Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:24][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[N:6]=[CH:5][C:4]([C:3]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:9][CH:8]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Yield: 50 %

Procedure:
As described for example 90, 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) was converted, using morpholine instead of cyclopropylmethylamine, to the title compound (60 mg, 50%) which was obtained as a colourless gum. MS: m/e=398.3 [M+H]+.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[NH:5][C:4]=2[CH:3]=1.[CH3:14][S:15]([C:18]1[N:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[CH:21]=[CH:20][N:19]=1)(=[O:17])=[O:16]>O1CCOCC1.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>[CH3:12][C:6]1([CH3:13])[NH:5][C:4]2[CH:3]=[C:2]([C:20]3[CH:21]=[CH:22][N:23]=[C:18]([S:15]([CH3:14])(=[O:17])=[O:16])[N:19]=3)[S:10][C:9]=2[C:8](=[O:11])[NH:7]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(S(C)(=O)=O)n1
Reactant: CC1(C)NC(=O)c2sc(Br)cc2N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC1(C)NC(=O)c2sc(-c3ccnc(S(C)(=O)=O)n3)cc2N1
Yield: 56.3 %

Procedure:
A mixture of 6-bromo-2,2-dimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.110 g, 0.420 mmol), 2-(methylsulfonyl)-4-(tributylstannyl)pyrimidine (0.225 g, 0.504 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.097 g, 0.084 mmol) in 1,4-dioxane (10 mL) was purged with nitrogen and microwave-irradiated at 150° C. for 1 h. Then, the reaction mixture was cooled, and concentrated with silica gel, and the residue was purified by flash chromatography (Combiflash, silica gel, ethyl acetate) to give the title compound (0.080 g, 56%) as a yellow solid:
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([OH:21])=[O:20])=[C:8]([CH2:11]OC(=O)CC(=O)C)[CH2:9][S:10][C@H:5]12)=[O:2].[N:24]1[N:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]2=[CH:26][CH:25]=1>>[CH:1]([NH:3][C@@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O-:21])=[O:20])=[C:8]([CH2:11][C:26]3[CH:25]=[NH+:24][N:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=34)[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: c1ccn2nccc2c1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Product: O=CN[C@@H]1C(=O)N2C(C(=O)[O-])=C(Cc3c[nH+]n4ccccc34)CS[C@H]12

Procedure:
7β-Formamido-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid and pyrazolo[1,5-a]pyridine are reacted in the same manner as described in Example 5 to give the above-identified compound.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[CH:29][C:24]=2[O:23][CH2:22]1.[OH-].[Na+]>>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:16][CH2:15][CH2:14][O:13][C:10]4[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=4)=[CH:32][CH:31]=3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1ccc(-c2ccc3c(c2)OCO3)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3ccc4c(c3)OCO4)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4-Benzo[1,3]dioxol-5-yl-phenol from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C26H26O7 [M+NH4]+: 468, [M+Na]+: 473.
Reaction SMILES: [O:1]=[C:2]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10]([C@H:12]([NH:22][C:23](=[O:35])[C:24]([NH:27]C(OC(C)(C)C)=O)([CH3:26])[CH3:25])[CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3]1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[O:1]=[C:2]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:4]2([CH2:5][CH2:6][N:7]([C:10]([C@H:12]([NH:22][C:23](=[O:35])[C:24]([NH2:27])([CH3:26])[CH3:25])[CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:11])[CH2:8][CH2:9]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](CCCc1ccccc1)C(=O)N1CCC2(CC1)CC(=O)c1ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C(=O)N[C@H](CCCc1ccccc1)C(=O)N1CCC2(CC1)CC(=O)c1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the product obtained from Step A in 2 mL of dichloromethane was added 2 mL of trifluoroacetic acid and stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure to yield the title compound as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH:17]([C:19]1[NH:23][CH:22]=[C:21]([C:24]([OH:26])=[O:25])[C:20]=1[CH2:27][CH2:28][OH:29])=O>>[OH:29][CH2:28][CH2:27][C:20]1[C:21]([C:24]([OH:26])=[O:25])=[CH:22][NH:23][C:19]=1[CH:17]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[NH:11][C:10]1=[O:16]
Reactant: O=Cc1[nH]cc(C(=O)O)c1CCO
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: O=C1Nc2cccc(C3CCNCC3)c2C1=Cc1[nH]cc(C(=O)O)c1CCO

