Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:27])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[C:20]([Cl:26])[CH:19]=1)[CH3:14].I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1.CN1CCCN(C)C1=O>[CH2:13]([O:15][C:16](=[O:27])[CH:17]([C:18]1[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[C:20]([Cl:26])[CH:19]=1)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH3:14]
Reactant: ICC1CCCC1
Reactant: CCOC(=O)Cc1ccc(SC)c(Cl)c1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCCC1)c1ccc(SC)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
A solution of diisopropylamine (457 μL, 3.26 mmol) in tetrahydrofuran (5 mL) was cooled to −78° C. under a nitrogen atmosphere and then treated with a 2.5 M solution of n-butyllithium in hexanes (1.3 mL, 3.26 mmol). The mixture was stirred at −78° C. for 30 min, at which time, a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid ethyl ester (0.67 g, 2.75 mmol) in tetrahydrofuran (8 mL) was slowly added to the reaction mixture. The reaction mixture turned deep yellow in color. The reaction mixture was then further stirred at −78° C. for 30 min, at which time, a solution of iodomethylcyclopentane (0.65 g, 3.09 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (1 mL) was added via syringe. The reaction mixture was then allowed to warm to 25° C., where it was stirred for 16 h. The reaction mixture turned red in color during this time period. The reaction mixture was quenched with a 6 N aqueous hydrochloric acid solution (5 mL) and further diluted with water (20 mL). The reaction mixture was then extracted with methylene chloride (3×20 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid ethyl ester (0.50 g, 56%) as a light yellow oil.
Reaction SMILES: C(OC([N:6]1[CH2:10][CH2:9][C:8]([OH:21])([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:7]1)=O)C.[OH-].[K+]>O1CCOCC1.C(O)CCC>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:13]=[CH:12][C:11]([C:8]2([OH:21])[CH2:9][CH2:10][NH:6][CH2:7]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)N1CCC(O)(c2ccc(C(F)(F)F)cc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: C1COCCO1
Product: OC1(c2ccc(C(F)(F)F)cc2)CCNC1
Yield: 57 %

Procedure:
To a solution of 1.98 mmol rac-3-Hydroxy-3-(4-trifluoromethyl-phenyl)-pyrrolidine-1-carboxylic acid ethyl ester in 15 ml dioxane., was added 8 ml of a 2.5N solution of KOH in butanol. The solution was stirred under reflux for 2 hours. The solvent was removed in vacuo and the residue was taken in water. The aqueous phase was extracted 3 times with dichloromethane. The combined organic phases were dried over Na2SO4, evaporated and dried. The compound was suspended in hexane/ether (˜2:1), filtered and rinsed with hexane to yield the title compound (57%) as a light brown solid MS (m/e): 232.1 ([M+1], 100%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][O:9][C:10]1[C:11]([N:16]=[C:17](SC)[S:18][CH3:19])=[N:12][CH:13]=[CH:14][N:15]=1.O>C(#N)C>[CH3:8][O:9][C:10]1[C:11]2[N:12]([C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:17]([S:18][CH3:19])[N:16]=2)[CH:13]=[CH:14][N:15]=1
Reactant: CCOC(=O)CBr
Reactant: COc1nccnc1N=C(SC)SC
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1c(SC)nc2c(OC)nccn12
Temperature: 100 °C
Reaction time: 14 h

