Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[C:12]([O:16][C:17](=[O:22])[NH:18][CH2:19][CH2:20][NH2:21])([CH3:15])([CH3:14])[CH3:13].Cl.C(N=C=N)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:12]([O:16][C:17](=[O:22])[NH:18][CH2:19][CH2:20][NH:21][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNC(=O)Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of 3-fluorophenylacetic acid (1.93 g, 12.5 mmol) in CH2Cl2 (50 mL) was added tert-butyl-N-(2-aminoethyl)carbamate (2.0 g, 12.5 mmol), 4-dimethylaminopyridine (1.53 g, 12.5 mmol) and 1-[3-dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (2.4 g, 12.5 mmol). The mixture was stirred at room temperature for 16 h then washed with water (50 mL) and citric acid (10%, 2×50 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2 :MeOH (95:5→90:10), to afford the title amide (3.7 g, 100%) as a colourless solid. mp 125-128° C. 1H NMR (250 MHz, CDCl3) δ 1.43 (9H, s), 3.18-3.40 (4H, m), 3.53 (2H, s), 4.82 (1H, br s), 6.23 (1H, br s), 6.94-7.06 (3H, m), 7.26-7.40 (2H, m). MS (ES+) (297, M+1).
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[C:7]([CH:9](Br)[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)=O)[CH:6]=[CH:5][N:4]=1.[C:20]([NH2:24])(=[S:23])[CH2:21][CH3:22]>CN(C)C=O>[CH2:21]([C:20]1[S:23][C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([NH2:2])[CH:8]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[N:24]=1)[CH3:22]
Reactant: CCC(N)=S
Reactant: Cc1cccc(C(=O)C(Br)c2ccnc(N)c2)c1
Agent: Br
Solvent: CN(C)C=O
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(N)c2)s1
Yield: 81.9 %

Procedure:
A solution of 2-(2-amino-4-pyridyl)-2-bromo-1-(3-methylphenyl)ethanone hydrobromide (125 g, 0.323 mol) and thiopropionamide (28 g, 0.314 mol) in N,N-dimethylformamide (1200 mL) was stirred at room temperature for 14 hrs. The solvent was evaporated under reduced pressure. Aqueous sodium hydrogen carbonate solution was poured into the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried and concentrated. Crude crystals were washed with hexane-ethyl acetate=1:1 to give the title compound (76.0 g, yield 82%).
Reaction SMILES: [Si]([O:18][C:19]1[CH:58]=[CH:57][C:22]([O:23][CH2:24][C@@H:25]([OH:56])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:55]=[CH:54][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([C:43]4[NH:44][C:45]5[C:50]([CH:51]=4)=[CH:49][C:48]([O:52][CH3:53])=[CH:47][CH:46]=5)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:56][CH:25]([CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:58][CH:57]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:55]=[CH:54][C:33]([NH:34][CH:35]2[CH2:36][CH2:37][N:38]([C:41]([C:43]3[NH:44][C:45]4[C:50]([CH:51]=3)=[CH:49][C:48]([O:52][CH3:53])=[CH:47][CH:46]=4)=[O:42])[CH2:39][CH2:40]2)=[CH:32][CH:31]=1
Reactant: COc1ccc2[nH]c(C(=O)N3CCC(Nc4ccc(CCNC[C@H](O)COc5ccc(O[Si](c6ccccc6)(c6ccccc6)C(C)(C)C)cc5)cc4)CC3)cc2c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2[nH]c(C(=O)N3CCC(Nc4ccc(CCNCC(O)COc5ccc(O)cc5)cc4)CC3)cc2c1
Yield: 28.6 %

Procedure:
(4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-1-piperidinyl}(5-methoxy-1H-indol-2-yl)methanone (0.128 g, 0.161 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.026 g, 0.046 mmol).
