Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.Cl.[CH2:22]([NH2:25])[C:23]#[CH:24].C(N)C#C>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:25][CH2:22][C:23]#[CH:24])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: C#CCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCNc1c(C)c(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 416.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (137.9 g, 0.624 mol) in anhydrous DMF (1.4 L) was cooled to 0° C., and anhydrous triethylamine (109 mL, 0.780 mol) was added. Propargyl amine hydrochloride (4.72 g, 51.6 mmol) and propargyl amine (38.4 g, 0.697 mol) were sequentially added dropwise, and the reaction was allowed to warm to room temperature and then heated at 40° C. for 22 hours. The volatiles were removed under reduced pressure, and water (1.5 L) and solid sodium carbonate (75 g) were added to the resulting oil. The mixture was then extracted with dichloromethane, and the combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting sequentially with 60:40 dichloromethane/hexane and dichloromethane) to provide 51.54 g of 2-chloro-5,6-dimethyl-3-nitro-N-prop-2-ynylpyridin-4-amine as a brown solid.
Reaction SMILES: O=[C:2]([CH2:20][CH3:21])[CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:4]([O:6]CC)=O.[Br:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCOCC.C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:24]=[C:25]2[C:26](=[CH:28][CH:29]=1)[N:27]=[C:2]([CH2:20][CH3:21])[C:3]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=1)=[C:4]2[OH:6]
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
A round-bottomed flask equipped with a Dean-Stark apparatus was charged with ethyl 3-oxo-2-(4-(trifluoromethyl)benzyl)pentanoate (8.84 g, 29.2 mmol, Intermediate 5: step a), 4-bromoaniline (5.00 g, 29.2 mmol), para-toluenesulfonic acid (0.503 g, 2.9 mmol), and toluene (146 mL). The mixture was heated to 125° C. After 18 hours, the flask was cooled to room temperature. The toluene was removed by rotary evaporation to provide an amber colored solid. A mixture of the solid and diphenyl ether (29.1 mL) was heated to 220° C. After 70 minutes, the mixture was cooled to room temperature. Ether (100 mL) and hexanes (50 mL) were added. The mixture was allowed to stir for 30 minutes during which time a white solid crashed out of solution. The suspension was filtered through filter paper, rinsing with ether. The gummy solids were collected. Acetonitrile (20 mL) was added and the mixture was sonicated for 5 minutes. The slurry was filtered through filter paper and the solids were rinsed with acetonitrile. The off-white solids were collected, dried, and then used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=2)[NH:3]1.[O:15]=[C:16]1[C:21]2=[CH:22][NH:23][C:24]([CH:25]=O)=[C:20]2[CH2:19][CH2:18][NH:17]1.N1CCCCC1>C(O)C>[O:1]=[C:2]1[C:10](=[CH:25][C:24]2[NH:23][CH:22]=[C:21]3[C:20]=2[CH2:19][CH2:18][NH:17][C:16]3=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:12])=[O:13])[CH:8]=2)[NH:3]1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C
Yield: 82.8 %

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide (63 mg, 0.3 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (50 mg, 0.3 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give 89 mg (82%) of the title compound.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1>CO>[CH3:1][O:2][C:5]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc([N+](=O)[O-])cn1
Yield: 134.3 %

Procedure:
To a solution of sodium methoxide (0.090 g of sodium) in MeOH (12 mL) was added 0.486 g (3.03 mmol) of 2-chloro-5-nitropyrimidine, and the mixture was heated under reflux for 1 hr. After cooling, the mixture was concentrated in vacuo, extracted with EtOAc, and washed with water. The aqueous layer was extracted with CHCl3 and the combined organic layers were dried (Na2SO4), and concentrated, to give 0.347 g (75% yield) of 2-methoxy-5-nitropyrimidine as a yellow powder: 1H NMR (CDCl3) δ9.31 (s, 2H), 4.17 (s, 3H); LCMS (APCI+) m/z: 156 (MH+, 100%).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([CH3:12])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26]>C[O-].[Na+].CO>[OH:22][C:7]1[C:8]2[S:15][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:13][C:9]=2[C:10]([CH3:12])=[N:11][C:6]=1[C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5]
Reactant: CCOC(=O)c1nc(C)c2nc(-c3ccccc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 7-hydroxy-4-methyl-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (159 mg, 0.51 mmol) and glycine (760 mg, 1.01 mmol) in 0.5 M sodium methoxide/methanol (19.2 mL) was refluxed for three days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (50 mL) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (12 mL). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (127 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.01 (br s, 1H), 9.24 (br s, 1H), 8.14 (m, 2H), 7.62 (m, 3H), 4.03 (d, J=6.2 Hz, 2H), 2.87 (s, 3H); MS: (+) m/z 344.0 (M+1)
Reaction SMILES: [CH3:1][C:2]1[NH:3][S:4](=[O:11])(=[O:10])[N:5]([CH3:9])[C:6](=O)[N:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O>>[Cl:13][C:6]1[N:5]([CH3:9])[S:4](=[O:11])(=[O:10])[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: CC1=NC(=O)N(C)S(=O)(=O)N1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NS(=O)(=O)N(C)C(Cl)=N1
Temperature: 110 °C
Yield: 100 %

