Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:53]1([S:58]([NH:61][C:62]([C@@:64]2([NH:69][C:70]([C@@H:72]3[CH2:83][C@:75]4([C:80]([CH3:82])([CH3:81])[C:76]54[CH2:79][CH2:78][CH2:77]5)[CH2:74][NH:73]3)=[O:71])[CH2:66][C@H:65]2[CH:67]=[CH2:68])=[O:63])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:13]1([CH3:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:10]([N:73]1[C@H:72]([C:70](=[O:71])[NH:69][C@:64]2([C:62]([NH:61][S:58]([N:53]3[CH2:54][CH2:55][CH2:56][CH2:57]3)(=[O:60])=[O:59])=[O:63])[CH2:66][C@H:65]2[CH:67]=[CH2:68])[CH2:83][C@:75]2([C:80]([CH3:81])([CH3:82])[C:76]32[CH2:77][CH2:78][CH2:79]3)[CH2:74]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1(C)CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1(C)CCOCC1)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Reaction time: 8 h

Procedure:
A solution of (S)-tert-Butoxycarbonylamino-(4-methyl-tetrahydro-pyran-4-yl)-acetic acid (0.306 g; 1.12 mmol) (prepared according to Tetrahedron Let. 2007, 48, 6343-6347) and HATU (0.581 g; 1.53 mmol) in DCM (20 mL) was stirred for 10 min at ambient temperature. DIPEA (1.05 mL; 6.11 mmol) and (5R,8S)-10,10-Dimethyl-7-aza-dispiro[3.0.4.1]decane-8-carboxylic acid [(1R,2S)-1-(pyrrolidine-1-sulfonylaminocarbonyl)-2-vinyl-cyclopropyl]-amide (0.57 g; 1.02 mmol) were added, the reaction mixture was stirred overnight and purified without workup by preparative HPLC (method L) to yield the title compound. LC-MS (method E): Rt=2.55 min; M/z=706 [M+]; HPLC (method A3): Rt=6.16 min
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:21]=2[S:20](=[O:30])(=[O:29])[N:19]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:37][C:38]1[CH:39]=[C:40]([CH:45]=[C:46](Cl)[N:47]=1)[C:41]([O:43][CH3:44])=[O:42]>N1C=CC=CC=1.[Cu]=O>[Cl:37][C:38]1[CH:39]=[C:40]([CH:45]=[C:46]([O:28][C:26]2[CH:25]=[CH:24][C:22]3[NH:23][C:18]([C:3]4[C:4](=[O:17])[N:5]([NH:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:6]5[C:11]([C:2]=4[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=5)=[N:19][S:20](=[O:29])(=[O:30])[C:21]=3[CH:27]=2)[N:47]=1)[C:41]([O:43][CH3:44])=[O:42]
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc21
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COC(=O)c1cc(Cl)nc(Oc2ccc3c(c2)S(=O)(=O)N=C(c2c(O)c4ccccc4n(NCC(C)C)c2=O)N3)c1
Temperature: 125 °C

Procedure:
A mixture of the product of Example 321C (40.0 mg, 0.138 mmol), potassium carbonate (19.1 mg, 0.138 mmol), copper(II)oxide (18.4 mg, 0.23 mmol)and methyl 2,6-dichloroisonicotinate (28.4 mg, 0.138 mmol) in pyridine (0.2 mL) was stirred while heating at 125° C. in a microwave reactor for 100 minutes. After cooling to 25° C., the mixture was loaded directly onto silica gel gel and eluted with a 0-5% methanol in dichloromethane step gradient. The fractions containing the desired product were combined and concentrated. The title compound was isolated by recrystallization of the residue using ethyl acetate/hexane (4.3 mg, 68%). MS (ESI−) m/z 596 (M−H)−. 1H NMR (300 MHz, CDCl3) δ 1.13 (d, J=6.62 Hz, 6H) 2.00 (m, 1 H) 2.84 (br m, 2 H) 3.99 (s, 3 H) 5.73 (br s, 1 H) 7.43 (m, 4 H) 7.62 (d, J=8.46 Hz, 1 H) 7.80 (m, 2 H) 7.96 (d, J=8.46 Hz, 1 H) 8.28 (d, J=8.09 Hz, 1 H) 14.37 (s, 1 H) 15.04 (s, 1 H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[C:6]2=[N:7][C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([N:25]4[CH2:24][CH2:23][O:22][CH2:27][CH2:26]4)[CH:33]=3)=[CH:3][N:4]=[C:5]2[NH:11][CH2:10][CH2:9]1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4cccc(N5CCOCC5)c4)nc32)c1Cl

