Azzindani/Open_Reaction_Data huggingface dataset:
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](=O)[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:24][O:25][NH2:26]>CO>[CH3:24][O:25]/[N:26]=[C:21](/[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[N:13][N:14]=2)[N:17]=1)\[CH3:22]
Reactant: CON
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Solvent: CO
Product: CO/N=C(\C)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 60.8 %

Procedure:
A solution of 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (60 mg, 0.198 mmol) and O-methylhydroxylamine (49.6 mg, 0.593 mmol) in MeOH (10 mL) was stirred at rt overnight. Solvent was evaporated and the crude was purified by HPLC (acidic with 0.05% TFA and then neutralized to free base) to give 40 mg (60.8%) of the title compound as a white solid. 1H-NMR (400 MHz, MeOH-4 δ ppm 8.82 (s, 1H), 8.32 (d, 1H), 8.12 (d, 1H), 7.98 (m, 3H), 7.84 (d, 1H), 7.54 (m, 1H), 4.83 (s, 2H), 4.09 (s, 3H), 2.28 (s, 3H). LC-MS (method B): [MH]+=333.1, tR=2.34 min.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:3]=1[O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.O>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]2[O:4][CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: Cc1ccc(OCC(=O)c2ccccc2)c(Br)c1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(Br)c2occ(-c3ccccc3)c2c1

Procedure:
A mixture of 700 g. of polyphosphoric acid and 100 g. of α-(2-bromo-4-methylphenoxy)acetophenone is heated at 80°-90° C. for two hours, then poured into two liters of water with stirring. Chloroform (1 liter) is added, and the phases are separated. The organic layer is washed with water, dried, then evaporated to provide 7-bromo-5-methyl-3-phenylbenzofuran as a brown oil.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:16]([CH3:28])[CH:15]=1)(C)(C)C>ClCCl>[CH3:27][O:26][C:24]([CH2:23][CH2:22][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([OH:29])=[O:12])=[CH:15][C:16]=1[CH3:28])=[O:25]
Reactant: COC(=O)CCCCc1ccc(C(=O)OC(C)(C)C)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCCCc1ccc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Trifluoroacetic acid (20 ml) was added to a solution of 4-(4-methoxycarbonyl-butyl)-3-methyl-benzoic acid tert-butyl ester from Example E31.3 (1.43 g, 4.7 mmol) in di-chloromethane (40 ml) and the mixture was stirred for 2 h at room temperature. Solvents were concentrated in vacuo and azeotroped with dichloromethane to yield the title compound (1.07 g, 92%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)[N:13]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30]>ClCCl>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:20]=[CH:19][C:17]([NH:18][C:29](=[O:31])[CH3:30])=[CH:16][CH:15]=2)[N:13]=1
Reactant: Nc1ccc(-c2csc(-c3cnccc3C(F)(F)F)n2)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2csc(-c3cnccc3C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of compound (156) (0.20 g, 0.63 mmol) in dichloromethane (3 ml) were added pyridine (0.05 ml, 0.63 mmol) and acetyl chloride (0.04 ml, 0.63 mmol) under ice-cooling. The reaction mixture was warmed to room temperature and, after stirring for one hr., partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate, and the extracts were combined and dried (MgSO4). The solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give white crystals (0.17 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:26]#[C:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][CH:18]=1)[CH2:7]2
Reactant: CN(C)CC#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(Oc3ccccc3)cc1)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CO
Product: CN(C)CCCc1cc(Cl)c2c(c1)CN(Cc1ccc(Oc3ccccc3)cc1)C2=O
Yield: 41.8 %

