Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:22][CH2:23][N:24]3[C@H:29]4[CH2:30][CH2:31][C@@H:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[C:15]([CH3:20])([NH2:19])[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:42][CH:43]([Cl:47])[C:44](Cl)=[O:45].CCN(C(C)C)C(C)C>>[Cl:42][CH:43]([Cl:47])[C:44]([NH:19][C:15]([C:14]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)([CH2:22][CH2:23][N:24]2[C@H:29]3[CH2:30][CH2:31][C@@H:25]2[CH2:26][CH:27]([N:32]2[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:34]=[C:33]2[CH3:41])[CH2:28]3)[CH2:9][CH2:10]1)=[O:21])([CH3:20])[CH:16]([CH3:17])[CH3:18])=[O:45]
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(N)C(C)C)CC1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(NC(=O)C(Cl)Cl)C(C)C)CC1
Yield: 69.6 %

Procedure:
2,2-dichloro-N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}acetamide was obtained from treating 1,1-dimethylethyl {1-[(4-(3-fluorophenyl-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}carbamate, example 915, (0.623 g, 0.94 mmol) with HCl as outlined in the procedure for Example 890 to form 1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine (0.524 g, 99%). 1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), Dichloro-acetyl chloride (0.013 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2,2-dichloro-N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-1,2-dimethylpropyl}acetamide (0.042 g, 69%) as an oil. ES-LCMS m/z 643 (M+1).
Reaction SMILES: BrC1SC(Cl)=C(Cl)C=1C(=O)CCl.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Br:20].[Br:21][CH2:22][C:23](Br)=[O:24]>>[Br:21][CH2:22][C:23]([C:17]1[CH:18]=[CH:19][C:14]([Br:13])=[C:15]([Br:20])[CH:16]=1)=[O:24]
Reactant: O=C(Br)CBr
Reactant: Brc1ccccc1Br
Agent: O=C(CCl)c1c(Br)sc(Cl)c1Cl
Product: O=C(CBr)c1ccc(Br)c(Br)c1
Yield: 13 %

Procedure:
General procedure described for compounds 1 and 2 starting from 1,2-dibromobenzene and bromoacetyl bromide. Purified by column chromatography column (hexane:ethyl acetate 6:1), yield 13% m.p. 60-61° C., 1H-NMR (CDCl3): δ8.2 (s, 1H, Ar), 7.8 (d, 2H, Ar), 4.4 (s, 2H, CH2); 13C-NMR (CDCl3): δ189.7 (CO), 134.6 (CH), 134.4 (CH), 134.3 (C—CO), 132.0 (C—Br), 128.8(CH), 126.2 (C—Br), 30.4 (CH2); M/z (EI): 360, 358, 356, 354 (M+, 5, 14, 14, 5%), 265, 263, 261 (M-CH2Br, 62, 100, 65%); HPLC: Column μ Bondapack C18, 5 μm, 300 A, (300×3.9 mm), Purity 98%, r.t.=8.73 min, acetonitrile/H2O (0.05% H3PO4+0.04% Et3N) 50/50.
Reaction SMILES: F[C:2]1C=CC(C2C=C(C)N=CC=2NC)=C(OC)C=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][C:27]=2[N:32]([CH3:54])[C:33](=[O:53])[C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([S:44]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)(=[O:46])=[O:45])[CH:35]=2)=[C:22]([O:55][CH3:56])[CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[C:30]([CH3:2])[N:29]=[CH:28][C:27]=2[N:32]([CH3:54])[C:33](=[O:53])[C:34]2[CH:39]=[C:38]([C:40]([F:41])([F:43])[F:42])[CH:37]=[C:36]([S:44]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)(=[O:45])=[O:46])[CH:35]=2)=[C:22]([O:55][CH3:56])[CH:21]=1
Reactant: CNc1cnc(C)cc1-c1ccc(F)cc1OC
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1
Product: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(4-fluoro-2-methoxyphenyl)-N,6-dimethylpyridin-3-amine (example 301, intermediate a) and 3-(morpholinosulfonyl)-5-(trifluoromethyl)benzoic acid (example 256, intermediate) after a reaction time of 15.5 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system eluting with EtOAc (isocratic). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless oil (67%). MS (ESI): m/z=568.15 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][C:14]#[CH:15])=[O:12])=[CH:7][C:6]=1[NH2:16])(=[O:3])[CH3:2].[CH3:17][O:18][C:19]([N:21]=[C:22]=[S:23])=[O:20]>CC(C)=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][C:14]#[CH:15])=[O:12])=[CH:7][C:6]=1[NH:16][C:22]([NH:21][C:19]([O:18][CH3:17])=[O:20])=[S:23])(=[O:3])[CH3:2]
Reactant: COC(=O)N=C=S
Reactant: C#CCS(=O)c1ccc(NC(C)=O)c(N)c1
Solvent: CC(C)=O
Product: C#CCS(=O)c1ccc(NC(C)=O)c(NC(=S)NC(=O)OC)c1

