Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:12])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([CH3:3])[CH3:2].[OH-].[Na+].[Br:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([Br:25])[C:17]=1I.O>CN(C)C=O>[Br:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([Br:25])[C:17]=1[O:12][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Br)c(I)c(Br)c1
Reactant: COc1ccc(O)cc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2c(Br)cc([N+](=O)[O-])cc2Br)cc1C(C)C
Temperature: 5 °C

Procedure:
3-Isopropyl-4-methoxyphenol (197.2 g, 1.19 moles) was dissolved in dimethylformamide (4 L). The mixture was stirred while the reaction vessel was cooled in an icewater bath. Sodium hydroxide (1.278 L of 1.0M aqueous solution, 1.278 moles) was added while maintaining the temperature of the reaction mixture below 35° C. 1,3-Dibromo-2-iodo-5-nitrobenzene (400.0 g, 0.983 moles) dissolved in dimethylformamide (portion of 4 L) was added to the reaction mixture over approximately 45 min. The reaction mixture was stirred at 20° to 25° C. for 24 h. Deionized water (2 L) was added over 2 h and the reaction mixture was cooled to 5° C. The resulting crystals of 4-(2,6-dibromo-4-nitrophenoxy)-2-isopropylanisole (405.4 g, 92.6%) were recovered by filtration and dried for 48 h by evaporation under air flow at room temperature.
Reaction SMILES: [C:1]([C:3]1[N:4]=[N:5][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[CH:2].[CH2:20]([Li])CCC.CI.[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[C:1]([C:3]1[N:4]=[N:5][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[C:2][CH3:20]
Reactant: C#Cc1ccc([C@H]2CC[C@H](CCCCC)CC2)nn1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC#Cc1ccc([C@H]2CC[C@H](CCCCC)CC2)nn1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
2.56 g of 3-ethynyl-6-(trans-4-pentylcyclohexyl)pyridazine were dissolved in 25 ml of tetrahydrofuran under nitrogen. The solution was cooled to -70° C. and then 7.5 ml of a 1.6 M solution of butyl lithium in hexane were added dropwise within 20 minutes. The mixture was stirred at -70° C. for a further 1 hour and then 0.74 ml of methyl iodide was added dropwise within 5 minutes. The mixture was stirred overnight and warmed slowly to room temperature. After 15.5 hours, the dark mixture was poured into 100 ml of water and made neutral with solid ammonium chloride. The solution obtained was extracted three times with 100 ml of ether each time. The ether phases were washed twice with 100 ml of water each time, subsequently combined, dried with sodium sulphate, filtered and concentrated on a rotary evaporator. Recrystallization of the resulting dark crystals in ethyl acetate/hexane (1:9) gave 1.87 g (70%) of 3-(1 -propynyl)-6-(trans-4-pentylcyclohexyl)pyridazine as brown crystals of melting point 103°-104° C. and clearing point (S-I) 99.3° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=3)[C:14]([NH:16][CH:17]3[CH2:19][CH2:18]3)=[O:15])[C:6]=2[N:7]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)[CH3:24]>>[CH:17]1([NH:16][C:14](=[O:15])[C:13]2[CH:20]=[CH:21][CH:22]=[C:11]([C:8]3[C:6]4[N:7]=[C:2]([NH:37][C:34]5[CH:35]=[N:36][C:31]([N:28]6[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27]6)=[CH:32][CH:33]=5)[N:3]=[CH:4][C:5]=4[S:10][CH:9]=3)[CH:12]=2)[CH2:19][CH2:18]1
Reactant: O=C(NC1CC1)c1cccc(-c2csc3cnc(Cl)nc23)c1
Reactant: CCN1CCN(c2ccc(N)cn2)CC1
Product: CCN1CCN(c2ccc(Nc3ncc4scc(-c5cccc(C(=O)NC6CC6)c5)c4n3)cn2)CC1
Yield: 51.1 %

Procedure:
N-Cyclopropyl-3-(2-(6-(4-ethylpiperazin-1-yl)pyridin-3-ylamino)thieno[3,2-d]pyrimidin-7-yl)benzamide (23 mg, 50% yield) was prepared in the same manner as Step 10 of Example 1 using 3-(2-chlorothieno[3,2-d]pyrimidin-7-yl)-N-cyclopropylbenzamide (30 mg, 0.09 mmol) and 6-(4-ethylpiperazin-1-yl)pyridin-3-amine (28 mg, 0.14 mmol).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:24][C@@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4].COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+].[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>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>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:24][C@@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[CH:21][C:20]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: CC(C)(CO)NC(=O)c1nn(-c2ccc(Br)cn2)c2c1C[C@@H]1C[C@H]21
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(CO)NC(=O)c1nn(-c2ccc(-c3ccccc3)cn2)c2c1C[C@@H]1C[C@H]21
Temperature: 120 °C
Yield: 60.6 %

