Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH3:14])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.C([O:18]/[C:19](/[CH3:26])=[CH:20]/C(OCC)=O)C>>[Cl:1][C:2]1[CH:3]=[C:4](/[C:13](/[CH3:14])=[CH:20]/[C:19](=[O:18])[CH3:26])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)/C=C(\C)OCC
Reactant: CC(=O)c1ccc(C2CCCC2)c(Cl)c1
Product: CC(=O)/C=C(\C)c1ccc(C2CCCC2)c(Cl)c1
Yield: 82 %

Procedure:
(E)-4-(3-chloro-4-cyclopentyl-phenyl)-3-pentene-2-one was prepared analogous to Example 52 from 3'-chloro-4'-cyclopentyl-acetophenone (b.p. 130°-135°C at 0.1 mm Hg) and ethyl (E)-3-ethoxy-crotonate with a yield of 82% of theory. B.p. 130°-135°C at 0.1 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](Cl)[N:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C(#N)C>[C:12]([NH:16][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([C:8]#[N:9])=[CH:6][C:5]=1[F:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CC#N
Product: CC(C)(C)Nc1nc(Cl)c(C#N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of 7.6 g of 2,6-dichloro-3-cyano-5-fluoropyridine in 40 ml acetonitrile was added 8.8 g of t-butylamine, and the mixture was stirred overnight at room temperature. The solvent was distilled off the reaction solution. The residue was separated by adding methylene chloride and water. The organic layer was dried over magnesium sulfate, and the solvent was distilled off to obtain 6 g of the title compound as a pale yellow powder.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[C:8]([F:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1>ClCCl>[CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH:17][C:18]3[CH:22]=[CH:21][S:20][C:19]=3[C:23]([O:25][CH3:26])=[O:24])(=[O:14])=[O:13])=[C:8]([F:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1sccc1N
Reactant: O=S(=O)(Cl)c1ccc(C2CCCC2)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C2CCCC2)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-cyclopentyl-2-fluorobenzene-1-sulfonyl chloride, 134 (0.06 g; 0.21 mmol) in dichloromethane (1 mL) at room temperature, methyl 3-aminothiophene-2-carboxylate (0.033 g; 0.21 mmol) was added followed by pyridine (0.033 g; 0.42 mmol) and then stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was concentrated under reduced pressure and then taken up in ethyl acetate (10 mL) and washed with water. The aqueous layer was separated and extracted with ethyl acetate (2×10 mL). The combined organic phases were successively washed with water and aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 40% v/v over 900 mL gradient elution) to give the title product as an off-white solid (34 mg).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([S:9][CH3:10])[N:6]=[C:5]([CH3:11])[N:4]=1)[NH2:2].[C:12](OCC)(OCC)(OCC)[CH3:13]>>[CH3:12][C:13]1[N:4]2[C:5]([CH3:11])=[N:6][C:7]([S:9][CH3:10])=[CH:8][C:3]2=[N:1][N:2]=1
Reactant: CSc1cc(NN)nc(C)n1
Reactant: CCOC(C)(OCC)OCC
Product: CSc1cc2nnc(C)n2c(C)n1

Procedure:
A mixture of 2.5 g (0.015 mole) of 4-hydrazino-2-methyl-6-methylthiopyrimidine and 50 ml of triethyl orthoacetate was heated at its reflux temperature for five days, and was then cooled. The solid was separated by filtration and recrystallized with treatment with decolorizing charcoal from first an ethyl acetate-hexane mixture, and then a benzene-hexane mixture to provide 3,5-dimethyl-7-methylthio-1,2,4-triazolo[4,3-c]pyrimidine, m.p. 201°-203° C.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@H:5]([CH3:19])[N:6]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH2:9][CH3:10])C.[OH-].[Na+:22]>CO.O>[Na+:22].[CH3:18][S:17][C:14]1[CH:13]=[CH:12][C:11]([N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[C@H:5]([C:4]([O-:20])=[O:3])[CH3:19])=[CH:16][CH:15]=1
Reactant: CCCCN(c1ccc(SC)cc1)[C@@H](C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCN(c1ccc(SC)cc1)[C@@H](C)C(=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-(4-Methylthiophenyl)-N-(n-butyl)alanine ethyl ester (3.0 g, 10.1 mmol) was dissolved in 50 mL methanol and 5 mL of water was added. Sodium hydroxide (0.41 g, 10.1 mmol) was dissolved in a minimum amount of water, and added to the aqueous methanol solution. The mixture was stirred 18 h at room temperature, and then the solvent was removed at reduced pressure. The resulting white solid was used without purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.[Li][CH3:34]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)([OH:13])[CH3:34])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=1
Reactant: [Li]C
Reactant: COc1nc2ccc(C(=O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: COc1nc2ccc(C(C)(O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -78 °C