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and 3-(Morpholino)phenylboronic acid pinacol ester using Suzuki coupling conditions as described in Example 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[C:20]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)=[CH:29][CH:30]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: CC(C)(C)c1ccc(N)cc1
Product: CC(C)(C)c1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 4-tert-butylaniline were reacted to yield N2-(4-tert-butylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.85 (d, 1H, J=3.6 Hz), 7.44 (bdd, 2H, J=6.3 Hz), 7.35-7.31 (m, 3H), 6.93 (dd, 1H, J=2.7 and 8.7 Hz), 6.83 (d, 1H, J=9 Hz), 6.80 (bs, 1H), 4.23 (s, 4H), 1.28 (s, 9H); LCMS: ret. time: 27.67 min.; purity: 98%; MS (m/e): 395 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14]C(OCC2C=CC=CC=2)=O)[C@H:10]([CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:14][C@H:11]1[CH2:12][CH2:13][C@@H:8]([NH:7][C:6](=[O:30])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:9][C@H:10]1[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CS(C)(=O)=O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N)[C@H](CS(C)(=O)=O)C1
Reaction time: 3 h
Yield: 96.3 %

Procedure:
(1R,3R,4S)-(4-Benzyloxycarbonylamino-3-(methyl)sulfonylmethylcyclohexyl)carbamic acid tert-butyl ester (300 mg) was dissolved in MeOH (5 ml) prior to the addition of 10% Pd/C (200 mg). A hydrogen balloon was added and the solution was stirred for 3 h. The palladium was filtered off and the solution was concentrated to give tert-butyl(1R,3R,4S)-4-amino-3-(methylsulfonylmethyl)cyclohexylcarbamate (201 mg). MS found: (M+H)+307.2.
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:3]=1[OH:4].[CH2:11]([OH:13])C.C=O>Cl.O>[CH3:1][C:2]1([CH:11]=[O:13])[C:8]([OH:9])=[CH:7][C:6]([CH3:10])=[CH:5][CH:3]1[OH:4]
Reactant: Cc1cc(O)c(C)c(O)c1
Reactant: CCO
Agent: C=O
Agent: Cl
Solvent: O
Product: CC1=CC(O)C(C)(C=O)C(O)=C1

Procedure:
To a solution of 691 g. of 2,5-dimethylresorcinol in 1 l. of ethanol were added 348 g. of a 37% aqueous solution of formaldehyde and 0.5 ml. of 35% conc. hydrochloric acid as a catalyst. The resulting mixture was heated in the same manner as in the Synthesis example 1 and poured into 5 l. of a cold water to give a pale brown powdery resin.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH2:4][CH2:3]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[C:19]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH2:4][CH2:3]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1ccc2cc(N3CCC(O)CC3)ccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: O=C(OC1CCN(c2ccc3[nH]c(=O)ccc3c2)CC1)c1ccccc1
Temperature: 100 °C
Yield: 50.5 %

Procedure:
A mixture of 6-(4-hydroxypiperidino)carbostyril (0.25 g), benzoyl chloride (0.17 g) and dry pyridine (2 mL) was heated for 3 hours at 100° C. The reaction mixture was cooled and water (about 25 mL) and sodium bicarbonate (1 g) were added. The mixture was chilled in ice and stirred. The resulting solid was removed by filtration, washed with water and dried to give crude 6-(4-benzoyloxypiperidino)-2(1H)-quinolinone (0.25 g). Recrystallization twice from ethyl acetate gave 6-(4-benzoyloxypiperidino)-2(1H)-quinolinone (0.18 g); m.p. 212°-215° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:7][C:6]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[CH:4]=[CH:3]1>CCO.[Pd]>[CH3:13][O:12][C:9]1[CH:8]=[C:6]2[C:5]([CH2:4][CH2:3][C:2]([CH3:14])([CH3:1])[O:7]2)=[CH:11][CH:10]=1
Reactant: COc1ccc2c(c1)OC(C)(C)C=C2
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)OC(C)(C)CC2
Yield: 90 %