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=O.C1(P(=[CH:33][C:34]([O:36][CH3:37])=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:37][O:36][C:34](/[CH:33]=[CH:3]/[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:35]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 1.46 g, 36.6 mmol) was added to a solution of 4-formylbenzoic acid (5.0 g, 33.3 mmol) in toluene (200 ml) and the mixture was stirred for 2 h at room temperature. Methyl (triphenyl-phosphoranylidene)acetate (11.69 g, 35.0 mmol) was added and the mixture was heated at reflux for 20 h. Solvents were removed in vacuo and the residue was redissolved in dichloromethane and 1M NaHCO3. The layers were partitioned and the aqueous layer was acidified with 1M HCl solution then extracted with chloroform. The organic layer was dried and concentrated in vacuo to yield the title compound (3.65 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:25]([F:28])([F:27])[F:26])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:62][C:63]([F:73])([F:72])[CH2:64][CH2:65][N:66]1[C:70](=[O:71])[CH2:69][NH:68][CH2:67]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:25]([F:27])([F:28])[F:26])[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:68]4[CH2:69][C:70](=[O:71])[N:66]([CH2:65][CH2:64][C:63]([F:62])([F:72])[F:73])[CH2:67]4)=[O:20])=[C:17]([CH3:24])[CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C1CNCN1CCC(F)(F)F
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N1CC(=O)N(CCC(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N,N-dimethylformamide (2 mL), 4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoic acid (50 mg, 0.11 mmol, 1.00 equiv), HATU (174 mg, 0.46 mmol, 4.00 equiv), DIEA (60 mg, 0.46 mmol, 4.00 equiv), 3-(3,3,3-trifluoropropyl)imidazolidin-4-one (25 g, 137.25 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at room temperature. The crude product was purified by Prep-HPLC. This resulted in 22.1 mg (32%) of 1-([4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl]carbonyl)-3-(3,3,3-trifluoropropyl)imidazolidin-4-one as a white solid. 641 [Ms+CH3CN+H]+; (300 MHz, CD3OD, ppm): δ7.77-7.64 (m, 4H), 7.45-7.28 (m, 1H), 5.12-4.69 (m, 1H), 4.32-4.22 (m, 1H), 4.08-4.01 (m, 1H), 3.87-3.54 (m, 2H), 3.14-2.87 (m, 3H), 2.70-2.31 (m, 4H).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[C:32]([CH3:31])[CH:33]=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)c1
Yield: 94 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 3-methylphenylboronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless foam (94%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:26])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3](=[O:31])/[CH:4]=[CH:5]/[C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:10]=1[CH3:11].[ClH:33].CCOCC>C(O)C.[Pd]=O>[ClH:33].[ClH:33].[CH3:32][N:2]([CH3:1])[C:3](=[O:31])[CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11]
Reactant: Cc1c(/C=C/C(=O)N(C)C)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Cc1[nH]cnc1CCC(=O)N(C)C
Reaction time: 72 h

Procedure:
A solution of (E)-N,N-dimethyl-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-2-propenamide (6.0 g) in ethanol (100 ml) was hydrogenated at room temperature and pressure over 10% palladium oxide on carbon (dry, 2.0 g, pre-reduced in ethanol (25 ml)) for 48 h. The catalyst was filtered off (Hyflo), replaced with fresh palladium oxide (2.0 g) and hydrogenation continued for 72 h. The catalyst was filtered off (Hyflo) and the filtrate evaporated in vacuo to yield a yellow oil. This was dissolved in ethanol (15 ml) and acidified with ethanolic hydrogen chloride (to pH1). Dry ether (500 ml) was added and the resulting precipitate was filtered off to give the title compound (1.72 g) as a white powder, m.p. 142°-144°.
