Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:20]([O-])(=O)C.[NH4+].C=O.[H][H]>[Ni].CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH:11]([CH3:20])[C:10]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)NC1=NN(c2cccc(Cl)c2)C(=O)C1
Reactant: [H][H]
Agent: [Ni]
Agent: C=O
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)NC1=NN(c2cccc(Cl)c2)C(=O)C1C

Procedure:
112.6 g (0.4 mole) of 1-m-chlorophenyl-3-carbethoxyamino-2-pyrazolin-5-one were methylated under hydrogen atmosphere by using 20 g of Raney nickel, 46.2 g (0.6 mole) of ammonium acetate, 27 g (0.9 mole) of paraformaldehyde, and 0.9 mole of hydrogen in a total volume of 600 ml of methanol. Hydrogenation occurred at a pressure interval of 700 to 300 psi at a temperature of 80°-100° C. Yield: 74 g (62%). Melting point: 162° C.
Reaction SMILES: [C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31](Cl)=[O:32])[C@H:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]([CH3:48])[C:39](=[O:47])[CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[ClH:11].[C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([N:44]3[CH2:43][CH2:42][N:41]([CH2:40][C:39]([N:38]([CH3:48])[CH3:37])=[O:47])[CH2:46][CH2:45]3)=[O:32])[C@H:14]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(C)C(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12h) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 698.4 [(M+H)+]
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[N:9]([CH2:10][C:11]([C:13]2[C:14]([CH3:23])=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[O:17][CH2:16]3)=[O:12])[CH2:8][CH2:7][N:6]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:5]1.[BH4-].[Na+]>CO>[OH:12][CH:11]([C:13]1[C:14]([CH3:23])=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[O:17][CH2:16]2)[CH2:10][N:9]1[CH2:8][CH2:7][N:6]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:5][CH:4]1[CH2:3][CH2:2][OH:1]
Reactant: Cc1c(C(=O)CN2CCN(C(=O)OC(C)(C)C)CC2CCO)ccc2c1COC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)CC2CCO)ccc2c1COC2=O
Temperature: 25 °C

Procedure:
tert-Butyl 3-(2-hydroxyethyl)-4-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-oxoethyl)piperazine-1-carboxylate (6.16 g, 14.7 mmol) was dissolved in methanol (100 mL) at 0° C. and then NaBH4 (1.67 g, 44.2 mmol) was added. The reaction mixture was warmed up to RT. After ten minutes, TLC showed no SM left. The methanol was evaporated and the residue was taken up with brine and extracted with ethyl acetate twice. The combined organic layers were dried with MgSO4, filtered and concentrated. The crude product was chromatographed through an ISCO 330 g Redi-sep column and eluted with 5% MeOH/DCM to yield the title compound: LC-MS (IE, m/z): 421 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=O)[CH2:7][CH:6]2[CH2:15][CH2:16][NH:17]C(C1C=CC=CC=1)C.[Na]>C(O)CCC>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[N:9]([CH3:13])[C:8]3([CH:6]([C:5]4[CH:10]=[CH:11][CH:12]=[CH:3][CH:4]=4)[CH3:7])[CH2:7][CH:6]([CH2:15][CH2:16][NH:17]3)[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(CCNC(C)c1ccccc1)CC(=O)N2C
Agent: [Na]
Solvent: CCCCO
Product: COc1ccc2c(c1)C1CCNC(C(C)c3ccccc3)(C1)N2C
Yield: 117.3 %

Procedure:
To a stirred solution of 3.65 g of 3,4-dihydro-6-methoxy-1-methyl-4-[2-[(1-phenylethyl)amino]ethyl]-2(1H)-quinolinone in 270 ml of refluxing n-butanol was added, incrementally over a period of 1.5 hours, 7.40 g of sodium. The resulting mixture was stirred at reflux until all of the sodium was consumed, and then was cooled, and diluted with water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phase was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrate was purified by means of column chromatography on silica gel (elution with triethylamine/methanol/ethyl acetate) to afford 2.04 g (59%) of 1,2,3,4,5,6-hexahydro-8-methoxy-1-methyl-2-(1-phenylethyl)-2,6-methano-1,3-benzodiazocine as an oil.
Reaction SMILES: [CH:1]([C:3]1[C:16]([O:17]C)=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2].B(Cl)(Cl)Cl.C([O-])(=O)C.[Na+]>ClCCl.O>[CH:1]([C:3]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2]
Reactant: COc1cccc(OCCCCC(=O)O)c1C=O
Agent: CC(=O)[O-]
Agent: ClB(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=Cc1c(O)cccc1OCCCCC(=O)O
Temperature: -70 °C