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one was condensed with 5-formyl-4-(2-hydroxyethyl)-1H-pyrrole-3-carboxylic acid to give the title compound.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][NH:23][CH3:24].CO>>[CH3:22][N:23]([CH3:24])[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNC
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Solvent: CO
Product: COc1ccc(N(C)c2nc(N(C)C)nc3ccccc23)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (150 mg, 0.5 mmol), 2.0 M dimethylamine in methanol (2.0 ml, 4 mmol) in a sealed tube was stirred at 70-80° C. overnight. The mixture was filled and the filtration was concentrated by vacuum. The residue was extracted with ethyl acetate and was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by chromatography on silica gel with acetate and hexane (1:9) as eluent, yielding 128 mg of title compound (83%). 1H NMR (CDCl3): 7.44 (d, J=7.8 Hz, 1H), 7.36-7.30 (m, 1H), 7.11-7.08 (m, 2H), 6.90-6.85 (m, 3H), 6.65-6.59 (m, 1H), 3.82 (s, 3H), 3.51 (s, 3H), 3.30 (s, 6H).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[NH2:15])[C:9]([OH:11])=[O:10].[C:16](=O)(O)[O-].[Na+]>CO>[CH3:16][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([NH2:15])=[C:6]([NH2:5])[CH:7]=1
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(N)c(N)c1
Yield: 81 %

Procedure:
To dry methanol (20 ml) was carefully added thionyl chloride (1 ml) dropwise with stirring. The 3,4-diaminobenzoic acid (1 g) was added in portions at R.T. with stirring then the mixture heated at reflux for 3 h. Saturated sodium bicarbonate was added until the mixture was basic, then the mixture extracted into chloroform containing 25% methanol. The extract was dried and evaporated in vacuo to give the product (0.88 g, 81%) as a brown crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6]C(CO)=[CH:4][N:3]=1.[C:10]([O:13][C:14](=O)[CH3:15])(=[O:12])[CH3:11]>N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([CH3:6])=[CH:15][C:14]([O:13][C:10](=[O:12])[CH3:11])=[CH:4][N:3]=1
Reactant: Cc1ccc(CO)cn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cnc(C)c(C)c1

Procedure:
2-Methyl-5-hydroxymethylpyridine (0.1 mole) is stirred in pyridine (50 ml.) with acetic anhydride (0.15 mole) at room temperature overnight. The mixture is concentrated to dryness, and the residue is dissolved in 70 ml. of water and extracted with 3 × 25 ml. of chloroform. After drying over magnesium sulfate, the chloroform is concentrated to dryness to give 2-methyl-5-acetoxy-methylpyridine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=2)[CH2:29][CH2:28]1>C(Cl)Cl.CO>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:23]([C:20]3[CH:21]=[CH:22][C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])=[C:14]4[C:19]=3[N:18]=[CH:17][CH:16]=[CH:15]4)=[O:24])=[N:38][CH:39]=2)[CH2:29][CH2:28]1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3ncccc23)c1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), and stirring the reaction mixture for 20 h at rt. Title compound: ESI-MS: 566.1 [M+H]+; TLC: Rf=0.22 (DCM/MeOH, 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:13](=[O:18])(=[O:17])[N:14]([CH3:16])[CH3:15])=[C:6]([CH:12]=1)[CH2:7][NH:8]C(=O)C.Cl>C(O)C>[ClH:1].[NH2:8][CH2:7][C:6]1[CH:12]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[S:13]([N:14]([CH3:16])[CH3:15])(=[O:17])=[O:18]
Reactant: CC(=O)NCc1cc(Cl)ccc1S(=O)(=O)N(C)C
Agent: Cl
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccc(Cl)cc1CN

Procedure:
(Step 2) To a solution of N-[5-chloro-2-(dimethylsulfamoyl)benzyl]acetamide obtained in Step 1 (1.77% g) in ethanol (20 ml) was added 6N hydrochloric acid (20 ml) at room temperature. The mixture was stirred with heating under reflux for 3 hr, and then stirred overnight at 80° C. The solvent was evaporated under reduced pressure. The residue was collected by filtration, and washed with diethyl ether to give 2-(aminomethyl)-4-chloro-N,N-dimethylbenzenesulfonamide hydrochloride (1.61 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:27][OH:28])[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2cccc(Br)c2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3-(3-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (5.7:1) as a white foam, MS (ESI+): m/z=409.0895 ([M+H]+, 1Br).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.CN1CCOCC1>[Cu].[Cu]Cl.CN(C)C(=O)C>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: Nc1ccc(F)cc1
Agent: Cl[Cu]
Agent: [Cu]
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: O=C(O)c1ccc([N+](=O)[O-])cc1Nc1ccc(F)cc1
Temperature: 115 °C
Reaction time: 10 h