Procedure:
212 parts of 3,6-dimethyl-6H-1,2,4,6-thiatriazin-5-one-1,1-dioxide were introduced into a stirred mixture of 292 parts of phosphorus pentachloride and 1,400 parts of phosphorus oxychloride at room temperature, and the mixture was heated to 110° C. in the course of 30 minutes. The reaction mixture was stirred under reflux for 6 hours and then evaporated down under reduced pressure to give 234 parts (yield: 100% of theory) of 5-chloro-3,6-dimethyl-6H-1,2,4,6-thiatriazine-1,1-dioxide of melting point 86°-90° C. NMR (60 MHz, CDCl3): CH3 --C 2.4δ, CH3 --N 3.68).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[CH2:11]([S:14](Cl)(=[O:16])=[O:15])[CH2:12][CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:14]([CH2:11][CH2:12][CH3:13])(=[O:16])=[O:15])[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)N1CCc2cc(Br)ccc21
Yield: 52.6 %

Procedure:
This compound was prepared using the general procedure for sulfonylation of indolines and tetrahydroquinolines as described in Example 4 using 5-bromoindoline (0.396 g, 2.0 mmol) and propylsulfonyl chloride (0.34 mL, 3 mmol) to provide 5-bromo-1-(propylsulfonyl)indoline (0.32 g). MS (ES) m/z 303.6; HPLC purity 100.0% at 210-370 nm, 9.8 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:4]=1[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[N:19]3)[CH2:13][O:14]2)=[C:9]([F:28])[CH:8]=1.[OH-].[Na+].Cl>CCO.C1COCC1>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][C:4]=1[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][N:18]3[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[N:19]3)[CH2:13][O:14]2)=[C:9]([F:28])[CH:8]=1
Reactant: CCOC(=O)c1cnn(CC2=Cc3c(F)cc(OCc4ccc(C(F)(F)F)cc4C(F)(F)F)cc3OC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cnn(CC2=Cc3c(F)cc(OCc4ccc(C(F)(F)F)cc4C(F)(F)F)cc3OC2)c1
Yield: 74.9 %