Procedure:
To flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (250 mg, 0.54 mmol, Intermediate 9: step b) was added THF (15 mL). The solution was cooled to −78° C. and MeLi (1.6 M in Et2O, 0.4 mL, 0.64 mmol) was introduced. The reaction mixture was quenched after 25 minutes with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (4×30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness to afford an off white solid. Chromatography on silica gel (10% CH3CN-DCM increasing to 30% CH3CN) provided the title compound as a white amorphous solid. 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J=2.1 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.74 (d, J=2.9 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.45-7.35 (m, 3H), 4.35 (s, 2H), 4.07 (s, 3H), 3.71 (s, 3H), 2.82 (br. s, 1H), 2.06 (s, 3H); MS (ESI): mass calcd. for C23H20ClF3N4O2, 476.1, m/z found 477.1 [M+H]+. 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(1-methyl-1H-1,2,3-triazol-5-yl)ethanol was purified by chiral SFC (Stationary phase: Lux 5 m cellulose-3, 4.6 mm×250 mm, Mobile phase: 12% EtOH, 0.2% Et3N, 88% CO2) to give 2 enantiomers. The first eluting enantiomer was Example 11b and the second eluting enantiomer was Example 11c.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[NH:5][CH:6]=[C:7]([C:21]#[N:22])[C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=1[Cl:20])=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:23]([C:8]([NH:10][C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=3[Cl:20])=[C:7]([C:21]#[N:22])[CH:6]=[N:5]2)=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1cc(NC(=O)C(C#N)=CNc2ccc(OC)c(Br)c2)c(Cl)cc1Cl
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2c(C#N)cnc3cc(Br)c(OC)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
A suspension of 3-bromo-4-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide (4.00 g, 8.50 mmol) in 200 mL of acetonitrile was heated to reflux and phosphorous oxychloride (5.0 mL) was added dropwise, via syringe. The reaction mixture was heated at reflux overnight, then cooled to room temperature and concentrated in vacuo. The residue was cooled to 0° C. and saturated aqueous sodium bicarbonate was added. The mixture was stirred for 1 hour and then extracted with a large volume of ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and filtered. The filtrate was reduced in volume until solids appeared. The solids were collected by filtration, washed with diethyl ether and hexanes to provide 1.73 g of 7-bromo-4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-3-quinolinecarbonitrile as a light tan solid, mp >250° C. 1H NMR (400 MHz, DMSO-d6) δ 3.87 (s, 3H), 4.04 (s, 3H), 7.41 (s, 1H), 7.78 (s, 1H), 7.99(s, 1H), 8.22 (s, 1H), 8.48 (s, 1H), 9.93 (s, 1H); MS (ES) m/z449.9, 451.9, 453.9 (M−H)−
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C@@H:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]3[C:15]([F:18])([F:17])[F:16])[C:5]=2[CH2:19][O:20][CH:21]2[CH2:27][CH:26]3[N:28]([C:29]4[S:30][C:31]5[CH:37]=[C:36]([C:38]([O:40]CC)=[O:39])[CH:35]=[CH:34][C:32]=5[N:33]=4)[CH:23]([CH2:24][CH2:25]3)[CH2:22]2)[CH2:3][CH2:2]1.[OH-].[K+]>C(O)C>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C@@H:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]3[C:15]([F:17])([F:16])[F:18])[C:5]=2[CH2:19][O:20][CH:21]2[CH2:22][CH:23]3[N:28]([C:29]4[S:30][C:31]5[CH:37]=[C:36]([C:38]([OH:40])=[O:39])[CH:35]=[CH:34][C:32]=5[N:33]=4)[CH:26]([CH2:25][CH2:24]3)[CH2:27]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc2nc(N3C4CCC3CC(OCc3c([C@@H]5CCCC[C@H]5C(F)(F)F)noc3C3CC3)C4)sc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2nc(N3C4CCC3CC(OCc3c([C@@H]5CCCC[C@H]5C(F)(F)F)noc3C3CC3)C4)sc2c1
Temperature: 60 °C

