Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>>[C:26]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:24])([F:25])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:30])[CH:27]([CH3:29])[CH3:28]
Reactant: Cc1cc(C(C)NC(=O)c2ccnc(N)n2)cnc1OCC(F)(F)F
Reactant: CC(C)C(=O)Cl
Product: Cc1cc(C(C)NC(=O)c2ccnc(NC(=O)C(C)C)n2)cnc1OCC(F)(F)F

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.06 mmol, Step-1 of Example 223, single enantiomer) and isobutyryl chloride (30 mg, 0.28 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[O:16])[CH2:11][CH2:10]1)C1C=CC=CC=1>[Pd].O>[ClH:1].[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[C:15]([N:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1)=[O:16]
Reactant: O=C(c1ccc2ccccc2n1)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: O=C(c1ccc2ccccc2n1)N1CCNCC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
After a mixture consisting of 1-benzyl-4-(2-quinolylcarbonyl)piperazine hydrochloride (18.81 g, 51.1 mmol), 10% palladium-charcoal catalyst (3.00 g) and water (150 ml) was stirred for 3 hours at a bath temperature of 70° C. under a hydrogen gas stream, the catalyst was removed and the solvent was then distilled off. The residue was crystallized from ethanol, whereby 11.03 g of the title compound were obtained as colorless prisms (yield: 77.7%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:10].[K+].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N+:3]=1[O-:10]
Reactant: Clc1nccnc1Cl
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: [O-][n+]1ccnc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 15 grams (0.1 mole) of 2,3-dichloropyrazine in 120 milliliters of concentrated sulfuric acid, maintained at 5° C, was gradually added 30 grams (0.11 mole) of potassium persulfate. The reaction mixture was stirred overnight at room temperature and thereafter poured into 400 milliliters of ice water. The resulting solution was thoroughly extracted with chloroform and the extract washed with both a saturated sodium bicarbonate solution and a saturated sodium chloride solution and dried over magnesium sulfate. The chloroform was thereafter removed by evaporation leaving the 2,3-dichloropyrazine-1-oxide as a white solid residue. The product was recrystallized from methanol and was recovered in a yield of 14.0 grams (85 percent of theoretical). The product melted at 104°-106° C, and upon analysis was found to have carbon, hydrogen, nitrogen and chlorine contents of 29.40, 1.41, 17.08 and 43.20 percent, respectively, as compared with the theoretical contents of 29.09, 1.21, 16.97 and 43.03 percent, respectively, calculated for the above-named compound.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:29])[C:19]=2[N:18]=[C:17]1[CH2:30][CH2:31][CH2:32][CH3:33].ClCCl>N1C=CC=CC=1>[NH2:29][C:20]1[C:19]2[N:18]=[C:17]([CH2:30][CH2:31][CH2:32][CH3:33])[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:28]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
Benzenesulfonyl chloride (0.45 ml in 10 ml dichloromethane, 3.5 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (1.0 g, 3.2 mmol), dichloromethane (140 ml), and pyridine (0.8 ml). The reaction was maintained at room temperature for four hours and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane\methanol, Rf 0.28) followed by recrystallization from dichloromethane\diethyl ether to provide 1.14 g of N1-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-1-benzenesulfonamide as a white powder, m.p. 75.5-79.0° C. 1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J=7.7 Hz, 1H), 7.76 (d, J=7.2, 2H), 7.63-7.53 (m, 5H), 7.42 (m, 1H), 7.25 (m, 1H), 6.43 (broad s, 2H), 4.45 (t, J=7.6 Hz, 2H), 2.87 (t, J=7.7 Hz, 2H), 2.78 (m, 2H), 1.79 (m, 4H), 1.55-1.40 (m, 4H), 0.95 (t, J=7.4 Hz, 3H); MS (EI) m/e 451.2036 (451.2042 calcd for C24H29N5O2S); Anal calcd for C24H29N5O2S: C, 63.83; H, 6.47; N, 15.51. Found: C, 63.89; H, 6.42; N, 15.30.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.[C:20](Cl)(=[O:22])[CH3:21]>ClC1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[C:20]([C:15]1[CH:16]=[CH:17][C:10]2[O:9][C:8]([C:6]([OH:5])=[O:7])=[C:12]([CH3:13])[C:11]=2[C:14]=1[O:18][CH3:19])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: COc1cccc2oc(C(=O)OC(C)(C)C)c(C)c12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: COc1c(C(C)=O)ccc2oc(C(=O)O)c(C)c12
Temperature: 0 °C
Reaction time: 6 h
Yield: 57 %

