Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[C:2]([CH:10]([N+:12]1[N:13]=[C:14]([CH2:32][CH2:33][CH2:34][CH3:35])[N:15]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]#[N:31])=[CH:20][CH:19]=2)[CH:16]=1)[CH3:11])(=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([N:38](CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>>[CH2:32]([C:14]1[N:15]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]#[N:31])=[CH:20][CH:19]=2)[C:16]2[N:12]([C:10]([CH3:11])=[C:2]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[N:38]=2)[N:13]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCN(CC)CC
Reactant: CCCCc1n[n+](C(C)C(=O)c2ccccc2)cn1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Br-]
Product: CCCCc1nn2c(C)c(-c3ccccc3)nc2n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 39 %

Procedure:
A mixture of 303 mg (0.556 mmol) of 5-amino-1-(1-benzoylethyl-3-butyl-4-[(2'-cyanbiphenyl-4-yl)-methyl]-4H-1,2,4-triazolium bromide (from Step E) and 6 g of polyphosphoric acid was stirred at 80° C. under N2 for 5 hours. The cooled mixture was treated with an excess of ice. After the ice had melted, the water was decanted off, and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residual oil was dissolved in a minimum volume of CH2Cl2 and treated with 200 μl (145 mg, 1.43 mmol) of triethylamine. The resulting solution was cooled to 0° C. and stirred under N2 as 137 μl (223 mg, 1.23 mmol) of trichloroacetyl chloride was added. The solution was allowed to warm to room temperature. After 1 hour at room temperature, the solution was concentrated in vacuo. The residue was leached with 25 ml of ether. The filtered ether solution was washed with 25 ml of 0.2N HCl and then with 25 ml of 0.2N NaOH. The ethereal phase was dried (Na2SO4), filtered, and evaporated. Column chromatography of the residue on silica gel (elution with 99:1 and then 98:2 CH2Cl2 -MeOH) afforded 95.0 mg (39%) of the title compound as a brown solid of indefinite mp, suitable for use in the next step; homogeneous by TLC in 19:1 CH2Cl2 -MeOH.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[OH-].[K+].[N+]([O-])([O-])=O.[Ag+:16]>O>[Ag:16].[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1
Reactant: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: O=c1[nH]cc(F)c(=O)[nH]1
Agent: [K+]
Solvent: O
Product: [Ag]
Reaction time: 0.5 h

Procedure:
In 5 ml. of distilled water, 100 mg. of 5-fluoro-2,4-dioxo-pyrimidin (5-Fu) was dispersed and then KOH aqueous solution (10 ml. of water; 50.8 mg. of KOH) was slowly added. After the addition, the mixture was stirred for 30 minutes to form a transparent solution having pH of 8 to 9 and then 2.6% aqueous solution of AgNO3 was added dropwise and the mixture was stirred for 1 hour in the dark. The precipitate was separated by a filtration and washed with water and dried under a reduced pressure to obtain silver salt of 5-Fu (yield: 93.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.CN(C)C(N(C)C)=N.[N+:23]([CH3:26])([O-:25])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([CH2:26][N+:23]([O-:25])=[O:24])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C=Cc1ccc(Cl)cc1
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Product: CCOC(=O)CC(C[N+](=O)[O-])c1ccc(Cl)cc1
Yield: 92.9 %

Procedure:
The solution of ethyl 4-chlorocinnamate (12.6 g) and N,N,N′,N′-tetramethylguanidine (1.2 g) in nitromethane (36.6 g) was kept at rt for three days. The excess of nitromethane was evaporated and the residue dissolved in diethyl ether (250 ml). The organic layer was washed with 2M HCl (2×150 ml), dried (sodium sulfate), and evaporated. The residue was subjected to purification by flash chromatography on silica gel (petrol ether/ethyl acetate 10:1) to give ethyl 3-(4-chlorophenyl)-4-nitrobutanoate (15.1 g) as yellowish oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[OH:13][C@H:14]([CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CCCCCC.O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C.C(Cl)(Cl)Cl.O>[OH:13][C@H:14]([CH3:21])[C@H:15]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C[C@@H](C)O
Reactant: CCCCCCCCBr
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCCCCCCC[C@H](C(=O)OCC)[C@@H](C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
A mixture of 83.5 g of diisopropylamine and 400 ml of tetrahydrofuran was treated dropwise at -20° C. within 30 minutes with 500 ml of a 1.6M solution of butyllithium (0.800 mol) in hexane. The mixture was stirred at -20° C. to -50° C. for a further 30 minutes. Subsequently, the mixture was treated dropwise at -50° C. within 30 minutes with a solution of 50 g (0.378 mol) of ethyl (3R)-3-hydroxybutyrate in 250 ml of tetrahydrofuran and stirred at -30° C. for a further 30 minutes. Thereafter, the reaction mixture was treated dropwise at -50° C. within 30 minutes with a solution of 108 g of 1-bromooctane (0.560 mol) in 96.5 g of hexamethylphosphoric acid triamide. The reaction mixture was left to warm to room temperature and was stirred at 25° C. for a further 3 hours. Subsequently, the brown reaction solution was poured into 1.3 l of water and extracted three times with ethyl acetate. The organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. High vacuum distillation of the brown oil obtained (128 g) gave 54 g of ethyl (2S,3R)-3-hydroxy-2-octylbutyrate with b.p. 99° C./0.03 Torr and [a]D =+6.2° (c=1% in chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][CH3:14])[CH:6]=[C:5]2[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([C:24](=[O:26])[CH3:25])[CH2:13][CH3:14])[CH:6]=[C:5]2[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CCNc1cc(-c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2n1
Reactant: CC(=O)OC(C)=O
Product: CCN(C(C)=O)c1cc(-c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2n1