Procedure:
A solution of ethyl 2-(3-((5-cyclopropyl-3-((trans)-2-(trifluoromethyl)cyclohexyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylate (16 mg, 0.03 mmol) in ethanol (1 mL) was treated with potassium hydroxide (4.5 mg, 0.08 mmol) and heated to 60° C. for 2 hours. The reaction cooled RT, was concentrated in vacuo and then treated with 10% citric acid (aq.) and extracted with EtOAc. Organics were collected and concentrated. The crude material was purified via mass-directed reverse phase HPLC.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1.P(C#N)(=O)(OCC)OCC.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)O)c2n1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCNCC3)c2n1
Yield: 90 %

Procedure:
A mixture of 5-amino-6-chloro-2-ethylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 10, Step 2, 10.00 g, 41.72 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (J. Prugh, L. A. Birchenough and M. S. Egbertson, Synth. Commun., 1992, 22, 2357-60) (15.20 g, 70.93 mmol), diethyl phosphorocyanidate (10.76 mL, 70.93 mmol) and diisopropylethylamine (18.17 mL, 104.4 mmol) in N,N-dimethylformamide (267 mL) was stirred at room temperature for 43 h. The solvent was removed by evaporation. The residue was basified with aqueous sodium bicarbonate (40 mL), and extracted with dichloromethane (5×100 mL). The combined extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue eluting with dichloromethane/methanol (100:1 to 20:1) afforded 19.08 g (90%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:23])[CH2:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:36].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>ClCCl>[NH2:36][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][C:19]3([OH:23])[CH2:22][CH2:21][CH2:20]3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCC1
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol (4.05 g, 13.0 mmol) in dichloromethane (85 mL) at rt was added m-CPBA (55%, 4.08 g, 13.0 mmol). After 1 h, concentrated ammonium hydroxide (85 mL) was added, followed by TsCl (2.73 g, 14.3 mmol). The reaction was stirred rapidly for 2 d. More TsCl (0.25 g) was added and the mixture was stirred one day more. The layers were separated. Water was added to the aqueous layer, which was extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated to a pale yellow foam. Acetonitrile was added to the foam, causing a solid to form. The solid was triturated with hot acetonitrile to yield an off white solid that was crystallized from acetonitrile/dichloromethane. Pale yellow crystals were isolated by filtration and dried under vacuum 80° C. to yield 1.81 g (43%) of 1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclobutanol, mp 174-175° C. 1H NMR (CDCl3, 300 MHz) δ 8.23 (dd, J=8.3, 1.4 Hz, 1H), 7.78 (dd, J=8.4, 1.4 Hz, 1H), 7.50 (ddd, J=8.4, 7.0, 1.4 Hz, 1H), 7.31 (ddd, J=8.4, 7.0, 1.4 Hz, 1H), 5.41 (br s, 2H), 4.893 (s, 2H), 4.886 (s, 2H), 3.64 (q, J=7.0 Hz, 2H), 3.50 (br s, 1H), 2.35-2.27 (m, 2H), 2.10-1.78 (m, 4H), 1.25 (t, J=7.0 Hz, 3H); MS (APCI) m/z 327 (M+H+); Anal. calcd for C18H22N4O2: C, 66.24; H, 6.79; N, 17.16. Found: C, 66.02; H, 6.87; N, 17.09.
Reaction SMILES: C(N(CCCC)CCCC)CCC.FC(F)(F)S(O[C:20]1[C:21]([C:26]([O:28][CH3:29])=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=1)(=O)=O.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH2:38])=[CH:35][CH:34]=1>CN(C=O)C.[Cu]I>[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[CH:38][C:20]2[C:21]([C:26]([O:28][CH3:29])=[O:27])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:35][CH:34]=1
Reactant: COC(=O)c1ncccc1OS(=O)(=O)C(F)(F)F
Reactant: C=Cc1ccc(F)cc1
Agent: [Cu]I
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ncccc1C=Cc1ccc(F)cc1
Temperature: 90 °C

