Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:11](Br)/[CH:12]=[C:13](/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])\[CH3:14].[OH:22][C:23]1[CH:33]=[CH:32][C:26]2[N:27]=[C:28]([C:30]#[N:31])[S:29][C:25]=2[CH:24]=1>CCCCCCC.C(OCC)(=O)C>[CH2:11]([O:22][C:23]1[CH:33]=[CH:32][C:26]2[N:27]=[C:28]([C:30]#[N:31])[S:29][C:25]=2[CH:24]=1)/[CH:12]=[C:13](/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])\[CH3:14]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)=CCC/C(C)=C/COc1ccc2nc(C#N)sc2c1
Reaction time: 20 h
Yield: 120 %

Procedure:
To a dry 25-ml round-bottomed flask containing acetone (5 mL), anhydrous potassium carbonate (1.2 g, 8.4 mmole), and geranyl bromide (1.5 mL, 7.3 mmole) was added 6-hydroxy-2-cyanobenzothiazole (1 g, 5.6 mmole). The mixture was refluxed under argon with stirring. Reaction progress was monitored by TLC analysis, developing with 2:1 heptane-ethyl acetate. After 20 h, the potassium carbonate was filtered from the cooled reaction mixture. The solution was concentrated in vacuo to yield 2.1 g of solid. The solid was further purified by flash chromatography using a mixture of 9:1 heptane-ethyl acetate. Appropriate fractions were pooled and evaporated to yield 0.84 g of solid. The structure was confirmed by 1H NMR analysis in DMSO-d6.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=1
Reactant: NCCc1ccccc1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccccn3)nc(NCCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-phenethylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1>>[CH:18]([N:13]1[C:12]([C:34]2[CH:35]=[C:30]([CH3:29])[CH:31]=[CH:32][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-c2c3c(nn2C(C)C)CCNCC3)c1
Yield: 17.4 %