Procedure:
Ethyl bromoacetate (18.5 mL) and iso-dipropylethylamine (29 mL) were added to a solution of methyl N-(3-methoxy-2-pyrazinyl)-(methylsulfanyl)methaneimidothioate (19.1 g) in acetonitrile (42 mL), and the mixture was heated under stirring at 100° C. for 14 hours. After the reaction mixture was cooled to room temperature, water was added thereto, which was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and evaporated. The resulting residue was washed with n-hexane to give the title compound (10.7 g) as pale yellow crystals.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][CH:3]([CH2:7][O:8][C:9]1[C:17]([CH:18]3[CH2:20][CH2:19]3)=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([F:21])[CH:10]=1)[CH2:2]2.CS(N)(=O)=O.[N:27]1([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:30][CH2:29][CH2:28]1>>[N:27]1([S:31]([NH:34][C:13](=[O:14])[C:12]2[CH:16]=[C:17]([CH:18]3[CH2:19][CH2:20]3)[C:9]([O:8][CH2:7][CH:3]3[CH2:4][CH:5]4[CH:1]([CH2:6]4)[CH2:2]3)=[CH:10][C:11]=2[F:21])(=[O:33])=[O:32])[CH2:30][CH2:29][CH2:28]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CC3CC3C2)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2CC3CC3C2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(bicyclo[3.1.0]hexan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a white solid (0.037 g, 27%): 1H NMR (300 MHz, CDCl3) δ11.60 (br, s, 1H), 7.13 (d, J=8.31 Hz, 1H), 6.94 (d, J=12.98 Hz, 1H), 4.11-3.96 (m, 4H), 3.83 (d, J=7.42 Hz, 2H), 2.83-2.67 (m, 1H), 2.25-2.07 (m, 4H), 2.05-1.92 (m, 1H), 1.58-1.45 (m, 2H), 1.37-1.26 (m, 2H), 0.94-0.82 (m, 2H), 0.72-0.54 (m, 3H), 0.14-0.06 (m, 1H); MS (ES+) m/z 409.1 (M+1).
Reaction SMILES: C(O[SiH](OCC)OCC)C.[C:11]1([CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>CC(C)[O-].[Dy+3].CC(C)[O-].CC(C)[O-].C1COCC1>[C:11]1([CH2:17][CH2:18][CH:19]([OH:21])[CH3:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CCc1ccccc1
Agent: CC(C)[O-]
Agent: CCO[SiH](OCC)OCC
Agent: [Dy+3]
Solvent: C1CCOC1
Product: CC(O)CCc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
A dry Schlenk tube under argon was charged with 51 mg (0.15 mmol) of dysprosium (III) isopropoxide. Triethoxysilane (1.4 mL, 7.5 mmol) was added, and the reaction mixture was heated to 60° C. After 0.5 hours, 4-phenyl-2-butanone (450 μL, 3 mmol) was added. After 24 hours, the reaction was complete, as determined by GLC analysis of a aliquot taken from the reaction mixture. THF (8 mL) and aqueous NaOH (1 N, 15 mL) were added, and the mixture was stirred vigorously for 12 hours. After work-up as in Example 13, the crude material was purified by flash chromatography (ether:hexane=3:7) to afford 234 mg (52% yield) of 4-phenyl-2-butanol (>95% pure by 1H-NMR analysis).
Reaction SMILES: Br[CH:2]([CH3:31])[C:3]([NH:5][C:6]1[S:21][C:9]2[CH2:10][N:11]([C:14]([O:16][CH2:17][CH2:18][C:19]#[CH:20])=[O:15])[CH2:12][CH2:13][C:8]=2[C:7]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])=[O:4].[NH3:32]>C(OCC)(=O)C>[NH2:32][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[S:21][C:9]2[CH2:10][N:11]([C:14]([O:16][CH2:17][CH2:18][C:19]#[CH:20])=[O:15])[CH2:12][CH2:13][C:8]=2[C:7]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])=[O:4]
Reactant: C#CCCOC(=O)N1CCc2c(sc(NC(=O)C(C)Br)c2C(=O)c2ccccc2Cl)C1
Reactant: N
Solvent: CCOC(C)=O
Product: C#CCCOC(=O)N1CCc2c(sc(NC(=O)C(C)N)c2C(=O)c2ccccc2Cl)C1
Temperature: 100 °C

