Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](N2CCC(=C)CC2)[C:5]([N+]([O-])=O)=[CH:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1([C:40]#[N:41])[CH2:39][CH2:38][C:27]2([CH2:31][C:30]([C:32]#[C:33][Si](C)(C)C)=[N:29][O:28]2)[CH2:26][CH2:25]1>>[CH3:1][C:2]1[N:7]=[C:6]([C:33]#[C:32][C:30]2[CH2:31][C:27]3([CH2:38][CH2:39][C:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)([C:40]#[N:41])[CH2:25][CH2:26]3)[O:28][N:29]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#CC1=NOC2(CCC(C#N)(c3ccccn3)CC2)C1
Reactant: C=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Product: Cc1cccc(C#CC2=NOC3(CCC(C#N)(c4ccccn4)CC3)C2)n1

Procedure:
The title compound was prepared following the method described for the compound of Example 3, replacing Compound 3c with Compound 48b. The crude was purified by automated flash chromatography (SP1®TM-Biotage; gradient Petroleum ether-EtOAc from 65:35 to 4:6) to give the title compound as yellow oil. Yield: 43.4%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH3:18].[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[C:27]3[NH:33][CH2:32][C:31]4([CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[C:28]3=[N:29][CH:30]=2)[CH2:21][CH2:20]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[CH3:18][C:3]1[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:5][C:6]2[C:11]([C:2]=1[N:33]1[C:27]3[C:28](=[N:29][CH:30]=[C:25]([N:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)[CH:26]=3)[C:31]3([CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:32]1)=[CH:10][CH:9]=[CH:8][N:7]=2
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: Cc1c(-c2ccccc2)nc2ncccc2c1Cl
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: Cc1c(-c2ccccc2)nc2ncccc2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 4-chloro-3-methyl-2-phenyl-1,8-naphthyridine (46.3 mg, 0.182 mmol), 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (50 mg, 0.182 mmol), sodium tert-butoxide (34.9 mg, 0.363 mmol) and XPhos precatalyst (0.0182, 13.5 mg). Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 1′-(3-methyl-2-phenyl-1,8-naphthyridin-4-yl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 9.12 (1H, dd, J=4.1, 2.0 Hz), 8.12 (1H, dd, J=8.4, 2.0 Hz), 7.71-7.77 (2H, m), 7.65 (1H, d, J=2.3 Hz), 7.47-7.56 (3H, m), 7.43 (1H, dd, J=8.3, 4.2 Hz), 5.80 (1H, d, J=2.3 Hz), 4.12-4.21 (2H, m), 4.02 (2H, q, J=9.6 Hz), 3.71-3.80 (4H, m), 3.56-3.65 (2H, m, J=11.4, 11.4, 2.5, 2.4 Hz), 2.95-3.05 (4H, m), 2.28-2.41 (5H, m), 1.75-1.90 (2H, m). Mass Spectrum (ESI) m/e=494.2 (M+1).
Reaction SMILES: CC1(C)CC(=O)CC(=O)C1.C(=O)(O)[O-].[Na+].P(OCC)(OCC)OCC.[I-].[C:27]([CH2:30][N+:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([C:39]2[N:40]=[CH:41][N:42]3[CH:46]=[C:45]([C:47]4[C@H:48]([CH3:64])[C@@H:49]5[C@@H:59]([C@H:60]([OH:62])[CH3:61])[C:58](=[O:63])[N:50]5[C:51]=4[C:52]([O:54]CC=C)=[O:53])[S:44][C:43]=23)=[O:38])[CH:32]=1)(=[O:29])[NH2:28]>O.O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:27]([CH2:30][N+:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([C:39]2[N:40]=[CH:41][N:42]3[CH:46]=[C:45]([C:47]4[C@H:48]([CH3:64])[C@@H:49]5[C@@H:59]([C@H:60]([OH:62])[CH3:61])[C:58](=[O:63])[N:50]5[C:51]=4[C:52]([O-:54])=[O:53])[S:44][C:43]=23)=[O:38])[CH:32]=1)(=[O:29])[NH2:28]
Reactant: C=CCOC(=O)C1=C(c2cn3cnc(C(=O)c4ccc[n+](CC(N)=O)c4)c3s2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)CC(=O)CC(=O)C1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(C(=O)c5ccc[n+](CC(N)=O)c5)c4s3)[C@H](C)[C@H]12
Reaction time: 0.17 h
Yield: 71 %