Procedure:
The title compound (24 mg) was prepared according to Example 189 using 219 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 209 mg of 3-methylphenylboronic acid. MS (ESI): exact mass calculated for C17H23N3, 269.19; found, m/z 270.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.44-7.41 (m, 1H), 7.34-7.33 (m, 1H), 7.13-7.10 (m, 2H), 4.37 (m, 1H), 3.42-3.40 (m, 2H), 3.19-3.17 (m, 2H), 2.78-2.76 (m, 2H), 2.42 (s, 3H), 1.38 (d, J=6.7 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18](=S)[NH:17][C:16]3=[O:21])[CH:12]=2)[N:7]=[C:6]([NH:22][C:23](=[O:25])[CH3:24])[CH:5]=1)[CH3:2].C(N(C(C)C)CC)(C)C.CI.[NH2:37][CH2:38][CH2:39][CH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C(#N)C>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[C:15]3[S:19][C:18]([NH:37][CH2:38][CH2:39][CH:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[N:17][C:16]3=[O:21])[CH:12]=2)[N:7]=[C:6]([NH:22][C:23](=[O:25])[CH3:24])[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(NC(C)=O)nc2ccc(C=C3SC(=S)NC3=O)cc12
Reactant: NCCC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CC#N
Product: CCOc1cc(NC(C)=O)nc2ccc(C=C3SC(NCCC4CCOCC4)=NC3=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
A suspension of N-[4-ethoxy-6-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-quinolin-2-yl]-acetamide (example 6a, 50 mg, 0.11 mmol) in acetonitrile (1.5 ml) was reacted with diisopropylethyl amine (0.200 ml, 1.15 mmol) and methyl iodide (0.15 ml, 2.3 mmol) at rt for 30 min. The mixture was concentrated to dryness and the residue suspended in acetonitrile (1.5 ml). Diisopropylethyl amine (0.20 ml, 1.15 mmol) and 4-(2-aminoethyl)tetrahydropyran (0.075 ml, 0.58 mmol) were successively added at rt, and the mixture was stirred at rt overnight. The precipitate was collected by suction filtration, an washed with acetronitrile. It was then absorbed on SiO2 and purified on a silica gel column with a 0–10% methanol/ethyl acetate gradient to afford the product N-(4-ethoxy-6-{4-oxo-2[2-(tetrahydro-pyran-4-yl)-ethylamino]-4H-thiazol-5-ylidenemethyl}-quinolin-2-yl)-acetamide as a pale yellow solid (22 mg, 50%). LC-MS m/e 469 (MH+).
Reaction SMILES: CN(C)C=[CH:4][C:5]1[CH:10]=[CH:9][N:8]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[C:7](=[O:16])[CH:6]=1.I([O-])(=O)(=O)=[O:19].[Na+]>O1CCCC1>[S:13]1[CH:14]=[CH:15][C:11]([N:8]2[CH:9]=[CH:10][C:5]([CH:4]=[O:19])=[CH:6][C:7]2=[O:16])=[CH:12]1
Reactant: CN(C)C=Cc1ccn(-c2ccsc2)c(=O)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccn(-c2ccsc2)c(=O)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4-(2-dimethylamino-vinyl)-1-thiophen-3-yl-1H-pyridin-2-one (3.8 mmol) in 50% aqueous tetrahydrofuran (130 mL) is added sodium periodate (2.4 g, 11 mmol). After 17 hours of stirring at room temperature, the reaction mixture is filtered. The filtrate is washed 3× with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide 1-thiophen-3-yl-2-oxo-1,2-dihydro-pyridine-4-carbaldehyde as a yellow powder (0.27 g, 34% over 2 steps).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][N:13]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[N:11]=1.Cl>O.CO>[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][N:13]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[N:11]=1
Reactant: COC(=O)CCCCc1noc(-c2ccccc2O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCc1noc(-c2ccccc2O)n1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
Add boron tribromide (4.9 mL, 51.7 mmol) dropwise to a stirred solution of methyl 5-[5-(2-methoxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (3.0 g, 10.3 mmol) in methylene chloride (70 mL) at 0° C. under nitrogen. Allow to warm to room temperature and stir for 5 hours. Cool the mixture to 0° C., add methanol (20 mL) dropwise and allow to warm to room temperature. Remove the solvents under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:9), to provide methyl 5-[5-(2-hydroxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate, which is used without further purification. Add a solution of sodium hydroxide (800 mg, 20 mmol) in water (15 mL) to a solution of methyl 5-[5-(2-hydroxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (2.6 g, 9.4 mmol) in methanol (30 mL) at room temperature and stir the mixture for 2 hours. Adjust the pH of the mixture to 2 with 1 N HCl and extract with ethyl acetate (2×150 mL). Wash the combined organic extracts with water (3×150 mL), dry over sodium sulfate and remove the solvent under reduced pressure. Triturate the residue with hexanes/ethyl acetate and collect the solids by vacuum filtration to afford the title compound (2.4 g, 89% over two steps). APCI MS m/z 261 [C13H14N2O4−H]−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([O:20]CC)=[O:19])=[CH:16][N:17]=2)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([OH:20])=[O:19])=[CH:16][N:17]=2)[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc2ccc(CCC(=O)OC(C)(C)C)cn12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc2ncc(C(=O)O)n2c1
Temperature: 60 °C