Reaction SMILES: COC1N=C2C(=CC=1)N[C@@H](C)C[C@H]2NC(=O)C.[CH:18]1([C@H:21]2[CH2:30][C@@H:29]([NH:31][C:32](=[O:34])[CH3:33])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:35]([F:38])([F:37])[F:36])[N:27]=3)[NH:22]2)[CH2:20][CH2:19]1.Cl[C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[CH:43]([O:42][C:40]([N:22]1[C:23]2[C:28](=[N:27][C:26]([C:35]([F:37])([F:38])[F:36])=[CH:25][CH:24]=2)[C@H:29]([NH:31][C:32](=[O:34])[CH3:33])[CH2:30][C@@H:21]1[CH:18]1[CH2:20][CH2:19]1)=[O:41])([CH3:45])[CH3:44]
Reactant: CC(=O)N[C@@H]1C[C@H](C2CC2)Nc2ccc(C(F)(F)F)nc21
Reactant: CC(C)OC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: COc1ccc2c(n1)[C@H](NC(C)=O)C[C@H](C)N2
Solvent: c1ccncc1
Product: CC(=O)N[C@@H]1C[C@H](C2CC2)N(C(=O)OC(C)C)c2ccc(C(F)(F)F)nc21
Yield: 31 %

Procedure:
Prepare the title compound by essentially following the procedure described in Example 46, Step 2, by replacing (+/−)-cis-N-(6-methoxy-2-methyl-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)acetamide, with (+/−)-cis-N-(2-cyclopropyl-6-trifluoromethyl-1,2,3,4-tetrahydro-[1,5]naphthyridin-4-yl)acetamide (1.05 g, 3.512 mmol), and using isopropyl chloroformate, pyridine, and dimethylaminopyridine. Purify using silica gel column chromatography (gradient eluent, 0-5% MeOH in ethyl acetate) to provide the title compound (0.416 g, 31%). MS (ES+): 386 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1.[C:30](O)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:30]([NH:1][CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCOC(=O)CCCCc1c(CN)nn2c(CC)ccc2c1-c1cncc(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCc1c(CNC(=O)c2ccccc2)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
A mixture of ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (75 mg), benzoic acid (27.9 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (54.7 mg) and 1-hydroxybenotriazole (385 mg) in dimethylformamide (2 mL) was stirred at ambient temperature for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-[2-[(benzoylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (60 mg).
Reaction SMILES: [CH3:1][C:2]12[O:13][C:8]([CH3:14])([CH2:9][C:10](=[O:12])[CH2:11]1)[CH:7]1[CH:3]2[O:4][C:5]([CH3:16])([CH3:15])[O:6]1.C([N-]C(C)C)(C)C.[Li+].[F:25][C:26]([F:41])([C:37]([F:40])([F:39])[F:38])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[S:29](F)(=[O:31])=[O:30]>C1COCC1.O>[CH3:14][C:8]12[O:13][C:2]([CH3:1])([CH:11]=[C:10]([O:12][S:29]([C:28]([F:33])([F:34])[C:27]([F:35])([F:36])[C:26]([F:25])([F:41])[C:37]([F:40])([F:39])[F:38])(=[O:31])=[O:30])[CH2:9]1)[CH:3]1[CH:7]2[O:6][C:5]([CH3:16])([CH3:15])[O:4]1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC1(C)OC2C(O1)C1(C)CC(=O)CC2(C)O1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC2C(O1)C1(C)CC(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)=CC2(C)O1
Temperature: -78 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A solution of 1,4,4,7-tetramethyl-3,5,11-trioxa-tricyclo[5.3.1.02,6]undecan-9-one (Bulletin of the Chemical Society of Japan (1983), 56(9), 2680-99, 386 mg, 1.71 mmol) in THF (10 mL) was cooled to −78° C. under Ar and treated with lithium diisopropylamide (LDA) (1.00 mL of 2M in heptane/THF/ethylbenzene, 2 mmol). The resulting mixture was stirred at −78° C. for 2 h and treated dropwise with nonafluoro-1-butanesulfonylfluoride (0.60 mL, 3.4 mmol). The reaction mixture was allowed to warm to RT and stirred overnight and diluted with water (10 mL). The product was extracted with ether (4×10 mL). The organic layers were combined, dried (Na2SO4) and the product was purified on silica gel (0-2% EtOAc/hexane) to give the title compound (546 mg, 63%). 