Procedure:
1 G. of 1-acetamido-2-amino-4-propargylsulfinylbenzene in 30 ml. acetone is treated overnight at room temperature with 2 g. methoxy carbonyl isothiocyanate. The solution is concentrated and the residue triturated with ether. Recrystallization yields 2-acetamido-1-(3-methoxycarbonyl-2-thioureido)-5-propargylsulfinylbenzene.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:29]1[CH2:31][C@@H:30]1[CH2:32][O:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]=[CH:36][CH:35]=1>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:31][C@@H:30]([OH:29])[CH2:32][O:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=[CH:36][CH:35]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(OC[C@H]3CO3)ccnc2c1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C[C@@H](O)COc2ccnc3ccccc23)CC1
Temperature: 25 °C
Yield: 46.4 %

Procedure:
Piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (70.3 mg; 0.186 mmol) is dissolved in ethanol (10 mL) at ambient temperature. (R)-4-Oxiranylmethoxy-quinoline (91) (37.4 mg; 0.186 mmol) is added, then the mixture is refluxed for 22 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (50 mg) as a yellow solid. ESMS: MH+ 580.4.
Reaction SMILES: [CH3:1][N:2]([N:4]=[N:5][C:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[Se:8][C:7]=1[C:15]([O:17]C)=[O:16])[CH3:3].[OH-].[Na+]>>[CH3:3][N:2]([N:4]=[N:5][C:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[Se:8][C:7]=1[C:15]([OH:17])=[O:16])[CH3:1]
Reactant: COC(=O)c1[se]c2c(c1N=NN(C)C)CCCC2
Agent: [Na+]
Agent: [OH-]
Product: CN(C)N=Nc1c(C(=O)O)[se]c2c1CCCC2

Procedure:
The hydrolysis of methyl 3-[(dimethylamino)diazenyl]-4,5,6,7-tetrahydrobenzo[2,1-d]selenophene-2-carboxylate with sodium hydroxide gave the required 3-[(dimethylamino)diazenyl]-4,5,6,7-tetrahydrobenzo[1,2-b]selenophene-2-carboxylic acid (compound 9).
Reaction SMILES: [F:1][C:2]1([F:36])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:33][CH3:34])=[C:27]([C:29]([O:31]C)=[O:30])[CH:28]=5)[C:20]([CH3:35])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[OH-].[Li+]>O1CCOCC1>[F:36][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:33][CH3:34])=[C:27]([C:29]([OH:31])=[O:30])[CH:28]=5)[C:20]([CH3:35])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COC(=O)c1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cnc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a flask containing methyl 6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-6′-methoxy-3-methyl-2,3′-bipyridine-5′-carboxylate (0.22 g, 0.45 mmol) was added a mixture of 2M Lithium hydroxide (2.5 mL of 2 M, 5.0 mmol) and 1,4-dioxane (2.5 mL) and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was evaporated and residue was suspended between dichloromethane (10 mL) and 1N hydrochloric acid (10 mL). The organics were dried over sodium sulfate and evaporated to give the product (0.20 g, 95%). ESI-MS m/z calc. 483.12. found 484.5 (M+1)+ Retention time 1.85 minutes.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]([O:13]CC)=[O:12])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CCOC(=O)c1c(C)nn2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nn2ccccc2c1C(=O)O
Temperature: 4 °C

