Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][S:11][CH2:12][CH2:13][C:14]([O:16]C)=O.[NH2:18][CH2:19][C:20]([N:22]1[CH2:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[O:25][C:24]2[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:23]1=2)=[O:21].CO>C1(C)C=CC=CC=1>[Cl:37][C:35]1[CH:34]=[CH:33][C:24]2[O:25][C:26]3[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=3[CH2:28][N:22]([C:20](=[O:21])[CH2:19][NH:18][C:14](=[O:16])[CH2:13][CH2:12][S:11][CH2:10][C:6]3[O:5][CH:9]=[CH:8][CH:7]=3)[C:23]=2[CH:36]=1
Reactant: COC(=O)CCSCc1ccco1
Reactant: NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(CCSCc1ccco1)NCC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 5 h

Procedure:
Trimethylaluminum (2.0 M in toluene; 4.6 mi) was added dropwise via syringe to a stirred solution of methyl 3-[(2-furanylmethyl)thio]propanoate (0.75 gram) and 10-(aminoacetyl)-8-chloro-10,11-dihydrodibenz-[b,f][1,4]oxazepine (1.00 gram) in toluene (30 mi) at room temperature under nitrogen, and the reaction was stirred for 5 hours. Methanol (14 mi) was then added, and the reaction was stirred at room temperature overnight. The reaction was evaporated in vacuo, and the resulting orange residue was partitioned between chloroform (50 mi) and 1N NAOH (50 mi). The layers were separated and the aqueous layer was extracted with chloroform (50 mi). The combined chloroform extracts were washed with 1N NAOH (50 mi), 1 N HCl (2 x 50 mi), and brine (50 mi), dried over MgSO4, and evaporated in vacuo. The crude product was purified by flash chromatography through silica gel 60 (350 mi) using 3:1 chloroform:ethyl acetate followed by recrystallization from cyclohexane/ethyl acetate. The yield of the title compound was 0.63 gram (40%) in the form of a tan solid. Analysis calculated for C23H21ClN2O4S: C, 60.46; H, 4.63; N, 6.13; Cl, 7.67; S, 7.02. Found: C, 60.16; H, 4.62; N, 6.05; Cl, 8.06; S, 7.02. DSC: 90°-95° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17](=[O:28])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>C1COCC1>[CH3:32][S:29]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:17](=[O:28])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1)(=[O:31])=[O:30]
Reactant: CCOc1ccccc1NC(=O)OCCN1CCN(c2cccc(N)c2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCOc1ccccc1NC(=O)OCCN1CCN(c2cccc(NS(C)(=O)=O)c2)CC1
Reaction time: 20 h
Yield: 65.9 %