1H-NMR (CDCl3; 400 MHz): δ 5.78 (br s, 1H), 4.37 (d, 1H, J=5.5 Hz), 4.28 (d, 1H, J=5.5 Hz), 2.52 (dd, 1H, J=17.6, 2.0 Hz), 2.04 (d, 1H, J=17.6, 1.4 Hz), 1.43 (s, 3H), 1.38 (s, 3H), 1.32 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: C(OC(N1CCC(NC(C2SC=CC=2NC2C=CN=C3NC=CC=23)=O)C1)=O)(C)(C)C.[CH2:31]([NH:38][CH2:39][CH2:40][NH2:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[NH:42]1[C:46]2=[N:47][CH:48]=[CH:49][C:50]([NH:51][C:52]3[C:53]4[CH:63]=[CH:62][CH:61]=[CH:60][C:54]=4[S:55][C:56]=3[C:57](O)=[O:58])=[C:45]2[CH:44]=[CH:43]1>>[CH2:31]([NH:38][CH2:39][CH2:40][NH:41][C:57]([C:56]1[S:55][C:54]2[CH:60]=[CH:61][CH:62]=[CH:63][C:53]=2[C:52]=1[NH:51][C:50]1[CH:49]=[CH:48][N:47]=[C:46]2[NH:42][CH:43]=[CH:44][C:45]=12)=[O:58])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)c1sc2ccccc2c1Nc1ccnc2[nH]ccc12
Reactant: NCCNCc1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCCNCc1ccccc1)c1sc2ccccc2c1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using N-benzylethylenediamine instead of 1-BOC-3-aminopyrrolidine and 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-benzo[b]thiophene-2-carboxylic acid instead of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid. LCMS (ESI) 393 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.42 (1H, br. s.) 8.89 (1H, s) 8.23 (1H, t, J=5.37 Hz) 8.04 (1H, dt, J=8.07, 0.92 Hz) 7.82 (1H, d, J=5.37 Hz) 7.50 (2H, dddd, J=6.92, 5.94, 0.78, 0.61 Hz) 7.26-7.41 (3H, m) 7.08-7.25 (7H, m) 6.48 (1H, d, J=2.34 Hz) 6.03 (1H, d, J=5.42 Hz) 3.46 (2H, s) 2.46 (2H, t, J=6.20 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]([C:18](=[N:22][OH:23])[CH:19]([CH3:21])[CH3:20])=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1.C[Si]([N:28]=[C:29]=[O:30])(C)C.N1C=CC=CC=1>C1COCC1>[C:29]([O:23][N:22]=[C:18]([C:17]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)[CH:19]([CH3:20])[CH3:21])(=[O:30])[NH2:28]
Reactant: C[Si](C)(C)N=C=O
Reactant: COc1ccc(-c2nn3ccccc3c2C(=NO)C(C)C)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(-c2nn3ccccc3c2C(=NOC(N)=O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 29.8 %

Procedure:
To a solution of 775 mg (2.5 mmol) of 1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime in 5 ml of anhydrous THF was added 2 ml of trimethylsilyl isocyanate (85%) dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature over 48 hours, followed by addition of 500 μl pyridine. After stirring for another 4 hours the solvent was removed, and the residue was extracted with ethyl acetate three times. The combined organic layers were washed with 10% citric acid twice and dried over MgSO4. After evaporation of the solvent, 900 mg of crude product was obtained, which was purified on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant to yield 263 mg (29.8%) of 1-(2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one O-carbamoyl oxime. Compound 1023.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.CC1C=CC(S(O[CH2:21][C@@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:23])(=O)=O)=CC=1.O>CN(C=O)C>[CH3:23][C@H:22]([NH:24][C:25](=[O:26])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:21][O:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1
Reactant: Oc1ccncc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COc1ccncc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To a suspension of sodium hydride (oil, 60%, 1.61 g) in DMF (50 mL) was added 4-hydroxypyridine (3.83 g) under ice-cooling. The reaction mixture was stirred for 30 min under ice-cooling, and (2S)-2-[(tert-butoxycarbonyl)amino]propyl 4-methylbenzenesulfonate (13.3 g) was added thereto in small portions under ice-cooling. The reaction mixture was stirred for 2 hr under ice-cooling, and at 60° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.10 g).