Procedure:
A solution of precocene I (5.0 g, 26.3 mmol) in EtOH (200 mL) was hydrogenated by using 10% Pd/C (0.5 g) as catalyst. The catalyst was filtered of and EtOH was removed under reduced pressure. The crude material was then washed with dichloromethane (2×50 mL) to afford the desired product as white solid (4.55 g, 90%). 1H-NMR (CD3CN) δ 6.97 (d, J=8.0 Hz, 1H), 6.42 (d, J=8.0 Hz, 1H), 6.27 (s, 1H), 3.74 (s, 3 H), 2.72 (t, 2 H), 1.80 (t, 2 H), 1.32 (s, 6 H); MS LC-MS (MH+=193).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.I[CH2:40][CH2:41][OH:42].CCN(CC)CC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[N:23]4[CH2:28][CH2:27][N:26]([CH2:40][CH2:41][OH:42])[CH2:25][CH2:24]4)[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: OCCI
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2N2CCNCC2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2N2CCN(CCO)CC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 48.3 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(piperazin-1-yl)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.09 mmol), 2-Iodo-ethanol (155 mg, 0.9 mmol) and Et3N (18 mg, 0.18 mmol) in acetone (1 mL) was heated at 80° C. for 1 h. Then the mixture was concentrated and the residue was purified by Prep-HPLC to give the title compound as a white solid (26 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C:12]1([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16](=[O:26])[NH:17][C@@H:18]([C@H:23]([OH:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:41][C:42](OC(C)=O)=[O:43]>C1COCC1.C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C:12]1([C:16](=[O:26])[NH:17][C@@H:18]([C@H:23]([O:25][C:42](=[O:43])[CH3:41])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@@H](NC(=O)C1(Cc2ccccc2)CCCN1C(=O)OCc1ccccc1)[C@@H](C)O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)C1(Cc2ccccc2)CCCN1C(=O)OCc1ccccc1)[C@@H](C)OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
Compound 4 (3 g, 6.60 mmol) was dissolved in THF (30 mL), Et3N (1.11 mL, 7.92 mmol) and Ac2O (742 mg, 7.26 mmol) were added at RT. The reaction mixture was stirred at RT for 2 h. The volatiles were evaporated under reduced pressure and the residue obtained was diluted with CH2Cl2 and washed with dilute HCl. The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography using 30% EtOAc/Hexane as eluent to yield compound 5 (2.5 g, 76%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH:8]([CH3:11])[CH:9]=O.CC1C(C)(C)[CH:17]([CH2:21][CH:22]=[O:23])CC=1.C(=O)CC.C[O-].[Na+].[Na]>C(O)(=O)C.CO>[CH3:17][C:21](=[CH:9][CH:8]([CH:3]1[CH2:4][CH:5]=[C:6]([CH3:7])[C:2]1([CH3:12])[CH3:1])[CH3:11])[CH:22]=[O:23]
Reactant: CC1=CCC(C(C)C=O)C1(C)C
Reactant: CC1=CCC(CC=O)C1(C)C
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCC=O
Product: CC(C=O)=CC(C)C1CC=C(C)C1(C)C
Temperature: 10 °C
Reaction time: 42 h
Yield: 38 %

Procedure:
60.0 g (0.36 mol) of 2-(2,2,3-trimethylcyclopent-3-enyl)propionaldehyde, prepared from campholenic aldehyde as known per se, and 42.0 g (0.72 mol) of propanal was added successively during 15 min and 2 hours, respectively, to the sodium methylate solution prepared from 0.83 g of sodium and 200 ml of anhydrous methanol, at 10° C. The reaction mixture was stirred at 10° C. for 2 hours and at room temperature for the following 42 hours. After addition of 5 ml of acetic acid the solvent was evaporated in vacuo at the temperature maintained below 50° C. The residue was diluted with 500 ml of MTBE, washed with 2×200 ml of brine, dried (MgSO4), concentrated in vacuo and distilled at 76-95° C./0.1 Torr to give 28.1 g (38%) of 2-methyl-4-(2,2,3-trimethylcyclopent-3-enyl)pent-2-enal. An analytical sample was prepared by flash chromatography on silica gel (eluent: hexane/MTBE 12:1).
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1>>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]([NH:2][NH:1][C:3]2[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CC(C)c1cc(NN)nc2ccccc12
Product: CC(C)c1cc(NNC(=O)Nc2cc(Cl)cc(Cl)c2)nc2ccccc12

Procedure:
A solution of 2-hydrazinyl-4-isopropylquinoline (97 mg, 0.48 mmol) and 91 mg (1.0 eq) of 3,5-dichlorophenyl isocyanate was reacted as outlined in Scheme 1 above to give the desired title compound.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl[CH:7]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].O>CN(C=O)C>[C:1]([S:3][CH:7]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: CCOC(=O)C(Cl)c1ccc(C)c(C)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(SC(C)=O)c1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
Potassium thioacetate (CH3COSK, 8.31 g) was added in small portions to a solution of ethyl 2-chloro-2-(3,4-dimethylphenyl)acetate (15 g) in DMF (80 ml). The mixture was stirred at room temperature for 2 hours, at the end of which time it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give ethyl 2-acetylthio-2-(3,4-dimethylphenyl)acetate (16.5 g, 94%) as an oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11](O)=[O:12])[N:2]=1.B.C1COCC1.CO>C1COCC1>[OH:12][CH2:11][C:3]1[N:2]=[CH:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc2ccccc2cn1
Temperature: 0.75 °C
Reaction time: 17 h
Yield: 12.3 %