Procedure:
A stirring mixture of ethyl 6-(3-tert-butoxy-3-oxopropyl)imidazo[1,2-a]pyridine-3-carboxylate (71) (400 mg, 1.26 mmol) and 2N LiOH (1 mL) in THF:MeOH (4:1, 4 mL) was heated at 60° C. for 30 minutes. The reaction was cooled to room temperature and the pH was adjusted between 3-5 with 10% citric acid. The solvent was partially reduced. The resulting solid was collected by vacuum filtration and washed with excess water. Crude 6-(3-(tert-butoxy)-3-oxopropyl)imidazo[1,2-a]pyridine-3-carboxylic acid (72) was dried and used in the next step without further purification. 1H NMR (400 MHz, d6-DMSO) δ 9.11 (s, 1 H), 8.20 (s, 1 H), 7.72 (dd, J=0.8, 9.2 Hz, 1 H), 7.50 (dd, J=1.6, 9.2 Hz, 1 H), 2.91 (t, J=6.8 Hz, 2 H), 2.60 (t, J=7.2, 2 H), 1.33 (s, 9 H). MS m/z 291.13 (M+1)+.
Reaction SMILES: [BH4-].[Na+].CO.[Cl:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][C:11]2[N:16]=[C:15]3[S:17][C:18]([NH:20][C:21]([CH:23]4[CH2:25][CH2:24]4)=[O:22])=[N:19][C:14]3=[CH:13][CH:12]=2)=[CH:8][C:7]=1[NH:28]C(=O)C(F)(F)F>C(O)C.C(OCC)(=O)C>[NH2:28][C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][C:6]=1[Cl:5])[O:10][C:11]1[N:16]=[C:15]2[S:17][C:18]([NH:20][C:21]([CH:23]3[CH2:25][CH2:24]3)=[O:22])=[N:19][C:14]2=[CH:13][CH:12]=1
Reactant: O=C(Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
Sodium borohydride (5.63 g, 149 mmol) was suspended in ethanol (100 mL), and methanol (66 mL) was slowly added. To the obtained reaction mixture was added N-(5-{4-chloro-3-[(trifluoroacetyl)amino]phenoxy}[1,3]thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide (3.4 g, 7.44 mmol) powder in a small portions under cooling in a water bath, and then, the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (150 mL), and partitioned with water (200 mL), and the organic layer was concentrated under reduced pressure. The residue was diluted with ethyl acetate (200 mL), washed with saturated brine (100 mL), the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0), and triturated with diisopropyl ether to give the title compound (2.00 g, 75%) as a white solid.
Reaction SMILES: C([O:4][C:5]1[C:10]2[C:11]([CH3:16])=[C:12]([CH2:14][CH3:15])[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)C=C.Cl[C:18]1[CH:23]=CC=C[C:19]=1Cl>>[CH2:23]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH3:15])=[C:11]([CH3:16])[C:10]=2[C:5]=1[OH:4])[CH:18]=[CH2:19]
Reactant: C=CCOc1cccc2oc(CC)c(C)c12
Reactant: Clc1ccccc1Cl
Product: C=CCc1ccc2oc(CC)c(C)c2c1O

Procedure:
A mixture of 4-allyloxy-2-ethyl-3-methylbenzofuran (1.0 g; 4.8mmoles) and orthodichlorobenzene (40 ml) was refluxed for 4 hours. The mixture was chromatographed to obtain 1.0 g of the title compound as an oil. The oil was recrystallized from hexane.
Reaction SMILES: O1CCCC1.[O:6]1[CH2:10][CH2:9][O:8][CH:7]1[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1.C([Li])CCC.[CH2:21]([Sn:25](Cl)([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24]>O.CCCCCC>[CH2:30]([Sn:25]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:26][CH2:27][CH2:28][CH3:29])[C:13]1[O:12][C:11]([CH:7]2[O:8][CH2:9][CH2:10][O:6]2)=[CH:15][CH:14]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1coc(C2OCCO2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
Tetrahydrofuran (10 mL) solution of 2-(1,3-dioxolan-2-yl)furan (1.0 g, 7.1 mmol) was cooled to −78° C., and n-hexane solution of 1.6 mol/L n-butyllithium (4.5 mL, 7.2 mmol) was dropwise added thereto, and stirred for 3 hours. Tributyltin chloride (2.6 g, 7.9 mmol) was dropwise added to the reaction mixture, and stirred for 5 hours with heating up to room temperature. Water (10 mL) was added to the reaction mixture, and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through silica gel column chromatography (n-hexane to ethyl acetate/n-hexane=1/20) to obtain tributyl[5-(1,3-dioxolan-2-yl)furan-2-yl]tin (2.3 g, 75%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[CH:21]=[C:22]([CH:24]=O)[N:23]=[C:13]2[C:12]1=[O:26])[CH3:10]>O.C(O)C>[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]2[CH:21]=[C:22]([CH:24]=[N:2][OH:3])[N:23]=[C:13]2[C:12]1=[O:26])[CH3:10]
Reactant: NO
Reactant: CCn1c(=O)c2nc(C=O)cn2c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCn1c(=O)c2nc(C=NO)cn2c2ccccc21
Temperature: 90 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
A solution of 0.2 g of hydroxylamine hydrochloride and 0.25 g of sodium acetate in 2 ml of water was added to a suspension of 0.5 g of the product of Example 22 in 10 ml of ethanol and the mixture was stirred at 90° C. for 4 hours and was then filtered. The recovered product was washed with water and dried in vacuo to obtain 0.435 g of pure 4,5-dihydro-5-ethyl-4-oxo-imidazo-[1,2-a]-quinoxaline-2-carboxaldehyde oxime melting at 286°-288° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.C(O)(=O)CC.[C:18]1([NH:24][C:25](=O)[CH2:26][CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.B.[N:35]1[C:43]2[C:38]3[C:39](=[CH:44][CH:45]=[CH:46][C:37]=3[C:36]=1S)[CH:40]=[CH:41][CH:42]=2>O1CCCC1>[N:28]1([CH2:27][CH2:26][CH2:25][N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:36]2[C:37]3[CH:46]=[CH:45][CH:44]=[C:39]4[C:38]=3[C:43](=[CH:42][CH:41]=[CH:40]4)[N:35]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: SC1=Nc2cccc3cccc1c23
Reactant: O=C(CCn1ccnc1)Nc1ccccc1
Agent: B
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCC(=O)O
Product: c1ccc(N(CCCn2ccnc2)C2=Nc3cccc4cccc2c34)cc1

