Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][N:7]=2)=[CH:2]1.[CH:14]1([Mg]Br)[CH2:16][CH2:15]1>>[CH:14]1([CH:10]([C:9]2[CH:8]=[N:7][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:13][CH:12]=2)[OH:11])[CH2:16][CH2:15]1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1ccc(-c2ccsc2)nc1
Product: OC(c1ccc(-c2ccsc2)nc1)C1CC1

Procedure:
Synthesized using compound 56b (270 mg, 1.43 mmol) and cyclopropylmagnesium bromide (5.72 mL, 2.86 mmol, 0.5 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (1:1) as eluent. Yellow solid. Yield: 138 mg, 42%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=0.37-0.45 (m, 1H), 0.50 (dq, J=9.7, 4.8 Hz, 1H), 0.57-0.71 (m, 2H), 1.18-1.29 (m, 1H), 2.48 (br. s., 1H), 4.06 (d, J=8.2 Hz, 1H), 7.39 (dd, J=5.0, 3.2 Hz, 1H), 7.60 (dd, J=8.2, 0.6 Hz, 1H), 7.64-7.68 (m, 1H), 7.78-7.85 (m, 1H), 7.89 (dd, J=3.0, 1.4 Hz, 1H), 8.60-8.64 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=2.8, 3.6, 19.1, 76.1, 120.0, 123.4, 126.2, 126.3, 134.5, 137.2, 141.9, 147.6, 152.8; (ESI): m/z=232.26 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:5]([NH2:13])[NH:4][N:3]=1.O.C(N(C(C)C)[CH:19]=[C:20]([F:23])[CH:21]=O)(C)C>CS(C)=O>[NH2:13][C:5]1[C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:2]2[N:1]=[CH:19][C:20]([F:23])=[CH:21][N:3]2[N:4]=1
Reactant: C=CCOC(=O)c1c(N)n[nH]c1N
Reactant: CC(C)N(C=C(F)C=O)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: C=CCOC(=O)c1c(N)nn2cc(F)cnc12
Temperature: 100 °C

Procedure:
To a suspension of allyl 3,5-diamino-1H-pyrazole-4-carboxylate 3 (42.72 g, 234.5 mmol) in DMSO (270.8 mL)/Water (270.8 mL), was added p-TsOH hydrate (46.72 g, 245.6 mmol) and 3-(diisopropylamino)-2-fluoro-prop-2-enal (described in Tetrahedron Letters, 33(3), 357-60; 1992) (38.69 g, 223.3 mmol). The reaction mixture was heated to 100° C. for 3 h during which time a solid slowly precipitated out of solution. The orange suspension was allowed to cool down to RT overnight. The solid was filtered, washed with water and dried under vacuum to give allyl 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 4a as a sand solid (45.05 g, 85% yield).
Reaction SMILES: O1[C:5]2([CH2:9][CH2:8][N:7]([C@H:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]3[O:16][CH2:17][CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:6]2)[O:4]CC1.[ClH:31].CC(=O)CC>>[ClH:31].[O:4]=[C:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[O:16][CH2:17][CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:6]1
Reactant: c1ccc(C(CO[C@H]2CCCC[C@@H]2N2CCC3(C2)OCCO3)c2ccccc2)cc1
Agent: Cl
Solvent: CCC(C)=O
Product: O=C1CCN([C@H]2CCCC[C@@H]2OCC(c2ccccc2)c2ccccc2)C1
Yield: 80 %

Procedure:
A mixture of (1R,2R)/(1S,2S)-2-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-1-(2,2-diphenylethoxy)cyclohexane (1.55 g, 3.8 mmol) in 6M HCl-butanone (1:4, v/v, 50 mL) was refluxed for 2 hours. The butanone was evaporated in vacuo and the residue was taken up with water (50 mL). The aqueous solution was extracted with diethyl ether (2×50 mL); the aqueous layer was collected and extracted with dichloromethane (2×50 mL). The combined dichloromethane extracts were dried over sodium sulfate and concentrated in vacuo to yield the crude title compound. The product was crystallized by triturating in diethyl ether and reprecipitated from a mixture of dichloromethane-diethyl ether to yield 1.21 g (80% yield) of the title compound, having the elemental analysis indicated in Table 1.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=S)[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[CH:22]([NH:24][NH2:25])=O>C(O)C>[CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[CH:22]=[N:24][N:25]=[C:11]3[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1
Reactant: CN(C)c1ccc2c(c1)C(c1ccccc1)=NCC(=S)N2
Reactant: NNC=O
Solvent: CCO
Product: CN(C)c1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 7-(dimethylamino)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione is heated in ethanol with formic acid hydrazide and the resulting product is heated to 250° C. to give 8-(dimethylamino)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:12][C:13]([NH2:15])=[S:14].O>C(O)C.Cl>[ClH:1].[NH2:12][CH:13]1[N:15]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:3]=[CH:2][S:14]1
Reactant: NC(N)=S
Reactant: O=C(CCCl)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: NC1N=C(c2ccccc2)C=CS1