Procedure:
A solution of ethyl 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]-1H-pyrazole-4-carboxylate (100 mg) and a 1 M aqueous NaOH solution (0.55 mL) in EtOH/THF (3 mL/1 mL) was stirred at 100° C. for 2 hours, neutralized with 1 M HCl, and extracted with chloroform. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 90:10) and the obtained solid was washed with IPE to obtain 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]-1H-pyrazole-4-carboxylic acid (71 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13](=O)[C:12]3[CH:15]=[C:16]([O:19][C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH:17]=[CH:18][C:11]=3[C:10]=2[O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=2)=[CH:5][CH:4]=1.Cl.C([O-])(O)=O.[Na+].C(Cl)Cl>C(O)CC.CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:15]=[C:16]([O:19][C:20](=[O:26])[N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[CH:17]=[CH:18][C:11]=3[C:10]=2[O:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:32][CH:33]=2)=[CH:7][CH:8]=1
Reactant: CCN(CC)C(=O)Oc1ccc2c(c1)S(=O)C(c1ccc(OC)cc1)=C2Oc1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCN(CC)C(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OC)cc3)sc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dissolve diethyl-carbamic acid 2-(4-methoxy-phenyl)-1-oxo-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-1H-1Lambda*4*-benzo[b]thiophen-6-yl ester (Example 1) (4.0 g, 6.8 mmol) in 80 mL n-propyl alcohol with stirring and then cool the resultant solution to −10° C. Add 37% hydrochloric acid (6.7 g, 67 9 mmol) dropwise at −10° C. within a 10 minute time period. After the mixture is warmed up to ambient temperature, add Na2S2O3.5H2O (6.7 g, 27 0 mmol) and allow the reaction to occur at ambient temperature for 4 hours. Monitor the reaction by 11H NMR for completion. Carefully add 100 mL of saturated aqueous NaHCO3 to neutralize the reaction mixture and then adjust the pH of the mixture to 7. Add 100 mL CH2Cl2 and stir. Separate the organic phase, and extract the aqueous phase with CH2Cl2 (2×50 mL). Wash (with successive washes) the combined organic phase with brine (50 mL) and water (50 mL), dry over anhydrous Na2SO4, and filter. Remove all the volatiles under reduced pressure, affording 3.4 g of the crude product as a viscous material. Pass this viscous material through a short pad of silica gel with 100% petroleum ether (30-60° C.) and 100% ethyl acetate as the eluents. Collect the ethyl acetate phase and evaporate all the volatiles under reduced pressure, producing 3.2 g of the crude product as a pale yellow viscous material. Add 20 mL of hexane and the mixture is kept at 4° C. overnight, affording the desired product Diethyl-carbamic acid 2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thiophen-6-yl ester as a white solid (2.9 g, yield 74%, NMR purity>96%) after dried at 40° C./2 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][O:8][C:9]=1[CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:4].Cl.C[OH:25]>>[O:8]=[C:9]([CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH:5]([NH:6][CH:7]=[O:25])[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1ncoc1CCNC(=O)OCc1ccccc1
Reactant: CO
Agent: Cl
Product: COC(=O)C(NC=O)C(=O)CCNC(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 6 h

Procedure:
A mixture of 36.5 g of 4-methoxycarbonyl-5-{2-(benzyloxycarbonylamino)ethyl}oxazole, 90 ml of concentrated hydrochloric acid and 270 ml of methanol was stirred at 55° C. for 6 hours. After removing the solvent, the residue was dissolved in tetrahydrofuran, and the solution was neutralized with 21 ml of triethylamine. Further, the solution was cooled to 0° C., and to the solution was added 450 ml of formic acid and was added dropwise 150 ml of acetic anhydride at the same temperature. The mixture was stirred at 10° C. for 3 hours, and ice water was added thereto. The solvent was removed, and then the residue was dissolved in ethyl acetate. The mixture was washed and dried, and then the solvent was removed. The residue was purified by silica gel chromatography to obtain 20 g of methyl 3-oxo-5-(benzyloxycarbonylamino)-2-(formylamino)pentanoate as a colorless oily product.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:7](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:6][N:5]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:4]1.[N-:29]=[N+:30]=[N-:31].[Na+]>O.CN(C=O)C.CC(=O)OCC.O>[N:29]([C@H:7]1[C@@H:3]([O:2][CH3:1])[CH2:4][N:5]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:6]1)=[N+:30]=[N-:31]
Reactant: CO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1OS(=O)(=O)c1ccc(C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Yield: 89.8 %

Procedure:
(+/−)-Trans-benzyl 3-methoxy-4-(tosyloxy)pyrrolidine-1-carboxylate (10.3 g, 25.4 mmol) was added to the soln. of sodium azide (5.78 g, 89 mmol) in water (10 mL) and DMF (60 mL) and heated to 100 deg. Celsius overnight. Diluted with EA/water and stirred. The organic layer dried (Na2SO4) and concentrated to give (+/−)-Cis-benzyl 3-azido-4-methoxypyrrolidine-1-carboxylate (6.3 g, 22.80 mmol, 90% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.34-7.43 (5 H, m), 5.13-5.21 (2 H, m), 4.01-4.04 (2 H, m), 3.47 (3 H, s), 3.49-3.69 (4 H, m), Hz), LCMS: M+23=299, Rt=2.15 min.
Reaction SMILES: [NH3:1].[NH:2]1[CH:6]=[N:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[N:3]1>>[NH:2]1[CH:6]=[N:5][C:4]([S:7]([NH2:1])(=[O:9])=[O:8])=[N:3]1
Reactant: N
Reactant: O=S(=O)(Cl)c1nc[nH]n1
Product: NS(=O)(=O)c1nc[nH]n1

