Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:20][CH:19]=2)[N:3]=1.N([O-])=[O:32].[Na+].C(=O)([O-])O.[Na+]>Cl.O1CCOCC1.O>[CH2:11]([O:10][C:8]([C:7]1[C:2](=[O:32])[NH:3][C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:20][CH:19]=2)=[CH:5][C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cc(-c2ccc(OCOCCOC)cc2)nc(N)c1C(=O)OCC
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ccc(OCOCCOC)cc2)[nH]c(=O)c1C(=O)OCC
Reaction time: 1 h

Procedure:
In 250 ml of 1N hydrochloric acid and 100 ml of dioxane was dissolved 32.2 g of 2-amino-3,4-diethoxycarbonyl-6-(4-methoxyethoxymethoxyphenyl)pyridine, whereto a solution of 6.9 g (1.3 eq.) of sodium nitrite dissolved in 30 ml of water was added dropwise under ice-cooling. The mixture was stirred for 1 hour and left standing in a refrigerator overnight. The mixture was neutralized with sodium hydrogencarbonate, and dioxane was distilled off, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried. Then, the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent:dichloromethane→ethyl acetate).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].Cl.Cl.[NH2:7][C@@H:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:24]=1)[C@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[CH:14]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][NH:11][CH2:10][C@@H:9]([OH:21])[C@@H:8]([NH:7][C:1](=[O:4])[CH3:2])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:24]=1)[CH3:20]
Reactant: CCCCCCOc1cccc(C[C@H](N)[C@H](O)CNCc2cccc(CC)c2)c1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCOc1cccc(C[C@H](NC(C)=O)[C@H](O)CNCc2cccc(CC)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.7 %

Procedure:
To a stirred solution of acetic acid (15 pg, 0.2 mmol), amine 92 (100 mg, 0.2 mmol), and HATU (80 mg, 0.2 mmol) in methylene chloride (3 mL) was added N,N-diisopropylethylamine (130 μL, 0.7 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, gradient 95:5 to 90:10 methylene chloride/methanol) provided N-{(1S,2R)-3-[(3-ethylbenzyl)amino]-1-[3-(hexyloxy)benzyl]-2-hydroxypropyl}acetamide 93B (20 mg): mp 102–105° C.; IR (KBr) 3304, 2929, 1637, 1603, 1550 cm 1; 1H NMR (500 MHz, CD3OD)δ 7.26–7.11 (m, 5H), 6.75–6.70 (m, 3H), 4.03–3.60 (m, 6H), 3.10–3.05 (m, 1H), 2.80–2.55 (m, 5H), 1.78–1.72 (m, 2H), 1.78 (s, 3H), 1.46–1.44 (m, 2H), 1.36–1.33 (m, 4H), 1.24–1.21 (m, 3H), 0.93–0.91 (m, 3H); ESI MS m/z 441 [M+H]+.
Reaction SMILES: [C:1]([OH:11])(=O)[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:25][NH:26][O:27][CH3:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:28][O:27][N:26]([CH3:25])[C:1](=[O:11])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
A suspension of 10.2 grams (68.1 mmol) of hydrocinnamic acid, 14.4 grams (74.9 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 7.31 grams (74.9 mmol) of N,O-dimethylhydroxylamine hydrochloride in 250 mL of methylene chloride was cooled to 0° C. and treated with 19.1 mL (13.9 grams, 136 mmol) of triethylamine. The mixture was stirred for 16 hours with slow warming to rt and was then concentrated. The residue was taken up in 250 mL of ethyl acetate, washed with aqueous 1N hydrochloric acid solution (2×150 mL), saturated aqueous sodium hydrogencarbonate solution (2×100 mL), brine (1×100 mL), dried (Na2SO4), and evaporated to give 13.11 grams (99%) of the title compound as an oil. Anal. Calcd for C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found: C, 68.65; H, 8.11; N, 7.18.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:26][NH2:27]>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:26][NH2:27])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: NN
Reactant: O=C(O)c1ccc2cnccc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: NNC(=O)c1ccc2cnccc2c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
Isoquinoline-6-carboxylic acid (1.2 g, 6.94 mmol) purchased from Gateway Chemical Technology, Inc. was mixed with CDI (1.68 g, 10.4 mmol) in DMF (20 Ml) in a round bottom flask. After the mixture was stirred for 30 minutes at 20° C., anhydrous hydrazine (2 mL) was added and the resulting mixture was stirred at 20° C. for one hour. After removing the solvent at a reduced pressure, the remaining residue was mixed with 20 mL water. After filtration, washing with water and air drying, an off-white solid was obtained as the desired product. LCMS (API-ES) m/z (%): 188.0 (100%, M++H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:35][CH3:36])[CH:3]=1.[S:37]1[CH:41]=[N:40][N:39]=[C:38]1[NH2:42].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:42][C:38]4[S:37][CH:41]=[N:40][N:39]=4)(=[O:21])=[O:22])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: Nc1nncs1
Reactant: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Reaction time: 2 h
Yield: 53.7 %