Procedure:
20.3 g (0.1 mol) of β-chloroethyl-phenyl ketone together with 7.6 g (0.1 mol) of thiourea in 100 ml of ethanol in which 0.5% by weight of hydrogen chloride is dissolved, are heated to the boil (for about 3 to 4 hours) until the starting compounds can no longer be detected in a sample by thin-layer chromatography. Thereafter ethanol is azeotropically distilled off whilst toluene is continuously added in the same amount as ethanol distils off and the resulting toluene reaction mixture is boiled for a further 1/2 hour on the water separator. 23 g (about 88% of the theory) of crude 2-amino-4-phenyl-1,3-thiazine hydrochloride (m.p. 204° C.) separate out as faintly yellow-coloured crystals and are filtered off. By recrystallizing from ethanol, pure 2-amino-4-phenyl-1,3-thiazine-hydrochloride is obtained with a melting point of 210° C.
Reaction SMILES: C[C:2]1[C:6]2[N:7]=[C:8](SC)[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]=2[S:4][C:3]=1[CH2:19][N:20]1[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]1.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[C:39]([NH:41]C(=O)C)[N:38]=[C:37]([NH:45]C(=O)C)[CH:36]=1)CCC>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[O:14]1[CH2:13][CH2:12][N:11]([C:10]2[C:5]3[S:4][C:3]([CH2:19][N:20]4[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]4)=[CH:2][C:6]=3[N:7]=[C:8]([C:35]3[CH:40]=[C:39]([NH2:41])[N:38]=[C:37]([NH2:45])[CH:36]=3)[N:9]=2)[CH2:16][CH2:15]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(NC(C)=O)nc(NC(C)=O)c1
Reactant: CSc1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)c(C)c2n1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cc(N)nc(N)c4)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C

