 g) and TEA (9077 mmol; 1265 mL) in methanol (62.44 mol; 2.53 L) and stir the mixture overnight at 55-60° C. Partition the reaction mixture between water (10 L) and EA (10 L). Extract the organic layer with 2 N HCl (5 L). Separate and extract the aqueous layer with EA (5 L). An oil separates in the aqueous layer. Decant the aqueous liquid and hold the oil for recovery of product. Stir the decanted aqueous layer with EA (5 L) and adjust the pH of the mixture to 10-11 with 2 N NaOH. Separate the organic layer, wash with brine, and dry over Na2SO4. Filter and evaporate the solvent to give the title compound (473.3 mmol; 316.0 g; 60%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]2[C:8](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:10]=[CH:11][C:4]=2[O:3]1.[CH3:20][C:21]([Si:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[CH:33])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>>[CH3:23][C:21]([Si:24]([CH3:25])([CH3:26])[O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[C:33][C:8]1[C:5]2[CH:6]=[CH:7][C:2](=[O:1])[O:3][C:4]=2[CH:11]=[CH:10][CH:9]=1)([CH3:20])[CH3:22]
Reactant: C#CCCCCO[Si](C)(C)C(C)(C)C
Reactant: O=c1ccc2c(OS(=O)(=O)C(F)(F)F)cccc2o1
Product: CC(C)(C)[Si](C)(C)OCCCCC#Cc1cccc2oc(=O)ccc12
Yield: 87 %

Procedure:
Using the procedure of example 120, trifluoromethanesulfonic acid 2-oxo-2H-1-benzopyran-5-yl ester from example 119 was converted to the title compound by reaction with (1,1-dimethylethyl)(5-hexynyloxy)dimethylsilane. The product was a solid, obtained in 87% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25][Si](C)(C)C)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+].O>CO>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:10](=[C:4]2[CH2:3][C:2]([CH3:30])([CH3:1])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5]2)[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:19][CH:20]=1)#[CH:25]
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C#C[Si](C)(C)C)cc2)CC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
4-((3,3,5,5-Tetramethylcyclohexylidene){4-[(trimethylsilyl)ethynyl]phenyl}methyl)phenol (146) (0.175 g, 0.42 mmol) was dissolved in MeOH (10 mL). To this solution was added K2CO3 (0.18 g, 1.26 mmol). The reaction mixture was stirred at room temperature overnight, poured into water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic phase washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as brown solid. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 15% EtOAc:hexanes to give 0.14 g (97%) of the title compound 147 as white solid. mp 138-139° C. 1H NMR (400 MHz, CDCl3): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.28 (s, 2H), 1.93 (s, 2H), 1.97 (s, 2H), 3.03 (s, 1H), 4.55 (br s, 1H), 6.73 (d, J=8.5 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H). LCMS (ESI): m/z 343 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[H][H]>[Ni].C(O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Agent: [Ni]
Solvent: CCO
Product: O=C(O)C(O)Cc1ccc(O)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
10 g of 3-(4-hydroxyphenyl)pyruvic acid and 50 ml of ethanol were charged to a pressure reactor to form a solution, and 1.0 g of Raney nickel was added thereto. The atmosphere was displaced with hydrogen, and the mixture was stirred at 70° C. under a hydrogen pressure of 30 kg/cm2 for 0.5 hour. After completion of the reaction, the reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure to give 8.7 g of 3-(4-hydroxyphenyl)lactic acid as colorless crystals.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][CH2:16]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>C1COCC1>[Br:38][CH2:16][C:15]#[C:14][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: OCC#Cc1ccc(Oc2ccccc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCC#Cc1ccc(Oc2ccccc2)cc1