Procedure:
A solution of 0.28 g of dimedone, 0.13 g of sodium bicarbonate, and 0.06 ml of triethyl phosphite in 1 ml of water and 3 ml of tetrahydrofuran was stirred at room temperature for 10 min. The atmosphere was then replaced by argon, 22.4 mg of palladium acetate was added thereto, and the mixture was stirred for 10 min. Allyl (1S,5R,6S)-2-[7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate iodide (0.66 g) was added thereto, and the mixture was stirred at 40° C. for 2 hr. The reaction mixture was stirred in an ice-water bath for 30 min, and the resultant precipitate was collected by filtration to give 0.47 g of a crude product of (1S,5R,6S)-2-[7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate. This crude product was dissolved in 2 ml of water, and the solution was filtered through a filter with a pore diameter of 0.45 μm, followed by washing three times with 0.5 ml of water. The filtrate and the wash liquids were combined, and stirring was carried out at 4° C. for 12 hr. The resultant precipitate was collected by filtration to give 0.35 g of (1S,5R,6S)-2-[7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate.
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:5]=1[O:6][CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9].[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:18][C:7]([O:6][C:5]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:4]=1[Cl:3])([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(C)Oc1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(Br)Oc1ccc(Cl)cc1Cl
Temperature: 77 °C
Reaction time: 0.75 h
Yield: 91.5 %

Procedure:
A saturated aqueous solution of 0.01 part of bromine and one part of carbon tetrachloride is added to a mixture of 37.5 parts of methyl 2-(2',4'-dichlorophenoxy)-propionate, 26.7 parts of N-bromosuccinimide, 0.1 parts of azo-bis-isobutyronitrile and 300 parts of carbon tetrachloride. After 45 minutes of heating, 0.1 part of azo-bis-isobutyronitrile and 0.01 part of bromine in 1 part of carbon tetrachloride are added, at 70° C., and the batch is then stirred for 45 minutes at 77° C. It is then cooled to 40° C. and filtered, and the filtrate is concentrated under reduced pressure. 45 parts (91.5% of theory) of methyl 2-bromo-2-(2',4'-dichlorophenoxy)-propionate, of nD22 =1.5390, are obtained.
Reaction SMILES: ClC(Cl)=C[C@H]1[C@H](C(Cl)=O)C1(C)C.[Cl:13][C:14]([Cl:40])=[CH:15][C@H:16]1[C@H:18]([C:19]([O:21][CH2:22][C:23]2[C:28]3[CH2:29][CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:27]=3[CH:26]=[CH:25][CH:24]=2)=[O:20])[C:17]1([CH3:39])[CH3:38]>>[Cl:13][C:14]([Cl:40])=[CH:15][CH:16]1[CH:18]([C:19]([O:21][CH2:22][C:23]2[C:28]3[CH2:29][CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:27]=3[CH:26]=[CH:25][CH:24]=2)=[O:20])[C:17]1([CH3:38])[CH3:39]
Reactant: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1cccc2c1CCCc1ccccc1-2
Agent: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OCc1cccc2c1CCCc1ccccc1-2

