Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[O:17]1[CH2:18][CH2:19][N:14]([C:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH2:15][CH2:16]1
Reactant: C1COCCN1
Reactant: O=C1CCCCCCCCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C1=C(N2CCOCC2)CCCCCCCCCC1
Yield: 59.8 %

Procedure:
A two liter three-necked flask was charged with 366 grams (2.0 moles) cyclododecanone, 348 grams (4.0 moles) morpholine, 600 ml toluene and 3.0 grams (0.0158 moles) para-toluene sulfonic acid catalyst. A magnetic stir bar was added along with a few carbon boiling chips. A Dean-Stark water trap and condenser were then attached and the mixture brought to reflux with stirring. After 46 hours reflux, 75 ml. of aqueous phase had been collected. The mixture was then cooled and the excess toluene and morpholine removed at reduced pressure (25-50 mm Hg). The residue was then distilled under vacuum (0.6 mm Hg) to yield 300.5 grams of a viscous clear oil, 1-morpholino-1-cyclododecene, b.p. 135°-150° C., 60% yield.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH:16]([C:20]([OH:22])=O)[CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C=O)C.C(N(CC)CC)C.[NH2:35][CH2:36][C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=1)=[O:38]>C(Cl)Cl.O>[Cl:45][C:41]1[CH:40]=[C:39]([C:37](=[O:38])[CH2:36][NH:35][C:20]([CH:16]2[O:17][CH2:18][CH2:19][N:14]([CH2:13][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:15]2)=[O:22])[CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Reactant: NCC(=O)c1cccc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CNC(=O)C1CN(Cc2ccccc2)CCO1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.4 %

Procedure:
Oxalyl chloride (1.32 mL, 15.03 mmol) was added to the suspension of 4-(phenylmethyl)-2-morpholinecarboxylic acid (2.218 g, 10.02 mmol) and DMF (0.155 mL, 2.005 mmol) in CH2Cl2 (100 mL) at 0° C. in 10 minutes, and the resulting mixture was stirred at 25° C. for 2 hours. The mixture was concentrated, and the resulting residue was dissolved in CH2Cl2 (100 mL) and triethylamine (3.07 mL, 22.05 mmol). 2-Amino-1-(3-chlorophenyl)ethanone (1.7 g, 10.02 mmol) was added to the brown solution at 0° C., and the reaction mixture was stirred at 25° C. for 3 hours. Water (150 mL) was added to the reaction mixture, and the aqueous mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered, and evaporated. The resulting residue was purified by silica gel chromatography using as eluent 50% EtOAc in petroleum ether to afford the title compound (800 mg) as a pale yellow solid. LC-MS (ES) m/z=373 [M+H]+.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([N:16]1[CH2:22][CH2:21][CH2:20][C@H:17]1[CH:18]=[O:19])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[C:9]([N:16]1[CH2:22][CH2:21][CH2:20][C@H:17]1[C:18](=[O:19])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: Cl[Mg]c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)c1ccccc1

Procedure:
10 ml (20 mmol) 2 M phenylmagnesium chloride (tetrahydrofuran) and 1.99 g (10 mmol) BOC-L-prolinal were allowed to react at −60–40° C. for 60 min according to procedure F. Yield of the crude product 3.06 g. The product was purified with a silica column using 16% ethyl acetate in petroleum ether as eluent. Yield 2.18 g (7.6 mmol, 76%). The product was oxidized to the corresponding ketone according to procedure G. Yield of crude product 3.15 g. The product was purified with a silica column using 20–25% ethyl acetate in petroleum ether as eluent. Yield 1.65 g (6.0 mmol, 79%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:3]1.Cl[CH2:43][C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]=1[O:54][CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60]>>[CH3:60][Si:59]([CH3:61])([CH3:62])[CH2:58][CH2:57][O:56][CH2:55][O:54][C:45]1[C:46]2[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:52]=[CH:53][C:44]=1[CH2:43][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][O:15][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:3]1
Reactant: C[Si](C)(C)CCOCOc1c(CCl)ccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2OCOCC[Si](C)(C)C)C1