Procedure:
1.16 g of 2-(2-bromopropionylamino)-3-(2-chlorobenzoyl)-6-(3-butynyloxycarbonyl)-4,5,6,7-tetrahydro-thieno[2,3-C]pyridine was dissolved in 36 ml of ethyl acetate, into which ammonia gas was introduced under cooling conditions, followed by heating in a sealed tube at 100° C. After completion of the reaction, the mixture was cooled, to which 50 ml of ethyl acetate was added. The mixture was washed with 1N hydrochloric acid, after which the aqueous phase was neutralized with a sodium carbonate aqueous solution and extracted with chloroform. The resultant organic phase was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced conditions and the resultant residue was purified by the use of silica gel column chromatography (elution solvent: dichloromethane), thereby obtaining 0.36 g of the intended compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11].O>CN(C)C=O>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:11]
Reactant: CCOC(CBr)OCC
Reactant: Nc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CNc1ncccn1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
A solution of 2-aminopyrimidine (1.9 g.) in dried dimethylformamide (8 ml.) was dropwise added to a suspension of 50% sodium hydride (1.25g.) in dried dimethylformamide (2 ml.) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and for 2 hours at ambient temperature. Bromoacetaldehyde diethyl acetal (4.3 g.) and dried dimethylformamide (2 ml.) were added thereto, and the mixture was stirred for 2 hours and 20 minutes at ambient temperature and for 2.5 hours at 80° C. The reaction mixture was cooled to at ambient temperature and to the mixture was added water, and then the mixture was extracted 3 times with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution in turn, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residual oil was purified by column chromatography on silica gel (25 g.) using chloroform as developing solvent to give 2-pyrimidinylaminoacetaldehyde diethyl acetal (1.4 g.), oil. This oil was allowed to stand to give crystals.
Reaction SMILES: [C:1]([C:3]1([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=4)[CH2:24][CH2:23]3)[C@@H:18]([CH3:35])[CH2:17]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#N.C[Mg]Br>C1COCC1.CCOCC>[CH3:1][C:3]1([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=4)[CH2:24][CH2:23]3)[C@@H:18]([CH3:35])[CH2:17]2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:5][CH2:4]1
Reactant: C[C@H]1CN(C2(C#N)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CCc2ccc(C(F)(F)F)cc21
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CCc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a solution of tert-butyl 4-cyano-4-{(3S)-3-methyl-4-[6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl}piperidine-1-carboxylate (0.72 g, 1.3 mmol) in THF (20 mL) was added a 3 M solution of methylmagnesium bromide in ether (4.0 mL). After being stirred at room temperature overnight, the reaction was quenched by addition of water. The resulting solution was extracted with EtOAc twice. The combined EtOAc layers were dried and concentrated. Column chromatography on silica (20-30% EtOAc in hexane) provided the title compound (0.32 g, 50%) as a viscous oil. MS calculated for C26H38F3N3O2: (M+H)+482; found 482.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[O:16]=[C:14]1[CH2:15][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:10]([O:12][CH3:17])=[O:11])[CH2:13]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tetrapropylammonium perruthenate (287 mg, 0.82 mmol) was added to a solution of trans-N-(tert-butoxycarbonyl)-4-hydroxy-L-proline (2.0 g, 8.15 mmol) and 4-methylmorpholine N-oxide (2.1 g, 17.9 mmol) in dichloromethane (50 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 1-tert-butyl 2-methyl (2S)-4-oxopyrrolidine-1,2-dicarboxylate.
Reaction SMILES: FC1C=C(C2CC(=O)C3C(=CC=C(O)C=3)O2)C=CC=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[C:28](=[O:30])[CH3:29].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:33]=1[CH:34]=O>>[OH:27][C:24]1[CH:23]=[C:22]2[C:21](=[CH:26][CH:25]=1)[O:20][CH:34]([C:33]1[C:32]([F:31])=[CH:39][CH:38]=[CH:37][C:36]=1[F:40])[CH2:29][C:28]2=[O:30]
Reactant: O=Cc1c(F)cccc1F
Reactant: CC(=O)c1cc(O)ccc1O
Agent: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Product: O=C1CC(c2c(F)cccc2F)Oc2ccc(O)cc21

Procedure:
6-Hydroxy-2-(2,6-Difluorophenyl)chroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 3.0 g of 2′,5′-dihydroxyacetophenone and 2.6 ml of 2,6-difluorobenzaldehyde. The product was triturated from ethanol. 1H NMR (400 MHz, d6-DMSO) δ: 7.55 (m, 1H) 7.22-7.18 (m, 2H), 7.14 (d, 1H, J 3.0 Hz), 7.03 (dd, 1H, J 8.9, 3.0 Hz), 6.93 (d, 1H, J 8.9 Hz), 5.84 (dd, 1H, J 14.0, 3.0 Hz), 3.38 (dd, 1H, J −17.0, 14.0 Hz), 2.80 (dd, 1H, J −17.0, 3.0 Hz).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.B(O)(O)[C:33]1[S:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[S:41]1[C:33]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:13])=[O:14])[CH:9]=3)[NH:4][N:3]=2)=[CH:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:40]1=2
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Reactant: OB(O)c1cc2ccccc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1
Yield: 35.8 %