Procedure:
To N,N-dimethylacetamide 150 mL solution of 2-chloro-4-nitrobenzoic acid 30 g, were added 4-fluoroaniline 29 mL, copper powder 2.8 g, copper (I) chloride 5.3 g and N-methylmorpholine 33 mL at room temperature, and it was stirred at 110 to 120° C. for 10 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and 1.0 mol/L hydrochloric acid 700 mL and ethyl acetate 700 mL were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the obtained residue, solid matter was filtrated to give 2-(4-fluoroanilino)-4-nitrobenzoic acid 9.7 g of red solid.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:19])[CH2:18][CH2:17][CH2:16][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]2)[CH2:4]1.[N-:20]=[N+:21]=[N-:22].[Na+]>CS(C)=O.O>[N:20]([CH2:2][C:3]1([CH3:19])[CH2:18][CH2:17][CH2:16][C:5]2([O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6]2)[CH2:4]1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)CN1CC2(CCCC(C)(CBr)C2)OC1=O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)CN1CC2(CCCC(C)(CN=[N+]=[N-])C2)OC1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a solution of 7-(bromomethyl)-7-methyl-3-neopentyl-1-oxa-3-azaspiro[4.5]decan-2-one (11.3 g, 34.1 mmol) in DMSO (171 mL) was added sodium azide (2.89 g, 44.4 mmol). The reaction flask was placed behind a blast shield and heated to 80° C. for 4 days. The temperature was increased to 100° C. After 16 h, additional sodium azide (0.665 g, 10.23 mmol) was added to the reaction. After 19 h, the reaction was cooled to rt and diluted with water (300 mL). The product was extracted into EtOAc (2×300 mL). The combined organics were washed with water (3×400 mL). The organic layer was dried over MgSO4, filtered, and concentrated to provide the title compound (10.0 g, 95% crude yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 3.33 (q, J=8.53 Hz, 2H), 3.09 (s, 2H), 3.06 (d, J=14.00 Hz, 1H), 2.94 (d, J=14.05 Hz, 1H), 1.96-2.05 (m, 1H), 1.83-1.96 (m, 1H), 1.69 (dt, J=2.04, 14.24 Hz, 1H), 1.59-1.65 (m, 1H), 1.47 (d, J=14.05 Hz, 1H), 1.26-1.44 (m, 3H), 1.15 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([N:26]=[C:27]=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:20]([NH:26][C:27](=[O:28])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C:10]2([CH3:19])[CH3:18])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC1(C)CN(Cc2ccccc2)c2ccc(O)cc21
Reactant: CCCCCCN=C=O
Product: CCCCCCNC(=O)Oc1ccc2c(c1)C(C)(C)CN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzyl-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with n-hexylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (3.4 mg, 11%) having the following characteristics.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](O)=[O:13])=[CH:2]1.C([N:24](CC)C(C)C)(C)C.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>ClCCl>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([NH2:24])=[O:13])=[CH:2]1
Reactant: O=C(O)C(=Cc1c[nH]c2ncccc12)c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: ClCCl
Product: NC(=O)C(=Cc1c[nH]c2ncccc12)c1ccccc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
To a solution of 264 mg (1 mmol.) of 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenyl-2-propenoic acid in 1.5 ml of THFd and 3 ml of DMFd was added 350 μl of N,N-diisopropylethylamine and 154 mg (1.4 mmol.) of N-hydroxybenzotriazole ammonium salt. The obtained mixture was cooled to −20° C. and 266 mg (1.4 mmol.) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide were added. The reaction mixture was stirred for 2 hours at −20° C. and then warmed to room temperature. After additional 12 hours, the organic layer was diluted with dichloromethane, washed with saturated sodium bicarbonate, brine, dried over sodium sulphate and evaporated. The residual solid was triturated with EtOAc to afford 76 mg of the title compound as a white solid (yield 29%) m.p. 222-224° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][OH:29].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:29][CH2:28][C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: OCc1ccc2ccccc2c1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccc3ccccc3c2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-naphthalenemethanol and DBU in DME. ES-MS m/e (%): 343 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C:17]1([CH2:22][OH:23])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[OH:23][CH2:22][C:17]1([NH:16][C:8]([C:5]2[CH:4]=[C:3]([O:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1(CO)CCCC1