Procedure:
A vial was charged with perfluorophenyl 1-(4-chloro-5-cyano-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE VVVV, 145.2 mg, 0.268 mmol). 1,3,4-thiadiazol-2-amine (32.6 mg, 0.322 mmol), and cesium carbonate (262 mg, 0.805 mmol). Acetonitrile (1342 μl) was added, and the mixture was stirred for 2 h. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the aq. layer was extracted with 10% MeOH/EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was concentrated from MeOH, then the mixture was filtered through a membrane filter. The collected solid was washed with MeOH (3×), dried under a stream of N2 (g), then dried under vacuum to give 1-(4-chloro-5-cyano-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (65.89 mg, 0.144 mmol, 53.6% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=14.51 (br. s., 1H), 8.80 (s, 1H), 8.70 (d, J=5.7 Hz, 1H), 8.58 (d, J=1.6 Hz, 1H), 8.16 (d, J=5.7 Hz, 1H), 7.98 (s, 1H), 7.89-7.82 (m, 1H), 7.80-7.72 (m, 1H), 7.65 (s, 1H), 3.78 (s, 3H). m/z (ESI) 458.2 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][O:10][N:9]=1.[Cl:16][C:17]1[C:18]([NH2:24])=[N:19][C:20]([NH2:23])=[CH:21][N:22]=1>CN(C)C=O.N1C=CC=CC=1>[NH2:24][C:18]1[N:19]=[C:20]([NH:23][C:13]([C:12]2[C:8]([CH3:7])=[N:9][O:10][CH:11]=2)=[O:15])[CH:21]=[N:22][C:17]=1[Cl:16]
Reactant: Nc1cnc(Cl)c(N)n1
Reactant: Cc1nocc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1nocc1C(=O)Nc1cnc(Cl)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
Oxalyl chloride (0.06 ml, 0.69 mmol) was added to a solution of 3-Methyl-isoxazole-4-carboxylic acid (0.06 g, 0.48 mmol) followed by 1 drop of dimethylformamide. The mixture was stirred at room temperature for 4 hours before concentrating in vacuo and azeotroping with dichloromethane. The residue was taken up in pyridine (1 ml) and added to a solution of 3-chloro-pyrazine-2,6-diamine (Preparation 1) (0.035 g, 0.24 mmol) in anhydrous pyridine (3 ml) and the mixture heated at 50° C. for 3 hours before cooling to room temperature and concentrating to dryness in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate:heptane 1:1, to afford the product as a white solid (30 mg).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[N:13]=[C:12]2I)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[CH2:25]([Sn:29]([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:31][CH2:32][CH2:33][CH3:34])Cl)[CH2:26][CH2:27][CH3:28]>C1COCC1>[Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[N:13]=[C:12]2[Sn:29]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:35][CH2:36][CH2:37][CH3:38])[CH2:25][CH2:26][CH2:27][CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cn1nc(I)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(O[Si](C)(C)C(C)(C)C)cc12
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
The solution of 5-(tert-butyldimethylsilyloxy)-3-iodo-1-methyl-1H-indazole (3.8 g, 10 mmol) in 30 mL of dry THF was cooled to −20° C. under nitrogen, isopropylmagnesium chloride (6 mL, 12 mmol, 2M in THF) was added and stirred for 15 min at −20° C. Tributylchlorostannane (12 mL, 14 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was quenched with saturated solution of ammonium chloride, extracted with ethyl acetate (3×50 mL), dried over sodium sulfate and concentrated to give 5-(tert-butyldimethylsilyloxy)-1-methyl-3-(tributylstannyl)-1H-indazole (5.2 g, crude) as a colourless oil, which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH3:11])[CH:7]=[CH:6][C:5]=2[CH3:12].C([Li:17])CCC.CCCCCC>C1COCC1>[CH3:1][C:2]1[CH:10]([Li:17])[C:9]2[C:4]([CH:3]=1)=[C:5]([CH3:12])[CH:6]=[CH:7][C:8]=2[CH3:11]
Reactant: [Li]CCCC
Reactant: CC1=Cc2c(C)ccc(C)c2C1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]C1C(C)=Cc2c(C)ccc(C)c21