Procedure:
To a 5 mL heavy-walled sealed tube with a stir bar were added (1aS,5aS)-2-(5-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (0.020 g, 0.051 mmol) and DME (0.31 mL, 0.051 mmol), cesium carbonate (0.033 g, 0.10 mmol), phenylboronic acid (0.0094 g, 0.077 mmol). Water (0.051 mL, 0.051 mmol) was added and the tube was flushed with argon. Tetrakis(triphenylphosphine)palladium(0) (0.0060 g, 0.0051 mmol) was added and tube was capped and again flushed with argon. The reaction was heated under microwave irradiation at 120° C. for 35 min. The sample was cooled and filtered. The filtrate was concentrated and the residue was purified by preparative HPLC to give the title compound as a tan solid (12 mg). LCMS m/z=389.5 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.51 (td, J=4.8 and 3.5 Hz, 1H), 1.26-1.33 (m, 1H), 1.41-1.47 (m, 6H), 2.28-2.36 (m, 1H), 2.80-2.87 (m, 1H), 2.94 (d, J=16.5 Hz, 1H), 3.03 (dd, J=16.5 and 6.3 Hz, 1H), 3.77 (s, 2H), 7.08 (bs, 1H), 7.42-7.47 (m, 1H), 7.52 (t, J=7.2 Hz, 2H), 7.60-7.65 (m, 2H), 7.96 (d, J=8.5 Hz, 1H), 8.05 (dd, J=8.5 and 2.4 Hz, 1H), 8.74 (d, J=2.3 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12](O)=[O:13])=[CH:10][O:9][N:8]=1.FC1C=CC(C2C(C(O)=O)=CON=2)=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][OH:13])=[CH:10][O:9][N:8]=1
Reactant: O=C(O)c1conc1-c1ccccn1
Agent: O=C(O)c1conc1-c1ccc(F)cc1
Product: OCc1conc1-c1ccccn1
Yield: 76.1 %

Procedure:
As described for example 323e, 3-pyridin-2-yl-isoxazole-4-carboxylic acid (39.0 g, 200 mmol) was converted, instead of 3-(4-fluoro-phenyl)-isoxazole-4-carboxylic acid, to the title compound (26.8 g, 76%) which was obtained as a white solid. MS: m/e=177.2 [M]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15](F)=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[C:23]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:26])[CH2:24][OH:25].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:22])=[CH:14][C:15]([O:25][CH2:24][C:23]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(F)cc2F)c(Cl)c1C(F)(F)F
Reactant: CCCCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)COc1cc(F)c(-c2nn(C)c(C(F)(F)F)c2Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A solution of 3.4 g (0.01 mole) 4-chloro-3-(2,4-difluoro-5-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole and 1.4 mL (0.011 mole) butyl glycolate in 25 mL anhydrous THF was chilled to 0° C. Maintaining the temperature below 5° C., 0.33 g (0.011 mole) NaH was added in portions. Once the addition was completed, the reaction mixture was allowed to warm to 25° C. After 3 hours the mixture was carefully quenched with water and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified chromatographically with 20% ethyl acetate/hexanes to yield 3.25 g (72%) (4-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-fluoro-2-nitrophenoxy)acetic acid, butyl ester as a light yellow solid; mp 65° C.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].C(Cl)(=O)C.[CH2:9](O)[CH2:10][CH:11]([CH3:13])[CH3:12].N1C=CC=CC=1.Cl>ClCCl.C(O)CCC>[C:1]([O:4][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(C)CCO
Reactant: CC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: CCCCO
Solvent: ClCCl
Product: CC(=O)OCCC(C)C