Procedure:
The reaction of 1,1'-carbonyldiimidazole and 3-(1e,uns/H/ -imidazol-1yl)propanoic acid in tetrahydrofuran solution, followed by treatment with aniline leads to the formation of N-phenyl-3-(1H-imidazol-1-yl)propanamide. Reduction with borane in tetrahydrofuran solution then gives N-phenyl-3-(1H-imidazol-1-yl)propanamide. Reduction with borane in tetrahydrofuran solution then gives N-phenyl-3-(1H-imidazol-1-yl)propanamide. The latter compound with molar equivalents of benz(cd)indol-2-thiol and mercuric acetate in refluxing ethanol leads tot eh formation of the title compound, under the conditions of Example 55.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH2:30][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:28][CH:27]=2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc(Oc2ccc(Cl)cc2)cc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(Oc5ccc(Cl)cc5)cc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-(4-chlorophenoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[4-(4-chlorophenoxy)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O-:15])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.[N-:22]=[N+:23]=[N-:24].[Na+].[CH2:26]1COCC1.CN(C=O)C>>[N:22]([CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:26])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: C1CCOC1
Reactant: O=C([O-])c1c(CBr)c(-c2ccccc2)nc2ccccc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(CN=[N+]=[N-])c(-c2ccccc2)nc2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.7 %

Procedure:
To a solution of 3-(bromomethyl)-2-phenylquinoline-4-carboxylate (2a) (2000 mg, 5.618 mmol) in THF/DMF (50 mL/10 mL) was added sodium azide (402 mg, 6.18 mmol) and the reaction mixture stirred at RT under N2 for 12 h. All solvent was removed in vacuo and the residue was partitioned between ethyl acetate and brine, dried over sodium sulfate and then concentrated in vacuo. The residue was purified by chromatography eluting with 10% ethyl acetate/hexane to give the title compound (1781 mg, 99.7%) as an off white solid. MS APCI, m/z=319 (M+1). LCMS: 2.34 min.
Reaction SMILES: [NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1)([O-:11])=[O:10]>C1C=CC=CC=1>[CH3:8][N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[N:1][C:19]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:17][CH:16]=1)=[O:20]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCCCC1=N
Solvent: c1ccccc1
Product: CN1CCCCC1=NC(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 6 h

Procedure:
The hydrochloride salt of 2-imino-1-methylpiperidine (7.43 g.; 0.05 mole) is converted to the free base in benzene in the usual manner. After drying over K2CO3 and filtering, a benzene solution of 0.05 mole of p-nitrophenylisocyanate is added dropwise with stirring. After addition is complete, further stirring is continued for about 6 hours at room temperature. The benzene is evaporated in vacuo and the solid residue is recrystallized from methanol to give the product, 1-(1-methyl-2-piperidylidene)-3-(4-nitrophenyl)urea:
Reaction SMILES: [Cl:1]C1C=CC(OCC2CCNCC2C2C=CC(F)=C(F)C=2)=NC=1.Cl.C(OC([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][N:41]=2)[CH:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:33]1)=O)(C)(C)C>>[ClH:1].[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([O:39][CH2:38][C@H:35]2[CH2:36][CH2:37][NH:32][CH2:33][C@@H:34]2[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[N:41][CH:42]=1
Reactant: Fc1ccc(C2CNCCC2COc2ccc(Cl)cn2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)cn2)C(c2ccccc2)C1
Agent: Cl
Product: Clc1ccc(OC[C@H]2CCNC[C@@H]2c2ccccc2)nc1