Procedure:
To a mixture of 77 mg (0.2 mmol) of 2-[4-(3-aminophenyl)piperazino]ethyl-N-(2-ethoxyphenyl)carbamate derivative and 56 μl (0.4 mmol, 2 eq) of TEA in 5 ml of THF, 31 μl (0.4 mmol, 2 eq) of mesyl chloride is added. Shaking is carried out at room temperature for about 20 hours. After concentration under reduced pressure, H2O is added and the aqueous phase is extracted with CH2Cl2. After drying on Na2SO4 and concentration of the organic phase, a brown oil is obtained which is purified by column chromatography (eluent AcOEt/petroleum ether 8:2) to produce 61 mg of the expected product as a brown oil (yield: 66%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]/OCC)[CH:5]=[CH:6][CH:7]=1>OS(O)(=O)=O>[Cl:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]2[C:5]([CH:11]=[CH:10][C:9]([OH:15])=[N:8]2)=[CH:6][CH:7]=1
Reactant: CCO/C=C/C(=O)Nc1cccc(Cl)c1OC
Agent: O=S(=O)(O)O
Product: COc1c(Cl)ccc2ccc(O)nc12
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To conc H2SO4 (30 mL) was added to (E)-N-(3-chloro-2-methoxyphenyl)-3-ethoxypropenamide (3b) (3.73 g, 14.6 mmol) and allowed to stir overnight. The solution was poured over ice, filtered, washed and dried to give a yellow solid (2.85 g, 93% yield): 1H NMR (400 MHz, DMSO-d6) 11.45 (bs, 1H), 7.89 (d, J=10 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 6.52 (d, J=10 Hz, 1H), 3.81 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:15][C@H:14]2[N:16](C(OC(C)(C)C)=O)[C@H:10]([CH2:11][C:12]([C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][O:48][C:49]4[C:54]([Cl:55])=[CH:53][C:52]([CH3:56])=[CH:51][C:50]=4[Cl:57])=[CH:41][CH:40]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:28]=2[CH3:34])[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl>[CH:35]1([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:28]=2[CH3:34])[C:24]([C:13]2[C@@H:14]3[NH:16][C@H:10]([CH2:11][C:12]=2[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][O:48][C:49]4[C:54]([Cl:55])=[CH:53][C:52]([CH3:56])=[CH:51][C:50]=4[Cl:57])=[CH:41][CH:40]=2)[CH2:9][NH:8][CH2:15]3)=[O:38])[CH2:37][CH2:36]1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(C3=C(C(=O)N(Cc4cccc(C)c4C)C4CC4)[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H](C3)N4C(=O)OC(C)(C)C)cc2)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(Cl)c(OCCOc2ccc(C3=C(C(=O)N(Cc4cccc(C)c4C)C4CC4)[C@H]4CNC[C@@H](C3)N4)cc2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A sol. of compound 10 (13.8 g, 16.9 mmol) in CH2Cl2 (120 mL) was cooled to 0° C. HCl (4M in dioxane, 120 mL) was added. The mixture was stirred for 1 h at 0° C., then 2 h at rt. The solvents were removed under reduced pressure, and the residue was dried under high vacuum. The residue was diluted with CH2Cl2, and washed with aq. 1M NaOH until the aq. layer staid basic. The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (MeOH/CH2Cl2 5:95→10:90→20:80 with 1% Et3N all the time) yielded the title compound (9.45 g, 90%). LC-MS: tR=0.87 min; ES+: 620.40.
Reaction SMILES: C(O)(=O)C(O)=O.C[O:8][C:9]1[CH:10]=[C:11]([C:15]23[CH2:22][CH:19]([NH:20][CH2:21]2)[CH2:18][CH2:17][CH2:16]3)[CH:12]=[CH:13][CH:14]=1.[BrH:23]>>[BrH:23].[OH:8][C:9]1[CH:10]=[C:11]([C:15]23[CH2:22][CH:19]([NH:20][CH2:21]2)[CH2:18][CH2:17][CH2:16]3)[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(C23CCCC(C2)NC3)c1
Agent: Br
Agent: O=C(O)C(=O)O
Product: Oc1cccc(C23CCCC(C2)NC3)c1

Procedure:
A mixture of 9 g of 1-(3-methoxyphenyl)-6-azabicyclo[ 3,2,1]octane oxalate and 90 ml of aqueous 48% hydrobromic acid is refluxed for 1.5 hours. After the reaction, the mixture is concentrated under reduced pressure. The residue thus obtained is recrystallized from a mixture of ethanol and ether. 7.7 g of 1-(3-hydroxyphenyl)-6-azabicyclo[3,2,1]octane hydrobromide are obtained. M.p. 239° - 242°C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][CH2:19][CH2:20][CH3:21])[C@H:3]([NH:10]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:9]=[CH:8][S:7][CH:6]=1.C([C@H](NC(=O)OC(C)(C)C)[C@@H](O)CCCC)C1C=CC=CC=1>>[NH2:10][C@@H:3]([C@@H:2]([OH:1])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][C:5]1[CH:9]=[CH:8][S:7][CH:6]=1
Reactant: CCCC[C@H](O)[C@@H](Cc1ccsc1)NC(=O)OC(C)(C)C
Agent: CCCC[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Product: CCCC[C@H](O)[C@H](N)Cc1ccsc1

Procedure:
Prepared from the Boc removal of the anti diastereoisomer tert-butyl (1R,2S)-2-hydroxy-1-(thien-3-ylmethyl)hexylcarbamate using a similar procedure as described in intermediate I step D. ES MS (M+H)=214.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:35]>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34](=[O:35])[O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Reactant: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 25 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of dichloromethane. 85 μl (2 molar equivalents) of triethylamine and 77 μl (2 molar equivalents) of butyl chloroformate were respectively added. The reaction mixture was maintained at room temperature for 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 119 mg of the desired product the desired product (formula shown hereinabove) were isolated as an orange powder (yield=83%) which was characterized as follows:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[O:1]=[C:2]1[CH2:11][C:10]2[CH:9]=[C:8]([O:12][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: O=C1CCc2ccc(O)cc2C1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CC(=O)CC3)nc1
Yield: 22.7 %