Procedure:
A mixture of 7-chloro-5-(3-dimethylamino-prop-1-ynyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.047 g, 0.11 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-chloro-5-(3-dimethylamino-propyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.020 g, 42%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.78 (m, 2H), 2.2 (m, 6H), 2.31 (t, 2H), 2.66 (t, 2H), 4.22 (s, 2H), 4.74 (s, 2H), 6.88-7.38 (m, 11H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:31]=[CH:30][C:18]2[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:20]=[N:21][C:17]=2[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:31]=[CH:30][C:18]3[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[N:20]=[N:21][C:17]=3[CH:16]=2)[C:9]1=[O:13]
Reactant: C[Si](C)(C)CCOCn1nnc2cc(Br)ccc21
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3c(c2)nnn3COCC[Si](C)(C)C)C1=O
Yield: 83.5 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 175 mg, 0.9875 mmol) was reacted with 5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzotriazole (353 mg, 1.08634 mmol), 1,4-dioxane (50 mL), copper iodide (80.76 mg, 0.09875 mmol), trans-1,2-diamino cyclohexane (33.9 mg, 0.2962 mmol) and potassium phosphate (524 mg, 2.4689 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 350 mg of 1-(4-Methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzotriazol-5-yl]-imidazolidin-2-one (79% yield).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([O:60][CH3:61])[C:52]([O:58][CH3:59])=[CH:53][CH:54]=4)[O:49][C:48]=3[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([O:60][CH3:61])[C:52]([O:58][CH3:59])=[CH:53][CH:54]=4)[O:49][C:48]=3[C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1OC
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1ccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2c1OC
Yield: 81 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(7,8-dimethoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (41 mg, 0.078 mmol) was reacted to give the title compound (27 mg, 82%). LCMS (Method E): RT=3.55 min, [M+H]+=428. 1H NMR (400 MHz, DMSO-d6): δ 7.79 (d, J=9.2 Hz, 1H), 7.40-7.24 (m, 8H), 7.06 (d, J=8.8 Hz, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 2.36-2.17 (m, 4H), 2.07-1.87 (m, 3H), 1.64-1.53 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26](=[O:40])[NH:27][CH:28]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[N:35][C:36]([NH2:39])=[CH:37][CH:38]=2)[CH2:29]1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:40])[NH:27][CH:28]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[N:35][C:36]([NH:39][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:37][CH:38]=2)[CH2:29]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)nc2)C1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCC(NC(=O)OC(C)(C)C)C4)cn3)nc2n1C1CCCC1
Yield: 14.7 %

Procedure:
Using Buchwald Procedure A, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethyl amide (0.13 g, 0.444 mmol) and [1-(6-amino-pyridin-3-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (0.136 g, 0.488 mmol) gave {1-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (35 mg, 15%) (following SiO2 chromatography, eluting with 0-3% MeOH/dichloromethane). MS (ESI) m/z 535.3 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][C:17]2[N:18]=[C:19]([NH2:31])[C:20]3[N:21]([N:23]=[C:24]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([NH2:31])[C:20]3[N:21]([N:23]=[C:24]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(CC#Cc2cn3nc(-c4ccco4)nc3c(N)n2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CCCc2cn3nc(-c4ccco4)nc3c(N)n2)CC1

Procedure:
To a stirred solution of 4-[3-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-prop-2-ynyl]-piperazine-1-carboxylic acid tert-butyl ester (20 mg; see Example 12 above) in EtOH (1 mL) was added palladium (10 wt.% on activated carbon, ca. 5 mg). The reaction mixture was hydrogenated (45 psi) overnight, filtered through Celite and concentrated in vacuo. The resulting oil was purified by radial chromatography using 5% MeOH/CH2Cl2as eluent to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 1.94 (m, 2H), 2.44 (m, 4H), 2.65 (t, 2H), 3.45 (m, 4H), 5.67 (s, 2H), 6.57 (dd, 1H), 7.13 (dd, 1H), 7.60 (s, 1H), 7.76 (s, 1H).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.[OH:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:23](=[O:33])[C:22]=1[N+:34]([O-:36])=[O:35].C(O)(C)C.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1>[CH3:27][C:25]1[N:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:23](=[O:33])[C:22]([N+:34]([O-:36])=[O:35])=[C:21]([O:20][CH:1]([CH3:6])[CH3:2])[CH:26]=1
Reactant: COC(=O)Cn1c(C)cc(O)c([N+](=O)[O-])c1=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CC(C)O
Solvent: c1ccccc1
Product: COC(=O)Cn1c(C)cc(OC(C)C)c([N+](=O)[O-])c1=O
Reaction time: 48 h

Procedure:
A solution of 11.38 g (43.4 mmol) of triphenylphosphine in 80 ml of benzene is cooled to 0° C. and 10 g (41.3 mmol) of methyl 4-hydroxy-6-methyl-3-nitro-2-oxo-1,2-dihydropyridine-1-acetate and 3.30 ml (43.37 mmol) of isopropanol are added. 6.83 ml (43.4 mmol) of diethylazodicarboxylate are then added dropwise and the mixture is left stirred for 48 hours. The reaction medium is washed successively with 50 ml of a saturated sodium hydrogen carbonate solution, 50 ml of water and 50 ml of a saturated sodium chloride solution. The medium is dried over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on a silica gel column, eluting with a dichloromethane:methanol (98:2) mixture.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([O:10][CH2:9][CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:13])[CH3:12]
Reactant: OCC=Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC=Cc1ccccc1
Yield: 81.7 %