Procedure:
To a solution of 2,4,7-trimethylindene (2.90 g, 18.3 mmol) in 50 ml of THF at 0° C. was added dropwise a 1.6 molar solution of butyllithium in hexane (11.45 ml, 18.3 mmol) in order to produce 2,4,7-trimethylindenyllithium. The solution was stirred for 6 h at room temperature and then added via a cannula to a solution of 1-(9-fluorenyl)-2-bromoethane (5.00 g, 18.3 mmol) in 30 ml THF cooled at -10° C. The mixture was stirred overnight at room temperature and then hydrolyzed with 50 ml of aqueous NH4Cl. The organic phase was separated and the aqueous layer was extracted with ether. The combined organic phases were dried on MgSO4, filtered and the solvent was removed. The residue was crystallized from hot 100% ethanol to give 1.86 g (29%) of 1-(9-fluorenyl)-2-[1-(2,4,7-trimethyl)indenyl]ethane precursor as a white solid; melting point 178-179° C.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[CH3:24][N:25]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CC(N(C)C)=O>[CH3:24][N:25]([CH:33]1[CH2:34][CH2:35][N:36]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=3)[N:16]=2)[CH2:37][CH2:38]1)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
DIPEA (1.355 mL, 7.78 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.865 g, 3.89 mmol) and tert-butyl methyl(piperidin-4-yl)carbamate (1 g, 4.67 mmol) in DMA (15 mL). The resulting solution was stirred at 50° C. for 2 hours. The reaction mixture was evaporated and diluted with DCM (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl methyl[1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]carbamate (1.500 g, 96%) as a solid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:8](Cl)[C:7]=2[N+:18]([O-:20])=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[OH2:23]>>[N:1]1([C:6]2[CH:11]=[C:10]([Cl:12])[C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:8]([OH:23])[C:7]=2[N+:18]([O-:20])=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1c(Cl)cc(N2CCCC2)c([N+](=O)[O-])c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: NS(=O)(=O)c1c(Cl)cc(N2CCCC2)c([N+](=O)[O-])c1O
Yield: 85.9 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, (N-pyrrolidinyl)-2,6 dichloro-3-nitrobenzenesulfonamide (1.12 g, 3.4mmol), 80% NaH (0.31 g, 10.3 mmol) and water (74 μL, 4.1mmol) were reacted to form the desired product (0.94 g, 69%). LC-MS m/z 307(M+).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[OH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O.CN(C)C=O>[O:12]=[C:6]1[NH:7][C:8]2[N:9]=[CH:10][CH:11]=[C:2]([O:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17]4)[C:3]=2[CH2:4][CH2:5]1
Reactant: O=C(O)c1cnc2ccc(O)cc2c1
Reactant: O=C1CCc2c(F)ccnc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2c(Oc3ccc4ncc(C(=O)O)cc4c3)ccnc2N1
Temperature: 150 °C