Procedure:
Using a method similar to Example A, using 7-hydroxy-2-tetralone (1.88 g, 11.6 mmol), 6-chloronicotinamide (1.81 g, 11.6 mmol) and K2CO3 (2.40 g, 17.4 mmol) gives the title compound (742 mg), after purification on silica gel (30% THF/DCM), as an amber foam. Mass spectrum (ion spray): m/z=283 (M+1); 1HNMR (DMSO-d): 8.57 (s, 1H), 8.23 (d, 1H), 8.01 (s, 1H), 7.46 (s, 1H), 7.30 (d, 2H), 7.05 (d, 1H), 6.96 (m, 2H), 3.59 (s, 2H), 3.02 (t, 2H), 2.45 (t, 2H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][C:10]=2[C:11]([OH:13])=O)=[CH:5][CH:4]=1.[CH2:24]([N:29](CCCCC)[C:30](=O)[C:31]1C=C(C=O)[CH:34]=[CH:33][C:32]=1OC)[CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:30]([N:29]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:11](=[O:13])[C:10]1[CH:14]=[C:15]([CH:18]=[O:19])[CH:16]=[CH:17][C:9]=1[O:8][CH2:7][C:6]1[CH:20]=[CH:21][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:4][CH:5]=1)[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCN(CCCCC)C(=O)c1cc(C=O)ccc1OC
Reactant: O=Cc1ccc(OCc2ccc(C(F)(F)F)cc2)c(C(=O)O)c1
Product: CCCCCN(CCCCC)C(=O)c1cc(C=O)ccc1OCc1ccc(C(F)(F)F)cc1

Procedure:
N,N-Di-n-pentyl-2-(4-trifluoromethylbenzyloxy)-5-formylbenzamide was prepared from 2-(4-trifluoromethylbenzyloxy)-5-formylbenzoic acid (300 mg, 1 eq) using the same procedure as for N,N-di-n-pentyl-2-methoxy-5-formylbenzamide. The product was obtained as a pale brown oil (424 mg, 99%). 1H NMR (CDCl3) δ9.88 (s, 1H, O═C—H), 5.21 (s, 2H, CH2Ar), 3.72 (m, 1H, NCH2), 3.20 (m, 1H, NCH2), 3.05 (m, 2H, NCH2).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:22]([C:24]3[O:25][C:26](=[O:40])[C:27]4[C:32]([C:33]=3[C:34]3[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH3:23])[N:19]=[C:20]([I:21])[C:13]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:66][N:67]([CH3:74])[CH2:68][CH2:69][CH2:70][C:71](O)=[O:72].C(=O)(O)[O-].[Na+]>C1COCC1.CN(C=O)C.C(O)=O.O.CC#N>[CH:26]([OH:40])=[O:25].[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:22]([C:24]3[O:25][C:26](=[O:40])[C:27]4[C:32]([C:33]=3[C:34]3[CH2:35][CH2:36][N:37]([C:71](=[O:72])[CH2:70][CH2:69][CH2:68][N:67]([CH3:74])[CH3:66])[CH2:38][CH:39]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH3:23])[N:19]=[C:20]([I:21])[C:13]=12
Reactant: CN(C)CCCC(=O)O
Reactant: CC(c1oc(=O)c2ccccc2c1C1=CCNCC1)n1nc(I)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O=CO
Solvent: C1CCOC1
Product: CC(c1oc(=O)c2ccccc2c1C1=CCN(C(=O)CCCN(C)C)CC1)n1nc(I)c2c(N)ncnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 125.1 %