Procedure:
7-Methyl-2-(methylthio)-4-morpholino-6-((4-N-methylsulfonylpiperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (0.29 mM) was added to 4-tributylstannyl-2,6-diacetylaminopyridine dissolved in 10 mL 1,2-DME followed by the addition of Cu(I)Br-dimethylsulfide and stirred at room temperature for ten minutes. Finally, Pd(PPH3)4 was added and the reaction mixture was heated to reflux under N2 for 2 hours. Complete product formation was confirmed by LCMS. The reaction was diluted with EtOAc, extracted 1× with water and 1× with 1 M HCl. The combined aqueous layers were basified with 10% w/w KOH and extracted the product with EtOAc, dried over MgSO4, and concentrated in vacuo. This crude product was dissolved in 2 N HCl and heated to reflux for 12 hours to remove the acetyl groups and after concentrating in vacuo and HPLC purification gave 279. MS (Q1) 506 (M+)
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:13][CH2:14][O:15][C:16]3[C:17]([N:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[N:18][S:19][N:20]=3)=[CH:7][CH:8]=2)[O:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:21]1([C:17]2[C:16]([O:15][CH2:14][CH2:13][O:12][C:6]3[CH:5]=[C:4]4[C:9]([CH:10]=[CH:11][C:2](=[O:1])[O:3]4)=[CH:8][CH:7]=3)=[N:20][S:19][N:18]=2)[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsnc2OCCOc2ccc3ccc(=O)oc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1ccc2ccc(OCCOc3nsnc3N3CCNCC3)cc2o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product obtained in Step 3 (176 mg) was diluted in CH2Cl2 (1.5 mL) and cooled to ˜0° C. Trifluoroacetic acid (0.5 mL) was added and the reaction mixture was stirred for 1 h at 5° C. After solvent removal in vacuo, the residue was purified by chromatography on silica gel using hexane/EtOAc (1:1) followed by CH2Cl2/MeOH/Et3N (90:5:5) as eluents This furnished 45 mg (40%) of the title product as a white solid. MS m/z 375 (M+H)+.
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH3:44][N:45]([CH2:63][CH2:64][CH3:65])[C:46](=[O:62])[C:47]1[CH:48]=[C:49]([CH:53]=[C:54]([N:56]2[CH2:60][CH2:59][CH2:58][C:57]2=[O:61])[CH:55]=1)[C:50](O)=[O:51].[CH:66]12[CH2:72][CH:69]([CH2:70][CH2:71]1)[CH2:68][CH:67]2[NH:73][C:74](=[O:89])[C@H:75]([CH3:88])[CH2:76][C@H:77]([OH:87])[C@@H:78]([NH2:86])[CH2:79][C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1>>[CH2:79]([C@H:78]([NH:86][C:50](=[O:51])[C:49]1[CH:53]=[C:54]([N:56]2[CH2:60][CH2:59][CH2:58][C:57]2=[O:61])[CH:55]=[C:47]([C:46]([N:45]([CH3:44])[CH2:63][CH2:64][CH3:65])=[O:62])[CH:48]=1)[C@@H:77]([OH:87])[CH2:76][C@H:75]([C:74](=[O:89])[NH:73][CH:67]1[CH2:68][CH:69]2[CH2:72][CH:66]1[CH2:71][CH2:70]2)[CH3:88])[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: CCCN(C)C(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CC3CCC2C3)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to E6, from N-methyl-5-(2-oxo-pyrrolidin-1-yl)-N-propyl-isophthalamic acid (D65) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: [CH:1]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH:10]([N-]C(C)C)([CH3:12])[CH3:11].[Li+].ICCC>C1COCC1.CS(C)=O>[CH2:8]([O:7][C:5]([C:1]1([CH2:11][CH2:10][CH3:12])[CH2:4][CH2:3][CH2:2]1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C1CCC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCC1(C(=O)OCC)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
Ethyl cyclobutanecarboxylate 1 (25.0 g, 0.195 mol) was added to a solution of lithium diisopropylamide (97.5 mL of a 2.0M solution in THF, 0.195 mol) in THF (200 mL) at −78° C. After 30 min the reaction solution was warmed to room temperature and transferred via canula to a solution of 1-iodopropane (49.7 g, 0.293 mol) in DMSO (104 mL) while maintaining the temperature between 15-20° C. After stirring for an additional 30 min the precipitated salts were removed by vacuum filtration. The filtrate was concentrated in vacuo, diluted with hexane and washed with 1N HCl, saturated aqueous NaHCO3 and brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by vacuum distillation (105-108° C., 20-30 mmHg) to give 16 g (48%) of the ester 2 as a clear, colorless oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:31]2[CH2:43][CH2:42][N:34]3[C:35]4[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=4[CH:41]=[C:33]3[C:32]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:28]=[C:22]3[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:29])[N:14]([CH3:30])[CH:13]=1)(=O)C.O[Li].O>CC(O)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:31]2[CH2:43][CH2:42][N:34]3[C:35]4[CH2:36][CH2:37][CH2:38][CH2:39][C:40]=4[CH:41]=[C:33]3[C:32]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:28]=[C:22]3[CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:29])[N:14]([CH3:30])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 30 °C
Reaction time: 2 h
Yield: 32.8 %

Procedure:
A mixture of 113j (300 mg, 0.50 mmol) and LiOH.H2O (120 mg, 2.50 mmol) in iPrOH/THF (1:1, 3 mL) and H2O (1 mL) was stirred at 30° C. for 2 h. The mixture was evaporated in vacuo and the residue was extracted with EtOAc (10 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 113 (91 mg, 32%) as a white solid. LCMS: [M+H]+ 555. 1H NMR (500 MHz, CDCl3) δ 8.47 (d, J=5.0, 1H), 7.95 (d, J=5.0, 1H), 7.72 (d, J=2.0, 1H), 7.42 (s, 1H), 7.35 (d, J=5.0, 1H), 6.89 (s, 1H), 5.69 (s, 1H), 5.01-5.02 (m, 1H), 4.61-4.62 (m, 1H), 4.48-4.49 (m, 1H), 4.32-4.33 (m, 1H), 4.15-4.07 (m, 4H), 3.86-3.87 (m, 1H), 3.69 (s, 3H), 3.60-3.59 (m, 2H), 2.88 (t, J=6.0, 2H), 2.61-2.56 (m, 4H), 2.47 (s, 3H), 1.89-1.90 (m, 2H), 1.78-1.79 (m, 2H)
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:43])([C:39]([F:42])([F:41])[F:40])[C:21]([F:38])([F:37])[C:22]([F:36])([F:35])[O:23][C:24]([F:34])([F:33])[C:25]([F:32])([F:31])[C:26]([F:30])([F:29])[CH2:27][OH:28]>>[CH2:1]([O:8][CH2:9][C@@H:10]([OH:12])[CH2:11][O:28][CH2:27][C:26]([F:29])([F:30])[C:25]([F:31])([F:32])[C:24]([O:23][C:22]([F:35])([F:36])[C:21]([F:37])([F:38])[C:20]([F:43])([F:19])[C:39]([F:42])([F:41])[F:40])([F:34])[F:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O[C@H](COCc1ccccc1)COCC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 120 °C
Reaction time: 3 h