Procedure:
600 mg of 6-chloro-2-ethylamino 4-(4-nitrophenyl)quinoline (compound 2a) were added to 0.19 g of acetic anhydride. The mixture was boiled at 70° C. for 4 hours and cooled, and the acetic anhydride was removed by distillation. The residue was mixed with water, extracted with ethyl acetate and washed with water, and the product was obtained as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=O)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[F:18][C:19]([F:33])([F:32])[C:20](=[N:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[NH2:21].C(N(C(C)C)CC)(C)C>ClCCl.O1CCOCC1.CN(C)C=O>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([N:23]2[C:7]([C:6]3[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:21][C:20]([C:19]([F:32])([F:33])[F:18])=[N:22]2)=[CH:29][CH:28]=1
Reactant: COc1ccc(NN=C(N)C(F)(F)F)cc1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(-n2nc(C(F)(F)F)nc2-c2ccc(C#N)cc2)cc1
Reaction time: 1 h
Yield: 12.8 %

Procedure:
To a suspension of 4-cyanobenzoic acid (353 mg, 2.4 mmol) in dichloromethane (3 mL), was added oxalyl chloride (0.209 mL, 2.4 mmol). And then 10 micro-L of dimethylformamide was added to the mixture. The mixture was stirred for 1 hour and the solvent was removed under reduced pressure. The residue was azeotroped with dichloromethane. To the residue, was added 3 mL of dioxane. Then a solution of 2,2,2-trifluoro-N′-(4-methoxyphenyl)ethanehydrazonamide (466 mg, 2 mmol) and diisopropylethylamine (0.418 mL, 2.4 mmol) in 4.5 mL of dioxane was added to the mixture and the mixture was refluxed with stirring for 3.5 hours. The solvent was removed under reduced pressure, and dichloromethane and 0.1 N hydrochloric acid were added to the residue. The organic layer was separated, washed with 0.1 N hydrochloric acid, water, and brine, dried over magnesium sulfate. The crude product was purified by silica gel column chromatography (20:1-10:1 toluene-ethyl acetate). The desired product was rinsed with diisopropyl ether and dried in vacuo to give 4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]benzonitrile (88 mg, 12.8% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:11]3[CH2:16][CH2:15][CH:14]([C:17]4[O:21][N:20]=[C:19]([CH:22]([CH3:24])[CH3:23])[N:18]=4)[CH2:13][CH2:12]3)[N:9]=[CH:10][C:3]=12.[OH:25][C:26]1[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH:22]([C:19]1[N:18]=[C:17]([CH:14]2[CH2:15][CH2:16][CH:11]([N:8]3[C:4]4=[N:5][CH:6]=[N:7][C:2]([O:25][C:26]5[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=5)=[C:3]4[CH:10]=[N:9]3)[CH2:12][CH2:13]2)[O:21][N:20]=1)([CH3:24])[CH3:23]
Reactant: Cc1ncccc1O
Reactant: CC(C)c1noc(C2CCC(n3ncc4c(Cl)ncnc43)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCC(c2nc(C(C)C)no2)CC1
Yield: 38.1 %

