Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2].[Cl:10][CH2:11][C:12](Cl)=[O:13].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:1]([N:3]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:12](=[O:13])[CH2:11][Cl:10])[CH3:2]
Reactant: CCNC1CCCCC1
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCN(C(=O)CCl)C1CCCCC1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
N-Ethyl-cyclohexylamine (2.6 g) is dissolved in dry benzene (20 ml). To the solution are added dropwise with stirring chloroacetyl chloride (2.6 g) and triethylamine (2.4 g) under ice-cooling. The mixture is stirred under ice-cooling for one hour and further at room temperature for one hour. The reaction mixture is poured onto ice-water and extracted with ether. The ether layer is washed with an aqueous sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting residue is distilled under reduced pressure to give N-ethyl-N-cyclohexyl-chloroacetamide (3 g), b.p. 118°-120° C./0.2 mmHg.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl.N1C=CC=CC=1>[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[S:18]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:18]([C:10]1[O:9][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=1)(=[O:19])=[O:20])(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: Nc1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccccc1NS(=O)(=O)c1cc2ccccc2o1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.9 %

Procedure:
To a solution of benzene-1,2-diamine (0.5 mmol) in DCM (2 mL) and pyridine (0.5 mL) at 0° C., benzofuran-2-sulfonyl chloride (1.1 mmol; prepared as in Example 12) was added at 0° C. in small portions over 10-15 min. The reaction mixture was then gradually warmed to RT with stirring continued for 6 h. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% aqueous HCl (5 mL), water (5 mL), and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM followed by EtOAc/DCM (1% to 3%) to give 117 mg of N-{2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}-1-benzofuran-2-sulfonamide. Tr 1.18 min; MS: 469.7 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[NH:14][CH2:13][CH2:12]3)[O:3]1.I[CH2:22][CH3:23]>>[CH2:22]([N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([B:4]3[O:3][C:2]([CH3:20])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:10]=2)[C:15]1=[O:19])[CH3:23]
Reactant: CCI
Reactant: CC1(C)OB(c2ccc3c(c2)CCNC3=O)OC1(C)C
Product: CCN1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 9, Step 1 starting from 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one and iodoethane. LCMS (M+H)+=302.1.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]([N:9]1[C:13](=[O:14])[C:12](Cl)=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10]1(=[O:23])=[O:22])([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C.CCOC(C)=O>[NH2:3][CH2:2][CH2:1][NH:4][C:12]1[C:13](=[O:14])[N:9]([C:5]([CH3:7])([CH3:6])[CH3:8])[S:10](=[O:23])(=[O:22])[C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCN
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NCCN)=C(c2ccccc2)S1(=O)=O
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
Ethylenediamine (0.60 g, 10.0 mmol) was dissolved in dry DMF (50 ml) and heated to 60° C. 2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (1.00 g, 3.34 mmol) dissolved in DMF (10 ml) was added dropwise over 30 mins and stirred at 60° C. for 10 mins. The reaction mixture was diluted with EtOAc (300 ml) and washed with water (400 ml and 2×200 ml), dried (Na2SO4), filtered and evaporated to give the title compound (0.97 g, 90%). 1H-NMR (500 MHz, CDCl3): δ 7.50-7.45 (m, 2H), 7.42-7.37 (m, 3H), 5.83-5.76 (m, 1H), 2.84-2.78 (m, 2H), 2.67-2.62 (m, 2H), 1.71 (s, 9H); 13C-NMR (125 MHz, CDCl3): δ 159.7, 135.4, 131.6, 129.5, 128.6, 125.2, 106.9, 61.5, 46.2, 40.8, 27.7; Mass Spectrum: M+H+ 324.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[N:32]=[C:31]([CH3:33])[C:30](Br)=[CH:29][CH:28]=1>>[CH3:33][C:31]1[N:32]=[C:27]([NH2:26])[CH:28]=[CH:29][C:30]=1[C:2]#[C:1][C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12
Reactant: Cc1nc(N)ccc1Br
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(N)ccc1C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 6-amino-3-bromo-2-methylpyridine (168 mg, 1.0 mmol) according to general procedure II. Obtained as a dark-red solid (90 mg, 19%). MS (ISP) 462.2 [(M+H)+]; mp 251-254° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])NC(CC1C=C(F)C=C(F)C=1)C(O)CNC1(C2C=CC=C(C#C)C=2)CC1)([CH3:4])([CH3:3])[CH3:2].Cl.O1CCO[CH2:37][CH2:36]1>CO>[C:6]([C:36]#[CH:37])([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:33]
Reactant: C1COCCO1
Reactant: C#Cc1cccc(C2(NCC(O)C(Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CO
Product: C#CC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 360 %

