Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC.[CH2:15]([O:17][C:18]([C:20]1[CH:21]=[N:22][NH:23][CH:24]=1)=[O:19])[CH3:16].Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>O1CCOCC1.[Cu]I.O>[CH2:15]([O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)[CH:24]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccc(C(F)(F)F)cn2)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 12.7 %

Procedure:
Copper (I) iodide (2.87 g), tripotassium phosphate (15.89 g) and N,N′-dimethylethylenediamine (4.8 ml) were added to a solution of 1H-pyrazole-4-carboxylic acid ethyl ester (2.1 g) and 2-chloro-5-(trifluoromethyl)pyridine (3.26 g) in 1,4-dioxane (150 ml), and the mixture was stirred at 120° C. for three hours. After completion of the reaction, the reaction solution was cooled to room temperature, water was added therein and extracted with ethyl acetate three times. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (544 mg) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:36])[CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:13]>C(Cl)Cl>[CH2:12]([O:14][C:15](=[O:36])[CH:16]=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:13]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a solution of 4-nitrobenzaldehyde (15.1 g, 0.1 mol) in CH2Cl2 (200 mL) was added dropwise (triphenylphosphanylidene)acetic acid ethyl ester (34.8 g, 0.1 mol) in CH2Cl2 (100 mL) at 0° C. After the addition was completed, the resulting mixture was stirred for 2 h. After removal the solvent under reduced pressure, the residue was purified by column chromatography to afford 3-(4-nitrophenyl)acrylic acid ethyl ester (16.5 g, 74.6% yield). 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J=8.8 Hz, 2H), 7.71 (d, J=16.0 Hz, 1H), 7.67 (d, J=8.8 Hz, 2H), 6.55 (d, J=16.0 Hz, 2H), 4.29 (q, J=7.2 Hz, 2H), 1.34 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[NH:6][C:5](=[O:17])[CH2:4][C:3]1=[O:18].C([O-])(=O)C.[K+].Cl[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:14])[F:15])=[CH:12][C:7]=2[N:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[C:5](=[O:17])[CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC(=O)Nc2cc(C(F)(F)F)ccc21
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CN1C(=O)CC(=O)N(c2ccccc2[N+](=O)[O-])c2cc(C(F)(F)F)ccc21

Procedure:
26 gm. (0.1 mol) of 1-methyl-7-trifluoromethyl-1,5-benzodiazepine-2,4-(3H,5H)-dione were heated with 13 gm. of potassium acetate, 1 gm. of anhydrous copper sulfate and 350 gm. of o-chloro-nitrobenzene for one hour at 150°C. The reaction solution was diluted with methylene chloride, washed with dilute ammonia, sodium hydroxide solution and water, the organic phase was dried, and the solvent evaporated in vacuo. The residue was carefully admixed with petroleum ether, whereby a precipitate was formed, which was recrystallized from methylene chloride/isopropylether. Yield: 30 gm. (80% of theory) of the compound of the formula ##SPC9##
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][CH3:15])[NH:10][C:9]=2[C:8](=O)[NH:7][C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].O>N1C=CC=CC=1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][CH3:15])[NH:10][C:9]=2[C:8](=[S:19])[NH:7][C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)[nH]c(=O)c2[nH]c(CC)nc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: c1ccncc1
Product: CCCCn1c(=O)[nH]c(=S)c2[nH]c(CC)nc21
Temperature: 25 °C

Procedure:
11.8 g (50 mM.) of 3-butyl-8-ethyl-xanthine (mp 304°-9° C., and 18.2 g (82 nM.) of phosphorus pentasulfide were refluxed in 170 ml of pyridine for 2 hrs. The solution was cooled to ambient temperature and treated slowly with 110 ml. of water (exothermic). The suspension was concentrated to 100 ml. in vacuo at 60° C., further diluted with 140 ml. of water, and concentrated again to about 120 ml. The crude product was collected and washed with ice water. The dried material (11.1 g.) was dissolved in about 100 ml. of chloroform, and the solution filtered through 55 g. of silicagel. The chloroform was evaporated and the residue crystallized from acetone-ether: 7.2 g. (57.5%) of 3-butyl-8- ethyl-6-thioxanthine, mp. 206°-7° C. From the mother liquor, a second crop of 2.1 g. (16.3%) was obtained.
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:6][CH:7]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9](=[O:11])[CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1[O:6][CH:7]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9](=[O:11])[CH:10]=1
Reactant: [N-]=[N+]=NCc1cc(=O)c(OCc2ccccc2)co1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(=O)c(OCc2ccccc2)co1
Yield: 48.2 %