Procedure:
N-(3-Benzo[b]thiophen-2-yl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 59 from 0.5 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 300 mg of thianaphthene-2-boronic acid, 20 ml of dimethylformamide, 1.9 ml of a saturated aqueous solution of sodium hydrogencarbonate and 25 mg of tetrakis(triphenylphosphine)palladium[0]. 150 mg of N-(3-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting at 270° C. (analysis C22H17N3O4S3 % calculated C, 54.64; H, 3.54; N, 8.69; O, 13.23; S, 19.89. % found C, 54.59H: 3.47; N, 8.79; S, 19.98).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:5]=[C:4]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[CH:3]=1.C([N:25]([CH2:29][CH3:30])[CH:26](C)C)(C)C.N1CCC1>C(O)CCC>[N:25]1([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:14])[N:5]=[C:4]([NH:15][C:16]3[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=3)[CH:3]=2)[CH2:26][CH2:30][CH2:29]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(Nc2cc(Cl)nc(-c3ccccc3Cl)n2)n[nH]1
Agent: C1CNC1
Solvent: CCCCO
Product: Cc1cc(Nc2cc(N3CCC3)nc(-c3ccccc3Cl)n2)n[nH]1
Temperature: 108 °C
Yield: 76.6 %

Procedure:
A mixture containing 6-chloro-2-(2-chlorophenyl)-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (430 mg, 1.34 mmol), N,N-diisopropylethylamine (1.17 ml, 6.72 mmol), azetidine (272 mL, 4.03 mmol) and n-butanol (20 mL) was heated at 108° C. overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo. The concentrate was treated with ethyl acetate/Petroleum ether and water and the resulting solid filtered. The solid was washed with further quantities of ethyl acetate/Petroleum ether and water and dried in vacuo to give the title compound as a white solid (350 mg, 76%). MS (ES+) m/e=341. 1H NMR: (DMSO) 2.28-2.40 (2H, m), 3.91-4.03 (4H, m), 5.90 (1H, brs), 6.30 (1H, brs), 7.31-7.60 (4H, m), 9.28 (1H, brs), 11.88 (1H, brs).
Reaction SMILES: C1(C[O:8][C:9](=[O:53])[CH2:10][N:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:25]([O:41][C:42](=[O:52])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH:24]=2)[CH2:12][C:13](=[O:22])[O:14]CC2C=CC=CC=2)C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.C1COCC1>[C:13]([CH2:12][N:11]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:25]([O:41][C:42](=[O:52])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH:24]=1)[CH2:10][C:9]([OH:53])=[O:8])([OH:22])=[O:14]
Reactant: CCCCCCCCCC(=O)Oc1ccc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)cc1OC(=O)CCCCCCCCC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCC(=O)Oc1ccc(N(CC(=O)O)CC(=O)O)cc1OC(=O)CCCCCCCCC
Reaction time: 10 h
Yield: 78.5 %

Procedure:
A mixture of 2.2 g of N-[3,4-bis[(1-oxodecyl)oxy]phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester and 0.5 g of 10% palladium on carbon in 20 ml of ethyl acetate and 30 ml of THF was stirred in a hydrogen atmosphere at room temperature until uptake ceased after 10 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a semisolid which was crystallized from ethyl acetate-hexane to give 1.3 g (78% yield, mp 131°-133°) of N-(carboxymethyl)-N-[3,4-bis[(1-oxodecyl)oxy]phenyl]glycine.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[CH:15]=2)=[CH:7][CH:6]=1.[CH2:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH2:31][CH3:32])[CH:30]=1)[C:25](Cl)=[O:26])[CH3:21]>>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[C:15]=2[C:25](=[O:26])[C:24]2[CH:28]=[C:29]([CH2:31][CH3:32])[CH:30]=[C:22]([CH2:20][CH3:21])[CH:23]=2)=[CH:7][CH:6]=1
Reactant: BrCCOc1ccc(-c2cc3ccccc3o2)cc1
Reactant: CCc1cc(CC)cc(C(=O)Cl)c1
Product: CCc1cc(CC)cc(C(=O)c2c(-c3ccc(OCCBr)cc3)oc3ccccc23)c1