Procedure:
[1-(3,5-difluorobenzyl)-3-[1-(3-ethynylphenyl)cyclopropylamino]-2-hydroxypropyl]-carbamic acid tert-butyl ester (2.34 g, 5.13 mmol) was treated with 4N HCl in dioxane (15.8 mL, 63.3 mmol). The resulting heterogeneous mixture was treated with methanol (10 mL) whereupon it became homogeneous over 30 min. The volatiles were evaporated in vacuo. Dioxane (20 mL) was added and the mixture was evaporated in vacuo to produce a white solid (2.33 g, 106%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]3([CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH2:9][N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[C:5]2=[CH:4][C:3]=1[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.COC1C=CC(C[NH2:47])=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[F:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([N:10]3[C:5]4[C:6](=[N:7][C:2]([NH2:47])=[C:3]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH:4]=4)[C:8]4([CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH2:9]3)=[C:12]([CH3:28])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2nc(Br)c(N3CCOCC3)cc21
Reactant: COc1ccc(CN)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2nc(N)c(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5′-bromo-1′-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (60 mg, 0.102 mmol) in 1,4-dioxane (1.5 mL) was added 4-methoxybenzylamine (19.78 μL, 0.152 mmol) and sodium tert-butoxide (19.53 mg, 0.203 mmol). The reaction was heated at reflux for 2 h. After this time the reaction was partitioned between EtOAc (50 mL) and water (15 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. The crude mixture was then dissolved in DCM (3 mL) and treated with TFA (0.5 mL) and stirred at rt for 2 h. At this time the reaction was evaporated in vacuo and partitioned between DCM (30 mL) and NaHCO3 (10 mL, sat. aqueous solution). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. The resulting crude product was purified by reverse phase HPLC (10 to 60% acetonitrile water) to give 1′-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-5′-amine. 1H NMR (400 MHz, chloroform-d) δ ppm 8.71-8.78 (1H, m), 7.77-7.94 (4H, m), 7.40 (1H, ddd, J=7.2, 4.9, 1.6 Hz), 7.18-7.26 (1H, m), 6.10-6.15 (1H, m), 4.13 (2H, q, J=7.2 Hz), 3.92-4.02 (2H, m), 3.68-3.86 (4H, m), 3.51-3.60 (2H, m), 2.67-2.82 (4H, m), 2.24-2.41 (5H, m), 1.67-1.84 (2H, m). Mass Spectrum (ESI) m/e=527.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7].Cl[C:35]1[N:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[N:36]=1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([C:35]3[N:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[N:36]=3)[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: COc1cc(OC)nc(Cl)n1
Product: COc1cc(OC)nc(N2CN(c3ccccc3)C3(CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)C2=O)n1

Procedure:
The title compound, MS: m/e=610.0 (M+H+), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and 2-chloro-4,6-dimethoxypyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18]>C(O)C.N1C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:17][OH:18])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C(c1ccccc1)c1ccc(Br)cc1
Yield: 94 %

Procedure:
A mixture of 4-bromobenzophenone (10.0 g, 0.0383 mol) and hydroxylamine hydrochloride (13.3 g, 0.192 mol) was heated in a mixture of ethanol (250 mL) and pyridine (50 mL) at reflux for 2 hours under an atmosphere of nitrogen. The solvents were removed under the reduced pressure and the residue was partitioned between water (300 mL) and dichloromethane (300 mL). The water phase was further extracted with dichloromethane twice (180 mL each) and the combined organic extracts were dried over magnesium sulfate. The solvent was removed under the reduced pressure and the residue was purified by flash chromatography on silica gel using ethyl acetate/n-heptane (1:9) as mobile phase to yield (4-bromophenyl)(phenyl)methanone oxime as a white solid (9.93 g, 0.036 mol): 1H NMR (DMSO-d6, 400 MHz) 7.66 (d, 1H), 7.57(d, 1H), 7.33 (m, 7H) TLC (ethyl acetate/heptane 1:5) Rf 0.38.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[CH3:10][O:11]/[N:12]=[C:13](/[C:36]1[N:37]=[CH:38][S:39][CH:40]=1)\[C:14]([NH:16][CH:17]1[C:34](=[O:35])[N:19]2[C:20]([C:31]([O-:33])=[O:32])=[C:21]([CH2:24][S:25][C:26]3[S:30][N:29]=[CH:28][N:27]=3)[CH2:22][S:23][C@H:18]12)=[O:15].[Na+]>CN(C)C=O>[CH3:8][C:7]1[O:6][C:5](=[O:9])[O:4][C:3]=1[CH2:2][O:33][C:31]([C:20]1[N:19]2[C:34](=[O:35])[CH:17]([NH:16][C:14](=[O:15])/[C:13](=[N:12]\[O:11][CH3:10])/[C:36]3[N:37]=[CH:38][S:39][CH:40]=3)[C@H:18]2[S:23][CH2:22][C:21]=1[CH2:24][S:25][C:26]1[S:30][N:29]=[CH:28][N:27]=1)=[O:32]
Reactant: Cc1oc(=O)oc1CBr
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(CSc3ncns3)CS[C@H]12)c1cscn1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OCc3oc(=O)oc3C)=C(CSc3ncns3)CS[C@H]12)c1cscn1
Reaction time: 1.3 h
Yield: 31 %