Procedure:
A solution of 3-(4-phenoxyphenyl)prop-2-yn-1-ol of Example 51 (415 mg, 1.85 mmol), triphenylphosphine (514 mg, 1.96 mmol), carbon tetrabromide (650 mg, 1.96 mmol) in THF (3 ml) was stirred at room temperature for 3 days. Evaporation of the solution, and chromatography of the residue gave the title compound as a brown oil: NMR (CDCl3) δ 4.16 (s, 2H), 6.91 (d, J=2.1, 1H), 6.93 (d, J=2.1, 1H), 7.01 (d, J=0.93, 1H), 7.04 (d, J=1.14, 1H), 7.12-7.17 (m, 1H), 7.36 (d, J=0.75, 1H), 7.39 (d, J=1.98, 2H), 7.42 (d, J=2.64, 1H). MS m/z 288 (M+1 calcd. for C15H11BrO 287.155).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N:14][C:15]2[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)(Cl)=O.C(N(CC)CC)C.[CH3:41][CH2:42][O:43][Si:44]([O:52][CH2:53][CH3:54])([O:49][CH2:50][CH3:51])[CH2:45][CH2:46][CH2:47][NH2:48]>CCOCC>[CH2:50]([O:49][Si:44]([O:52][CH2:53][CH3:54])([O:43][CH2:42][CH3:41])[CH2:45][CH2:46][CH2:47][NH:48][C:25](=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:18]1[CH:17]=[CH:16][C:15]([N:14]=[N:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][CH:9]=2)=[CH:29][CH:28]=1)[CH3:51]
Reactant: CCCCCCc1ccc(N=Nc2ccc(OCCCCCC(=O)O)cc2)cc1
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCCCCCc1ccc(N=Nc2ccc(OCCCCCC(=O)NCCC[Si](OCC)(OCC)OCC)cc2)cc1
Reaction time: 2 h
Yield: 71.3 %

Procedure:
One g. (3.73×10-3 mol) of 4'-hexyl-4-hydroxyazobenzene (1) converted into a sodium salt with sodium methylate and 1.03 g (3.69×10-3 mol) of 2-tetrahydropyranyl 6-bromohexanoate and 5 ml of dimethylacetamide added thereto were heated for reaction at 100° C. for 73 hours. After the reaction was completed, the reaction mixture was diluted with water and left to cool to room temperature. The yellow crystals which were consequently precipitated were separated by filtration. The crystals were extracted with ethyl acetate, dried with magnesium sulfate, and subjected to vacuum distillation for expulsion of the solvent. The residue of the vacuum distillation was recrystallized with a mixture of hexane with benzene. Consequently, 1 g of 6-[4-(4-hexylphenylazo)-phenoxy]-hexanoic acid was obtained. A mixture of 200 mg (5.05×10-4 mol) of this carboxylic acid with 5 ml of thionyl chloride was refluxed for 2 hours to expel excess thionyl chloride and then mixed with 3 ml of dry ether and 0.15 g (1.485×10-3 mol) of triethylamine. This mixture kept cooled with ice and a solution of 0.11 g (4.98×10-4 mol) of triethoxyaminopropylsilane in 3 ml of dry ether added dropwise thereto were stirred for two hours, then filtered to expel the formed salt in an atmosphere of nitrogen gas, and subjected to vacuum distillation at room temperature to expel the solvent. Consequently, 213 mg of yellow waxy N-(3-triethoxysilylpropyl)-6-[4-(4-hexylphenylazo)phenoxy]hexanoic acid amide was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=3)[CH:20]=[C:19]([C:30]([OH:32])=[O:31])[N:18]=2)[O:9][N:8]=1.S(=O)(=O)(O)O.[CH3:38]O>>[CH3:38][O:31][C:30]([C:19]1[N:18]=[C:17]([N:13]2[CH2:14][CH2:15][CH2:16][CH:12]2[C:10]2[O:9][N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:11]=2)[N:22]=[C:21]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[CH:20]=1)=[O:32]
Reactant: CO
Reactant: Cc1cc(Nc2cc(C(=O)O)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Yield: 51 %