Procedure:
The above alcohol (2.05 g) in pyridine (1.6 ml) with acetic anhydride (1.8 g) was stirred at 25° for 3 hours before being partitioned between ether and dilute hydrochloric acid. Work-up in the conventional manner gave 3-phenylprop-2-enyl acetate (2.2 g). NMR 1H: 7.15 (5H,m), 6.52 (1H,d), 6.22(1H,t), 4.57 (2H,d), 2.00(3H,s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[C:18]1([CH3:26])[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1.N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](/[C:9](=[CH:26]\[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)/[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:17]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccccc1O
Reactant: Cc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: Cc1ccc(/C=C(/C(=O)OC(C)(C)C)C(=O)c2ccccc2O)cc1
Yield: 69 %

Procedure:
Prepared according to general procedure A using tert-butyl 3-(2-hydroxyphenyl)-3-oxopropanoate (18) (354 mg, 1.5 mmol), p-tolualdehyde (150 μL, 1.5 mmol), 15.0 mL benzene, piperidine (15 μL, 0.15 mmol) and glacial acetic acid (8.6 μL, 0.15 mmol), refluxed for 3 h. Purified via recrystallization from hexanes/CH2Cl2, yielding 350 mg (69%) of clear prisms. mp=86-89° C.; IR (film) 2978.2; 1712.8; 1624.5; 1155.2 cm−1; 1H NMR (100.7 MHz, CDCl3) δ 11.93 (bs, 1H), 7.82 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.48 (t, J=8.2 Hz, 1H), 7.25-7.08 (AA′BB′, 4H), 7.03 (d, J=8.2 Hz, 1H), 6.81 (t, J=7.6 Hz, 1H), 2.30 (s, 3H), 1.40 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 202.0, 163.9, 162.8, 142.3, 141.3, 137.1, 131.9, 130.4 (x2), 130.1, 129.9, 120.2, 119.5, 118.4, 82.6, 28.1, 21.6; LRMS (electrospray): Mass calculated for C21H22O4, [M]+, 338.14. Found [M+23]+, 361.4.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[C:19]1([C:29](Cl)=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:29]([C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)=[O:30])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: O=C(Cl)c1cccc2ccccc12
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc4ccccc34)CC2)ccc1Cl
Yield: 62 %

Procedure:
The title compound (26 mg, 62%) was prepared analogously to example 7 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 1-napthoyl chloride. MS: 423.4 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[F:23].[CH2:24]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:25]#[CH:26]>C(N(CC)CC)C>[F:23][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:7][C:2]=1[C:26]#[C:25][CH2:24][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C#CCN1CCCC1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(Br)c(F)c1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(C#CCN2CCCC2)c(F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
A 100 mL Schlenk flask was charged with (4-bromo-3-fluorophenyl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (1.10 g, 2.90 mmol), tetrakis(tri-phenylphosphine)Palladium(0) (0.34 g, 0.29 mmol, 10 mol %), cuprous iodide (0.11 g, 0.58 mmol, 20 mol %), triethylamine (20 mL), and 1-(prop-2-ynyl)pyrrolidine (0.63 g, 5.80 mmol), and the flask was flushed with nitrogen three times. The mixture was stirred at 80° C. for 2 h. The solvent was evaporated under vacuum and the residue was purified by column chromatography to afford the desired product as a yellow solid (0.43 g, 36.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](SCC(O)=O)=[S:7])=[CH:4][CH:3]=1.O.[NH2:16][NH2:17].C(O)(=O)C>[OH-].[Na+].C(Cl)Cl>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:16][NH2:17])=[S:7])=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)CSC(=S)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: NNC(=S)c1ccc(Cl)cc1