Procedure:
1-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-4-(2-methyl-pyridin-3-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (60 mg, 76%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 23; 130 mg, 0.375 mmol) with 3-hydroxy-2-methylpyridine (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 42 mg, 0.385 mmol) in the presence of potassium carbonate (114 mg, 0.825 mmol). The compound was purified by column chromatography, eluting with 5% methanol/dichloromethane. Mass spectrum MH+=420.
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19].C(OC(C)C)(C)C>>[O:17]([CH2:21][CH2:22][NH:23][C:9](=[O:11])[CH:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:12])[N+:18]([O-:20])=[O:19]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(Oc1ccccc1)C(=O)O
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: CC(Oc1ccccc1)C(=O)NCCO[N+](=O)[O-]
Yield: 54.3 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.71 g of 2-phenoxypropionic acid and 0.60 g of 2-nitroxyethylamine nitrate, 0.49 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[O:13])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:27][CH2:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[Cl:27][CH2:28][S:29]([N:1]([S:29]([CH2:28][Cl:27])(=[O:31])=[O:30])[C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:17][CH:16]=3)=[O:13])=[CH:25][CH:26]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)CCl
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N(S(=O)(=O)CCl)S(=O)(=O)CCl)cc2)cc1

Procedure:
The product from Example 3 (500 mg, 1.45 mmol), chloromethanesulfonyl chloride (0.65 g, 4.36 mmol), and triethylamine (1 mL, 7.19 mmol) were stirred in CH2Cl2 (15 mL) overnight at room temperature. The reaction mixture was then diluted with CH2Cl2, washed with H2O and brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (99:1 CH2Cl2:CH3OH, eluant) to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.87 (dd, J=4.7 Hz, 1.3 Hz, 1H), 8.32 (dd, J=8.2 Hz, 1.7 Hz, 1H), 8.14 (d, J=8.5 Hz, 2H), 7.68-7.77 (m, 3H), 7.38 (d, J=8.8 Hz, 2H), 5.46 (s, 1H), 5.42 (s, 1H), 4.97 (s, 1H), 4.92 (s, 1H), 1.29 (s, 9H).
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:8]=1)[CH3:5])([OH:3])=O.[C:19](N1C=CN=C1)([N:21]1C=CN=[CH:22]1)=O.CNC>>[Cl:18][C:14]1[CH:13]=[C:12]([N:9]2[CH:10]=[N:11][C:7]([O:6][CH:4]([C:1]([N:21]([CH3:22])[CH3:19])=[O:3])[CH3:5])=[N:8]2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(Oc1ncn(-c2cccc(Cl)c2)n1)C(=O)O
Agent: CNC
Product: CC(Oc1ncn(-c2cccc(Cl)c2)n1)C(=O)N(C)C
Yield: 66.6 %

Procedure:
The process was carried out as was Example 45, starting with 3 g of the compound of Example 25, 2.7 g of carbonyldiimidazole and 3.6 ml of 40% aqueous dimethylamine. The product was recrystallized from toluene to obtain 2.2 g of desired product, m.p. 136°-139°.
Reaction SMILES: [CH:1]1([SH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Co].C(C(CCCC)C([O-])=O)C.[Co+2].C(C(CCCC)C([O-])=O)C>[CH:1]1([S:7][S:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: SC1CCCCC1
Agent: [Co+2]
Agent: [Co]
Agent: CCCCC(CC)C(=O)[O-]
Product: C1CCC(SSC2CCCCC2)CC1

Procedure:
This example is of inventive runs illustrating the enhanced activity of adding a soluble cobalt-containing compound to the synthesis described in Example III. The charge and procedure described in Example III was repeated except 0.01 gram of cobalt 2-ethylhexanoate was added. The run, IVa, was complete in 0.75 hour with a 99.5 percent cyclohexyl mercaptan conversion and a 100 percent disulfide selectivity giving a 99.5 mole percent yield of dicyclohexyl disulfide. The reaction describing the use of cobalt 2-ethylhexanoate, methyl alcohol, and sodium hydroxide was repeated (Run IV(b)), on a larger scale (373X) involving a charge of 5 grams of cobalt 2-ethylhexanoate, 39.1 pounds cyclohexyl mercaptan, 0.9 pound of-sodium hydroxide and 15.85 pounds of methyl alcohol. A 100 percent conversion of cyclohexyl mercaptan was obtained after one hour of reaction time giving 100 percent disulfide selectivity. The effluent was diluted with 2.5 gallons of water, stirred 30 minutes at about 25° C. and the oil phase separated. The oil phase was then heated to about 116° C. while nitrogen was bubbled through at 6 scfh at one atmosphere pressure for 4 hours. There was obtained 34.45 pounds (93.4 mole percent yield) of essentially pure dicyclohexyl disulfide.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][N:14]([CH3:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([OH:24])=O.Cl.[Cl:27][C@H:28]1[C@@H:36]2[C@@H:32]([CH2:33][NH:34][CH2:35]2)[C:31]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:30][CH2:29]1.Cl>ClCCl.C(OCC)C.C(N(CC)CC)C>[ClH:27].[Cl:27][C@H:28]1[C@@H:36]2[C@@H:32]([CH2:33][N:34]([C:22](=[O:24])[CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([CH3:13])[CH3:25])[CH2:35]2)[C:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:30][CH2:29]1
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: Cl[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C)c1ccccc1CC(=O)N1C[C@@H]2[C@H](Cl)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 1 h
Yield: 54.7 %