Procedure:
DIPEA (0.253 ml, 1.452 mmol) was added at 0° C. to a stirred suspension of 3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one hydrochloride (Intermediate D23, 0.200 g, 0.363 mmol), HATU (0.166 g, 0.436 mmol) and 4-dimethylaminobutyric acid hydrochloride (0.073 g, 0.436 mmol) in THF/DMF 5:1 (6 mL). The mixture was stirred at 0° C. for 15 min, then at rt for further 45 min. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with DCM. The collected organic phases were concentrated under reduced pressure and the crude purified by RP-flash chromatography (Biotage 30 g C18 column, gradient elution from 100:0 to 70:30 A/B in 15 CV; A: water/MeCN 95/5+0.01% HCOOH, B: water/MeCN 5/95+0.01% HCOOH) to give title compound (0.153 g, 0.227 mmol, 62.6% yield) as a white powder.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[N+:19]([C:22]1[CH:33]=[CH:32][C:25]([O:26][CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)=[CH:24][CH:23]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:11][C:10]([F:13])([F:12])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:29]2[CH2:30][CH2:31][CH:27]([O:26][C:25]3[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:33][CH:32]=3)[CH2:28]2)=[CH:4][CH:5]=1)([OH:18])[C:14]([F:17])([F:16])[F:15]
Reactant: O=[N+]([O-])c1ccc(OC2CCNC2)cc1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)C2)cc1
Yield: 16.8 %

Procedure:
2-(4-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (9.61 mmol, 4.63 mL, 3.24 g), 3-(4-nitrophenoxy)pyrrolidine (9.61 mmol, 2 g) and potassium carbonate (19.21 mmol, 2.65 g) were combined and stirred at room temperature in acetonitrile (50 mL) for 1 hour. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by silica column chromatography (eluent: dichloromethane to 15% methanol in dichloromethane) and SCX chromatography to afford the intermediate 1,1,1,3,3,3-hexafluoro-2-(4-((3-(4-nitrophenoxy)pyrrolidin-1-yl)methyl)phenyl)propan-2-ol (750 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH3:9][C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1>CCO>[CH3:9][C@H:10]1[NH:11][CH2:12][CH2:13][N:14]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH2:15]1
Reactant: Cc1ccc(Cl)nc1
Reactant: C[C@@H]1CNCCN1
Solvent: CCO
Product: Cc1ccc(N2CCN[C@H](C)C2)nc1

Procedure:
A solution of 2-chloro-5-methyl-pyridine (127 mg, 1 mmoles), (2R)-2-methyl-piperazine (200 mg, 2 mmoles) in EtOH (3 mL) was heated in microwave to 180° C. for 5 minutes. The mixture was cooled, concentrated under reduced pressure and partitioned with DCM and the saturated aqueous sodium bicarbonate layer. The aqueous solution was extracted three times with additional DCM. The combined organic extracts were washed twice with water, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide the crude title compound.
Reaction SMILES: C[O:2][C:3](=[O:12])[CH2:4][C:5]([OH:11])([CH3:10])[CH2:6][C:7]([NH2:9])=[O:8]>[OH-].[Na+].O>[OH:11][C:5]([CH3:10])([CH2:4][C:3]([OH:12])=[O:2])[CH2:6][C:7]([NH2:9])=[O:8]
Reactant: COC(=O)CC(C)(O)CC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)(CC(N)=O)CC(=O)O

Procedure:
1.56 g. (0.01 moles) of 3-hydroxy-3-methylglutaric acid monoamide methyl ester is dissolved in 10 ml of 1 N sodium hydroxide. After 24 hours at room temperature the solution is diluted to 50 ml with water and passed through a 50 ml column of Dowex 50 (H30 ) resin. The column is washed with 100 ml of water and the washings collected and evaporated to afford 3-hydroxy-3-methylglutaric acid monoamide.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]([C:11]([O:13]CC)=[O:12])=[O:10])=[N:5][CH:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].O.C(O)C>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]([C:11]([OH:13])=[O:12])=[O:10])=[N:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1ncc(CC)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1cnc(NC(=O)C(=O)O)s1
Reaction time: 0.17 h