Procedure:
To a mixture of (4-chloro-thiobenzoylsulfanyl)-acetic acid (8.31 mmol) in 9 mL of NaOH (1N) is added hydrazine hydrate (36.7 mL). Glacial acetic acid (2.7 mL) is then added to the solution and the mixture is vigorously stirred. The reaction mixture is diluted with CH2Cl2 and the organic layer dried over MgSO4 to yield 4-chloro-thiobenzoic acid hydrazide: LC/MS (ES+) 186.9 (M+1)+.
Reaction SMILES: [CH3:1][C:2](=[CH2:15])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ClC1C=CC=C(C(OO)=[O:24])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:7]([O:6][C:5](=[O:14])[NH:4][CH2:3][C:2]1([CH3:1])[CH2:15][O:24]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C(C)CNC(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC1(CNC(=O)OCc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
Benzyl N-(2-methyl-2-propenyl)carbamate (3.90 g, 19.0 mmol) prepared in Reference Example 173 was dissolved in methylene chloride (80 ml), to which m-chloroperbenzoic acid (5.15 g, 20.9 mmol) was added, and the mixture was stirred at room temperature overnight. Sodium thiosulfate aqueous solution and saturated sodium hydrogencarbonate aqueous solution were added to the reaction mixture, which was stirred for a while. The organic layer was separated, washed with saturated sodium hydrogencarbonate aqueous solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to afford benzyl(2-methyl-2-oxiranylmethyl)carbamate (4.31 g, quantitative) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([F:28])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:17]([O-])=O)=[C:9]([S:11][CH:12]([CH3:16])[C:13](O)=[O:14])[CH:10]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([F:28])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:17][C:13](=[O:14])[CH:12]([CH3:16])[S:11][C:9]=2[CH:10]=1
Reactant: CC(Sc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)O
Solvent: CC(=O)O
Product: CC1Sc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2NC1=O
Reaction time: 20 h
Yield: 67.4 %

Procedure:
Reduced iron (1.3 g) was suspended in acetic acid (6 ml), a solution of 2-[5-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2-nitrophenylthio]propionic acid (1.5 g) in acetic acid (2 ml) was added to the suspension, and the mixture was vigorously stirred for 20 hr. After the completion of the reaction, the reaction mixture was filtered and concentrated in vacuo, and the residue was extracted with ethyl acetate (50 ml×2), washed with water and a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, and the residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=3/1) to prepare the title compound (0.9 g) as a colorless crystal (yield: 69%).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.O>COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccn2c(Br)cnc2c1
Reactant: COc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cccc(-c2cnc3cc(C)ccn23)c1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A mixture of 3-bromo-7-methylimidazo[1,2-α]pyridine (18.0 g, 86 mmol) and 3-methoxyphenylboronic acid (17.0 g, 112 mmol) in 1,2-dimethoxyethane (250 ml) and sodium carbonate (120 ml of a 2M aqueous solution) was degassed for 25 minutes. Tetrakis(triphenylphosphine)pallidum(0) (500 mg, 0.4 mmol) was then added and the mixture heated at reflux for 17 hours. After cooling to ambient temperature the reaction was poured into water (400 ml), extracted with ethyl acetate (3×400 ml) and the combined organics dried over anhydrous magnesium sulphate. Filtration and evaporation to dryness afforded 3-(3-methoxyphenyl)-7-methylimidazo[1,2-α]pyridine as a colourless oil (19 g, 93%). 1H NMR (360 MHz, CDC3) δH 2.40 (3H, s), 3.84 (3H, s), 6.63-6.65 (1H, m), 6.91-6.95 (1H, m), 7.05-7.07 (1H, m), 7.10-7.12 (1H, m), 7.30-7.38 (1H, m), 7.42 (1H, s), 7.66 (1H, s), 8.22 (1H, d, J 7); m/z (ES+) 239 (M++H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]([N:11]([CH3:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: COC(=O)CCCCCNC(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCN(C)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Methyl 6-benzyloxycarbonylamino-hexanoate (4.15 g) is dissolved in N,N-dimethylformamide (2.5 mL) and thereto is added sodium hydride (63%) (552 mg) under ice-cooling and the mixture is stirred at the same temperature for 1 hour and thereto is added methyl iodide (1.72 ml), and the mixture is stirred at the same temperature for an additional 2 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give methyl 6-(benzyloxycarbonyl-methyl-amino)-hexanoate (2.25 g). MS (m/z): 294 [M+H]+
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][N:5]([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[F:18][C:2]1([F:1])[CH2:3][CH2:4][N:5]([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([O:11][C@@H:21]2[CH:22]3[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]3)[CH2:20]2)=[O:10])[CH2:6][CH2:7]1
Reactant: O=C(O)C(c1ccccc1)N1CCC(F)(F)CC1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCC(F)(F)CC1
Temperature: 25 °C
Yield: 47.5 %

Procedure:
A mixture of 2-(4,4-difluoropiperidin-1-yl)-2-phenylacetic acid (512 mg, 2.01 mmol), (R)-quinuclidin-3-ol (306 mg, 2.41 mmol), DCC (497 mg, 2.41 mmol) and HOBT (369 mg, 2.41 mmol) in THF (20 ml) was stirred at room temperature over a week-end. THF was evaporated, the crude was taken up with EtOAc and washed twice with 2M K2CO3 and then with brine. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash-chromatography (DCM/MeOH=9/1) to obtain the title compound (348 mg, 47.6% yield) as a yellow sticky oil.