Procedure:
5-(2-Formyl-3-methoxyphenoxy)pentanoic acid (Example 1) (25 g, 0.099 M) was dissolved in dry dichloromethane (600 ml) with stirring at -70° C. Boron trichloride (50 g) in dry dichloromethane (100 ml) was then added from a pressure-equalising dropping funnel at such a rate that the temperature of the reaction mixture did not rise above -60° C. (~1/4 hr). The mixture was stirred at -70° C. (1/4 hr) and then warmed to room temperature by immersion in lukewarm water (~1/4 hr). After stirring at room temperature (1 hr) the mixture was carefully poured into 10% sodium acetate solution (500 ml). The resulting mixture was filtered and the layers separated. The aqueous phase was extracted once with dichloromethane and the combined organic solutions evaporated. The residue was dissolved in ethyl acetate/ether (1:1) and extracted with 5% sodium bicarbonate solution (4×250 ml). The combined extracts were acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water, dried (sodium sulphate) and evaporated. The residue was dissolved in acetone (100 ml) and treated, with swirling, with 40/60 petrol (400 ml). The pale-yellow supernatant solution was decanted from the red tarry residue and filtered. Evaporation gave 5-(2-formyl-3-hydroxyphenoxy)pentanoic acid, m.p. 96°-98° C. from benzene/petrol.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=O)=[CH:4][C:3]=1[N+:36]([O-])=O>C(O)C.O.Cl.[Fe]>[Cl:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]2[N:8]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:15]=2)=[CH:4][C:3]=1[NH2:36]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCn1c(-c2ccc(Cl)c(N)c2)nc2ccccc21
Reaction time: 4 h
Yield: 88.9 %

Procedure:
A solution of 42 g of N-(4-chloro-3-nitrobenzoyl)N-n-hexadecyl-2-nitro-aniline in 700 ml of ethanol is allowed to run rapidly into a mixture, which has been heated to 60° C., of 89 g of iron powder in 120 ml of water and 40 ml of concentrated hydrochloric acid, with vigorous stirring. The reaction mixture is then stirred for four hours at the reflux temperature. A further 100 ml of concentrated hydrochloric acid and 200 ml of ethanol are then added and the mixture is filtered hot. About 400 ml of ethanol are then distilled off and the residue is left to crystallise out at 4° C. After filtering and drying, 32 g of the compound are obtained in the form of the hydrochloride with a melting point of 162° to 163° C.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.F[P-](F)(F)(F)(F)F.[N:23]1([O:32][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.NO.C(N(CC)CC)C>N1C=CC=CC=1.C(Cl)Cl>[OH:32][NH:23][C:7]([C:2]1[C:1]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(O)c1ccccc1-c1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NO)c1ccccc1-c1ccccc1
Yield: 3.3 %