Procedure:
To 4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester (310 mg, 1.18 mmol) dissolved in 9 mL of chlorobenzene was added acetyl chloride (0.3 mL, 3.6 eq). The solution was cooled to <0° C. while titanium tetrachloride (0.61 mL, 4.8 eq) was added dropwise. The reaction mixture was stirred at 0° C. and below for 6 h and then heated in an 85° C. oil bath for 3.5 h. The reaction mixture was poured into ice/water, and the mixture was extracted with ethyl acetate. The combined organic solution was washed with 2N HCl and water. Removal of the solvents in vacuo gave 167 mg (57% yield) of 5-acetyl-4-methoxy-3-methyl-benzofuran-2-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([C:10]#[C:11][Si](C)(C)C)[C:3]=1[F:16].[Cl-].[NH4+]>CN(C=O)C.[Cu](I)I>[Br:1][C:2]1[C:3]([F:16])=[C:4]2[C:5](=[CH:7][C:8]=1[F:9])[NH:6][CH:11]=[CH:10]2
Reactant: C[Si](C)(C)C#Cc1c(N)cc(F)c(Br)c1F
Agent: I[Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Fc1cc2[nH]ccc2c(F)c1Br
Temperature: 110 °C
Yield: 26.1 %

Procedure:
A solution of 4-bromo-3,5-difluoro-2-[(trimethylsilyl)ethynyl]aniline (1.75 g, 5.77 mmol) in DMF (80 mL) was treated with copper iodide (2.2 g, 11.5 mmol). The reaction mixture was sealed and heated to 110° C. for 3.75 hours. The black reaction mixture was cooled to room temperature, and poured into saturated aqueous ammonium chloride (300 mL). The product was extracted with ethyl acetate/heptane (2:1, 3×200 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a black oil. The crude product was purified using flash chromatography on silica gel, eluting with heptanes/EtOAc (100:0 to 1:1) to give the title compound (350 mg). MS (ES+) 233.9 ((M+2)+H)+
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[CH2:14][C:13](=[O:15])[CH2:12]1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].O>C1COCC1>[CH2:1]([NH:8][CH2:9][C@@H:11]1[CH2:14][C@H:13]([OH:15])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(C(=O)NCc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O[C@H]1C[C@@H](CNCc2ccccc2)C1
Yield: 84.1 %