Procedure:
0.17 g of carbonyldiimidazole is added to a solution, cooled to +4° C., of 0.19 g of (2-dimethylaminophenyl)-acetic acid in 15 cm3 of dry dichloromethane. The mixture is stirred for one hour at +4° C. and then a solution of 0.35 g (3aR,7R,7aR)-7-chloro-4,4-diphenylperhydro-isoindole hydrochloride in 10 cm3 of dry dichloromethane is then added followed by a solution of 0.15 cm3 of triethylamine in 10 cm3 of dry dichloromethane. The reaction mixture is stirred at room temperature for 20 hours and then diluted with 120 cm3 of dichloromethane, washed with 80 cm3 of water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 22 cm), eluting under a nitrogen pressure of 0.4 bar with an ethyl acetate and cyclohexane mixture (75/25 by volume) and collecting fractions of 20 cm3. Fractions 6 to 9 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The product, which is obtained in the form of a base, is converted to the hydrochloride by dissolving in 25 cm3 of ethyl ether, followed by the addition of 5 cm3 of a 3.2N solution of hydrochloric acid to the ethyl ether, washing with ethyl ether and drying. 0.14 g of (3aR,7R,7aR)-7-chloro-2-[(2-dimethylamino-phenyl)acetyl]-4,4-diphenylperhydroisoindole hydrochloride is obtained in the form of white crystals; melting point 190° C.
Reaction SMILES: [CH:1]12[CH2:11][CH:7]3[CH:8](C[CH2:10]1)[CH:3]([CH2:4][CH2:5][CH2:6]3)[CH2:2]2.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:16](Cl)Cl>>[CH3:16][C:5]12[CH2:4][CH:3]3[CH2:2][CH:1]([CH2:11][CH:7]([CH2:8]3)[CH2:6]1)[CH2:10]2
Reactant: ClCCl
Reactant: C1CC2CC3CCC2C(C1)C3
Agent: [Al+3]
Agent: [Cl-]
Product: CC12CC3CC(CC(C3)C1)C2
Temperature: 0 °C

Procedure:
A solution of 15 g (0.1 mole) of tricyclo[5.3.1.03,8 ]-undecane (II) in 100 ml of methylene chloride was agitated at 0°C, and 2.0 g (0.015 mole) of anhydrous aluminum chloride was added to the solution. The mixture was heated and refluxed under agitation for 6 hours, and the resulting reaction mixture was allowed to cool and poured over 100 ml of ice water. The organic layer was separated, and the water layer was extracted with methylene chloride. The methylene chloride extract was combined with the organic layer, and the mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water, and then dried over anhydrous sodium sulfate. Methylene chloride was distilled off and the residue was sublimed to obtain 13.7 g (yield: 91 wt.%) of 1-methyladamantane. All of the IR, NMR and MS spectra were in agreement with those of the authentic sample synthesized from tetramethylenenorbornane according to the method of Schleyer, et al. [Tetrahedron Letters, 305 (1961)].
Reaction SMILES: C(OO)(=[O:3])C.[C:6]1([CH:12]=[CH:13][C:14]2[S:15][C:16]3[C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[N:19]=[CH:18][C:17]=3[N:26]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)C>C(OC)(=O)C>[C:6]1([CH:12]=[CH:13][C:14]2[S:15][C:16]3[C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[N+:19]([O-:3])=[CH:18][C:17]=3[N:26]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C(=Cc1nc2cnc3ccccc3c2s1)c1ccccc1
Reactant: CC(=O)OO
Solvent: CCO
Solvent: COC(C)=O
Product: [O-][n+]1cc2nc(C=Cc3ccccc3)sc2c2ccccc21
Temperature: 25 °C