Procedure:
A solution of 2-biphenylcarboxylic acid 1 (0.25 g, 1.261 mmol), BOP (0.558 g, 1.261 mmol), hydroxylamine hydrochloride (0.088 g, 1.261 mmol) and triethylamine (0.527 mL, 3.78 mmol) was stirred in pyridine (5 mL) at room temperature overnight then diluted with DCM, washed with water (2×), dried over MgSO4, filtered and solvent evaporated to provide title compound 2 (8.8 mg, 3% yield) as a white solid after purification by Biotage (50 to 100% EtOAc in Hexane) followed by trituration (Et2O). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.77 (s, 1H), 8.97 (s, 1H), 7.52 to 7.42 (m, 1H), 7.40 to 7.33 (m, 8H). LRMS (ESI): (calc.) 213.23 (found) 214.2 (MH)+
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[C:8]#[CH:9].[F:11][C:12]1[CH:17]=[C:16](F)[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23].[K+].[Br-]>CC(C)=O.O.C(N(CC)CC)C>[CH2:7]([NH:10][C:16]1[CH:17]=[C:12]([F:11])[C:13]([N+:22]([O-:24])=[O:23])=[CH:14][C:15]=1[N+:19]([O-:21])=[O:20])[C:8]#[CH:9]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1F
Reactant: C#CCN
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: C#CCNc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of potassium carbonate (6.0 g) in acetone (25 ml) was added triethylamine (1.5 ml) and 2-propyn-1-amine (2.35 g, 4.25×10-2 mole). 1,5-Difluoro-2,4-dinitrobenzene (10.00 g, 4.90×10-2 mole) was added and the reaction mixture was stirred at room temperature for 24 hours. The mixture was poured into excess water and filtered. The resulting dark solid was chromatographed on a silica column, eluting with benzene, and recrystallized from benzene to afford yellow crystals; m.p. 113°-115° C. Yield: 8.33 g (82%). I.R. (KBr): 3340 (NH), 3280 (CH), 1615, 1260 (Ar-NO2) and 1210 cm-1 (Ar-F).
Reaction SMILES: [CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([Cl:14])[C:8]=1Cl)[CH2:2][CH2:3][CH3:4].[CH2:16]([Mg]Br)[CH3:17]>[Cl-].[Mn+2].[Cl-]>[CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([Cl:14])[C:8]=1[CH2:16][CH3:17])[CH2:2][CH2:3][CH3:4]
Reactant: CC[Mg]Br
Reactant: CCCC/N=C/c1c(F)ccc(Cl)c1Cl
Agent: [Mn+2]
Agent: [Cl-]
Product: CCCC/N=C/c1c(F)ccc(Cl)c1CC

Procedure:
Butyl-[1-(3-chloro-2-ethyl-6-fluoro-phenyl)-meth-(E)-ylidene]-amine was prepared from butyl-[1-(2,3-dichloro-6-fluoro-phenyl)-meth-(E)-ylidene]-amine, ethylmagnesium bromide and manganese(II) chloride in analogy to Example 194a): yellow oil; 1H-NMR (CDCl3): 0.97 (3H, t, CH3), 1.15 (3H, t, CH3), 1.43 (2H, sextet, CH2), 1.70 (2H, quintet, CH2), 3.06 (2H, q, CH2), 3.66 (2H, t, CH2), 6.88 (1H, dd, ArH), 7.34 (1H, dd, ArH), 8.51 (1H, s, CH═N).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[I:21])=[O:13].[Sn](Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[I:21])=[O:13]
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1I
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(NC(=O)Nc2ccccc2I)c(O)c1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of N-(2-hydroxy-4-nitrophenyl)-N'-(2-iodophenyl)urea (220 mg, 0.55 mmol) in ethanol (15 mL), Tin chloride (522 mg, 2.75 mmol) was added. The reaction mixture was stirred at reflux for 16 hours then cooled to room temperature. The reaction mixture was basified to pH8 with aq. NaHCO3 then extracted with ethyl acetate (3×). The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure to give product (180 mg, 89%). EI-MS m/z 370 (M+H)+
Reaction SMILES: I[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]1[N:33]=[C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:31]=[CH:30][CH:29]=1)CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([NH:14][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]([N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)[N:33]=3)=[CH:3][C:4]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:5][C:6]=2[N:7]=1)=[O:13])[CH3:16]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(N2CCOCC2)n1
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(I)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cccc(N4CCOCC4)n3)c2s1
Temperature: 120 °C
Yield: 6.2 %