Procedure:
A solution of intermediate 26 N-Benzyl-3-oxocyclobutanecarboxamide (9.5 g, 0.046 mol) in absolute THF (50 mL) was added to a suspension of LiAlH4 (3.55 g, 0.093 mol) in absolute THF (50 ml) under stirring in argon. The mixture was refluxed under stirring for 1 h and cooled. Then 10 N NaOH (10 mL) and water (5 mL) were added. The organic layer was decanted, and the aqueous one was extracted with THF (2×50 mL). The organic layers were evaporated to give the title compound (7.4 g, 83%) as a yellow oil. 1H NMR-data (DMSO-d6): 7.00-7.49 (m, 6H, NH, Ph); 4.80 (br.s, 1H, OH); 3.81-3.95 (m, 1H); 3.67 (s, 2H, CH2); 2.48 (d, 2H, CH2, J=6.8 Hz); 2.19-2.30 (m, 2H); 1.70-1.84 (m, 1H); 1.35-1.50 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH:37]([OH:40])[CH2:38][CH3:39]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:35][CH2:36][CH:37]([OH:40])[CH2:38][CH3:39])=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCC(O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: CCC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-amino-2-butanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.83-0.93 (m, 3 H), 1.38-1.45 (m, 2 H), 1.54-1.65 (m, 4 H), 2.04 (t, J=6.00 Hz, 2 H), 3.18-3.30 (m, 3 H), 3.44-3.57 (m, 4 H), 4.16 (s, 2 H), 4.31-4.45 (m, 2 H), 4.95 (d, J=5.26 Hz, 1 H), 7.11-7.18 (m, 2 H), 7.38-7.44 (m, 2 H), 8.20 (s, 1 H), 8.56 (d, J=1.68 Hz, 1 H), 10.42 (t, J=5.58 Hz, 1 H), 17.23 (s, 1 H); ES+ MS: 511 (M+H+).
Reaction SMILES: C([O:3][C@@H:4]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:6]([CH2:7][C:8](=[O:35])[C@@H:9]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:25])[CH2:15][CH2:16][C:17]([NH:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=[O:18])[CH2:5]1)=O.CC(C)=O.[OH-].[Na+]>O>[OH:3][C@@H:4]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:6]([CH2:7][C:8](=[O:35])[C@@H:9]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:25])[CH2:15][CH2:16][C:17]([NH:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=[O:18])[CH2:5]1
Reactant: C[C@H](CCC(=O)NC(C)(C)CO)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](OC=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C[C@H](CCC(=O)NC(C)(C)CO)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h

Procedure:
To 10 grams of 2-(3α-formyloxy-7-keto-5β-cholan-24-amido)-2-methyl-1-propanol in 300 ml. of acetone was added dropwise, 200 ml. of 0.2N sodium hydroxide over a period of 30 minutes and the mixture was then permitted to stand for 1 hour. One liter of water was added to yield white crystals which were then filtered washed with water, dried and recrystallized from chloroform-acetone to obtain 2-(3α-hydroxy-7-keto-5β-cholan-24-amido)-2-methyl-1-propanol.
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([OH:14])=[O:13])[CH2:4]1.[CH3:15][C:16](Cl)([CH3:18])[CH3:17]>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.CN1CCCC1=O>[C:7]([O:8][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:16]([CH3:18])([CH3:17])[CH3:15])=[O:13])[CH2:4]1)(=[O:6])[CH3:9]
Reactant: CC1(C)O[C@H](CCl)C[C@H](CC(=O)O)O1
Reactant: CC(C)(C)Cl
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN1CCCC1=O
Product: CC(=O)OC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O1
Temperature: 85 °C
Reaction time: 0.75 h