Procedure:
To a stirred solution of isoquinoline-3-carboxylic acid (0.3179 g, 1.84 mmol) in dry THF (10 mL) at room temperature was added BH3-THF (1.0 M, 7.5 mL, 7.5 mmol). The mixture was stirred for 17 hrs, dry CH3OH (10 mL) was added, and the reaction was heated to 0.75° C. with stirring for a further 24 hrs. The mixture was concentrated and the residue was treated with dry CH3OH (3×10 mL), removing the solvent by evaporation each time. The crude product was purified by column chromatography (12 g silica gel, 19:1 CH2Cl2: CH3OH) to give 0.0359 g of 3-(hydroxymethyl)isoquinoline as a white film. The solid was dissolved in dry CH2Cl2 (5 mL) and treated with MnO2 (˜85%, 0.2978 g, 2.91 mmol) with stirring for 19 hrs then filtered through celite. Concentration of the filtrate afforded 0.0252 g (9%) of isoquinoline-3-carboxaldehyde as yellow oil. 1H NMR (CDCl3) d 7.73–7.82 (m, 2H), 7.97–8.07 (m, 2H), 8.37 (s, 1H), 9.36 (s, 1H), 10.25 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:18]1(=O)[CH2:23][CH2:22][CH2:21][C:20](=O)[CH2:19]1.C([O-])(=O)C.[NH4+:30]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]2[C:11]3[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][C:16]=3[NH:30][C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=3)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: O=C1CCCC(=O)C1
Reactant: O=C1CCCCC1=Cc1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Solvent: CCO
Product: O=C1CCCC2=C1C(c1cccc([N+](=O)[O-])c1)C1=C(CCCC1)N2
Yield: 7.6 %

Procedure:
A mixture of 2-(3-nitrophenylmethylene)cyclohexanone (4.69 g), 1,3-cyclohexanedione (2.28 g), ammonium acetate (2.35 g) and 90 mL of ethanol was stirred at reflux under nitrogen for 48 hours. The mixture was cooled in an ice bath and orange crystals were collected by filtration. The material was chromatographed with dichloromethane, ethyl ether:dichloromethane (2:98) and ethyl ether:dichloromethane (10:90) as the elutents. The solvent was evaporated and the residue recrystallized from toluene/hexane to yield the title compound as yellow crystals (0.50 g); mp 218°-221° C.; NMR (CDCl3): 1.57-1.59 (m,4, CH2) 1.74-1.80 (m,2, CH2) 1.88-2.01 (m,2, CH2) 2.14 (broad s,2, CH2) 2.28-2.36 (m,2, CH2) 2.42-2.46 (m,2, CH2) 4.50 (s,1, CH) 5.40 (s,1, NH) 7.38 (t,1, J=7.8, Ar) 7.71 (d,1, J=7.6, Ar) 7.98 (q,1, J=7.3, 1.4, Ar) 8.09 (d,1, J=1.9, Ar); MS (CI, CH4): m/z=325(M+1). Analysis for C19H20N2O3.0.6 H2O: Calculated C, 68.08; H, 6.37; N, 8.36; Found: C, 68.27; H, 6.28; N, 8.01.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N+:7](C)([CH3:13])[CH2:6][CH:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)C([O-])=O.CI>Cl.CC(C)=O.C(N(C(C)C)CC)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[N+]1(C)Cc2c(Cl)cc(Cl)cc2C(c2ccccc2)C1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccccc2)C1
Reaction time: 62 h