Procedure:
Liquid ammonia is reacted with 1,2,4-triazol-3- sulfonylchloride to give 1,2,4-triazol-3-sulfonamide in U.S. Pat. No. 2,554,816.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28]C(=O)C(C)(C)C)[N:10]=1.Br[C:36]1[CH:37]=[C:38]([CH:42]([OH:46])[C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=1>C1COCC1.C(#N)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[OH:46][CH:42]([C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][OH:28])[C:12]3=[N:13][CH:14]=2)[CH:37]=1)[C:43]([OH:45])=[O:44]
Reactant: COc1ccccc1-c1nn(COC(=O)C(C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C(O)C(O)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccccc1-c1nn(CO)c2ncc(-c3cccc(C(O)C(=O)O)c3)cc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 43.2 %

Procedure:
A mixture of 2,2-dimethyl-propionic acid 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (4.5 g, 9.7 mmol), (±)-(3-bromo-phenyl)-hydroxy-acetic acid (2.7 g, 11.6 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (355 mg, 0.5 mmol) in THF/Acetonitrile/saturated NaHCO3 (20 ml/20 ml/50 ml) was stirred at 100° C. for 4 hours. The mixture was allowed to cool down to room temperature and then extracted with ethyl acetate (3×). The combined organic layers were extracted with brine, dried with Na2SO4, decanted, and concentrated to dryness. The crude was purified by reverse phase HPLC afforded hydroxy-{3-[1-hydroxymethyl-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid (1.7 g, 35% yield). 1H NMR (500 MHz, DMSO-d6) δ 3.86 (s, 3H), 5.05 (s, 1H), 5.14 (s, 2H), 7.10 (m, 1H), 7.21 (d, 1H), 7.40-7.50 (m, 3H), 7.67 (d, 1H), 7.79 (s, 1H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([C:17]4[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([F:26])[CH:18]=4)[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S(=O)(=O)(O)O>CCOCC>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([C@H:11]3[CH2:12][CH2:13][C@H:14]([C:17]4[CH:25]=[CH:24][C:20]([CH2:21][OH:22])=[C:19]([F:26])[CH:18]=4)[CH2:15][CH2:16]3)[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc([C@H]2CC[C@H](C3CCC4(CC3)OCCO4)CC2)cc1F
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: OCc1ccc([C@H]2CC[C@H](C3CCC4(CC3)OCCO4)CC2)cc1F
Temperature: 0 °C

Procedure:
5.7 g of 4-[trans-4-(1,4-dioxaspiro[4,5]dec-8-yl)cyclohexyl]-2-fluorobenzoic acid were added to a suspension of 3 g of lithium aluminium hydride in 100 ml of dry ether and, after stirring under reflux for 23 hrs., cooled to 0° C., treated cautiously with 25 ml of water and then 100 ml of 3N sulfuric acid. The reaction mixture was thereupon extracted with ether, the organic phase was dried over sodium sulfate, filtered and the filtrate was evaporated. Chromatography of the residue on silica gel with methylene chloride/acetone (95:5) gave 3.1 g of 4-[trans-4-(1,4-dioxaspiro[4,5]dec-8-yl)cyclohexyl]-2-fluorobenzyl alcohol as colorless crystals.
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.[O:16]=[C:17]1[N:22]2[CH2:23][CH2:24][NH:25][C:21]2([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[CH2:20][N:19]2[CH:34]=[CH:35][CH:36]=[C:18]12.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl.N1C=CC=CC=1>[CH3:7][C:8]1[C:12]([C:13]([N:25]2[C:21]3([C:26]4[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=4)[CH2:20][N:19]4[CH:34]=[CH:35][CH:36]=[C:18]4[C:17](=[O:16])[N:22]3[CH2:23][CH2:24]2)=[O:15])=[CH:11][O:10][N:9]=1
Reactant: N#Cc1ccc(C23Cn4cccc4C(=O)N2CCN3)cc1
Reactant: Cc1nocc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nocc1C(=O)N1CCN2C(=O)c3cccn3CC12c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To generate the acid chloride, oxalyl chloride (70 μL, 0.83 mmol) and DMF (1 drop) were added to a suspension of 3-methyl-1,2-oxazole-4-carboxylic acid (50 mg, 0.40 mmol) in CH2Cl2 (0.5 mL) at 0° C. The suspension was allowed to stir for 15 min at 0° C., followed by 2 h at room temperature. The resulting solution was concentrated in vacuo to give a brown oil that was suspended in n-hexanes (2×1 mL) and concentrated in vacuo. To a chilled (ice bath) suspension of the acid chloride (generated as above; 0.40 mmol) in pyridine (0.5 mL) and CH2Cl2 (0.5 mL) was added 4-(5-oxo-2,3-dihydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-10a(10H)-yl)benzonitrile (22 mg, <79 μmol) in pyridine (0.5 mL). The brown reaction mixture was warmed to room temperature and stirred for a further 64 h. Saturated aqueous NaHCO3 (25 mL) was then added and the mixture extracted with CH2Cl2 (3×25 mL). The organic fractions were combined, dried (MgSO4) and concentrated in vacuo to yield a residue that was purified using flash chromatography (Biotage SP4 12 g cartridge; 0-10% MeOH gradient in CH2Cl2) to give a mixture of products containing the desired product. The mixture was further purified using flash chromatography (Biotage SP4, 12 g cartridge, C18 phase, 20-40% acetonitrile gradient in water) to give 4-{1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-5-oxo-2,3-dihydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-10a(10H)-yl}benzonitrile (37) as a white solid (13 mg, yield 42%).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2/[C:5]/1=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:3])[CH3:2]>O1CCCC1.CC#N.CC#N.Cl[Pd]Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2/[C:5]/1=[CH:14]/[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(/C=C2\C3=C(CCCC3)CCN2C(C)=O)cc1
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccc(/C=C2/C3=C(CCCC3)CCN2C(C)=O)cc1
Yield: 95 %