Procedure:
Solid tetra-n-butylammonium acetate prepared in step (e)(i) of Example 1 above (106.2 g, 0.352 mole) was added in one portion to a mechanically stirred solution of the chloride (4R-cis)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, 1,1-dimethylethyl ester prepared in step (d) of Example 1 above (32.7 g, 0.117 mole) in HPLC grade 1-methyl-2-pyrrolidinone (471 ml) under argon. The resulting solution was stirred at 85° C. (internal temperature). After 30 to 60 minutes the reaction mixture became homogeneous and brown in color. The progress of the reaction was followed by TLC and GC analysis. (TLC: Rf =0.54 for the title compound; Rf =0.63 for the chloride starting material (silica gel, Ethyl acetate:Hexane, 1:1, visualization by Ce(SO4)2 spray).) After 9 hours the reaction was completed.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH2:7][C:8](O)=[O:9]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=2)[S:5][C:6]=1[CH2:7][CH2:8][OH:9]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CC(=O)O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A solution of [4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-acetic acid (6.01 g, 20 mmol) in tetrahydrofuran (180 ml) was treated at 0° C. with a 1 M solution of BH3*THF in tetrahydrofuran (49.8 ml, 49.8 mmol). The cooling bath was removed and the reaction mixture stirred at ambient temperature for 16 h. Careful quenching with MeOH and ice water, twofold extraction with AcOEt, washing with ice water/brine 1/1, drying over magnesium sulfate, and evaporation of the solvent left a crude product which was refluxed for 30 min in MeOH to liberate quantitatively the free alcohol. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel, dichloromethane/MeOH) to yield 5.68 g (20 mmol, 99%) of the title compound as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34](Br)[CH:33]=1>>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:35]2[CH:36]=[CH:37][C:32]([C:31]([O:30][CH3:29])=[O:39])=[CH:33][CH:34]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: COC(=O)c1cccc(Br)c1
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Product: COC(=O)c1ccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 33A and methyl-3-bromobenzoate were processed as described in Example 52A to provide the title compound. MS (ESI+) m/z 519 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][NH2:32])[CH:29]=2)[CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:32][CH2:31][C:28]4[CH:29]=[C:30]5[C:25]([CH:24]=[CH:23][CH:22]=[N:21]5)=[CH:26][CH:27]=4)[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: NCc1ccc2cccnc2c1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NCc4ccc5cccnc5c4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (480 mg, 1.69 mmol) and quinolin-7-ylmethanamine (400 mg, 2.53 mmol) in acetonitrile (5 mL) and N,N-diisopropylethylamine (1.5 mL, 8.6 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by semi-prep HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM diethylamine]) to yield an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[O:12][C:13](C=O)=[CH:14][CH:15]=1.[CH:19]([O:24][CH3:25])([O:22][CH3:23])OC.[Cl-].[NH4+]>CO>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[O:12][C:13]([CH:19]([O:22][CH3:23])[O:24][CH3:25])=[CH:14][CH:15]=1
Reactant: COC(OC)OC
Reactant: COC(=O)CCCCCCCc1ccc(C=O)o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)CCCCCCCc1ccc(C(OC)OC)o1

Procedure:
32.8 g of 8-(5-formyl-2-furyl)-octanoic acid methyl ester, 15.5 g of trimethyl orthoformate, 16 ml of methanol and 0.3 g of ammonium chloride were mixed and refluxed for 4 hours. The solution was concentrated to dryness on a water bath. The residue was then absorbed in ether, washed with water, dried and distilled. Boiling point 136°-138° C at 0.2 mm Hg.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[O:28][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:11][CH:10]=1)(=O)=O.[Na].[NH:41]1[CH:45]=[N:44][CH:43]=[N:42]1>CN(C)C=O>[CH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:38]=[CH:39][C:30]=1[CH2:29][O:28][CH:16]1[CH:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:41]3[CH:45]=[N:44][CH:43]=[N:42]3)=[CH:10][CH:11]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOS(C)(=O)=O)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCn3cncn3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 100 °C
Yield: 85 %

Procedure:
A solution of 11 0 mg (0.2 mmol) of crude tert-butyl (3RS,4RS)-4-[4-(2-methylsulphonyloxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 5 ml of dimethylformamide was treated with 70 mg (1.0 mmol) of 1,2,4-triazole sodium salt and the reaction mixture was heated to 100° C. for 6 hours. Subsequently, the mixture was cooled to room temperature and the dimethylformamide was distilled off in an oil pump vacuum. The residue was taken up in 10 ml of methylene chloride, washed with 2 ml of water, the organic phase was dried over sodium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica gel using a 95:5:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. There were obtained 90 mg (85% of theory) of tert-butyl (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-[4-(2-[1,2,4]triazol-1-yl-ethoxy)-phenyl]-piperidine-1-carboxylate as a colourless oil; MS: 529 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:24][CH:23]=1.Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([CH:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[CH:26][CH:27]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCC(c2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: Cl
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)cc2)CC1