Procedure:
6,8-Dichloro-2,2-dimethyl-4-phenyl-1,2,3,4-tetrahydroisoquinolinium, trifluoroacetate; Intermediate 4 (100 mg) was dissolved in the form of its hydrochloride in acetone (1 ml) in the presence of diisopropylethylamine (58 μl). Methyl iodide (38 μl) was then added dropwise with stirring. The mixture was then stirred at room temperature for two hours and subsequently left to stand for 62 h. Since the reaction was still not complete, further methyl iodide (38 μl) was added and the mixture was heated to reflux. After two hours, the reaction mixture was cooled and then concentrated to dryness in a rotary evaporator. The residue was purified by preparative HPLC on RP-18 with acetonitrile/water (0.05% TFA), and the pure fractions were combined. The acetonitrile was stripped off and then the aqueous residue was freeze dried. 132 mg of the desired product were obtained as a solid. (Rt=4.22 min (method A); MS (Cl+): 306.0).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:6].[Na+].C1(CC([O-])=O)C=CC=CC=1.[C:24]1([NH:30][C:31](=[O:54])[CH:32]([CH:38]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:39]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=O)[C:33](=O)[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:24]1([NH:30][C:31]([C:32]2[C:38]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[C:39]([C:41]3[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=3)[N:2]([CH2:3][CH2:4][C:5]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[O:6])[C:33]=2[CH:34]([CH3:36])[CH3:35])=[O:54])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCC(=O)N1CCOCC1
Reactant: CC(C)C(=O)C(C(=O)Nc1ccccc1)C(C(=O)c1ccc(F)cc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])Cc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC(=O)N1CCOCC1
Yield: 78 %

Procedure:
A nitrogen inerted reactor, equipped with a suitable reflux condenser and soxhlet extractor containing freshly activated 3A molecular sieves (4-8 mesh; 36 g), is charged with 3-amino-1-morpholin-4-yl-propan-1-one hydrochloride (170 mmol), phenylacetic acid sodium salt (170 mmol) and 2-[2-(4-fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoic acid phenylamide (100 mmol). THF (150 mL) is added, and the resulting solution is stirred vigorously as the reaction is heated at reflux temperature for ca. 24 hours, during which time the product begins to precipitate. Aqueous NaHCO3 (100 mL) is added slowly, and the reaction mixture is cooled with continued stirring to ca. 0° C. MtBE (100 mL) is added, and the solids are collected via filtration. The yellow-colored solid is washed with distilled water (15 mL) and MtBE (2×15 mL), collected, and dried under vacuum at ≦50° C. to afford 5-(4-fluorophenyl)-2-isopropyl-1-(3-morpholin-4-yl-3-oxo-propyl)-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide as a white solid (42.1 g). This material is carried on to subsequent steps without further purification.
Reaction SMILES: [Li][CH2:2]CCC.CCCCCC.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[O:25][C@@H:24]([CH:26]=O)[C:23]([CH3:29])([CH3:28])[CH2:22][O:21]2)=[CH:16][CH:15]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:29][C:23]1([CH3:28])[CH2:22][O:21][CH:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)[O:25][C@H:24]1[CH:26]=[CH2:2]
Reactant: COc1ccc(C2OCC(C)(C)[C@H](C=O)O2)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C[C@@H]1OC(c2ccc(OC)cc2)OCC1(C)C
Yield: 81 %

Procedure:
Following the general procedure for the methylenation by Wittig-olefination of Description 8, a phosphorous ylide generated from 73.4 g (205.5 mmol) of methyltriphenylphosphonium bromide and 125.7 mL of 1.6 M n-BuLi in hexane (201.1 mmol) in 440 mL of anhydrous tetrahydrofuran (THF), was reacted with 25.0 g (100.0 mmol) of (4R)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxan-4-carbaldehyde (8b). Aqueous work-up followed by purification using column chromatography with mixtures of diethyl ether (Et2O), ethyl acetate (EtOAc), and hexanes (Hxn) as eluent (Et2O/Hxn=1:25→EtOAc/Hxn=1:9) provided 20.0 g (81% yield) of the title compound (8c) as a yellow liquid. Rf=0.42 (MTBE/Hxn=1:9). 3H NMR (400 MHz, CHCl3): δ=0.81 (s, 3H), 1.15 (s, 3H), 3.65 (d, J=10.8 Hz, 1H), 3.76 (d, J=11.2 Hz, 1H), 3.81 (s, 3H), 4.03 (d, J=6.4 Hz, 1H), 5.23-527 (m, 1H), 5.29-5.35 (m, 1H), 5.50 (s, 1H), 5.86 (ddd, J=17.2, 10.8, 6.4 Hz, 1H), 6.87-6.92 (m, 2H), 7.43-7.48 (m, 2H) ppm. MS (ESI) m/z: 249.1 (M+H)+. The analytical data was consistent with the proposed structure and with the data given in the literature for the compound (Blakemore, et al., J. Org. Chem. 2005, 70, 5449-5460; and Shiina, et al., Bull Chem. Soc. Jpn. 2001, 74, 113-122).