Procedure:
To a solution of ethyl 2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (5.6 g, 24 mmol) in methanol (40 mL, 1000 mmol) was added aqueous sodium hydroxide solution (5.0 mL, 8 M) and the mixture heated to 4° C. for 60 h. The reaction was allowed to cool, hydrochloric acid (5.0 mL, 12 M) and water (150 mL) was added to give a colorless precipitate. The solid was filtered, washed with water and dried in a vacuum oven to give crude 2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid, 2.63 g. A suspension of 2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (2.0 g, 11 mmol), in Acetonitrile (120 mL) and water (60 mL) was degassed and [I,I-Bis(trifluoroacetoxy)iodo]benzene (2.90 g, 6.74 mmol) was added and the reaction heated under argon to 60 C for 15 min. Gave a clear solution. N-Bromosuccinimide (2.40 g, 13.5 mmol) was added and the solution was stirred at 60° C. for 30 minutes under an atmosphere of argon. The color turned dark. The reaction was heated for a further 30 min, allowed to cool, concentrated to remove acetonitrile and the aqueous extracted with EtOAc (3×50 ml). The organics were combined, washed with ascorbic acid solution, water, dried (MgSO4) and concentrated. The product was purified by column chromatography on silica gel eluting with DCM to 0.5% MeOH in DCM. The title compound was isolated as an off white solid, 0.56 g. LC/MS (FA) ES+ 210.9, 212.9.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)=[O:4].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]#[CH:27]>C(OCC)(=O)C.O.O1CCCC1>[CH2:27]([NH:11][CH:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:1])([F:12])[F:13])[CH2:6][CH2:7]1)[C:26]#[CH:25]
Reactant: C#CCBr
Reactant: NC1CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C#CCNC1CCN(C(=O)C(F)(F)F)CC1
Reaction time: 2 h