Procedure:
A solution of 0.2 g of (E)-2-acetyl-1,2,3,4,5,6,7,8-octahydro-1-(p-methoxybenzylidene)isoquinoline and 8.7 mg of dichlorobis(acetonitrile)palladium(II) in 10 ml of dry tetrahydrofuran was heated at reflux for 7 hours under argon. The yellow solution was evaporated at 15 mbar and the residue was dissolved in diethyl ether. In order to separate the catalyst, the ether solution was filtered through a thin layer of silica gel. After evaporation of the filtrate there was obtained 0.19 g of (Z)-2-acetyl-1,2,3,4,5,6,7,8-octahydro-1-(p-methoxybenzylidene)-isoquinoline with a m.p. of 101-102° C.; content according to GC 96%:
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:14][C:15]([C@H:17]1[CH2:19][C@@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:4]1C=N[C:7]([O:10][CH2:11][CH2:12]C)=[CH:8][CH:9]=1.[NH2:26][C@H:27](C1C=CC(OCC)=CN=1)CO.BrC1C=CC(OCC)=CN=1>>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C@@H:3]([NH:14][C:15]([C@H:17]2[CH2:19][C@@H:18]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:16])[CH2:2][OH:1])=[N:26][CH:27]=1)[CH3:12]
Reactant: CCCOc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Reactant: CCOc1ccc([C@@H](N)CO)nc1
Agent: CCOc1ccc(Br)nc1
Product: CCOc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2ccccc2)nc1

Procedure:
Prepared analogously to Compound 21 using IM46 and (R)-2-Amino-2-(5-ethoxy-pyridin-2-yl)-ethanol (prepared from commercially available 2-Bromo-5-ethoxy-pyridine CAS 42834-01-5 analogously to IM36). Compound 52 was further purified by SFC (Column: Chiralpack OJ250×30 mm, Mobile phase: Supercritical CO2/MeOH+NH4OH=55/45 at 50 mL/min, column temperature: 38° C., Nozzle Pressure: 100 Bar, Nozzle Temp=60° C., Evaporator temp=20 C, Trimmer temp=25° C., Detector: 220 nm). Yield=163 mg. 1H NMR (CDCl3 400 MHz, TMS): δ 8.15 (d, J=2.8 Hz, 1H), 7.08-7.31 (m, 6H), 7.06 (d, J=7.2 Hz, 2H), 5.11-5.15 (m, 1H), 4.00-4.08 (m, 3H), 3.87-3.90 (m, 1H), 2.47-2.52 (m, 1H), 1.63-1.76 (m, 3H), 1.43 (t, J=7.2 Hz, 3H), 1.27-1.31 (m, 1H); [α]20, D=182.0 (c=0.234 g/100 mL, EtOH)