Procedure:
Tributylamine (24.6 ml) was added to a stirred mixture of methyl 3-(trifluoromethanesulfonyloxy)pyridin-2-carboxylate (19.6 g), bis (triortho-tolylphosphine)palladium(II) chloride (1.08 g), copper (I) iodide (0.1 3 g) and 4-fluorostyrene (12.3 ml) in DMF (300 ml). The solution was heated under an inert atmosphere at 90° C. for 26 hours then cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (300 ml), the solid filtered and the filtrate washed with 1M. citric acid (3×100 ml), saturated aqueous sodium bicarbonate (150 ml), dried and concentrated under reduced pressure. The brown oil obtained was pre-absorbed onto silica then purified on a silica flash column eluting with ethyl acetate/iso-hexane (4:6) to give methyl 3-[2-(4-fluorophenyl)ethenyl]pyridin-2-carboxylate as a pale yellow solid (12.4 g).
Reaction SMILES: O.[SH-:2].[Na+].Br[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:12])[N:6]=1.O>C(O)CO>[C:16]1([CH3:19])[CH:17]=[CH:18][C:13]([C:11]([C:7]2[N:6]=[C:5]([SH:2])[CH:10]=[CH:9][CH:8]=2)=[O:12])=[CH:14][CH:15]=1
Reactant: [SH-]
Reactant: Cc1ccc(C(=O)c2cccc(Br)n2)cc1
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: Cc1ccc(C(=O)c2cccc(S)n2)cc1
Temperature: 110 °C
Yield: 43.6 %

Procedure:
To a stirred solution of sodium hydrosulphide hydrate (22.0 g) in ethylene glycol (100 ml) at 100° C. was added 2-bromo-6-(4-toluoyl)pyridine (27.6 g) in portions. The mixture was then heated at 110° C. for 3 hours, allowed to cool and then poured into water (600 ml). The yellow precipitate of the by-product 6-(4-methylbenzyl)pyridine-2-thiol was filtered off and the filtrate was acidified by the addition of glacial acetic acid (10 ml). The resultant orange solid was then filtered off and well washed with water and dried. This crude solid (19.4 g) was crystallised from a mixture of benzene (500 ml) and methanol (175 ml) to give 6-(4-toluoyl)pyridine-2-thiol (10.0 g) as orange needles. M.p. 179°-181°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[N:13]O)[CH2:6]2.C1(C)C=CC(S(Cl)(=O)=[O:22])=CC=1>[OH-].[Na+]>[C:7]([CH2:6][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=1[C:8]([OH:12])=[O:22])#[N:13]
Reactant: COc1ccc2c(c1)CC(=NO)C2=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=O)O)c(CC#N)c1
Temperature: 50 °C
Yield: 95.9 %

Procedure:
5-Methoxy-indan-1,2-dione-2-oxime (22 g, 0.12 mol) was added to a solution of 230 ml 8% NaOH. The mixture was heated to 50° C., and then p-toluenesulfonyl chloride (30 g, 0.16 mol) was added in portions. The mixture was heated at 80° C. for 15 min. After cooled to room temperature, the precipitate was removed, and the filtrate was acidified with concentrated HCl to pH=3-4. The precipitate was collected and dried to give colorless solid (22 g, 100% yield). LC-MS: 192 (MH+)
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].Cl.[O:15]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][NH2:22])=[N:16]1.C(=O)(O)[O-].[Na+]>O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:22][O:21][CH2:20][C:17]2[CH:18]=[CH:19][O:15][N:16]=2)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: NOCc1ccon1
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=CNc1nc(C(=NOCc2ccon2)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.8 %