Procedure:
4-(4-Bromo-phenyl)-1-methyl-piperidine; hydrochloride was prepared from 4-(4-bromo-phenyl)-piperidine; hydrochloride (1.0 g, 3.6 mmol) in a manner analogous to Step 34c. The reaction product was isolated an off-white solid (0.94 g) and was used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.58 (br s, 1H), 7.54 (d, J=7.2 Hz, 2H), 7.21 (d, J=7.3 Hz, 2H), 3.46 (d, J=11.4 Hz, 2H), 3.09-2.97 (m, 2H), 2.83-2.70 (m, 4H), 2.00-1.87 (m, 4H). MS=254, 256 (MH)+. 50b) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(1-methyl-piperidin-4-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(4-bromo-phenyl)-1-methyl-piperidine; hydrochloride (100.0 mg, 0.3441 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow foam (0.070 g, 58%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.8 Hz, 1H), 8.23 (d, J=8.2 Hz, 2H), 8.08 (d, J=8.1 Hz, 2H), 7.65 (d, J=7.4 Hz, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.23 (d, J=8.2 Hz, 2H), 7.01 (t, J=6.7 Hz, 1H), 6.85 (s, 1H), 3.10 (s, 3H), 3.01-2.94 (m, 2H), 2.51-2.41 (m, 1H), 2.33 (s, 3H), 2.10-2.01 (m, 2H), 1.87-1.77 (m, 4H). MS=462 (MH)+.
Reaction SMILES: [CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH3:8][CH2:9][N:10]([C:13]([SH:15])=[S:14])[CH2:11][CH3:12].C(=S)=S.C(N(CC)CC)C.C(NCC)C>>[CH2:9]([N:10]([CH2:11][CH3:12])[C:13](=[S:14])[S-:15])[CH3:8].[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)C(=S)S
Agent: CC[NH+](CC)CC
Solvent: CCNCC
Solvent: S=C=S
Solvent: CCN(CC)CC
Product: CCN(CC)C(=S)[S-]
Temperature: 50 °C

Procedure:
Preparation of triethylammonium salt of diethyl dithiocarbamate is as follows: 76 grams (1 mole) carbon disulfide and 101 grams (1 mole) triethylamine are mixed at 10° C. under nitrogen. To the mixture is added in slowly 80.5 grams (1.1 mole) diethylamine drop wise and maintain the temperature below 30° C. Then the mixture is heated to 50° C. for 1 hour. The solution is then stripped out under vacuum to remove the excess amine and for the removal of low volatiles to obtain final product. The acid number (normally below 30) is measured to check the acidity. The product purity (ranging between 85-95%) is measured by LC-MS and NMR.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH2:11])=[N:6][C:5]=1[NH2:12].[C-:14]#[N:15].C([Al+]CC)C.C1(C)C=CC=CC=1.[Cl-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:14]#[N:15])=[N:6][C:5]=1[NH2:12]
Reactant: C=Cc1ccc(C(=O)OC)c(N)n1
Reactant: [C-]#N
Agent: CC[Al+]CC
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCC#N)nc1N
Reaction time: 8 h
Yield: 21 %

Procedure:
To a solution of 2-amino-6-vinyl-nicotinic acid methyl ester (760 mg, 4.26 mmol) in tetrahydrofuran (76 mL) was added a solution of diethyl aluminum cyanide in toluene (12.8 mL, 12.8 mmol) dropwise under sodium chloride—an ice bath cooling, at an internal temperature of −5° C. or below, then, the solution was gradually allowed to room temperature and stirred overnight. The reaction solution was partitioned into an aqueous solution of saturated ammonium chloride and ethyl acetate. This organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography, and the title compound (180 mg, 0.878 mmol, 21%) was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.B(Br)(Br)Br>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(c1ccc(O)cc1)c1nc(Cl)nc2ccccc12
Temperature: -20 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
To a solution of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (100 mg, 0.334 mmol) in 30 ml dichloromethane cooled at −20° C. was added slowly 60 μl of BBr3 (0.668 mmol). The reaction mixture was stirred at −20° C. for 2 h then it was warmed to room temperature. It was stirred another 2 h at this temperature. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with cold 5% sodium bicarbonate. The organic phase was dried and concentrated. The residue was purified by a small silica column using ethyl acetate and hexane (1:3) as eluents to give the product (57 mg, 57%). 1H NMR (CDCl3): 7.65-7.56 (m, 2H), 7.04-6.87 (m, 5H), 3.59 (s, 3H).