Procedure:
To a solution of 0.50 g of 1-(trifluoroacetyl)piperidin-4-amine in 10 mL of a mixed solvent of N,N-dimethylformamide and tetrahydrofuran (1:1), 0.41 g of potassium carbonate, 0.42 mL of propargyl bromide were added, and the mixture was heated under reflux while stirring for 2 hours. Thereto were added water and ethyl acetate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.60 g of N-(2-propyn-1-yl)-1-(trifluoroacetyl)piperidin-4-amine as a crude product (crude product A). On the other hand, to a solution of 0.70 g of 1-(trifluoroacetyl)piperidin-4-amine in 7.2 mL of a mixed solvent of N,N-dimethylformamide and tetrahydrofuran (1:1), 0.59 g of potassium carbonate, and 0.30 mL of propargyl bromide were added, and the mixture was heated under reflux while stirring for 1 hour 50 minutes. Thereto were added water and ethyl acetate, and mixed with 0.60 g of the crude product A obtained above, and the mixture was adjusted to pH 1 with 6 mol/L hydrochloric acid. The aqueous layer was separated, and washed with ethyl acetate, ethyl acetate was added thereto, and the aqueous layer was saturated with potassium carbonate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.0 g of N-(2-propyn-1-yl)-1-(trifluoroacetyl)piperidin-4-amine as a brown oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH3:19][C:17]1([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:36]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:38])=[O:37]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NS(=O)(=O)c1ccccc1)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To an ice-cold mixture of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (60 mg, 0.19 mmol, 1.0 eq.) and pyridine (0.3 mL, 3.8 mmol, 20 eq.) in dichloro methane (5 mL) was added benzenesulfonyl chloride (51 mg, 0.29 mmol, 1.5 eq.) under nitrogen. Then the reaction mixture was stirred at room temperature for two hours. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The reaction was quenched with 20 mL water extracted with ethyl acetate (20 mL×2). The combined organic layers were concentrated and the residue was purified by silica gel (petroleum ether/ethyl acetate=2:1) to afford 70 mg of methyl 3,3-dimethyl-2-(2-(phenylsulfonamido)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; yield: 85%; MS (ESI+APCI) M+1=451.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[N:4][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[N:6][C:7]=1[Cl:8].[CH:14](O)=[O:15]>C(OC(=O)C)(=O)C>[Cl:8][C:7]1[C:2]([NH:1][CH:14]=[O:15])=[C:3]([Cl:13])[N:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[N:6]=1
Reactant: O=CO
Reactant: CC(=O)Nc1nc(Cl)c(N)c(Cl)n1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc(Cl)c(NC=O)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
N-(5-Amino-4,6-dichloropyrimidin-2-yl)acetamide (J. Org. Chem. 1975, 40, 3141) was formylated by addition of 96% formic acid (20 mL) to a solution of (0.75 g, 3.4 mmoles) dissolved in acetic anhydride (20 mL). The resulting solution was stirred at 25° C. for one hour and then evaporated to give N-(4,6-dichloro-5-formamido-2-pyrimidinyl)acetamide as tan powder (0.77 g, 91%); structure confirmed by 1H-NMR and mass spectrum. This tan powder (840 mg, 3.37 mmol), (±)-cis-4-amino-2-cyclopentene-1-methanol (940 mg, 8.2 mmol), and triethylamine (0.80 g, 8.0 mmol) were warmed in ethanol (50 mL) in an oil bath (70°-80° C.) under nitrogen for 50 minutes and evaporated to a dark oil which was chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform as a peach-colored solid foam (840 mg). Crystallization from methanol gave white granules (575 mg, 52%); m.p. 189°-193°; 1H-NMR (DMSO-d6) δ 10.23 (br, 1.0, NHAc), 9.3 (br, 1.0, NHCHO), 8.15 and 7.90 (both s, total 1.0, HC=O from two conformers, peaks coalesce at 60° C.), 7.42 and 7.22 (both d, J=8.3, total 1.0, CH--NH from two conformers, peaks coalesce at 60° C.), 5.9 and 5.7 (both m, 2.0, CH=CH), 5.05 (m, 1, CH--N), 4.73 (m, 1, OH) 3.39 (m, 2, CH2OH), 2.72 (m, 1, CH), 2.40 (m, 1, 1/2 CH2), 1.36 (m, 1, 1/2 CH2).
Reaction SMILES: [C:1]([C:3]1[C:4](=[C:18]([C:21]#[N:22])[C:19]#[N:20])[O:5][C:6]([CH3:17])([CH3:16])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][CH:9]=1)#[N:2].[N:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[N+:24]=[N-:25].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].O>C(O)C.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]([C:3]1[C:4](=[C:18]([C:19]#[N:20])[C:21]#[N:22])[O:5][C:6]([CH3:17])([CH3:16])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:25]=[N:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]=2)=[CH:10][CH:9]=1)#[N:2]
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: C#Cc1ccc(C2=C(C#N)C(=C(C#N)C#N)OC2(C)C)cc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(-c2cn(-c3ccccc3)nn2)cc1
Temperature: 50 °C