Procedure:
To a solution of 1-(7-iodo-5-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea (0.15 g, 0.35 mmol) in DMF (5 mL) was added 4-(6-tributylstannanyl-pyridin-2-yl)-morpholine (0.30 g, 0.70 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was then degassed for half an hour followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.018 mmol). The reaction mixture was then again degassed for half an hour and heated at 120° C. for 15 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), DMF was distilled off; water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude residue was purified by prep HPLC to get the title compound (0.01 g, 6.0%) as white solid.
Reaction SMILES: Cl.[N:2]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:21][C:22]=3[C:23]([F:26])([F:25])[F:24])=[O:17])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=1.C(N(CC)CC)C>CN(C=O)C>[C:27]1([C:20]2[O:21][C:22]([C:23]([F:26])([F:24])[F:25])=[C:18]([C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([N:2]4[CH2:8][CH2:7][CH2:6][N:5]([CH2:34][C:35]5[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=5)[CH2:4][CH2:3]4)=[CH:10][CH:11]=3)=[O:17])[N:19]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: O=C(Nc1ccc(N2CCCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(CN2CCCN(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-[1,4]diazepan-1-yl-phenyl)-amide hydrochloride (56 mg, 0.12 mmol), 4-bromomethyl-benzoic acid (28 mg, 0.13 mmol), triethylamine (0.07 mL, 0.50 mmol) in DMF (5 mL) was stirred at room temperature for 0.5 hr then concentrated and the residue was taken up in 50 mL of ethyl acetate and washed with 50 mL of saturated ammonium chloride, water (50 mL), and dried with anhydrous sodium sulfate. The solvent was removed and the residue was triturated with ethyl acetate, followed by filtration, to afford 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-[1,4]diazepan-1-ylmethyl)-benzoic acid as a yellow solid (20 mg, 29% yield) LCMS for C30H27F3N4O4 calcd. (m/e) 564, observed 565 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](Cl)=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].Cl.[CH3:32][O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:37][CH2:36][CH2:35][C:34]([O:33][CH3:32])=[O:38])=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: COCc1cc(-c2nc(-c3cccc(C(=O)Cl)c3)no2)ccc1-c1ccccc1C
Reactant: COC(=O)CCN
Agent: Cl
Product: COCc1cc(-c2nc(-c3cccc(C(=O)NCCC(=O)OC)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described in example 121 starting from 3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride, prepared as in example 130, and beta-alanine methyl ester hydrochloride. The title compound was obtained as a white foam. 1H NMR: (DMSO-d6, 300 MHz) δ 8.87 (m, 1H), 8.58 (m, 1H), 8.35 (m, 1H), 8.27 (m, 1H), 8.19 (dd, J=1.9 Hz, 7.9 Hz, 1H), 8.07 (m, 1H), 7.72 (t, J=7.9 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.38-7.25 (m, 3H), 7.15 (m, 1H), 4.23 (d, J=12.9 Hz, 1H), 4.17 (d, J=12.9 Hz, 1H), 3.63 (s, 3H), 3.54 (m, 1H), 3.25 (s, 3H), 3.64 (t, J=6.9 Hz, 2H), 2.04 (s, 3H). LC/MS (Method B): 486.2 (M+H)+ 484.2 (M−H)−. HPLC (Method A) Rt: 5 min (purity: 99.3%).
Reaction SMILES: [Cl-].[Li+].C([Mg]Cl)CC.I[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)[N:16]=2)[N:11]([Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH:10]=1.[CH3:40][C:41]([CH3:47])([CH:45]=[O:46])[CH2:42][C:43]#[N:44]>O1CCCC1>[OH:46][CH:45]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)[N:16]=2)[N:11]([Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH:10]=1)[C:41]([CH3:47])([CH3:40])[CH2:42][C:43]#[N:44]
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Reactant: CC(C)(C=O)CC#N
Agent: CCC[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3c(n2)c(C(O)C(C)(C)CC#N)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
Propyl magnesium chloride lithium chloride (1.3 M solution in THF, 1.7 mL, 2.2 mmol) was added to 3 mL of tetrahydrofuran cooled to −78° C. A solution of 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (0.250 g, 0.440 mmol) in 2 mL of tetrahydrofuran was slowly added, and the mixture was stirred at −78° C. for 2 h. A solution of 3,3-dimethyl-4-oxo-butyronitrile (0.241 g, 2.17 mmol) in 2 mL of tetrahydrofuran was added dropwise, and the mixture was stirred, allowing to slowly warm to RT, for 19 h, then quenched with 100 mL of a sat. aq. NaHCO3 solution. The resulting mixture was extracted with 100 mL of ethyl acetate, and the organic layer was dried over MgSO4, filtered and concentrated to a residue. Column chromatography (0→50% EtOAc/hexanes) afforded 0.152 g (62%) of 4-hydroxy-3,3-dimethyl-4-[5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-butyronitrile as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=1.[OH-].[Na+].Cl>CO>[CH3:28][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:26][CH:27]=1
Reactant: CCOC(=O)CCCOc1ccc(OCCCc2cnccc2N(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1ccncc1CCCOc1ccc(OCCCC(=O)O)cc1
Yield: 60.7 %