Procedure:
Similarly, but employing trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride, (6,7-dihydro-5H-dibenzo-[a,c]cyclohepten-4-yl)methyl trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate was prepared.
Reaction SMILES: C([Li])[CH2:2][CH2:3][CH3:4].[C:6]([Si:9]([CH:14]([CH3:16])[CH3:15])([CH:11](C)[CH3:12])Br)([CH3:8])=[CH2:7]>C1COCC1>[C:6]([Si:9]([C:11]#[CH:12])([CH:14]([CH3:16])[CH3:15])[CH:3]([CH3:4])[CH3:2])([CH3:8])=[CH2:7]
Reactant: [Li]CCCC
Reactant: C=C(C)[Si](Br)(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C#C[Si](C(=C)C)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
The crude isopropenyldiisopropylbromosilane (10.6 g) was treated with 75 mmol of lithium acetylide. The lithium acetylide was formed by saturating an anhydrous THF solution (at −78° C., 200 mL) with acetylene gas that had been passed through a −78° C. cold trap to remove acetone. No further drying of the acetylene gas was undertaken. Once the solution was presumed to be saturated (after 1 hour of flushing the gas through), the solution was treated with n-butyllithium (30 mL, 2.5 M in hexanes, 75 mmol) in a careful dropwise manner so as to maintain the temperature very close to −78° C. After this addition was completed, the isopropenyldiisopropylbromosilane was added as a concentrated solution (˜5 M) in anhydrous THF dropwise to the reaction mixture. The temperature was maintained for an additional 1 hour, then allowed to gradually warm to room temperature. The reaction was quenched by the slow addition of a small amount of saturated ammonium chloride (about 5 mL) and additional water (50 mL). Pentane (100 mL) was added, and the organic layer was separated. The aqueous layer was extracted a second time with pentane (50 mL), and the organic layer separated. The organic layers were washed with water (3×50 mL), dried over MgSO4, filtered, and concentrated on the rotary evaporator. No further purification was performed. Analysis of the liquid product was performed by GC-MS Analysis Method 2. This showed that the area under the peak corresponding to the desired product, (isopropenyldiisopropylsilyl)acetylene with a molecular weight of 180, was 87.34% of the total integrated area indicating a high purity.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([NH:12][CH2:13][CH2:14]Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1>[CH2:1]([O:8][N:9]1[CH2:14][CH2:13][NH:12][C:10]1=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCl)NOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCN1OCc1ccccc1
Yield: 95.5 %

Procedure:
To a stirred solution of benzyloxyamine (36.63 g, 0.297 mol) in THF (250 ml) was added a solution of 2-chloroethyl isocyanate (25.4 ml, 1.0 equiv.) in THF (50 ml) over 20 minutes. The resulting cloudy solution was refluxed for 10 minutes, cooled and evaporated. Trituration of the residue with ether-hexane gave N-benzyloxy-N'-(2-chloroethyl)urea as a white solid (65.82 g, 97% yield), mp 67°-68° C. after recrystallization from hexane-ether. To a stirred solution of this urea (65.8 g, 0.287 mol) in the THF (500 ml) at room temperature was added sodium hydride (11.8 g of 60% dispersion in oil, 1.02 equiv.) in portions over 30 minutes. The cloudy solution was refluxed for 10 minutes, cooled and evaporated. To the resulting semi-solid was added 2% aqueous citric acid (60 ml) and hexane (250 ml). After vigorous agitation, the resulting solid was collected by filtration and washed with water and hexane, to give 1-benzyloxy-2-imidazolidinone as a tan solid (52.66 g, 93% yield), mp 64°-65° C. after recrystallization from water.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:23][CH2:24][C:25](OC(=O)CCl)=O>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:25]([CH2:24][Cl:23])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)OC(=O)CCl
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Solvent: CN(C)C=O
Product: O=C1c2c(Br)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Yield: 65.3 %