Procedure:
To a stirred solution of 2-azidomethyl-5-benzyloxy-pyran-4-one (4) (30.0 g, 116.7 mmol) in tetrahydrofuran (500 mL) were added triphenyl phosphine (61.16 g, 233.46 mmol) and water (5.2 mL) and the mixture was refluxed for 16 h. After completion of the reaction, solvent was evaporated under reduced pressure, then it was purified by normal column chromatography to get (2-aminomethyl-5-benzyloxy-pyran-4-one (5) (13.0 g, 48.16%) as a brown solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1>CS(C)=O>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:25][CH2:24][C:21]3[CH:20]=[N:19][C:18]([CH3:17])=[CH:23][CH:22]=3)[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: C=Cc1ccc(C)nc1
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Solvent: CS(C)=O
Product: CCN1CCc2c(c3cc(C)ccc3n2CCc2ccc(C)nc2)C1
Yield: 3 %

Procedure:
Preparation of the title compound was carried out according to General Method 2. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-H-pyrido[4,3-b]indole was prepared from 2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example 6) (214 mg, 1 mmol), 2-methyl-5-vinylpyridine (1 mL, 2.3 mmol) and Nan (120 mg, 3 mmol) in DMSO (4 ml) at 120° C. for 48 h to obtain 10 mg of 2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole after purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:19])([CH3:18])[C:14]([F:17])([F:16])[F:15])[N:10]=[C:9]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])=[CH:4][CH:3]=1.[CH3:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>>[F:15][C:14]([F:17])([F:16])[C:13]([C:11]1[N:10]=[C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH:39]=3)=[CH:3][CH:4]=2)[CH:12]=1)([OH:19])[CH3:18]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CC(O)(c1cn(-c2ccc(Br)cc2)c(-c2ccccc2C(F)(F)F)n1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(O)(c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2C(F)(F)F)n1)C(F)(F)F
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
A mixture of 2-[1-(4-bromophenyl)-2-(2-trifluoromethyl-phenyl)-1H-imidazol-4-yl]-1,1,1-trifluoro-propan-2-ol (0.11 g, 0.23 mmol), 3-methanesulfonyl-phenylboronic acid (54 mg, 0.27 mmol), K2CO3 (95 mg, 0.69 mmol), Cl2Pd(dppf).DCM (15 mg, 8 mol %) and H2O (0.25 mL) in DME (2.5 mL) was sparged with Argon for 5 min and then heated at 80° C. as a sealed flask. After 90 min the reaction mixture was allowed to cool to ambient temperature, filtered (Celite™) and the filter agent rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and purified by chromatography (silica, EtOAc/Hex, 35:65 to 80:20) to give the title compound (116 mg, 89%) as a white solid. 1H-NMR (DCM-d2): δ 8.09 (m, 1H), 7.91 (m, 1H), 7.84 (m, 1H), 7.78 (d, 1H), 7.66 (m, 1H), 7.59 (d, 2H), 7.49-7.57 (m, 2H), 7.33 (m, 2H), 7.25 (d, 2H), 4.40 (s, 1H), 3.06 (s, 3H), 1.75 (s, 3H); MS (ES): 555 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[N:19]1[C:23]([NH2:24])=[N:22][C:21]([NH2:25])=[N:20]1>N1C=CC=CC=1>[NH2:24][C:23]1[N:19]([C:11]2[S:10][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=2)[N:20]=[C:21]([NH:25][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:22]=1
Reactant: Nc1nc(N)n(-c2nc3ccccc3s2)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Nc1nc(NC(=O)c2ccccc2)nn1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.7 %