Procedure:
1-Butanol, 3 methyl, acetate. Under an atmosphere of argon, acetyl chloride (6.5 ml, 91.8 mmol) was added dropwise to a 0° C. solution of isoamyl alcohol (5 ml, 45.9 mmol), N,N-dimethylpyridine (2.8 g, 23 mmol), and anhydrous pyridine (4.1 ml, 50.5 mol) in dichloromethane (92 ml). The reaction mixture was poured into 100 ml of 0.1 N HCl, and the resulting layers were separated. The organic layer was washed with 50 ml of saturated aqueous ammonium chloride then dried over magnesium sulfate. The organic layer was filtered and concentrated in vacuo to a clear oil. The resulting oil was purified by distillation (bp 134-136° C.) to give isoamyl acetate. 1H NMR (300 MHz, CDCl3) 4.08 (t, 2H, J 6.9), 2.03 (s, 3H), 1.68 (m, 1H), 1.51 (q, 2H, J 6.9), 0.92 (d, 6H, J 6.6).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH:18][CH3:19])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][N:9]=1.C(N(CC)CC)C.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>ClCCl>[Cl:3][C:4]1[C:5]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[S:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:35])=[O:34])[CH2:14][CH2:15]2)=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: CNCCN1CCN(c2nccnc2Cl)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN1CCN(c2nccnc2Cl)CC1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-amine dihydrochloride salt (2.0 g, 6.09 mmol) in dichloromethane (50 mL). Add triethylamine (3.39 mL, 24.4 mmol), and benzenesulfonylchloride (854 μL, 6.69 mmol). Stir at ambient temperature for 18 hr. Add dichloromethane and aqueous 1 N HCl solution. Separate the organic layer and extract the aqueous layer twice with dichloromethane. Combine the organic layers and dry (magnesium sulfate), filter, and concentrate. Purify via SCX chromatography, followed by silica gel chromatography (100:0 to 0:100 hexanes:ethyl acetate) to give the title preparation (1.88 g, 78%). MS (ES): m/z=396 [M+H]+.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[S:15]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([OH:24])=O)=[CH:16]1>CS(O)(=O)=O>[S:15]1[CH:19]=[CH:18][C:17]2[CH2:20][CH2:21][C:22](=[O:24])[C:16]1=2
Reactant: O=C(O)CCc1ccsc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=C1CCc2ccsc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
To a suspension of P2O5 (25.4 g, 179.0 mmol) in methanesulfonic acid (100 mL) was added 3-(thiophen-3-yl)propanoic acid (5.0 g, 32.0 mmol) and the reaction was stirred at room temperature for 1 h. At completion, the reaction was concentrated and the residue was purified by flash chromatography (20-30% EtOAc/hexane eluent) to give 4H-cyclopenta[b]thiophen-6(5H)-one (1.34 g, 30% yield) as a brown solid. 1H NMR (300 MHz, MeOH) δ ppm 8.14 (d, J=4.8 Hz, 1H), 7.17 (d, J=4.8 Hz, 1H), 2.94-3.15 (m, 4H); MS (EI) m/z=139.2 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])=[C:5]([CH3:22])[NH:4][C:3]=1[C:23]#[N:24].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].CN(C=O)C.C(OCC)(=O)C>[C:23]([C:3]1[N:4]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:5]([CH3:22])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[C:2]=1[CH3:1])#[N:24]
Reactant: Cc1[nH]c(C#N)c(C)c1Cc1ccccc1S(=O)(=O)N1CCCC1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C)c1C#N
Temperature: 60 °C
Yield: 109.4 %

Procedure:
To a mixture of 3,5-dimethyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrole-2-carbonitrile (29.1 mg, 0.085 mmol), cesium carbonate (110 mg, 0.339 mmol), and TBAI (3.13 mg, 8.47 μmol) in DMF (424 μl), was added ethyl bromoacetate (14.15 μl, 0.127 mmol). The mixture was heated at 60° C. for 5 hours and then allowed to cool down to room temperature and diluted with ethyl acetate (100 ml). The resulting mixture was washed with water (50 ml×3), dried, filtered, and evaporated to give an oil. This crude oil was purified by column chromatography (0 to 50% ethyl acetate in hexanes) to give ethyl 2-(2-cyano-3,5-dimethyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (40.0 mg, 0.093 mmol, 110% yield).
Reaction SMILES: [C:1]([O:5]CC)(=[O:4])[CH:2]=[CH2:3].[C:8]([O:13]C)(=[O:12])[C:9]([CH3:11])=[CH2:10].COC.C1(C=CC(O)=CC=1)O>>[CH2:10]=[C:9]([CH2:11][CH:2]([CH3:3])[C:1]([OH:5])=[O:4])[C:8]([OH:13])=[O:12]
Reactant: C=C(C)C(=O)OC
Reactant: C=CC(=O)OCC
Agent: COC
Agent: Oc1ccc(O)cc1
Product: C=C(CC(C)C(=O)O)C(=O)O
Temperature: 60 °C

