Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([N+:16]([O-])=O)[CH:8]=1)#[CH:2].O1CCCC1>[OH-].[NH4+].[Zn]>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([NH2:16])[CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c1
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: C1CCOC1
Product: C#Cc1cccc(Oc2ccc(N)c(N)c2)c1
Reaction time: 0.5 h

Procedure:
To a rapidly stirred suspension of 25 g (0.38 g atom) of powdered zinc in 25 ml of concentrated ammonium hydroxide was added a solution containing 5.0 g (17.6 mmoles) of 4-(3-ethynylphenoxy)-o-dinitrobenzene dissolved.in 25ml of tetrahydrofuran. The mixture was stirred at room temperature for one-half hour, at which time an additional 5 ml of ammonium hydroxide was added, and the solution stirred an additional half hour. At that time, the reaction mixture was filtered by suction, and the residue was washed with several portions of tetrahydrofuran. The filtrate was extracted with several portions of ether, and the combined ether extracts washed with water. Evaporation of the organic layer in vacuo yielded a dark red oil. Chromatography of the residue on 1 × 12 inch dry column of silica gel afforded an initial red band (elution with methylene chloride) of side-product. Further elution using ethyl acetate produced a second band of desired product. Evaporation of solvent in vacuo yielded 3.3 g (84%) of 4-(3-ethynylphenoxy)-o-phenylenediamine as a dark orange oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1.[C:12](=[O:15])([O-])[O-].[K+].[K+].[Cl-]>CC(C)=O.O>[C:12]([N:2]([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1)(=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccc(SC)cc1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CSc1ccc(CN(C)C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 199.6 %

Procedure:
N-Methyl-N-(4-methylthiobenzyl)amine (4.2 g) and potassium carbonate (5.2 g) are dissolved in a mixture of acetone (20 ml) and water (20 ml), and thereto is added dropwise benzoy chloride (3.7 ml) gradually under ice cooling. After the mixture is stirred at the same temperature for 30 minutes, the reacting mixture is poured into water, and then extracted with dichloromethane. The extract is washed with aqueous sodium chloride solution, and dried over magnesium sulfate. Dichloromethane is distilled off to give N-benzoyl-N-methyl-N-(4-methylthiobenzyl)amine (6.8 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[CH:21]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[N:28][CH:29]=1)[CH2:22][NH2:23])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:23][CH2:22][CH:21]([N:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[CH:12]([CH3:14])[CH3:13])[C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[N:28][CH:29]=1)=[O:6]
Reactant: Cc1ncc(C(CN)N2CCCCC2C(C)C)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCCCC2C(C)C)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-isopropylpiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[CH:37]=[CH:36][C:20]3[NH:21][C:22]([CH2:24][O:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[N:23][C:19]=3[CH:18]=2)[CH:9]([CH3:10])[O:8]1)(C)(C)C.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1COCC1>[OH:8][CH:9]([CH3:10])[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:37]=[CH:36][C:20]2[NH:21][C:22]([CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=3)=[N:23][C:19]=2[CH:18]=1)=[O:6]
Reactant: CC1OC1(O[Si](C)(C)C(C)(C)C)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(O)C(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 80 °C
Yield: 88.2 %

Procedure:
A mixture of 5-{2-[2-(tert-butyl-dimethyl-silanyloxy)-3-methyl-oxiranyl]-phenyl}-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.040 g, 0.0721 mmol) and toluenesulfonic acid monohydrate (0.016 g, 0.0865 mmol) in THF (2 mL) was heated to 80° C. for 4 hours. The reaction mixture was then concentrated, and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:2) to afford the title compound as a brown oil (0.028 g, 89%). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.66-7.56 (m, 4H), 7.53-7.45 (m, 4H), 7.26-7.22 (m, 3H), 5.43 (s, 2H), 4.12-4.03 (m, 1H), 1.03 (d, 3H, J=7.2 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H23F3N3O3: 482.4 (M+MeCN+H), Found 482.3.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1>[C:10]1([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2)s1
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a solution of 2-methoxycarbonyl-5-phenylthiophene (437 mg) in methanol (5 ml) and tetrahydrofuran (5 ml) was added an aqueous solution of sodium hydroxide (IN, 3 ml) followed by stirring for 2 hours. To the mixture was added hydrochloric acid (IN, 5 ml). The precipitate was collected by filtration and dried to give 5-phenylthiophene-2-carboxylic acid (397 mg, 97.1%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([SH:8])=[N:4]1.[CH:9](N(C(C)C)CC)(C)C.CI>CO>[OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([S:8][CH3:9])=[N:4]1
Reactant: OC[C@@H]1CSC(S)=N1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CO
Product: CSC1=N[C@H](CO)CS1
Yield: 59 %