Procedure:
Benzoyl chloride (0.34 mmol) was added dropwise to a stirred solution of 1-benzothiazol-2-yl-1H-[1,2,4]triazole-3,5-diamine (0.34 mmol) in pyridine (3 ml). The reaction mixture was stirred at room temperature for 2 hours then it was concentrated in vacuo. The residue was partitionned between ethyl acetate and 10% aqueous citric acid. At this stage, a white solid was filtered off. The solid was dried in vacuo to afford the pure title compound (10 mg; 15% yield). 1H (400 MHz, DMSO-d6) δ 7.40-7.45 (1H, t), 7.50-7.70 (3H, m), 7.85-8.00 (6H, m), 8.1 (1H, d), 10.95 (1H, s). MS (ES+) m/e=337
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@H:12]([CH3:23])[O:11][C@H:6]1[O:7][CH2:8][CH2:9][NH2:10])(=[O:3])[CH3:2].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@H:12]([CH3:23])[O:11][C@H:6]1[O:7][CH2:8][CH2:9][NH:10][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](OCCN)O[C@@H](C)[C@H]1OC(C)=O
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](OCCNCc2ccccc2)O[C@@H](C)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-aminoethyl 2,3,4-tri-O-acetyl-α-L-fucopyranoside (8.56 g, 25.7 mmol) in CH2Cl2 (100 mL) was added benzaldehyde (2.197 ml, 21.67 mmol), acetic acid (372 μL, 6.50 mmol) and NaCNBH3 (3.40 g, 54.2 mmol). After stirring at rt for 16 hr, the reaction mixture was concentrated and the residue was partitioned between EtOAc (50 mL) and sat. NaHCO3 (50 mL). The organic phase separated, washed with sat'd NaHCO3 (2×100 mL), brine (100 mL), dried over MgSO4, and concentrated. The residue was purified by flash chromatography on C18 reverse phase silica gel (130 g), eluting with 0-100% AcCN in water to give the title compound. UPLC Method B: m/e=424.2089 [M+1]; Rt=3.42 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:5][C:6](=[O:8])[CH:7]=1.Cl>[Pd].CCO>[CH3:1][C@@H:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][C@@H:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1CCC(=O)C=C1C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@H]1CCC(=O)C[C@H]1C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
To a Parr flask was added 10% palladium on carbon (wet degussa type) (4.47 g, 4.20 mmol) in EtOH (378 ml). Then ethyl 2-methyl-4-oxo-2-cyclohexene-1-carboxylate (23.65 ml, 140 mmol) and 5 N hydrochloric acid (1.679 ml, 8.40 mmol) were added into the reaction mixture. The atmosphere of the flask was degassed, and then filled with hydrogen (50 psi). The mixture was allowed to stir under hydrogenation conditions 30 min. The progress of the reaction was monitored by LC/MS and TLC (50% EtOAc/hexane; potassium permanganate stain), which suggested reaction completion. The mixture was filtered through a pad of celite and the filter cake was rinsed with EtOH. The mixture was concentrated in-vacuo. The crude material was purified by chromatography through an Interchim (15 micron) silica-gel column (220 g), eluting with a gradient of 0-50% EtOAc in hexane, to provide (1S,2R)-ethyl 2-methyl-4-oxocyclohexanecarboxylate (18.277 g, 99 mmol, 70.9% yield) (Racemic) as light-yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.19 (dtt, 2H), 2.85 (td, J=4.25, 8.31 Hz, 1H), 2.43-2.58 (m, 4H), 2.31 (ddd, J=6.06, 8.75, 14.72 Hz, 1H), 2.01-2.21 (m, 2H), 1.29 (t, J=7.14 Hz, 3H), 0.98 (d, J=6.85 Hz, 3H); LCMS (ESI) m/z 185.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[Br-]>C(OCC)(=O)C>[CH3:20][O:19][C:17](=[O:18])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3][CH:4]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)CNc1ccc(C(=O)OC)cc1