Procedure:
7 g (19.3 mmol) of (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxamidoxime were stirred with 3.8 g (22.2 mmol) of chloroacetic anhydride in 50 ml of N,N-dimethylformamide at room temperature for 1 hour and at 105° for 2 hours. After evaporating the reaction mixture the residue was dissolved in methylene chloride and the solution was washed with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated. After recrystallizing the residue from methanol there were obtained 5.3 g (65%) of (S)-8-bromo-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 210°-211°.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:29])[C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:21])[CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:30](Cl)(=[O:32])[CH3:31].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>O1CCCC1>[C:30]([N:26]1[CH2:25][CH2:24][CH:23]([NH:22][C:20](=[O:21])[C:19]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:18][CH2:17]2)=[O:29])[CH2:28][CH2:27]1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(NC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.8 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxo-N-piperidin-4-ylacetamide dihydrochloride (Example 182(A), 0.35 g, 0.79 mmol), acetyl chloride (72.5 mg, 1.02 mmol) and triethylamine (439 μL, 3.15 mmol) in tetrahydrofuran (4 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give The title compound (0.34 g, quant.) as a white powder.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9](O)(=[O:11])[CH3:10]>>[C:9]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:11])[CH3:10]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(=O)O
Product: CC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 150 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
Valine (1 g, 8.53 mmol) and acetic acid (20 mL) were mixed together and heated at 150° C. in a microwave for one hour. The excess acetic acid was removed using a rotary evaporator. The residue was stirred in MTBE at ambient temperature for one hour. The mixture was filtered and the solid was washed with MTBE. The solid was dried in a vacuum oven at 60° C. The product was obtained as a white solid (1.13 grams, 83.5%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.74-0.98 (m, 6H), 1.81-1.96 (m, 3H), 1.97-2.18 (m, 1H), 4.13 (dd, 1H), 7.99 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=3)[O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.FC(F)(F)C(O)=O.[ClH:37]>ClCCl.CCOCC>[ClH:37].[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=3)[O:18][CH2:19][C:20]([OH:22])=[O:21])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: Cc1csc(Nc2cc(Oc3cccc(OCC(=O)OC(C)(C)C)c3)ccn2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(Nc2cc(Oc3cccc(OCC(=O)O)c3)ccn2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)phenoxy)acetate (0.530 g, 1.28 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was stirred at room temperature for one hour, the concentrated. The TFA salt was dissolved in ether (15 mL). 1M HCl in ether (6 mL) was added, and the solids were collected by filtration, washed with hexanes and dried to afford the desired product as a white solid. 1H NMR (d6-DMSO) δ 11.85 (bs, 1H), 8.25 (d, 1H), 7.41 (t, 1H), 6.88 (d, 1H), 6.80-6.83 (m, 2H), 6.67-6.70 (m, 2H), 4.72 (s, 2H), 2.26 (s, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]1[CH2:33][CH2:32][C:9]2[N:10]([CH2:18][C:19]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([NH:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)(O)[CH3:20])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1.[OH-].[K+]>CN1C(=O)CCC1.O>[CH3:5][N:6]1[CH2:33][CH2:32][C:9]2[N:10]([CH:18]=[C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[CH3:20])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1
Reactant: CNC(=O)c1ccc(C(C)(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1ccc(C(C)=Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.9 %

Procedure:
Thionyl chloride (1.5 mL, 20.67 mmol) was added to a solution of 4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-hydroxy-1-methyl-ethyl]-N-methyl-benzamide (130 mg, 0.33 mmol) and the reaction mixture stirred at RT for 30 min. The solvent was removed under vacuum to obtain the crude as a foamy solid, which was dissolved in NMP (3 mL). The reaction mixture was stirred for 5 min. Powdered KOH (186 mg, 3.32 mmol) was added and the contents heated at 80° C. for 20 min. After completion of reaction, the reaction mixture was poured in water and the desired compound extracted with EtOAc (3×40 mL). The organic layer was washed with water, concentrated under vacuum to obtain the crude product (100 mg) which was purified by reverse phase HPLC to yield 6.0 mg of 4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1methyl-vinyl]-N-methyl-benzamide as the free base. 1H NMR (CDCl3, free base) δ (ppm): 7.78 (d, 2H), 7.58 (d, 2H), 7.22 (s, 1H), 7.05 (m, 2H), 6.96 (s, 1H), 6.20 (bs, 1H), 4.0 (s, 2H), 3.16 (m, 2H), 3.05 (d, 3H), 2.90 (m, 2H), 2.70 (s, 3H), 2.42 (s, 3H), 1.99 (s, 3H).
Reaction SMILES: CC1(C)COB([C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)OC1.Br[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[Cl:30])[NH:26][CH:25]=[C:24]2[CH:31]=[O:32].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:30][C:29]1[CH:28]=[C:27]2[C:23]([C:24]([CH:31]=[O:32])=[CH:25][NH:26]2)=[CH:22][C:21]=1[C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:17][CH:18]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Reactant: CC1(C)COB(c2ccc(OCCCO)cc2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(OCCCO)cc3)cc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
To a solution of 3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]propan-1-ol (4.9 g, 18.6 mmol) in ethanol (25 ml) was added 5-bromo-6-chloro-1H-indole-3-carbaldehyde (4.0 g, 15 mmol) followed by toluene (50 ml) and 2 N aq. potassium carbonate (26.3 ml, 52.6 mmol). Nitrogen was bubbled though the solution for 15 min, then Pd(dppf)Cl2 (0.46 g, 0.62 mol) was added and reaction heated to 100° C. An additional portion of 3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]propan-1-ol (1.0 g) in ethanol (4 ml) was added and heating continued for 30 min. The reaction was allowed to cool to room temperature and stirred for 3 days. The reaction was partitioned between water and EtOAc and stirred. The layers were separated and the organic layers were washed with water which resulted in a thick emulsion. The emulsion was filtered through celite to attempt to break the emulsion which had limited effect. Upon standing, emulsion was reduced. Layers were separated and organic washed with brine, dried over sodium sulfate, filtered and stripped. Residue was mostly dissolved in MeOH, filtered to remove solids then adsorbed onto silica gel then purified by silica gel chromatography (30-100% EtOAc/Heptane). The second peak was isolated to afford the title compound (2.2 g, 43%) as a yellow solid that was taken on to the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][NH:5][C:6]=1[NH2:7].CO[CH:16](OC)[CH2:17][CH:18](OC)OC.O.[NH4+].[OH-]>C(O)(=O)C>[Br:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][N:5]2[CH:18]=[CH:17][CH:16]=[N:7][C:6]=12
Reactant: COC(CC(OC)OC)OC
Reactant: Nc1[nH]nc(-c2ccccc2)c1Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Brc1c(-c2ccccc2)nn2cccnc12
Temperature: 110 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To a solution of 4-bromo-3-phenyl-1H-pyrazole-5-amine (5.0 g, 0.02 mol) in acetic acid (50 mL) is added 1,1,3,3-tetramethoxypropane (4.14 g, 0.025 mol). The mixture is stirred at 110° C. for 1 h. The reaction mixture is then poured into water, basified with NH4OH and extracted with dichloromethane (3×100 mL). The organic layer is dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material is purified by column chromatography using silica gel in dichloromethane and ethyl acetate (1:0 to 95:5) as eluent and 4.2 g (75%) of 3-bromo-2-phenylpyrazolo[1,5-a]pyrimidine are obtained as a beige solid.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.[CH3:32][S:33]SC>O1CCCC1.C(O)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:33][CH3:32])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: CSSC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)CC[C@H]1N(C)C(=O)CC[C@]21C
Temperature: -75 °C
Reaction time: 1.5 h