Procedure:
A mixture of 2-(2-formamidothiazol-4-yl)glyoxylic acid (5 g.), (3-isoxazolyl)methoxyamine hydrochloride (4.53 g.), sodium bicarbonate (4.2 g.) and water (200 ml.) was stirred at room temperature for 4 hours, while keeping at pH 5.0. After removing the insoluble substance from the resultant mixture by filtration, the filtrate was adjusted to pH 1.5 with 10% hydrochloric acid and stirred at 5° C. for 30 minutes. The precipitates were collected by filtration, washed with water and dried to give 2-(2-formamidothiazol-4-yl)-2-[(3-isoxazolyl)methoxyimino]acetic acid (syn isomer, 5.68 g.), mp 110° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([NH:21][CH2:22][C:23]3[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=3[CH3:29])=[O:20])=[C:11]2[CH3:32])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:33][N:34](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:33]([C:2]1[CH:3]=[C:4]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([NH:21][CH2:22][C:23]3[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=3[CH3:29])=[O:20])=[C:11]2[CH3:32])[CH3:9])[CH:5]=[CH:6][CH:7]=1)#[N:34]
Reactant: CN(C)C=O
Reactant: Cc1cc(C)c(CNC(=O)c2c(C)n(C(C)c3cccc(Br)c3)c3ccccc23)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C)c(CNC(=O)c2c(C)n(C(C)c3cccc(C#N)c3)c3ccccc23)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
1-(1-(3-bromophenyl)ethyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide (Compound 171; 100 mg, 0.2 mmol), Zn(CN)2 (36 mg, 0.3 mmol), Pd(PPh3)4 (47 mg, 0.04 mmol) were combined in 2 ml DMF, then stirred at 100° C. for 30 min under N2 in m.w. After the complete of the reaction, purified by pre-HPLC (A: CH3CN, B:water+0.1% HCl. A:B=32:62 ASB C18 150*25 mm) to afford the title compound (35 mg, yield: 40%), 1H NMR (400 MHz, Methanol-d4) δ 7.78 (d, J=8 Hz, 1H), 7.67 (d, J=7.2 Hz, 1H), 7.54 (m, 3H), 7.13 (m, 1H), 7.03 (d, J=4 Hz, 2H), 6.45 (s, 1H), 6.04 (m, 1H), 4.61 (s, 2H), 2.66 (s, 3H), 2.52 (s, 3H), 2.36 (s, 1H), 2.02 (d, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1>C(O)C.[Pt](=O)=O>[OH:1][CH2:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cccc(CO)n1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
t-Butyl 3-(6-hydroxymethylpyridin-2-yl)-trans-acrylate (trans form) (16.86 g) was dissolved in 200 mL of ethanol, and 0.5 g of platinum dioxide was added to the solution, and then the mixture was stirred under atmospheric hydrogen pressure at room temperature for 5 hours. After that, the catalyst was filtrated off, another platinum dioxide (0.5 g) was added, and then the mixture was stirred under atmospheric hydrogen pressure at room temperature for 6 hours. The catalyst was filtrated off from the reaction mixture, and the solvent was removed under reduced pressure to give 16.13 g of t-butyl 3-(6-hydroxymethylpyridin-2-yl)propionate as a light yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([CH3:16])[C:13]([CH3:15])=[CH:14][C:9]=2[N:8]=[N:7]1.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[CH3:15][C:13]1[C:12]([CH3:16])=[CH:11][C:10]2[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:27][CH2:26][N:25]([C:21]4[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:31])([F:32])[F:17])[CH:20]=4)[CH2:30][CH2:29]3)[N:7]=[N:8][C:9]=2[CH:14]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Cc1cc2nnn(CCCCCl)c2cc1C
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2nnn(CCCCN3CCN(c4cccc(C(F)(F)F)c4)CC3)c2cc1C
Temperature: 25 °C
Yield: 70.3 %

Procedure:
1-(4-chlorobutyl)-5,6-dimethyl-1H-benzotriazole (8.56 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoro methylphenylpiperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 9.1 g compound (I-33) with a yield of 70.3%. ESI-MS [M+H]+: m/z 432.2.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[N:12]([C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=3)[N:13]=[C:14]([CH3:24])[C:15]=2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:6][CH:5]=1)=[O:3].[OH-].[Na+:31]>O>[Na+:31].[NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[N:12]([C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=3)[N:13]=[C:14]([CH3:24])[C:15]=2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O-:23])=[O:22])=[CH:6][CH:5]=1)=[O:3]
Reactant: CCc1ccc2c(-c3ccc(C(N)=O)cc3)c(CCCCCC(=O)O)c(C)nn12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc2c(-c3ccc(C(N)=O)cc3)c(CCCCCC(=O)[O-])c(C)nn12
Reaction time: 5 h
Yield: 98.2 %

Procedure:
To a suspension of 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid (590 mg) in water (3 mL) was added 1N sodium hydroxide (15 mL) at ambient temperature. After 5 hours, the mixture became clear solution. The solution was filtered through membrane filter, washed with water (0.4 mL×3), and was freeze dried for 15 hours to give 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid sodium salt (612 mg, 98.2%) as a pale yellow powder.