Procedure:
4-Bromomethyl-5-methyl-1,3-dioxolene-2-one (386 mg) was added to a solution of sodium 7-[(Z)-2-methoxyimino-2-(thiazol-4-yl)acetamido]-3-(1,2,4-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylate (522 mg) in N,N-dimethylformamide (5 ml) at -5° C. and the mixture was stirred at this temperature for 1.3 hr. The reaction mixture was then treated in the same manner as in Example 14, giving the title compound (190 mg). ##STR39##
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:10][CH2:9][C:8]([O:12][CH3:13])=[O:11]
Reactant: C=CC(=O)OC
Reactant: NCc1cccs1
Solvent: CCO
Product: COC(=O)CCNCc1cccs1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of thiophen-2-ylmethanamine (20.0 g, 176.7 mmol) in ethanol (1 L) at 0° C. was added methyl acrylate (15.21 g, 176.7 mmol). The reaction was allowed to warm to room temperature overnight, at which point HPLC analysis indicated that the reaction was complete. The solvent was removed in vacuo to give methyl 3-(thiophen-2-ylmethylamino)propanoate (Compound 1040) as a pale tan oil (35.21 g, 99%); 1H NMR (300 MHz, CDCl3): δ 7.28 (s, CHCl3), 7.22 (dd, J=1.5, 4.7 Hz, 1H), 6.97-6.95 (m, 2H), 4.16 (q, J=7.1 Hz, 2H), 4.02 (s, 3H), 3.69 (d, J=5.0 Hz, 2H), 2.95 (t, J=6.5 Hz, 2H) and 2.57-2.48 (m, 2H).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]2[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)=[N:10]1)=[O:5])C.[OH-].[Na+]>O.CO>[C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]2[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=23)=[N:10]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Yield: 74.4 %