Procedure:
(R)-Benzylglycidyl ether (2.0 g, 12.2 mmol, prepared essentially as described by Byun et al. in Tet. Lett. 30, 2751 (1989)) was added dropwise to a 120° C. solution of potassium carbonate (0.17 g, 1.2 mmol) in 4-nonafluorobutoxy-2,2,3,3,4,4-hexafluoro-1-butanol (5.1 g, 12.2mmol). The resulting mixture was stirred for 3 hours at 120° C. and was then cooled to ambient temperature and distilled (0.6 torr, 110°-130° C.) to give 6.25 g of 1-benzyloxy-(R)-2-hydroxy-3-(4-(nonafluorobutoxy)-2,2,3,3,4,4-hexafluorobutoxy)propane.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>Cl>[ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:8]
Reactant: NCC(=O)CCC(=O)O
Reactant: CCCCCCO
Agent: Cl
Product: CCCCCCOC(=O)CCC(=O)CN
Reaction time: 72 h
Yield: 79.9 %

Procedure:
2 grams of 5-aminolevulinic acid hydrochloride was dissolved in 25 grams of dry n-hexanol with 5-6 drops of conc. hydrochloride added in a 50 ml glass reactor equipped with a reflux condenser and a thermometer. The reaction mixture was held at 50-60° C. for approx. 3 days. The excess n-hexanol was removed under vacuum and the product finally dried under high vacuum, giving 2.4 grams of n-hexyl 5-aminolevulinate hydrochloride. The structure was confirmed by 1H-NMR spectroscopy in DMSO-d6.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH:9](C(OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=1.Cl>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(OC)n1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1cccc(OC)n1
Temperature: 65 °C

Procedure:
A solution of diethyl 2-(6-methoxypyridin-2-yl)malonate (1.0 g, 3.74 mmol) and hydrochloric acid (1 M) (20 mL, 20.0 mmol) in ethanol (10 mL) was heated at 65° C. overnight. The solvent was removed under reduced pressure. The residue was dissolved in ethanol (15 mL) and hydrochloric acid (conc.) (0.5 mL, 6.00 mmol) was added. The reaction mixture was heated at 65° C. for 4 h. The solvent was removed under reduced pressure. Ethyl acetate and saturated NaHCO3 aqueous solution were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated to give the product. Yield: 0.69 g (94%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:10]#[CH:11]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[C:10][CH2:9][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: C#CCN1CCCC1
Product: Brc1ccc(C#CCN2CCCC2)cc1

Procedure:
Prepared according to general working method I from 4-bromo-iodobenzene (10.9 g, 38.5 mmol) and 1-prop-2-ynyl-pyrrolidine (4.20 g, 71% purity, 27.3 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:29](I)[CH2:30][CH3:31]>O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]3[CH2:13][CH2:14][N:15]([CH2:29][CH2:30][CH3:31])[CH2:16][CH:17]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1CC=C(c2c[nH]c3cc(OC)ccc23)CC1
Reaction time: 5 h
Yield: 83.6 %