Procedure:
To a mixture solution of 4.88 g of 4(R)-hydroxymethyl-2-mercapto-1,3-thiazoline [Compound (5)] and 22.8 ml of diisopropylethylamine in 65 ml of dry methanol was added 14.00 g of methyl iodide under refluxing condition, and the reaction mixture was refluxed for 1 hour. After removal of the solvent under reduced pressure, the resulting residue was dissolved in ethyl acetate and the organic layer was washed with saturated sodium bicarbonate solution, water and saturated saline solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform-acetone) to give 3.14 g (59%) of 4(R)-hydroxymethyl-2-methylthio-1,3-thiazoline [Compound (6)].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=2)[NH2:9])=[N:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([C:3]3[CH:4]=[CH:5][O:1][N:2]=3)[CH:7]=2)=[O:26])=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1cccc(-c2ccon2)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccon2)c1

Procedure:
Using the same method as in Example 15-(i), 3-(isoxazole-3-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(isoxazole-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 82%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[F:12][C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15](I)([F:20])[C:16]([F:19])([F:18])[F:17]>>[F:17][C:16]([F:18])([F:19])[C:15]([F:20])([C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:9]=1)[C:14]([F:22])([F:23])[C:13]([F:25])([F:24])[F:12]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: FC(F)(F)C(F)(F)C(F)(I)C(F)(F)F
Product: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1C(F)(F)F

Procedure:
According to the method of 1-1 of Example 1, a target compound was prepared from 2-(trifluoromethyl)aniline and nonafluoro-s-butyliodide under the light-shielding reaction condition.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1.Cl.C(N=C=NCCCN(C)C)C>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([O:12][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)On1nnc2ccccc21
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-2-methylpropionic acid (2.03 g) and 1-hydroxybenzotriazole (1.35 g) in N,N-dimethylfolmamide (20 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.91 g) and the mixture was stirred overnight. The reaction mixture was partitioned between a mixture of ethyl acetate and n-hexane and water. The separated organic layer was washed in turn with water, a saturated sodium hydrogencarbonate in water and brine and dried over magnesium sulfate. The organic layer was evaporated under reduced pressure to give benzotriazol-1-yl 2-tert-butoxycarbonylamino-2-methylpropionate (2.94 g, 91.9%) as a solid.
Reaction SMILES: Cl[C:2]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][C@@H:5]1[CH3:18])=[O:3].[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22][OH:23]>>[C:14]([O:13][C:11]([N:7]1[CH2:8][C@@H:9]([CH3:10])[N:4]([C:2]([O:23][CH2:22][C:21]2[C:20]([F:19])=[CH:27][CH:26]=[CH:25][C:24]=2[F:28])=[O:3])[C@@H:5]([CH3:18])[CH2:6]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Reactant: OCc1c(F)cccc1F
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)OCc1c(F)cccc1F