Procedure:
5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one (Int-28, 120 mg, 0.72 mmol), 6-hydroxyquinoline-3-carboxylic acid (1.5 mg, 0.794 mmol), and cesium carbonate (706 mg, 2.17 mmol) were weighed into a microwave vial. N,N-Dimethylformamide (3.5 mL) was added and the vial was sealed and heated in a microwave at 150° C. for 4 h. The vial was opened and water was added (5 mL). The resulting clear solution was neutralized by the addition of 1N HCl and washed with ethyl acetate. The washed aqueous phase was acidified to pH 3 and pure product was collected by suction filtration. LC-MS: (FA) ES+ 336; 1H NMR (400 MHz, d6-DMSO) δ ppm 13.55 (s, 1H), 10.60 (s, 1H), 9.27 (d, J=2.1 Hz, 1H), 8.94 (d, J=1.9 Hz, 1H), 8.17 (d, J=9.1 Hz, 1H), 8.07-8.02 (m, 1H), 7.85 (d, J=2.7 Hz, 1H), 7.74 (dd, J=9.1, 2.8 Hz, 1H), 6.52 (d, J=5.7 Hz, 1H), 2.92 (t, J=7.7, 7.7 Hz, 2H), 2.54 (dd, J=8.3, 7.1 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])[CH3:2].Br.C(N(CC)CC)C.[C:28]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)(=[O:30])[CH3:29].C(N=C=NCCCN(C)C)C.Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH:9][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([O:31][C:28](=[O:30])[CH3:29])=[CH:40][CH:39]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)c1ccc(OC(C)=O)cc1
Reaction time: 3 h

Procedure:
17.3 g (0.05 mol) of L-alanyl-L-phenylalanine ethyl ester·HBr was suspended in 250 ml of dichloromethane, and to this susension were added 5.1 g (0.05 mol) of triethylamine and 9 g (0.05 mol) of p-acetoxybenzoic acid, and then 9.6 g (0.05 mol) of 1-ethyl-3(3-dimethylaminopropyl)carbodiimide·HCl was added in an ice bath. This mixture was stirred for three hours, and then was washed with a 0.1% aqueous solution of Na2CO3 and with a 0.1 N HCl solution three times and then with distilled water three times, and was dried over anhydrous sodium sulfate. Dichloromethane was removed from the dried mixture under reduced pressure to obtain p-acetoxybenzoyl-L-alanyl-L-phenylalanine ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C([O:26]CC)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=1.[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O-:26])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOCC
Agent: OCCC#Cc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve 13.3 g (0.0736 mole) of 4-(4-chlorophenyl)-3- butyn-1-ol in 70 ml pyridine and cool to 0° C. Add 16 g (0.0837 mole) of p-toluenesulfonyl chloride and stir in ice bath for one hour. Store in freezer over night. Add 200 ml diethyl ether and then wash with 3×150 ml 1N hydrochloric acid. The organic layer is then washed with 50 ml saturated aqueous sodium bicarbonate solution and then dried over magnesium sulfate. Evaporate solvent to obtain the title compound.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])[C:27]([OH:29])=O)#[N:23].O[NH:38][C:39]([C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[NH:46][C:45]([CH2:50][OH:51])=[CH:44]2)=[NH:40]>CN(C=O)C.CCOC(C)=O>[OH:51][CH2:50][C:45]1[NH:46][C:47]2[C:43]([CH:44]=1)=[CH:42][C:41]([C:39]1[N:40]=[C:27]([C:26]3[CH:30]=[CH:31][C:32]([O:33][CH:34]([CH3:36])[CH3:35])=[C:24]([CH:25]=3)[C:22]#[N:23])[O:29][N:38]=1)=[CH:49][CH:48]=2
Reactant: N=C(NO)c1ccc2[nH]c(CO)cc2c1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]c(CO)cc4c3)no2)cc1C#N
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 26.6 %