Procedure:
A mixture of 10 g of the product of Step A, 200 ml of dimethylformamide, 9.28 g of sodium carbonate and 8.93 g of propyl iodide was stirred under an inert atmosphere for 5 hours and was then poured into 1.5 liters of water. The mixture was allowed to crystallize and was stirred for one hour and then vacuum filtered. The recovered product was rinsed with water and dried at 50° C. under reduced pressure in the presence of a dehydrating agent to obtain 9.9 g of 6-methoxy-3-(1-propyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at 219°-220° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:2].CC(C)([O-])C.[K+].[Cl:27][CH2:28][C:29]1[C:33]([CH2:34]Cl)=[CH:32][S:31][CH:30]=1.Cl>CN(C=O)C>[ClH:27].[CH2:1]([O:3][C:4]([C:5]1([NH2:6])[CH2:34][C:33]2=[CH:32][S:31][CH:30]=[C:29]2[CH2:28]1)=[O:20])[CH3:2]
Reactant: ClCc1cscc1CCl
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(N)Cc2cscc2C1
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
(Benzhydrylidene-amino)-acetic acid ethyl ester (0.113 g, 0.414 mmol) was dissolved in DMF (3 ml) and cooled in an ice bath. Potassium tert-butoxide (94.8 mg, 0.828 mmol) was added, and the mixture was stirred for 10 min. The mixture was cooled to −30° C., and 3,4-bis-chloromethyl-thiophene (50 mg, 0.276 mmol) was added in one portion. The mixture was then placed into an ice bath again, and the reaction allowed to proceed for 20 min. The mixture was acidified with 2 N hydrochloric acid, stirred for 10 min and partitioned between water and diethyl ether. The aqueous phase was neutralized with a saturated sodium hydrogencarbonate solution and extracted with EA. The combined EA extracts were washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in diethyl ether, filtered, evaporated to dryness, acidified with hydrogen chloride in methanol and evaporated to dryness. The residue was stirred with an diethyl ether/HEP mixture, and the solid was filtered and dried in vacuo to give crude 5-amino-5,6-dihydro-4H-cyclopenta[c]thiophene-5-carboxylic acid ethyl ester hydrochloride. A part of the crude compound (27 mg, 0.109 mmol) was reacted without further purification with 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 1 of example 15. After purification by preparative RP HPLC (water/ACN gradient), 23 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>C1(C)C(C)=CC=CC=1.N1C=CC=CC=1>[C:12]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: CCOC(=O)CC(C)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)N1CCCc2cc(C)ccc21
Temperature: 25 °C
Yield: 36.1 %

Procedure:
A solution of 6-methyl-1,2,3,4-tetrahydroquinoline (3.0 g) and ethyl acetoacetate (2.8 g) in xylene (7.0 ml) containing 2 drops of dry pyridine was refluxed for 12 hours. The solution was then allowed to cool to room temperature, washed in turn with 2N hydrochloric acid (2× 20 ml) and water (2 × 20 ml), dried over anhydrous magnesium sulphate and evaporated under reduced pressure at 100° to dryness, yielding 1-acetoacetyl-6-methyl-1,2,3,4-tetrahydroquinoline (1.7 g) as a crude solid, to be used directly in the next stage.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:17]([Cl:24])=[C:18](N)[CH:19]=[CH:20][C:21]=1Br)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]1[CH:21]=[CH:20][C:19]([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:34]=2)=[CH:18][C:17]=1[Cl:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1c(Br)ccc(N)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(Cl)c2)CC1
Temperature: 80 °C

Procedure:
A mixture of the product of Example 60A (380 mg, 1.23 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (380 mg, 1.23 mmol) and sodium carbonate (391 mg, 3.69 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was degassed and heated at 80° C. for 16 hours. After cooling to ambient temperature and concentration, the residue was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate (3×35 mL). The combined organic phase was washed with saturated brine, dried over sodium carbonate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 8/1 petroleum/ethyl acetate to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([C:8]([CH3:31])([CH3:30])[CH2:9][C:10]([OH:29])([C:25]([F:28])([F:27])[F:26])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[C:14]([CH2:23][OH:24])=[CH:13]2)[CH:7]=1.[CH3:34]I>C(#N)C.[Ag-]=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([C:8]([CH3:30])([CH3:31])[CH2:9][C:10]([OH:29])([C:25]([F:27])([F:28])[F:26])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[C:14]([CH2:23][O:24][CH3:34])=[CH:13]2)[CH:7]=1
Reactant: CI
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1cc(CO)c(=O)c2ccccc21)C(F)(F)F
Agent: O=[Ag-]
Solvent: CC#N
Product: COCc1cn(CC(O)(CC(C)(C)c2cc(F)ccc2OC)C(F)(F)F)c2ccccc2c1=O
Temperature: 50 °C

Procedure:
To a suspension of 1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-3-hydroxymethyl-1H-quinolin-4-one (51.5 mg) and silver(I) oxide (127 mg) in acetonitrile (3 mL) was added methyl iodide (68.5 p-L). After heating at 50° C. for 15 hours, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 50%-70% ethyl acetate-hexanes) to give the title compound as a white solid (37.5 mg).