Procedure:
A mixture of 3-[2-(3-ethoxycarbonylpropyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (13.7 g) and sodium hydroxide (2.73 g) in a mixture of water (8.6 ml) and methanol (96 ml) was refluxed for 2 hours and then the solvent was evaporated in vacuo. The residue was dissolved in water, and the aqueous solution was acidified with hydrochloric acid, and extracted with chloroform. The extract was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was recrystallized from a mixture of ethanol and n-hexane to give 3-[2-(3-carboxypropyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (9.48 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH:6]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=[O:16])[C:7]([O:9]C(C)(C)C)=[O:8].C(O)(C(F)(F)F)=O>ClC(Cl)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH:6]([NH:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:21][CH:22]=1)=[O:16])[C:7]([OH:9])=[O:8]
Reactant: COC(=O)CCC(NC(=O)c1ccc(-c2ccccc2)cc1)C(=O)OC(C)(C)C
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCC(NC(=O)c1ccc(-c2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
2-[(Biphenyl-4-carbonyl)-amino]-pentanedioic acid 1-tert-butyl ester 5-methyl ester (1.5 g, 3.8 mmol) was dissolved in dichloroethane (26 mL) and the mixture was added to TFA (13 mL). The mixture was stirred at room temperature for 4 hrs. TLC indicated the reaction was complete. Solvent was evaporated by rotovap. The solid obtained was washed with EtOAc and water. After drying, 2-[(Biphenyl-4-carbonyl)-amino]-pentanedioic acid 5-methyl ester was obtained in 87% yield (1.128 g). MS (ESI) m/z 342.
Reaction SMILES: C[O:2][C:3](=[O:45])[CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([O:35][Si](C(C)(C)C)(C)C)[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:43])[CH:23]=3)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][C:12]=2[CH3:44])[CH:8]=[CH:9][CH:10]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:18]([C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:45])=[O:2])[CH:6]=2)=[C:12]([CH3:44])[CH:13]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:33])([CH3:34])[CH3:32])=[C:24]([CH3:43])[CH:23]=1)[CH2:20][CH3:21])[CH3:19]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cccc(CC(=O)OC)c2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cccc(CC(=O)O)c2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
[4′-(1-{4-[3-(t-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2′-methyl-biphenyl-3-yl]-acetic acid methyl ester (Example 66-(1); 36 mg, 0.057 mmol) was dissolved in dichloromethane/trifluoroacetic acid=1/5 (1 mL), and the solution was stirred at room temperature for three hours. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel chromatography (hexane only to hexane/ethyl acetate=1/1). The product was dissolved in methanol/tetrahydrofuran=1/1 (1 mL). A 1 N sodium hydroxide aqueous solution (0.1 mL) was added, and the mixture was stirred at room temperature for one hour. A 30% sodium dihydrogenphosphate aqueous solution (0.3 mL) was added to the reaction mixture, and then the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=1/1) to give the title compound (23 mg, 80%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]([C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=1)/[CH:4]=[CH:5]/[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][NH2:17])=[CH:8][CH:7]=1.CCN(CC)CC.[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>C(Cl)Cl>[CH2:36]([NH:38][C:39]([NH:17][CH2:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6](/[CH:5]=[CH:4]/[CH:3]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:2]([F:1])([F:27])[F:28])=[CH:7][CH:8]=1)=[O:40])[CH3:37]
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine (0.1 g, 0.22 mmol) in CH2Cl2 at 0° C. were added Et3N (0.064 mL, 0.44 mmol) and ethylisocyanate (0.023 mL, 0.33 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 30% EtOAc in hexane) afforded the title compound as a solid (0.07 g, 60%): mp 84-87° C.; 1H NMR (400 MHz, CDCl3) δ 8.06 (m, 1H), 7.98 (m, 1H), 7.61 (m, 3H), 7.48 (s, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.38 (m, 2H), 6.42 (m, 1H), 4.92 (s, 2H), 4.6 (br s, 1H), 4.24 (m, 1H), 3.21 (m, 2H), 1.2 (t, J=4.6 Hz, 3H); ESIMS m/z 515.33 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[C@H:3]([NH2:10])[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][O:21][CH3:22]>CC#N>[CH3:22][O:21][CH2:20][CH2:19][NH:10][C@@H:3]([CH:2]([CH3:11])[CH3:1])[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COCCBr
Reactant: CC(C)[C@H](N)CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN[C@H](CN1CCCC1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3-Methyl-1-(pyrrolidin-1-yl)butan-2-amine (0.24 g, 1.54 mmol), which is commercially available, and potassium carbonate (0.139 mL, 2.30 mmol) was slurried in MeCN. 1-Bromo-2-methoxyethane (0.147 mL, 1.54 mmol) was added and the reaction was stirred at rt for 2 h. LMCS showed only traces of the desired product. DIPEA (0.535 mL, 3.07 mmol) was added and the resultant mixture was stirred at rt over night and heated at 60° C. for 4 h. The mixture was cooled to rt and diluted with water (50 mL) and DCM (50 mL). The two layers were separated and the water layer was extracted with DCM (3×100 mL). The organic layers were combined and washed with brine (100 mL), passed through phase separator and concentrated under reduced pressure to give the title compound (0.31 g, 97%). The obtained crude product was used without further purification. LCMS (M+H)+: 215.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[CH2:12]([N:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[NH:22][CH:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20]1=[O:36])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:26]2[CH2:27][CH2:28][C:23]3([N:19]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:20](=[O:36])[CH:21]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[NH:22]3)[CH2:24][CH2:25]2)=[O:11])=[CH:7][CH:8]=1
Reactant: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Reactant: COc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)N2CCC3(CC2)NC(Cc2ccccc2)C(=O)N3Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
4-Methoxyphenyl isocyanate (221 mg, 1.49 mmol) was added to a solution of 1,3-di-benzyl-1,4,8-triazaspiro[4,5]decan-2-one (499 mg, 1.49 mmol) in toluene (12.3 ml) with stirring under a blanket of nitrogen at RT. The reaction mixture was stirred at 115° C. for 4 h. After removal of the solvent, the desired product 11,3-dibenzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylic acid (4-methoxyphenyl)amide was obtained by means of preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:16](Br)([CH3:18])[CH3:17]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH:16]([CH3:18])[CH3:17])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: CC(C)Br
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1C(C)C

Procedure:
The title compound, MS: m/e=260.6 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and isopropylbromide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([OH:11])=[C:4]([N+:12]([O-])=O)[C:3]=1[CH3:15].C(OCC)(=O)C>C(O)(=O)C.[Zn]>[NH2:12][C:4]1[C:3]([CH3:15])=[C:2]([Cl:1])[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[C:5]=1[OH:11]
Reactant: Cc1c(Cl)cc(C(C)C)c(O)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1c(Cl)cc(C(C)C)c(O)c1N
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Zinc (6.4 g, 98 mmol) was added little by little to a solution of the nitro compound (1.88 g, 8.18 mmol) in acetic acid (30 ml) with ice cooling. After stirring for 1 hour, the reaction solution was diluted by adding ethyl acetate thereto and the mixture was filtered off. The filtrate was neutralized with an aqueous solution of sodium carbonate and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over magnesium sulfate and the solvent was evaporated therefrom to provide 1.63 g (yield 99%) of 2-amino-4-chloro-6-isopropyl-3-methylphenol as pale yellow oil.