Procedure:
A mixture of 2-[3-cyano-4-(4-ethynyl-phenyl)-5,5-dimethyl-5H-furan-2-ylidene]malononitrile (150 mg, 0.53 mmol) and azidobenzene (80 mg, 0.67 mmol) in 20 mL ethanol was heated to 50° C. and stirred under N2. Sodium ascorbate (30 mg, 0.15 mmol in 1 mL water) solution was added followed by copper sulfate (20 mg, 0.08 mmol in 2 mL water) solution. The mixture was stirred at 50° C. for 24 h, cooled and poured into cold water (100 mL) and was stirred at room temperature for 1 h. The precipitate formed was filtered off and air-dried. The crude product was further purified by silica gel column chromatography using hexane/EAC 30-50% and then recrystallized from dichloromethane/1-propanol. Yield: 140 mg (65%) mp 298° C.; IR (neat) 2930, 2232, 1580 cm−1; 1H NMR (400 MHz, DMSO) δ 9.44 (s, 1H), 8.19 (d, J=8.4 Hz, 2H), 7.94-8.00 (m, 2H), 7.63-7.65 (m, 2H), 7.53-7.62 (m, 1H), 1.86 (s, 6H); 13C NMR (CDCl3) δ 177.26, 176.73, 145.69, 136.31, 134.75, 129.74, 129.24, 128.76, 126.64, 125.91, 121.12, 120.02, 112.06, 111.17, 110.98, 102.32, 100.33, 55.58 23.82; Anal. Calcd for C24H16N6O: C, 71.28; H, 3.99; N, 20.78. Found: C, 70.95; H, 3.74; N, 26.04. UV-Vis (CH2Cl2): λmax=384 nm ε=3.22×104 L·mol−1 cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:9])=[O:8])[CH3:6])[CH3:2].ClC[C:21]1[CH:35]=[CH:34][C:24]([O:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:9])=[O:8])[CH2:6][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[CH:34][CH:35]=1)[CH3:2]
Reactant: CCCCCCCCS(=O)(=O)C(C)C(=O)OCC
Reactant: ClCc1ccc(OCCN2CCCCC2)cc1
Product: CCCCCCCCS(=O)(=O)C(Cc1ccc(OCCN2CCCCC2)cc1)C(=O)OCC

Procedure:
2-(Octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(octane-1-sulfonyl)-propionic acid ethyl ester (5.0g, 18 mmol) and 1-[2-(4-chloromethylphenoxy)-ethyl]-piperidine (5.6g, 19.7 mmol); Yield 8.9g (96%); amber oil, MS 495.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[NH:31]1[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:31]3[CH2:36][CH2:35][S:34][CH2:33][CH2:32]3)=[O:16])[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)N3CCSCC3)C2)cc1
Temperature: 150 °C

Procedure:
5.00 g (12.1 mmol) of 3-methyl 1-(4-nitrophenyl) 5-(4-ethylphenyl)piperidine-1,3-dicarboxylate (Example 30A), 3.57 g (36.4 mmol) of thiomorpholine and 5.03 g (36.4 mmol) of potassium carbonate were added to 76 ml of DMF and heated in 5 portions at 150° C. for 1.5 h in a single-mode microwave (Emrys Optimizer). For workup, the reaction solutions were combined and filtered, and the residue was purified by means of preparative HPLC. Yield: 3.07 g (67% of theory)
Reaction SMILES: [CH3:1][C@H:2]([NH2:11])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:11][C@@H:2]([CH3:1])[C@@H:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[OH:10])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)N[C@@H](C)[C@H](O)c2ccccc2)cc1
Yield: 37.8 %

Procedure:
Following a procedure similar to that described in Example 6, but using 3 g of (1R,2S)-(-)-norephedrine, 4.36 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 50 ml of absolute methanol and 3.41 g of sodium cyanoborohydride, 2.65 g of the title compound were obtained as crystals, melting at 124° C. (after recrystallization from a mixture of ethyl acetate and hexane).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[Cl:9].C([Sn](CCCC)(CCCC)[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)CCC.CCOC(C)=O.CCCCCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][C:3]=1[Cl:9]
Reactant: Clc1cc(I)ccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Clc1cc(-c2cccs2)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-bromo-2-chloro-4-iodobenzene (2.0 g, 6.30 mmol) in dioxane 30 mL, 2-tributylstannyl thiophene (2.352 g, 6.30 mmol), and 5% equivalent of Pd(PPh3)4 (0.364 g, 0.3155 mmol) is refluxed under nitrogen for 5 h. After cooling and evaporation of the solvent, the residue is dissolved in EtOAc 50 mL. 10% KF 30 mL is added and the solution is stirred at r.t. for 30 min. The resultant precipitate is removed by filtration. The solution is washed with water 20 mL×3, and dried with Na2SO4 and concentrated. The pure product (1.2 g, 4.39 mmol, white solid) is obtained by column chromatography using EtOAc/Hexane, 1-3% ration solvent system. 1H-NMR (CDCl3/300 MHz): 7.74 (d, J=2.1 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.37 (m, 3H), 7.14 (m, 1H). MS (ES−, m/z): 529.2 (M+−Br, 20.0).