Procedure:
EDCI (144 mg) and HOBT (104 mg) were added to a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described on WO2005/58848, 144 mg) in DMF (5 mL) at RT. The resulting solution was stirred for 15 min. N-Hydroxy-2-(hydroxymethyl)-1H-indole-5-carboximidamide (D25) (144 mg) was added and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was heated to 80° C. and stirred at that temperature for 4 hours. EtOAc (50 mL) was added and the organic solution was washed with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and water (50 mL). The organic fraction was dried over anhydrous magnesium sulfate. The dried solution was concentrated. The residue was recrystallized from EtOAc/ether to afford 5-{3-[2-(hydroxymethyl)-1H-indol-5-yl]-1,2,4-oxadiazol-5-yl}-2-[(1-methylethyl)oxy]benzonitrile (E12) (70 mg) as a light brown solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 4.65 (2H, d), 4.99 (1H, m), 5.36 (1H, t), 6.46 (1H, s), 7.49 (1H, d), 7.56 (1H, d), 7.79 (1H, dd), 8.28 (1H, dd), 8.42 (1H, d), 8.52 (1H, d), 11.43 (1H, s). MS (ES): C21H18N4O3 requires 374; found 375.0 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH:30]([NH:33][C@@H:34]([CH3:45])[CH2:35][O:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:33]([CH:30]([CH3:32])[CH3:31])[C@@H:34]([CH3:45])[CH2:35][O:36][C:37](=[O:44])[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CC(C)N[C@@H](C)COC(=O)c1ccccc1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COC(=O)c3ccccc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridin-6-yl)benzoic acid and benzoic acid (S)-2-isopropylamino-propyl ester as described for example 1.
Reaction SMILES: [CH2:1]([O:6][N:7]=[C:8]([C:14](=[O:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:20])(=O)=O>C(O)(=O)C>[CH2:1]([O:6][N:7]=[C:8]([C:14](=[O:16])[CH2:15][Cl:20])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCON=C(C(C)=O)C(=O)OCC
Solvent: CC(=O)O
Product: CCCCCON=C(C(=O)CCl)C(=O)OCC

Procedure:
Ethyl 2-pentyloxyimino-3-oxobutyrate (syn isomer, 57.5 g.), acetic acid (58.5 ml.) and sulfuryl chloride (20.9 were treated in a similar manner to that of Example F-(2) to give ethyl 2-pentyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 51.1 g.), oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH:15]=O>>[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:15][NH:1][CH2:2][CH2:3][OH:4]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: NCCO
Product: OCCNCc1ccc2ccccc2n1

Procedure:
prepared by reaction of 2-amino-ethanol with quinoline-2-carbaldehyde
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)C1CCNC(c2ccc(F)cc2F)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
Methyl 2-(2,4-difluorophenyl)piperidine-4-carboxylate hydrochloride (2.34 g, 8.02 mmol) was dissolved in DCM (50 mL), then DIPEA (3.50 mL, 20.05 mmol) was added. Methyl carbonochloridate (0.884 mL, 11.23 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 4 h, washed with 0.1 M HCl (100 mL) and satd NaHCO3 (100 mL), then dried through a phase-separator and evaporated yielding dimethyl 2-(2,4-difluorophenyl)piperidine-1,4-dicarboxylate (2.38 g, 95%) as an orange oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:10](=[O:21])[CH2:9]1)=[O:7])(C)(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH:26]=[CH:27]C(O)=O>>[Cl:22][C:23]1[CH:24]=[C:25](/[CH:26]=[CH:27]/[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[C:10](=[O:21])[CH2:9]2)=[O:7])[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN2CCCC2)C(=O)C1
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCN(CCN2CCCC2)C(=O)C1

Procedure:
The title compound was prepared in analogy to example 6 starting from 3-oxo-4-(2-pyrrolidin-1-yl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (intermediate 6) and 3,4-dichlorocinnamic acid. MS (ISP)=396.4 (M+H)+.