Procedure:
Peracetic acid (1.32 mL of 32% in acetic acid) was added to a suspension of 2-(2-phenyl-1-ethenyl)thiazolo[4,5-c]quinoline (1.20 g) in methyl acetate (50 mL). A precipitate formed. Ethanol was added to the reaction mixture until all of the precipitate was dissolved. The reaction mixture was heated at reflux overnight and then cooled to ambient temperature. The resulting precipitate was isolated by filtration, dried and then recrystallized from methanol/dichloromethane to provide 2-(2-phenyl-1-ethenyl)thiazolo[4,5-c]quinoline-5-oxide as a yellow solid, m.p. 268-270° C. Analysis: Calculated for: C18H12N2OS: % C, 71.03; % H, 3.97; % N, 9.20; Found: % C, 69.94; % H, 3.87; % N, 9.05.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:13])[CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[C:14]([O:18][C:19](=[O:25])[CH2:20][CH2:21][C:22](O)=O)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([CH2:20][CH2:21][C:22]1[O:13][C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:8]([C:9]([OH:11])=[O:10])[N:12]=1)=[O:25])([CH3:17])([CH3:16])[CH3:15]
Reactant: NC(C(=O)O)C(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CCC(=O)O
Product: CC(C)(C)OC(=O)CCc1nc(C(=O)O)c(-c2ccccc2)o1

Procedure:
Prepared starting from DL-3-phenylserine hydrate following sequentially general procedures W, X with succinic acid mono-tert-butyl ester, Y and Z. LC-MS-conditions 02: tR=0.95 min; [M+H]+=318.32.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1COCC1>[CH3:19][S:20]([NH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[O:11][S:20]([CH3:19])(=[O:22])=[O:21])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N[C@@H]1c2ccccc2C[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.3 %

Procedure:
(1R,2S)-1-Amino-2-hydroxyindan (3.0 g, 20mmol) was dissolved in dry THF (40 ml) and triethylamine (8.4 ml, 60.0 mmol) at 10° C. Methane sulphonyl chloride (5.0 g, 44.0 mmol) dissolved in THF (10 ml) was added at such a rate that the internal temperature remained below 15° C. Following the addition the mixture was stirred at room temperature for 20 hours and then evaporated. To the residue was added EtOAc (100 ml) and the mixture washed with saturated aqueous sodium bicarbonate and then water. The organic solution was dried over magnesium sulphate and evaporated to give (1R,2S)-1-methanesulphonamido-2-methylsulphonyloxyindan (5.7 g, 93%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)CCC>CN(C=O)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>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c1ccccc1n2C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2ccccc2)c2c(c1O)c1ccccc1n2C
Temperature: 120 °C

Procedure:
A mixture of 1-bromo-4-hydroxy-9-methyl-9H-beta-carboline-3-carboxylic acid ethyl ester (150 mg), tributyl phenyl tin (0.169 mL), and Pd(PPh3)2Cl2 (15 mg) in DMF (1.5 mL) was heated at 120° C. for 41 min. The reaction was then partitioned between EtOAc and water, the organic phase was subsequently washed with sat. NaCl solution, dried over anhydrous sodium sulfate and then filtered, concentrated; the residue was purified with column to give the title compound (94 mg). ESI MS (m/z): 347 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:29][CH3:30])=[C:17]([C:20]3[CH2:21][CH2:22][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][CH:25]=3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:31]([NH2:33])=[O:32].[ClH:34]>CO.[OH-].[OH-].[Pd+2].[C]>[ClH:34].[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:29][CH3:30])=[C:17]([CH:20]3[CH2:21][CH2:22][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:24][CH2:25]3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:31]([NH2:33])=[O:32]
Reactant: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1C1=CCN(C(C)C)CC1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1C1CCN(C(C)C)CC1
Yield: 86 %

Procedure:
A solution of 4-(2-fluoro-4-methylphenylamino)-6-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-7-methoxycinnoline-3-carboxamide (Example 29, 0.250 g, 0.56 mmol) in MeOH (20 ml) with a few drops of c.HCl, was run through an H-Cube apparatus at 1 mL/min using a 20 wt % Pd(OH)2/Carbon cartridge at 10 bar. When the reduction was judged complete by LCMS, the solution was concentrated under reduced pressure to give 0.234 g (86%) product. 1H NMR: 12.51 (s, 1H), 10.51 (s, 1H), 8.76 (s, 1H), 8.21 (s, 1H), 7.65 (s, 1H), 7.36 (m, 3H), 7.18 (m, 1H), 4.03 (s, 3H), 3.38 (m, 1H), 3.26 (m, 2H), 3.05 (m, 3H), 2.41 (s, 3H), 1.72 (m, 2H), 1.61 (m, 2H), 1.26 (d, 6H); m/z 452.