Procedure:
2,6-Difluorobenzyl 4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate was prepared from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and 2,6-difluorobenzyl alcohol according to the method described for Example 54 to give the product as a colourless gum (0.251 g, 65%); Rf (Silica, isopropyl ether) 0.35; δH (400 MHz, CDCl3) 7.29 (1H, m), 6.90 (2H, m), 5.23 (2H, s), 4.16 (2H, m), 3.92 (2H, br), 2.95 (2H, br), 1.47 (9H, s), 1.21 (6H, d, J 6.8 Hz).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:34]1([CH2:40][CH2:41][S:42][CH:43]([C:47](O)=[O:48])[C:44](O)=[O:45])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[OH:48][C:47]1[CH:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)[O:18][C:44](=[O:45])[C:43]=1[S:42][CH2:41][CH2:40][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(OCCc2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCCc3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(2-phenylethoxy)acetophenone (1.21 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 103-106° C.; 1H NMR (400 MHz, DMSO-d6) δ2.76 (t, 2 H), 2.97 (t, 2 H), 3.06 (t, 2 H), 4.27 (t, 2 H), 6.67 (s, 1 H), 7.21 (m, 12 H), 7.73 (d, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:26][CH3:27])=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:11]=1)[CH3:2].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:26][CH3:27])=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH3:25])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)cnc1OC
Product: CCOC(=O)Cc1cnc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCC)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-6-methoxy-pyridin-3-yl]-acetic acid ethyl ester and ethyl chloroformate were reacted as described in Example 5, Step 4 to provide (5-{2-[(N-ethoxycarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-6-methoxy-pyridin-3-yl)-acetic acid ethyl ester. The ester was hydrolyzed to the acid as described in Example 3, Step 7.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:28]I>C1COCC1.[H-].[Na+]>[C:1]([O:5][C:6](=[O:27])[N:7]([CH3:28])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
{2-[4-(3-Trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (333 mg, 0.873 mmol, 1 eq) was dissolved in dry THF (4.5 ml) and NaH, 60% (101 mg, 2.53 mmol, 2.9 eq) was added. After 30 min, the reaction mixture was treated with methyl iodide (545 μl, 8.73 mmol, 10 eq) and was stirred overnight. After overnight the excess NaH was quenched by a slow addition of water, diluted with brine (30 ml) and extracted with Et2O (3×20 ml). Combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give a product methyl-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (306 mg, yield=78%, purity=88%). [M+H]+=396.43 1H NMR (300 MHz; CDCl3) δ/ppm 1.43 (s, 9H), 2.74-2.93(m, 5H), 3.44 (t, J=8.53 Hz, 2H), 6.92-6.99 (m, 2H), 7.09-7.24 (m, 4H), 7.29-7.35 (m, 1H), 7.37-7.45 (m, 1H)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2([F:39])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[OH:24])[CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[ClH:40]>>[ClH:40].[CH2:32]([C:23]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([OH:24])[CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][C:15]([F:39])([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[CH2:16][CH2:17]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OC(CCN1CCC(F)(c2cccc(OCc3ccccc3)c2)CC1)(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Product: Oc1cccc(C2(F)CCN(CCC(O)(Cc3ccccc3)Cc3ccccc3)CC2)c1

Procedure:
The title compound was prepared via the debenzylation of 3-[4-(3-benzyloxyphenyl)-4-fluoropiperidin-1-yl]-1,1-dibenzylpropan-1-ol as described in Step 4 of Example 6, followed by salt formation using methanolic hydrogen chloride in 77% overall yield.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([CH2:15][C:16](=[O:34])[N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]4=[O:33])[CH2:19][CH2:18]3)[C:12]([OH:14])=O)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1>>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([CH2:15][C:16]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[NH:25][C:24]4=[O:33])[CH2:19][CH2:18]3)=[O:34])[C:12]([N:45]3[CH2:44][CH2:43][CH:42]([N:39]4[CH2:38][CH2:37][N:36]([CH3:35])[CH2:41][CH2:40]4)[CH2:47][CH2:46]3)=[O:14])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)Cc1ccc2c(c1)CCC2
Reactant: CN1CCN(C2CCNCC2)CC1
Product: CN1CCN(C2CCN(C(=O)C(CC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)Cc3ccc4c(c3)CCC4)CC2)CC1

Procedure:
Prepared analogously to Example 76e) from and 2-indan-5-ylmethyl-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 1-methyl-4-piperidin-4-yl-piperazine
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4]([CH2:5][C:6]2([CH3:11])[O:10][CH2:9][CH2:8][O:7]2)[C@H:3]1[C:12]([O:14]C)=[O:13].[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1([CH3:16])[C@@H:4]([CH2:5][C:6]2([CH3:11])[O:10][CH2:9][CH2:8][O:7]2)[C@H:3]1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)[C@@H]1[C@H](CC2(C)OCCO2)C1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C[C@H]2[C@@H](C(=O)O)C2(C)C)OCCO1
Temperature: 51 °C
Yield: 59.9 %

Procedure:
To a solution of 0.8 g of methyl (1R,cis)-2,2-dimethyl-3-(2-methyl-1,3-dioxolan-2-ylmethyl)cyclopropanecarboxylate in 5 ml of methanol, was added 1.6 ml of a 10% aqueous sodium hydroxide solution. The mixture was heated at 51° C. for 16 hours. The resulting mixture was diluted with water, acidified to pH 3 with 1 N hydrochloric acid, extracted with diethyl ether, and the extract was dried over magnesium sulfate and stripped to give 0.45 g of the desired product as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3CCCC[O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)O>C(O)=O.[Zn]>[CH:15]([O:14][CH2:13][CH2:12][CH2:11][N:8]1[C:9](=[O:10])[C:4]2[C:3]([CH2:25][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)=[C:2]([Br:1])[CH:24]=[N:23][C:5]=2[N:6]([CH3:22])[C:7]1=[O:21])=[O:16]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Br)cnc21
Agent: [Zn]
Solvent: O=CO
Product: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Br)cnc21
Temperature: 60 °C
Yield: 60 %