Procedure:
In analogy to the procedure described for the synthesis of 5-Chloro-2-[(3SR,4SR)-3-(3,4-difluoro-phenyl)-piperidin-4-ylmethoxy]-pyridine; hydrochloride the title compound was prepared from (3SR,4 SR)-4-(5-Chloro-pyridin-2-yloxymethyl)-3-phenyl-piperidine-1-carboxylic acid tert-butyl ester as off-white foam. MS (m/e): 303.3 [(M+H)+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:19][CH3:20])[C:3]=1[F:21].[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=N[C:27]([CH3:33])=[N:28]2.O.[C:35]1(C)C=CC=CC=1>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:21][C:3]1[C:4]([O:19][CH3:20])=[C:5]([CH:8]([CH3:18])[CH2:9][C:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:35][C:27]([CH3:33])=[N:28]3)[CH:6]=[CH:7][CH:2]=1
Reactant: Cc1ncc2c(N)cccc2n1
Reactant: Cc1ccccc1
Reactant: COc1c(C(C)CC(O)(C=O)C(F)(F)F)ccc(Cl)c1F
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Product: COc1c(F)cccc1C(C)CC(O)(C=Nc1cccc2nc(C)ccc12)C(F)(F)F

Procedure:
100 mg (0.3 mmol) of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 48 mg (0.3 mmol) of 5-amino-2-methylquinazoline and 0.1 ml of titanium tetraethoxide are stirred in 9 ml of toluene at 100° C. for 2 h. After cooling, the mixture is poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are dried over sodium sulphate and the solvent is removed in vacuo to give 130 mg of 4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol as a crude product. 130 mg of the crude imine in 6 ml of CH2Cl2 are admixed dropwise at −30° C. with 3 ml (3 mmol) of a 1 M of boron tribromide solution. The batch is allowed to warm to −5° C. over 3 hours. It is admixed with saturated NaHCO3 solution, the phases are separated, the aqueous phase is extracted with ethyl acetate and the combined organic phases are dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica gel (hexane/ethyl acetate 0-75%) yields 30 mg as a mixture of the title compound and 5α,6α,8β)-3-chloro-2-fluoro-8-methyl-5-[(2-methylquinazolin-5-yl)amino]-6-(trifluoromethyl)-5,6,7,8-tetrahydronaphthalene-1,6-diol (Ex. 23). Preparative thin-layer chromatography on amine phase (Merck) with ethyl acetate/methanol/triethylamine 25:3:1 yields 5 mg of product.
Reaction SMILES: [CH2:1]([S:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])(=[O:6])=[O:5])[CH2:2][CH3:3].[C:12](=[S:14])=[S:13].[OH-].[K+].Cl[CH:18](Cl)[CH2:19]Cl>O.C(Cl)(Cl)Cl.CN(C)C=O>[S:13]1[CH:19]=[CH:18][S:14][C:12]1=[CH:3][CH2:2][CH2:1][S:4]([CH2:7][C:8]([O:10][CH3:11])=[O:9])(=[O:6])=[O:5]
Reactant: CCCS(=O)(=O)CC(=O)OC
Reactant: S=C=S
Reactant: ClCC(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)CS(=O)(=O)CCC=C1SC=CS1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a mixture of 18.0 g of methyl n-propylsulfonylacetate, 7.6 g of carbon disulfide and 200 ml of dimethylformamide, 22.4 g of potassium hydroxide was added under ice-cooling. The resultant mixture was stirred for 2 hours. Thereafter, 13.3 g of 1,1,2-trichloroethane was added to the reaction mixture. followed by stirring at 80° C. for 3 hours. After cooling the reaction mixture, chloroform and water were added and the resulting organic layer was separated. Upon removal of the solvent by distillation under reduced pressure, 25.2 g of the title compound was obtained as pale yellow crystals. Upon recrystallization from methanol, they turned to white crystals. Melting point: 133°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O.[CH3:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1.N1C=CC=CC=1.O>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:16]1[C:15]([CH3:14])=[CH:19][C:18]([CH3:20])=[N:17]1
Reactant: Cc1cc(C)[nH]n1
Reactant: COc1ccc(B(O)O)c(OC)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-n2nc(C)cc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.5 %

Procedure:
610.2 mg of 2,4-dimethoxyphenylboronic acid was dissolved in 6 ml of methylene chloride, to the mixture were added 387 mg of 3,5-dimethylpyrazol, 730 mg of copper(II) acetate and 948 μl of pyridine, and the mixture was stirred overnight at room temperature. To the reaction mixture was added 60 ml of water and extracted with 60 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to yield 81.7 mg of the title compound.