Procedure:
A solution of aniline, triethyl amine, and ethyl bromoacetate was heated to 60° C. for 2.5 days. The reaction mixture was cooled, and TLC (25% EtOAc/hex) showed mostly starting material and a higher Rf spot. Additional base, bromide, and continued heat for 2 days brought little change by TLC. The reaction mixture was cooled, diluted with ethyl acetate, extracted with 10% HCl, dried over sodium sulfate, filtered, adsorbed onto silica, and purified by flash column using 10-30% ethyl acetate/hexanes to obtain 101 as a white solid.
Reaction SMILES: [Cl:1]CC([NH:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[C:8]=1[OH:21])=O>Cl.C(O)C>[ClH:1].[NH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:14])([CH3:15])[CH3:16])[CH:10]=[C:9]([S:17]([CH3:20])(=[O:18])=[O:19])[C:8]=1[OH:21]
Reactant: CC(C)(C)c1cc(CNC(=O)CCl)c(O)c(S(C)(=O)=O)c1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(CN)c(O)c(S(C)(=O)=O)c1

Procedure:
6.3 g (0.028 mol) of 2-chloro-N-[5-(1,1-dimethylethyl)-2-hydroxy-3-methylsulfonylbenzyl]acetamide in a mixture of 20 ml of concentrated hydrochloric acid and 40 ml of ethanol are boiled under reflux for 16 hours. The precipitated product is filtered off with suction and recrystallized from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[NH:19][CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:21][CH3:22])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4.C(=O)(O)[O-].[Na+].[CH2:28](Br)[CH:29]1[O:33][CH2:32][CH2:31][CH2:30]1.[ClH:35]>CN(C)C=O>[ClH:35].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH2:28][CH:29]4[O:33][CH2:32][CH2:31][CH2:30]4)[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@@:9]3([O:21][CH3:22])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13]4
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(OC)CCC(=O)C3
Reactant: BrCC1CCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@]13CCN(CC4CCCO4)[C@H](C2)[C@]1(OC)CCC(=O)C3

Procedure:
A slurry of 3,14-dimethylmorphinan-6-one (6a) (0.24 g, 0.71 mmol), sodium bicarbonate (0.6 g, 7.14 mmol) and (±) tetrahydrofurfuryl bromide (0.4 g, 2.42 mmol) and dimethylformamide (15 ml) was heated at 110° C. for 16 hours with stirring under a nitrogen atmosphere. The mixture was filtered hot and the residue was washed with dimethylformamide (15 ml). The filtrate was distilled under vacuum (bath temperature 35° C.) and the resulting brownish material was treated with chloroform (50 ml) and water (20 ml). After separation, the aqueous layer was saturated with sodium chloride and extracted with ethyl acetate (3×20 ml) whereupon the organic extracts were combined, dried over MgSO4 and filtered. The filtrate, upon concentration, was a brownish oily solid. This material was chromatographed twice over silica gel using graded methanol/chloroform mixtures to give 0.153 g (86% theory) of a mixture of the R and S isomers of the product. A part of this material (0.03 g) was converted into the hydrochloride salt by treatment with ethereal HCl to form the title compound as a tan-colored solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH2:26][CH2:27]O)[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:29]([N:31](CC)[CH2:32][CH3:33])[CH3:30].S(Cl)(C)(=O)=O.N1CCCC1>C1COCC1.C(Cl)Cl>[N:31]1([CH2:27][CH2:26][N:24]2[CH:25]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]4[N:16]([C:12]([CH2:11][C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)=[CH:13][N:14]=4)[N:17]=3)[CH:22]=[N:23]2)[CH2:32][CH2:33][CH2:30][CH2:29]1
Reactant: CCN(CC)CC
Reactant: OCCn1cc(-c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)cn1
Agent: CS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: c1cnc2ccc(Cc3cnc4ccc(-c5cnn(CCN6CCCC6)c5)nn34)cc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-[4-(3-quinolin-6-ylmethyl-imidazo[1,2-b]pyridazin-6-yl)-pyrazol-1-yl]-ethanol (Example 210, 74 mg, 0.200 mmol), triethylamine (61 μL, 0.440 mmol) and mesylchloride (33 μL, 0.420 mmol) in THF (10 mL) was stirred at rt for 24 h. Pyrrolidine (6 eq.) was then added and the mixture was stirred at 60° C. for 48 h. The mixture was diluted with DCM and washed with NaHCO3 10% and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(MeOH+NH3)=95:5→80:20) to afford the title compound (tR 2.70 min (conditions 3), MH+=424.3)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([C:19]([O:21]C)=[O:20])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:23]([O:25]C)=[O:24])[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[CH2:1]([O:8][C:9]1[C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:23]([OH:25])=[O:24])[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2cc(OCc3ccccc3)c(C(=O)OC)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2cc(OCc3ccccc3)c(C(=O)O)cc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
2-Benzyloxy-3,6-di-methoxycarbonylnaphthalene (0.52 g) obtained in Example 32 was dissolved in N-methyl-2-pyrrodidone (10 g) and methanol (10 g) and water (20 g) were added. Furthermore, an aqueous 1N-sodium hydroxide (4.5 g) was added, followed by stirring at about 60° C. for 2 hours. After the insoluble formed during the reaction was removed by filtration, the solution was adjusted to about pH 4 using aqueous 10% hydrochloric acid. The deposit was filtered and then washed with water to obtain 0.41 g of 2-benzyloxy-3,6-di-hydroxycarbonylnaphthalene as pale brown powder (DSC analysis value: 241.3° C.).
Reaction SMILES: [NH2:1][C:2]1[S:6]C(C2C=CC(F)=C(C=2)C#N)=[N:4][N:3]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[C:22](O)=O)[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C:22]2[S:6][C:2]([NH2:1])=[N:3][N:4]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH3:30])[CH3:17]
Reactant: N#Cc1cc(-c2nnc(N)s2)ccc1F
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Product: CCOc1ccc(-c2nnc(N)s2)cc1OCC