Procedure:
Acylation of 2-[4'-(2-bromoethoxy)phenyl]benzofuran with 3,5-diethylbenzoyl chloride as described hereinabove gave 2-[4'-(2-bromoethoxy)phenyl]-3-(3',5'-diethylbenzoyl)benzofuran.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:13])=[N:5][C:6]2[N:7]([N:10]=[CH:11][N:12]=2)[C:8]=1[NH2:9])#[CH:2].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:9][C:8]1[N:7]2[N:10]=[CH:11][N:12]=[C:6]2[N:5]=[C:4]([CH3:13])[C:3]=1[C:1]#[C:2][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1
Reactant: C#Cc1c(C)nc2ncnn2c1N
Reactant: COC(=O)C(C)(C)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C(C)(C)c1ccc(C#Cc2c(C)nc3ncnn3c2N)cc1
Yield: 45.8 %

Procedure:
A mixture of Example 72B (17 mg, 0.1 mmol), methyl 2-(4-bromophenyl)-2-methylpropanoate (38 mg, 0.15 mmol), bis(triphenylphosphine)palladium(II) dichloride (3.5 mg, 0.005 mmol), CuI (1 mg, 0.005 mmol), and triethylamine (28 μL, 0.2 mmol) in acetonitrile (500 μL) was heated at 95° C. under nitrogen for 1 h. The resulting mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated in vacuuo. The residue was purified by flash chromatograph on silica gel (eluting with ethyl acetate) to provide the title compound as a white solid (16 mg, 45% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.44 (s, 3H), 7.64 (d, J=8.48 Hz, 2H), 7.36 (d, J=8.48 Hz, 2H), 3.61 (s, 3H), 2.60 (s, 3H), 1.52 (s, 6H). MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]2)[N:6]=1.[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1B(O)O>>[NH2:33][C:4]1[S:3][C:2]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[C:42]([F:53])([F:52])[F:41])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]1)=[O:32]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4ccccc4C(F)(F)F)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-(trifluoromethyl)phenyl)boronic acid gave 220. 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 7.93-7.86 (m, 2H), 7.81-7.63 (m, 3H), 7.44 (s, 2H), 5.04 (t, J=5.1 Hz, 1H), 3.73-3.57 (m, 5H), 3.29-3.15 (m, 2H), 2.74 (s, 3H), 2.48-2.35 (m, 1H), 1.65-1.47 (m, 3H), 1.41 (br, 2H). LCMS (ES+) m/z 511 (M+1).
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][OH:17])[C:11]([O:18][CH3:19])=[CH:10][C:4]=1[CH2:5][NH:6]C(=O)C>C(O)C>[ClH:1].[Br:2][C:3]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][OH:17])[C:11]([O:18][CH3:19])=[CH:10][C:4]=1[CH2:5][NH2:6]
Reactant: COc1cc(CNC(C)=O)c(Br)cc1OCCO
Agent: Cl
Solvent: CCO
Product: COc1cc(CN)c(Br)cc1OCCO

Procedure:
37% Hydrochloric acid (0.2 ml) was added to a solution of 2-bromo-4-(2-hydroxyethoxy)-5-methoxy-N-acetyl benzylamine 4 (0.1 g, 0.31 mmol) in abs. ethanol (5 ml) and the mixture was refluxed for 12 hours. After cooling, the solvent was evaporated off under reduced pressure and the residue was recrystallized from a methanol/ethyl ether mixture to afford the title compound as pale yellow solid in quantitative yield.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([N:19]=[CH:20]OCC)[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].C(O)(C)C.O1CCOCC1.[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CN1CCCC1=O>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([N:19]=[CH:20][N:38]4[CH2:39][CH2:40][CH:35]([OH:34])[CH2:36][CH2:37]4)[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC=Nc1ccc2nnc(-c3ncc([N+](=O)[O-])n3C)n2n1
Reactant: OC1CCNCC1
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N=CN3CCC(O)CC3)nn12
Reaction time: 0.5 h

Procedure:
1.2 g. crude 3-(5-nitro-1-methyl-2-imidazolyl)-6-ethoxymethyleneamino-s-triazolo[ 4,3-b]pyridazine dissolved in 13 ml. of a mixture of isopropanol and dioxan ( 7:3), was mixed, N-methylpyrrolidone while stirring at 20° C., with 4-hydroxypiperidine. After 30 minutes, the precipitated crystals were filtered off with suction, washed with isopropanol and water and dried at 120° C. in a vacuum. There was thus obtained 0.6 g. of the desired 3-(5-nitro-1-methyl- 2-imidazolyl)-6-(4-hydroxy-1-piperidinyl-methyleneamino)-s-triazolo[ 4,3-b]-pyridazine, which has a melting point of 188° - 190° C.