Procedure:
To a solution of 6-bromo-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (800 mg, 1.50 mmol) in HCOOH (10 mL) was added Zn dust (484 mg, 7.50 mmol). The reaction was heated at 60° C. for 2 h, cooled to RT and filtered. The filtrate was concentrated to give 3-(6-bromo-5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (419 mg, 60% yield as a solid. LCMS: MH+ 466 and TR=1.589 min. Used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27].C(OC(C)C)(C)C>ClCCl>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:8][C:9]3[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=3)=[N:6][CH:7]=2)[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: COC(=O)Cc1ccc(Oc2ccc(N)cn2)cc1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: COC(=O)Cc1ccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(Cl)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-[4-(5-aminopyridin-2-yloxy)phenyl]acetate (0.44 g, 1.7 mmol) in dichloromethane (7 mL) was added 3,4-dichlorophenylisocyanate (0.353 g, 1.9 mmol), and the resulting reaction solution was stirred for 1 hour at room temperature. To the reaction solution was added diisopropyl ether. Insoluble matter was removed by filtration, to thereby yield 0.60 g of the title compound.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1)(=[O:3])[NH2:2].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:1]([CH:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11]([O:13][C@@H:47]2[CH:48]3[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]3)[CH2:46]2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[NH2:2]
Reactant: NC(=O)C1CCN(C(C(=O)O)c2ccccc2)CC1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)C1CCN(C(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.2 %

Procedure:
2-(4-Carbamoylpiperidin-1-yl)-2-phenylacetic acid (145 mg, 0.55 mmol) was suspended in dry THF (5.5 ml) and DCC (240 mg, 1.16 mmol), HOBT (157 mg, 1.16 mmol) and (R)-quinuclidin-3-ol (148 mg, 1.16 mmol) were sequentially added. The mixture was stirred at room temperature under nitrogen atmosphere for 24 hours. The white solid was filtered off and the solution was evaporated. The crude was purified by flash chromatography (DCM/MeOH/NH4OH=95/5/0.5) to obtain (R)-quinuclidin-3-yl 2-(4-carbamoylpiperidin-1-yl)-2-phenylacetate (78 mg, 38% yield) as an off-white spongy solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:13][O:12][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23])[CH:2]=[CH:3]2)=[O:11]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reaction time: 0.33 h

Procedure:
After a suspension of methyl indole-5-carboxylate (1) (0.30 g, 1.71 mmol), TB AHS (0.19 g, 0.26 mmol) and KOH (0.19 g, 3.42 mmol) in CH2Cl2 (15 mL) was stirred for 20 min, benzenesulfonyl chloride (0.32 ml, 2.57 mmol) was added. The reaction mixture was stirred at room temperature overnight before it was quenched with water and extracted with CH2Cl2 (20 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give a yellow residue.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2c3ccccc3c3ccccc32)cc1

Procedure:
A mixture of 334.4 (2 mol) of carbazole, 472.8 g of p-chloro-nitrobenzene (3 mol) and 691 g (5 mol) of anhydrous potassium carbonate were stirred in 1500 ml of dimethylacetamide for 13 h at reflex temperature. The reaction mixture was then poured into 7 of water and the precipitate separated by suction filtering. Said precipitate was stirred in 4 of water and neutralized with 1 N hydrochloric acid, whereupon the precipitate was filtered again. After drying the solid product was recrystallized from a mixture of tetrahydrofuran and methanol and the yellow product obtained was dried. Yield: 465 g. Melting point: 211° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2.Cl>>[ClH:1].[NH:17]1[C:18]2[C:14](=[CH:13][C:12]([NH:11][C:2]3[C:3]4[CH:10]=[CH:9][NH:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: Nc1ccc2[nH]ccc2c1
Agent: Cl
Product: c1nc(Nc2ccc3[nH]ccc3c2)c2cc[nH]c2n1

Procedure:
Following the procedure described in Example 1, the title compound was prepared from 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 5-aminoindole (7%). HRMS: Calcd. 250.1093, Found 250.1081; anal. RP18-HPLC RT: 2.58 min; HCl salt MP: 218-221° C.