Procedure:
5-(3,4-Diethoxyphenyl)-1,3,4-thiadiazol-2-amine TDZ INT-2 was synthesized in a similar manner as 5-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-1 using 3,4-diethoxybenzoic acid. LCMS-ESI (m/z) calculated for C12H15N3O2S: 265.3; found 266.1. [M+H]+, tR=2.58 min. 1H NMR (400 MHz, DMSO) δ 7.45-7.31 (m, 1H), 7.23 (dd, J=8.3, 2.1 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 4.31-3.94 (m, 4H), 3.4 (s, 2H), 1.42 (qd, J=6.8, 3.3 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:10](=O)[C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]1[C:13]1[C:14]([S:19][CH3:20])=[N:15][CH:16]=[N:17][CH:18]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:1][C:2]1([CH3:21])[CH2:10][C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]1[C:13]1[C:14]([S:19][CH3:20])=[N:15][CH:16]=[N:17][CH:18]=1
Reactant: CSc1ncncc1C1c2c(F)cccc2C(=O)C1(C)C
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: ClCCCl
Product: CSc1ncncc1C1c2c(F)cccc2CC1(C)C
Reaction time: 16 h
Yield: 31.5 %

Procedure:
A solution of 500 mg of 5-(2,2-dimethyl-7-fluoroindan-3-on-1-yl)-4-methylthiopyrimidine, 5.0 g of triethylsilane and 3.0 g of boron trifluoride etherate in 20 mL of 1,2-dichloroethane was heated to reflux with stirring for 16 hr. The resulting solution was cooled and then poured into an aqueous solution of sodium carbonate. The mixture obtained was extracted with ether and the ethereal extract was dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel to obtain a colorless oil. A portion of this oil was crystallized from hexane to obtain 150 mg of the title compound as a white solid melting at 81°-82° C.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:17])[CH:25]([N+:26]([O-:28])=[O:27])[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccccc1/C=C/[N+](=O)[O-]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1C1CN(Cc2ccccc2)CC1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (3.93 g, 16.55 mmol) in CH2Cl2 (60 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 1-methyl-2-((E)-2-nitro-vinyl)-benzene (2.70 g, 16.55 mmol) and trifluoroacetic acid (0.13 ml, 1.65 mmol) in CH2Cl2 (30 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:6) afforded 1.01 g (21%) of the title compound as a light yellow oil. ES-MS m/e: 297.4 (M+H+).