Procedure:
A mixture of 2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-6-yl carboxylic acid (Method 43) (1.73 g, 4.0 mmol), methanol (300 ml) and 98% sulphuric acid (1 ml) was heated at reflux for 18 hours. The volatiles were removed by evaporation, the residue dissolved in water and the pH of the resulting solution adjusted to pH 12 with 10M sodium hydroxide. The aqueous solution was extracted with DCM and purified by chromatography on silica gel, eluting with DCM/methanol (100:0 increasing in polarity to 90:10) to give the title compound (904 mg, 51%).
Reaction SMILES: C([Cu])#N.[CH3:4][Mg]Br.Br[CH2:8][C:9](=[CH2:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl-].[NH4+]>O1CCCC1>[CH2:8]([C:9](=[CH2:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:4]
Reactant: C[Mg]Br
Reactant: C=C(CBr)C(=O)OCC
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(CC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To CuCN (26.9 g, dried in advance under vacuum) was added under nitrogen atmosphere about 500 ml of dry tetrahydrofuran. The mixture was kept at −78□, and 100 ml of methyl magnesium bromide (3.0M diethylether solution) was slowly added thereto under mechanical stirring. The thick mixture was stirred for about 30 minutes at −78□. Ethyl 2-bromomethylacrylate (28.9 g, 150 mmol, Synthetic method: Villieras, J. and Rambaud, M. Synthesis, 1982, 914) dissolved in about 30 ml of dry tetrahydrofuran was slowly added thereto. The temperature of the reaction mixture was slowly raised to room temperature over two hours. The reaction was completed by slowly adding saturated ammonium chloride solution (˜50 ml). The reaction mixture was filtered through Celite to remove the precipitates, and then washed with diethylether. The organic layer was washed with water and saturated sodium bicarbonate solution (300 ml×2), dried (anhydrous Na2SO4), and concentrated under reduced pressure to give 26.7 g (stoichiometric yield) of a transparent liquid. This liquid was identified by 1H-NMR (500 MHz, CDCl3) and was confirmed to be the title compound having about 75% of w/w purity.
Reaction SMILES: O=C(CC1C=CC=CC=1)C(OC)=O.C([BH3-])#N.[Na+].C(OC([NH:25][C@H:26]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]([CH:33]([C:41]([O:43]C)=[O:42])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]1=[O:45])=O)(C)(C)C>>[NH2:25][C@H:26]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]([CH:33]([C:41]([OH:43])=[O:42])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]1=[O:45]
Reactant: COC(=O)C(Cc1ccccc1)N1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: COC(=O)C(=O)Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: N[C@H]1CCCCN(C(Cc2ccccc2)C(=O)O)C1=O

Procedure:
Methyl 2-oxo-3-phenylpropionate and α-t-Boc-L-lysine are condensed in the presence of sodium cyanoborohydride as described in Example 19. Subsequent ring closure to 3-(S)-t-butoxycarbonylamino-1-[1-carbomethoxy-2-phenylethyl]perhydroazepin-2-one is carried out as described in Example 3. Saponification of the methyl ester followed by removal of the t-butoxycarbonyl group affords 3-(S)-amino-1-[1-carboxy-2-phenylethyl]perhydroazepin-2-one. The caprolactam and 2-oxo-4-phenylbutyric acid are condensed in the presence of sodium cyanoborohydride to yield 1-[1-carboxy-2-phenylethyl]-3-(S)-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one.
Reaction SMILES: C([NH:9][C:10]([NH:22][CH2:23][CH2:24][CH2:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)=[N:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[N:17]=[CH:18][NH:19][C:20]=1[CH3:21])(=O)C1C=CC=CC=1.[ClH:31]>>[ClH:31].[ClH:31].[ClH:31].[NH:29]1[CH:30]=[C:26]([CH2:25][CH2:24][CH2:23][NH:22][C:10]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C:16]2[N:17]=[CH:18][NH:19][C:20]=2[CH3:21])=[NH:9])[N:27]=[CH:28]1
Reactant: Cc1[nH]cnc1CSCCN=C(NCCCc1c[nH]cn1)NC(=O)c1ccccc1
Agent: Cl
Product: Cc1[nH]cnc1CSCCNC(=N)NCCCc1c[nH]cn1

Procedure:
N-Benzoyl-N'-[3-(4-imidazolyl)propyl]-N"-[2-(5-methyl-4-imidazolylmethylthio)ethyl]guanidine (2.37 g) was heated overnight on a steam bath with conc. hydrochloric acid (135 ml). The aqueous reaction mixture was evaporated to ca 75% of its original volume to remove the excess of hydrogen chloride. The aqueous residue obtained was extracted with diethyl ether to remove benzoic acid. The aqueous phase was evaporated at reduced pressure and azeotroped with ethanol (100 ml). The oily residue was recrystallised from ethanol to yield N-[3-(4-imidazolyl)propyl]-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]guanidine trihydrochloride (1.93 g) m.p. 200°-201° C.