Procedure:
(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (20.0 grams, 64.9 mmole, in 150 mL of tetrahydrofuran) was added to a freshly prepared solution of lithium diisopropylamide in 500 mL of tetrahydrofuran at -20° C. After standing 90 minutes in an ice bath, the resulting amide-enolate solution was cooled to -70° C. and added via cannula over 10 minutes to a freshly mixed solution of n-butyllithium (60.0 mL=2.54 M in hexane, 152 mmole, 2.34 equivalents) at -72 to -75° C. in 300 mL of tetrahydrofuran. The homogeneous solution was allowed to stir at approximately -75° C. for 45 minutes and quenched with dimethyldisulfide (11.0 mL, 123 mmole, 1.9 equiv) at approximately -75° C. After 30 minutes at -75° C., the mixture was treated with acetic acid (18 mL) and all volatiles removed under vacuum. The resulting white solid was treated with 300 mL of heptane-water (1:1, v/v) and the pH adjusted to 3 with 1N hydrogen sulfate. The biphasic mixture was filtered and the wet cake was washed with 1% aqueous sodium bicarbonate (2×50 mL portion) and water (200 mL). The material was dried at 50° C. under vacuum affording (+)-(4aR)-(10bR)-4-methyl-8-methylthio-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (IR, NMR, MS). Calculated for C16H21NOS: C, 69.77; H, 7.69; N, 5.09. Found C, 69.70; H, 7.62; N, 5.06.
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]2[S:20][C:19](=[O:21])[N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:17]2=[O:41])=[CH:11][CH:10]=1)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[O:21]=[C:19]1[NH:18][C:17](=[O:41])[CH:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:42])=[O:5])=[CH:10][CH:11]=2)[S:20]1
Reactant: CC(C)(C)OC(=O)COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.1 %

Procedure:
To a solution of 4-(2,4-dioxo-3-tritylthiazolidin-5-ylmethyl)phenoxyacetic acid t-butyl ester (6.2 g) in toluene (25 ml) was added p-toluenesulfonic acid mono-hydrate (204 mg) and the mixture was heated under reflux for 3 hours. At elevated temperature ethyl acetate (10 ml) was added and the mixture was stirred at 25° C. for 1.5 hours. The precipitated crystals were filtered to give the desired compound (2.5 g).