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: O=C(NC1(CO)CCCC1)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 1-amino-cyclopentanemethanol (CAN 10316-79-7) as starting materials and isolated (40 mg, quant.) as white solid; MS (ESI, m/z): 325.1 (MH+).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].[CH3:11][S:12]([NH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([N:22]2[CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)(=[O:14])=[O:13].[OH-].[NH4+].[P:29](=[O:33])([OH:32])([OH:31])[OH:30]>C(#N)C.CO>[P:29](=[O:30])([OH:33])([OH:32])[OH:31].[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:24][CH2:23][NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([NH:15][S:12]([CH3:11])(=[O:13])=[O:14])=[CH:26][CH:25]=1)[CH3:2]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)N2CC2)cc1
Reactant: CCCCCCCNCC
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: CCCCCCCN(CC)CCNC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
0.60 g (4.16 mmol) of N-ethylheptanamine and 0.50 g (2.08 mmol) of 1-[4-[(methylsulfonyl)amino]benzoyl]aziridine are dissolved in 10 mL of acetonitrile and the solution is warmed to 50° C. for 48 hours. The reaction is monitored by thin-layer chromatography (silica gel (EM); acetonitrile:conc. ammonium hydroxide (90:10)). After 48 hours, the reaction mixture is evaporated and the resultant solid is dissolved in 20 mL of methylene chloride. This solution is extracted with 2×10 mL of 1N aq. sodium hydroxide. The aqueous extract is acidified to pH=1 with 6N aq. hydrochloric acid and extracted with 2×15 mL of methylene chloride. The combined organic extracts are neutralized with saturated aqueous sodium bicarbonate and washed with 10 mL of water. The organic layer is dried over sodium sulfate, filtered and evaporated on a rotary evaporator to provide an oil. This oil is dissolved in 20 mL of 50% aqueous methanol and titrated to pH=4.5 with 0.1N aq. phosphoric acid. This solution is evaporated on the rotary evaporator and residual water is removed by azeotroping with 20 mL of alcohol. This residue is crystallized from 8 mL of reagent alcohol to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[CH:34]=[C:33](O)[CH:32]=[CH:31][C:30]=1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][O:27][C:33]3[CH:32]=[CH:31][C:30]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:29]([F:28])[CH:34]=3)=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(COc2cc(C(C)(C)C)nn2Cc2ccc(CO)cc2)n1
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(C(C)(C)C)cc3OCc3cccc(C)n3)cc2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a mixture of [4-({3-tert-butyl-5-[(6-methylpyridin-2-yl)methoxy]-1H-pyrazol-1-yl}methyl)phenyl]methanol (0.80 g, 2.2 mmol), ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (0.49 g, 2.3 mmol), tributylphosphine (1.10 mL, 4.41 mmol) and tetrahydrofuran (40 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.11 g, 4.40 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, and diisopropyl ether was added to the residue. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:3) to give the title compound (1.11 g, yield 90%) as a yellow oil. MS: m/z 560 (MH+).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[C:39](Cl)=[O:40]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:39]([C:35]3[S:34][CH:38]=[CH:37][CH:36]=3)=[O:40])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cccs4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.620 g, 4.07 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione hydrochloride (0.600 g, 1.85 mmol) in CH3CN (50 ml). After stirring for 20 min, 2-thiophene-carbonyl chloride (0.3 g, 2.03 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 ml). The CH2Cl2 solution was washed with 1N HCl (30 ml), H2O (30 ml), brine (30 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}-2-thienylcarboxamide (0.35 g, 47%) as a white solid: mp 192-194° C.; 1H NMR (DMSO-d6) δ d 11.16 (s, 1H), 9.18 (t, J=5.8 Hz, 1H), 7.88-7.72 (m 5H), 7.20-7.17 (dd, J=3.9 and 4.7 Hz, 1H), 5.22-5.15 (dd, J=5.5 and 12.7 Hz, 1H), 4.94 (d, J=5.8 Hz, 2H), 2.98-2.85 (m, 1H), 2.66-2.50 (m, 2H), 2.11-2.06 (m, 1H); 13C NMR (DMSO-d6) δ d 172.72, 169.80, 167.51, 166.93, 161.52, 139.26, 139.14, 134.83, 133.14, 131.53, 131.11, 128.51, 127.96, 127.12, 121.93, 48.89, 38.09, 30.93, 21.99; Anal. Calcd. For C19H15N3O5S: C, 57.42; H, 3.80; N, 10.57. S, 8.07. Found: C, 57.80; H, 3.93; N, 10.22; S, 7.99.