Procedure:
To a solution of ethyl 4-[4-[3-(4-dimethylaminopyrid-3-yl)propyloxy]phenoxy]butyrate (160 mg) in methanol (10 ml) was added sodium hydroxide solution (2.0 ml of 1.0M) and the solution left until all starting ester had disappeared (Tlc). The reaction mixture was neutralised with hydrochloric acid (2.0 ml of 1.0 M) and evaporated in vacuo. A small amount (5 ml) of water was added and the resulting solution extracted with dichloromethane (3×15 ml). The organic extracts were combined, dried (PS paper) and evaporated to yield the title compound as colourless prisms, (90 mg) m.p. 106°-108° C. (from ethyl acetate); NMR (d6DMSO) : δ 1.8-2.1 (2H,q;2H,q); 2.4 (2H,t); 2.8 (2H,t;6H,s); 3.9 (2H,t;2H,t); 6.8(5H,m); 8.2 (2H,d); m/e 359 (M+H)+ ; calculated for C20 H26N2O4 : C,67.0; H,7.3; N,7.8; found : C,67.1; H,7.6;N,7.7%.
Reaction SMILES: C(O[C:4]([C:6]1[S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]=1)=[O:5])C.[CH:15]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22])([CH3:17])[CH3:16].C[Al](C)C.CCCCCC>ClCCl>[CH:15]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH:22][C:4]([C:6]1[S:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[N:14]=1)=[O:5])([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1nc2ccncc2s1
Reactant: CC(C)Oc1ccccc1CN
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)Oc1ccccc1CNC(=O)c1nc2ccncc2s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of thiazolo [5,4-c]pyridine-2-carboxylic acid ethyl ester (34 mg, 0.16 mmol) and 2-isopropoxy benzyl amine (67 mg, 0.41 mmol)in dichloromethane(1.7 mL) was added a solution of trimethylaluminum in hexane(0.203 mL, 2.0 M., 0.41 mmol). The solution was then stirred for 5 hours at room temperature. After usual work-up, the product was purified by flash chromatography (CH2Cl2/EtOAc 2:1) to give 30 mg of the thiazolo derivative.
Reaction SMILES: [CH3:1][C@H:2]1[C@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[C@:18]2([CH3:25])[C@H:4]([C@H:5]3[C@:15]([F:27])([C@@H:16]([OH:26])[CH2:17]2)[C@:14]2([CH3:28])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[CH2:7][CH2:6]3)[CH2:3]1.[C:29]1(=[O:35])[O:34][C:32](=[O:33])[CH2:31][CH2:30]1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][C@H:2]1[C@:19]([OH:24])([C:20]([CH2:22][O:23][C:29]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:35])=[O:21])[C@:18]2([CH3:25])[C@H:4]([C@H:5]3[C@:15]([F:27])([C@@H:16]([OH:26])[CH2:17]2)[C@:14]2([CH3:28])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[CH2:7][CH2:6]3)[CH2:3]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)COC(=O)CCC(=O)O
Reaction time: 48 h

Procedure:
An amount equivalent to 0.030 g of dexamethasone (1, 0.076 mmol, 1.0 equiv.) was completely dissolved in 1 mL of pyridine (non-anhydrous) and 0.038 g of succinic anhydride (0.382 mmol, 5.0 equiv.) was added to the clear solution. Then 1-2 mg of DMAP (7.6 μmol, 0.1 equiv.) was added to the solution and reaction was allowed to run for 48 h at r.t. under N2-flow. After 48 h, pyridine was evaporated under reduced pressure (in a rotary evaporator). A volume equivalent to 10 mL of H2O was added to the evaporated residue. A white precipitate was observed which was stirred for 10 minutes and then centrifuged. The resulting precipitate was washed again with 10 mL of H2O and the washed residue was lyophilized to yield the target product (2).