Procedure:
Ethyl acrylate (50 g.) is added dropwise under nitrogen to a solution maintained at 60° C. and containing 500 g. of methyl methacrylate, 2.0 g. of the methyl ether of hydroquinone, and 6.0 g. of hexa-n-propylphosphorus triamide. The reaction was held at 60° C. for a total of 24 hours. After removal of unrected ethyl acrylate and methyl methacrylate, the 69.2 g. of residue analyzes for 22.4 g. of ethyl 2-methylene-4-carbomethoxypentanoate and 27.8 g. of diethyl 2-methyleneglutarate. Spectral analysis is consistent for the structure of the products. Further, hydrolysis of the ethyl 2-methylene-4-carbomethoxypentanoate gives 2-methylene-4-methylglutaric acid, which was identical to that produced in Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:23]=[CH2:24])=[C:13]([C:17]3[CH2:18][CH2:19][O:20][CH2:21][CH:22]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:12]([CH2:23][CH3:24])[CH:11]=2)[CH2:16]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1cc2c(cc1C1=CCOCC1)CN(C(=O)OC(C)(C)C)C2
Agent: O=C[O-]
Agent: [NH4+]
Product: CCc1cc2c(cc1C1CCOCC1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A49(b) from 5-(3,6-dihydro-2H-pyran-4-yl)-6-vinyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and ammonium formate. Yellow oil. MS (m/e): 276.3 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[C:12]([O:25][CH2:26][CH:27]1[O:29][CH2:28]1)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH:21]1[O:23][CH2:22]1)=[O:18]>>[OH:23][CH:21]([CH2:22][N:5]1[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([OH:1])[CH2:3][C:4]1([CH3:11])[CH3:10])[CH2:20][O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][C:12]([O:25][CH2:26][CH:27]([OH:29])[CH2:28][N:5]1[C:4]([CH3:11])([CH3:10])[CH2:3][CH:2]([OH:1])[CH2:7][C:6]1([CH3:9])[CH3:8])=[O:24]
Reactant: O=C(CCCCC(=O)OCC1CO1)OCC1CO1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Product: CC1(C)CC(O)CC(C)(C)N1CC(O)COC(=O)CCCCC(=O)OCC(O)CN1C(C)(C)CC(O)CC1(C)C

Procedure:
A mixture of 18.0 g of 4-hydroxy-2,2,6,6-tetramethylpiperidine and 11.3 g of bis(2,3-epoxypropyl) adipate was reacted and treated following substantially the same procedure as described in Example 45. The desired Compound No. 122 was obtained in the form of a pale yellow, very viscous product having an Rf value of 0.33 on thin-layer chromatography on silica gel developed with a 20:4:2:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[I-].[K+].CC(C)=O>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)c(O)c1
Yield: 39.4 %

Procedure:
A mixture of 5.52 g (40 mmol) of 3,4-dihydroxybenzaldehyde, 6.09 g (44 mmol) of potassium carbonate, 70 mg of potassium iodide, 110 ml of acetone and 6.84 g (40 mmol) of benzyl bromide was refluxed for 15 hours. Thereafter, the mixture was cooled, the reaction suspension was filtered and the filtrate was evaporated down. Chromatography of the residue over silica gel using 9:1 toluene/ethyl acetate gave 3.6 g of 4-benzyloxy-3-hydroxybenzaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH:7]([C:13]([OH:15])=[O:14])[CH2:8][CH:9]1[CH2:12][CH2:11][CH2:10]1)=[O:5])[CH3:2].S(Cl)(Cl)=O.[CH3:20]O>>[CH2:1]([O:3][C:4]([NH:6][CH:7]([C:13]([O:15][CH3:20])=[O:14])[CH2:8][CH:9]1[CH2:10][CH2:11][CH2:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NC(CC1CCC1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)NC(CC1CCC1)C(=O)OC
Temperature: -15 °C
Reaction time: 2 h

Procedure:
11 g (51 mmol) of ethoxycarbonyl-3-cyclobutyl-DL-alanine (Example 1, Step A) is dissolved in 100 ml of methanol, cooled to −15° C. and 10 ml (137 mmol) of thionyl chloride is added at constant stirring. Stirring is continued without further cooling. When the reaction mixture reaches room temperature, stirring is continued for further 2 hours. The solution is then evaporated at a pressure of 2.0-2.5 kPa. The residual oil is dissolved in 40 ml of ethyl acetate, washed with 10 ml of 1N HCl, 2×10 ml of 5% NaHCO3 and 2×10 ml of water, dried over anhydrous sodium sulphate and evaporated to dryness at a pressure of 2.0-2.5 kPa. The residue is considered to be pure [yield: 10.8 g (92%), Rf(1)=0.85; Rf(6)=0.65] and is used without further treatment in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Reactant: O=C=Nc1ccc(F)c(C(F)(F)F)c1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1