Procedure:
Ethyl 5-ethylthiazol-2-ylcarbamoylcarboxylate (685 mg., 3 mmoles), 1 N potassium carbonate (3 ml., 3 equivalents), water (22 ml.) and ethanol (2--3 ml.) were heated on a steam bath. After 10 minutes, dissolution was nearly complete. After an additional 15 minutes, tlc (chloroform-5% acetic acid) indicated reaction was complete. The cooled reaction mixture was filtered, and crude product (380 mg.) precipitated from the filtrate by acidification with acetic acid. Recrystallization of the crude from isopropyl alcohol gave purified 5-ethylthiazol-2-ylcarbamoylcarboxylic acid [280 mg., m.p. 206.5° C. (dec)].
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[CH2:4][CH2:3]1.Br[C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([CH3:21])[CH:20]=1)[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)[CH2:15]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:21][C:19]1[CH:20]=[C:12]([C:10]#[C:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:13]=[C:14]2[C:18]=1[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:26][CH:25]=1)[CH2:15]2
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: C#CCN1CCN(C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc(C#CCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A mixture of 1-methyl-4-prop-2-ynyl-piperazine (0.033 mL, 0.33 mmol), 5-bromo-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.100 g, 0.25 mmol), PdCl2(PPh3)2 (0.011 g, 0.015 mmol), and CuI (0.0028 g, 0.015 mmol) in diisopropyl amine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-Methyl-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.076 g, 67%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]2[CH:12]=[CH:13][C:14]([O:16]C(=O)C)=[CH:15][C:10]=2[O:9][C:8](=[O:20])[C:7]=1[O:21][C:22](=[O:24])[CH3:23])[CH2:2][CH2:3][CH3:4].C[O-].[Na+]>CO>[C:22]([O:21][C:7]1[C:8](=[O:20])[O:9][C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:24])[CH3:23]
Reactant: CCCCOc1c(OC(C)=O)c(=O)oc2cc(OC(C)=O)ccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCOc1c(OC(C)=O)c(=O)oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a mixture of 17.31 g of 4-butoxy-3, 7-diacetoxy-2H-l-benzopyran-2-one (51.79 mmol) in 170 ml of methanol was added 2.66 g of sodium methoxide (49.20 mmol) and the reaction mixture was stirred at room temperature for 3 hours. Then 22.36 g of Amberlyst-15 was added, and the mixture was stirred at room temperature for 1 hour. Amberlyst-15 was filtered off and the filtrate was concentrated under reduced pressure to give a crystalline product. The product was reprecipitated from tertahydrofuran and hexane to give 12.87 g of the title compound. (yield=85%)
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.CO.C(Cl)(Cl)Cl.C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[NH:8][C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(C=C(Nc2cccnc2Cl)c2ccncc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1ccc(-c2c(-c3ccncc3)[nH]c3cccnc23)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 106.5 %

Procedure:
To a solution of (2-chloropyridin-3-yl)-[2-(4-fluorophenyl)-1-(pyridin-4-yl)-vinyl]amine (6.0 g, 18.5 mmol) and DABCO® (6.2 g, 55 mmol) in dimethylformamide (75 ml) was added bis(triphenylphosphine)palladium(II) chloride (650 mg, 0.926 mmol) and the reaction mixture was heated at 120° C. under an argon atmosphere. After 4 h, dimethylformamide was removed in vacuo and the residue was heated in ethyl acetate/methanol mixture. The product was filtered off to give a green solid which was redissolved in boiling methanol/chloroform mixture and treated with charcoal. The solution was filtered through a pad of Celite and the filtrate was concentrated to give 3-(4-fluoro-phenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine as a pale yellow solid (5.7 g).
Reaction SMILES: [C:1]([CH:4]([CH2:14][CH2:15][CH2:16][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[CH:24](O)=[O:25]>>[C:1]([CH:4]([CH2:14][CH2:15][CH2:16][CH:17]([O:23][CH:24]=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)O)C(C)=O
Reactant: O=CO
Product: CCCCCC(CCCC(CCCCCCC(=O)O)C(C)=O)OC=O

Procedure:
A mixture of 8-acetyl-12-hydroxyheptadecanoic acid (8.2 g., 0.025 mole) and 97% formic acid (10 ml.) is heated at 60° for 24 hours. The mixture is cooled, dissolved in 100 ml. ether, washed with 3 portions of water and dried over sodium sulfate. Evaporation of the ether leaves the product 8-acetyl-12-formyloxyheptadecanoic acid as a slightly yellowish viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N12CCCN=C1CCCCC2.[OH-].[Na+]>CN(C)C=O>[CH2:13]([O:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(C=O)c(O)cc1O
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(C=O)c(O)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
2,4-Dihydroxy-5-methoxybenzaldehyde (6.0 g), benzyl bromide (9.7 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (8.6 g) in N,N-dimethylformamide (30 ml) were heated at 100° C. under nitrogen for 5 hours. After cooling to room temperature, 1 N NaOH was added and the mixture washed with ethyl acetate. The water phase was acidified with HCl and the precipitate was filtered.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[N:23]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:29][C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: OCc1ccncc1
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2Cc1ccncc1

Procedure:
Compound IIo was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and pyridin-4-ylmethanol following the general procedure for the Mitsunobu reaction as described above.