Reaction SMILES: C([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:5]=1[S:14]([NH2:17])(=[O:16])=[O:15])(=O)C.Cl[Si](C)(C)C.S(=O)(=O)(O)[OH:24]>CO>[Cl:13][C:6]1[C:5]([S:14]([NH2:17])(=[O:16])=[O:15])=[C:4]([OH:24])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: CC(=O)c1c([N+](=O)[O-])ccc(Cl)c1S(N)(=O)=O
Reactant: O=S(=O)(O)O
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Yield: 68 %

Procedure:
A solution of 2-acetyl6-chloro-3-nitrobenzenesulfonamide (1.72 g, 5.83 mmol), chlorotrimethylsilane (2 mL) and fuming sulfuric acid (0.5 mL) in methanol was heated to reflux for 20 hours. The solvent was evaporated. The residue was diluted with ethyl acetate and washed with water. The organic layer was then dried (Na2SO4) and concentrated to give the desired product (1.0 g, 68%). EI-MS (m/z) 251.1, 253.2 (M−).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:7]1[CH:12]=[CH:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]1=[O:15])[CH:4]([CH3:6])[CH3:5].C1(C)C=CC(S([CH:25]([N+:27]#[C-:28])[CH3:26])(=O)=O)=CC=1>C1COCC1>[CH2:3]([N:7]1[C:12]2=[C:25]([CH3:26])[NH:27][CH:28]=[C:11]2[C:10](=[O:13])[N:9]([CH3:14])[C:8]1=[O:15])[CH:4]([CH3:6])[CH3:5]
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)Cn1ccc(=O)n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1[nH]cc2c(=O)n(C)c(=O)n(CC(C)C)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
Sodium hydride (95%, 116 mg, 4.6 mmol) is suspended in 10 mL of anhydrous THF, and then a mixture of 1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione (300 mg, 1.65 mmol) and 1-(p-toluenesulfonyl)-ethyl isocyanide (413 mg, 1.98 mmol) in 5 mL of anhydrous THF is added dropwise over 1 h at 0° C. The mixture is stirred at room temperature for 3 h at room temperature after the completion of the addition, and then carefully quenched with water. The mixture is diluted with saturated NaHCO3, and then extracted with CH2Cl2 five times. The combined organic phase is washed with brine, and then dried with anhydrous Na2SO4. After filtration, the filtrate is evaporated to dryness under reduced pressure, and the residue is purified by basic alumina column chromatography to give 247 mg of product (yield: 64%). MS (ESI) m/z 236.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@:8]([CH2:19][OH:20])([CH3:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:28](OS(C)(=O)=O)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].Cl>C(O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:21])[NH:7][C@:8]([CH2:19][OH:20])([CH3:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)CCc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(CC[C@](C)(CO)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of [(R)-1-hydroxymethyl-3-(4-hydroxy-phenyl)-1-methyl-propyl]-carbamic acid tert-butyl ester (2.06 g, 6.98 mMol) in ethanol (100 ml) is added potassium carbonate (2.90 g, 20.8 mMol) and methanesulfonic acid heptyl ester (2.04 g, 10.5 mMol). The mixture is heated to reflux temperature and stirred at that temperature for 6 hours. The mixture is then cooled to RT and stirred at RT overnight. The reaction mixture is then poured onto a biphasic mixture of AcOEt and HCl (aqueous, 1 M). The aqueous phase is extracted twice with AcOEt. The combined organic layers are washed with NaHCO3 (saturated aqueous solution), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography eluting with 8% AcOEt in toluene gives the title compound as a colourless oil.