Procedure:
76.5 mg of solid brown 3-{4-[3-(4-fluoro-3-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 4-fluoro-3-trifluoromethylphenyl isocyanate.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[N:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[O:32]1[C:37]2=[CH:38][N:39]=[C:40]([CH:42]=O)[CH:41]=[C:36]2[CH2:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO.C(Cl)Cl.CO>[ClH:1].[O:32]1[C:37]2=[CH:38][N:39]=[C:40]([CH2:42][NH:3][CH:4]3[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]4[N:21]5[C:22]6[N:13]([C:14](=[O:24])[CH:15]=[N:16][C:17]=6[CH:18]=[CH:19][C:20]5=[O:23])[CH2:12]4)[CH2:6][CH2:5]3)[CH:41]=[C:36]2[CH2:35][CH2:34][CH2:33]1
Reactant: O=Cc1cc2c(cn1)OCCC2
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)cnc4ccc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1cnc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2cc3c(cn2)OCCC3)CC1
Reaction time: 0.25 h
Yield: 87 %

Procedure:
A suspension of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione dihydrochloride (for a preparation see Example 13(k) or 15(d)) (50 mg, 0.100 mmol) in chloroform (4 ml) and methanol (0.200 ml) at room temperature under nitrogen was treated with triethylamine (0.042 ml, 0.301 mmol) and stirred for 0.25 h (the suspension turned into a solution). 3,4-Dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 126(e)) (16.35 mg, 0.100 mmol) was then added and the reaction was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (67.1 mg, 0.301 mmol) was then added and the reaction was stirred at room temperature. After 3 h there was still some starting material so 30 mg of sodium triacetoxyborohydride were added. After 1 h a saturated aqueous solution of sodium bicarbonate (25 mL) was added followed by 20% methanol/DCM (25 mL) and the aqueous layer was extracted and then separated from the organic layer. The aqueous layer was extracted again twice with 20% methanol/DCM (2×25 mL). The combined organic layers were dried on sodium sulphate, filtered and evaporated to afford 60 mg of crude product. The crude product was purified by silica chromatography (0-20% MeOH/DCM) to afford the free base of the title compound as a yellow solid (39 mg, 87%).
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2]2.S(=O)(=O)(O)O.[CH3:22][OH:23]>>[OH:23][C@H:22]1[C@H:1]([O:6][CH3:5])[CH2:2][N:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4]1
Reactant: CO
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Agent: O=S(=O)(O)O
Product: CO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Yield: 69.8 %

Procedure:
Benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (21.0 g, 96 mmol) was dissolved in MeOH (200 mL). Added sulfuric acid (3.64 g, 37.1 mmol) dropwise. After ˜3 hrs the reaction was concentrated and the residue was diluted with ethyl acetate and neutralized with 1N aq. NaOH. The organic extract was dried (Na2SO4) and concentrated. The reaction product was purified by silica gel column chromatography eluting with Hexane/Acetone mixtures to give (+/−)-Trans-benzyl 3-hydroxy-4-methoxypyrrolidine-1-carboxylate (16.8 g, 66.9 mmol, 69.8% yield) LCMS:M+1=252, Rt=1.42 min.
Reaction SMILES: C(C([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:16][C:15]=2[O:26][CH:27]([CH3:29])[CH3:28])[N:9]=1)=O)(C)(C)C.[OH-].[Na+].Cl>C(O)C>[CH:27]([O:26][C:15]1[CH:16]=[C:17]([CH2:20][C:21]([OH:23])=[O:22])[CH:18]=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([NH2:7])[CH:13]=[CH:12][CH:11]=1)([CH3:29])[CH3:28]
Reactant: CCOC(=O)Cc1ccc(-c2cccc(NC(=O)C(C)(C)C)n2)c(OC(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1cc(CC(=O)O)ccc1-c1cccc(N)n1
Reaction time: 1 h

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 577 mg (1.56 mmol) N-t-butylcarbonyl-6-(2-isopropoxy-4-carboethoxymethylphenyl)-pyridin-2-ylamine and 10 mL ethanol. The solution was heated to reflux, and 30 mL of a 10% aqueous sodium hydroxide solution added dropwise, and refluxing continued for 1 hour. The solution was cooled, and the pH adjusted at 0° C. with 1 N hydrochloric acid to pH 4-5, then extracted with methylene chloride, ethyl acetate, and acetonitrile/ethyl acetate. The combined organic layers were dried and evaporated to give a foam, 449 mg (98%).