Procedure:
(cc) In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-trityloxymethyl-phenyl)-piperidine-1-carboxylate [Example 22(h)] with 2-chloromethyl-1-(2-trimethylsilanyl-ethoxymethoxy)-naphthalene [Example 6(c)] there was obtained tert-butyl (3RS,4RS)-3-[1-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-4-(4-trityloxymethyl-phenyl)-piperidine-1-carboxylate. Selective cleavage of the trityl group analogously to Example 86(u) (β) gave tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-[1-(2-trimethylsilanyl-ethoxymethoxy)naphthalen-2-ylmethoxy]-piperidine-1-carboxylate, acylation of which with 3-methoxy-benzoyl chloride analogously to Example 22(k) gave tert-butyl (3RS,4RS)-4-[4-(3-methoxy-benzoyloxymethyl)-phenyl]-3-[1-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate as a colourless oil, MS: 745 (M+NH4)+.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[I:32]N1C(=O)CCC1=O>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([I:32])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Reactant: O=C1CCC(=O)N1I
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2I)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(R)-4-[6-(trans-4-tert-Butylcyclohexyloxy)naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.4719 g, 0.001237 mol) was dissolved in methylene chloride (5.00 mL, 0.0780 mol) in a 40 mL vial. N-Iodosuccinimide (0.312 g, 0.00138 mol) and zirconium tetrachloride (0.043 g, 0.00018 mol) were added and the mixture was stirred at room temperature. After 3 hours the reaction was complete. The mixture was adsorbed onto silica and purified by flash is chromatography (0-60% EtOAc in hexanes) to give 0.112 g of the title compound (42% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH2:8][CH:9]([NH2:11])[CH3:10])[CH:7]=1.Cl[C:14]1[CH:19]=[CH:18][NH:17][C:16](=[O:20])[C:15]=1[C:21]1[NH:37][C:24]2=[CH:25][C:26]3[C:27](=[O:36])[N:28]([CH:33]([CH3:35])[CH3:34])[C:29](=[O:32])[C:30]=3[CH:31]=[C:23]2[N:22]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH2:8][CH:9]([NH:11][C:14]2[CH:19]=[CH:18][NH:17][C:16](=[O:20])[C:15]=2[C:21]2[NH:22][C:23]3=[CH:31][C:30]4[C:29](=[O:32])[N:28]([CH:33]([CH3:35])[CH3:34])[C:27](=[O:36])[C:26]=4[CH:25]=[C:24]3[N:37]=2)[CH3:10])[CH:7]=1
Reactant: CC(C)N1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O
Reactant: Cc1ccc(F)cc1CC(C)N
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C(C)C)C3=O
Yield: 127.3 %

Procedure:
Racemic 1-(5-fluoro-2-methylphenyl)propan-2-amine (0.13 g) and 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-isopropylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.2965 mmol) were submitted to general procedure A to give 0.184 g the title compound. 1H NMR (500 MHz, CDCl3) δ 13.07 (s, 1H), 11.14 (d, 1H), 10.09 (s, 1H), 8.07 (s, 1H), 7.87 (s, 1H), 7.16-7.14 (m, 1H), 7.10-7.06 (m, 1H), 6.97 (d, 1H), 6.89-6.77 (m, 2H), 5.95 (d, 1H), 4.93 (br s, 1H), 4.57 (br s, 1H), 4.02 (br s, 1H), 3.14-3.04 (m, 1H), 3.04-2.94 (m, 1H), 2.36 (s, 3H), 1.54 (d, 6H), 1.48 (d, 3H). APCI MS: m/z 485.9 (M+1).
Reaction SMILES: C[S:2]([C:4]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])=O>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[SH:2][C:4]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CS(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1C#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1S
Reaction time: 1 h
Yield: 50.4 %

Procedure:
2.2 g (7.1 mmol) of 2-methylsulfinyl-4-(4-trifluoromethylphenyl)benzonitrile prepared in (b) was stirred in 15 ml of trifluoroacetic anhydride at room temperature for 12 hours, and the low-boiling matters were distilled off under reduced pressure. 50 ml of methanol and 3 g of 20% aqueous potassium hydroxide were added to the residue, and the reaction was carried out for 1 hour. The solvent was distilled off under reduced pressure, and the residue was mixed with 5% aqueous sulfuric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.0 g of 2-mercapto-4-(4-trifluoromethylphenyl)benzonitrile (yield 51.0%), which was used in Example 1 as the starting material.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[C:16]([CH:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)([CH3:19])([CH3:18])[CH3:17].[BH4-].[Na+]>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:16]([C@H:20]1[CH2:21][CH2:22][C@H:23]([NH:26][CH:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=3)[O:5][CH2:4][CH2:3]2)[CH2:24][CH2:25]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: COC(=O)c1ccc2c(c1)OCCC2=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)OCCC2N[C@H]1CC[C@H](C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of methyl 4-oxochromane-7-carboxylate (2.06 g, 9.99 mmol), titanium (IV) isopropoxide (3.27 mL, 10.99 mmol), 4-tert-butylcyclohexyl amine (3.10 g, 19.98 mmol) in absolute ethanol (40 mL) was stirred under nitrogen at room temperature for 17 h. Sodium borohydride (0.45 g, 11.99 mmol) was then added and the resulting mixture was stirred for an additional 3 h at room temperature. The reaction was quenched by pouring into aqueous ammonia (2N, 100 mL). The resulting inorganic precipitate was filtered off through Celite and washed with CH2Cl2 (200 mL). The organic layer was separated and the remaining aqueous layer was extracted once with CH2Cl2 (100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. Chromatography (15% EtOAc in Hexane) afforded methyl 4-[(trans-4-tert-butylcyclohexyl)amino]chromane-7-carboxylate and the corresponding cis product (less polar). HPLC/MS: m/z=346.3 (M+1), Rt=1.95 min. 1H NMR (CDCl3): δ 7.57 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.50 (1H, d, J=2.0 Hz), 7.35 (1H, d, J=8.0 Hz), 4.36 (1H, dt, J=2.5 Hz, 11.0 Hz), 4.27 (11H, dt, J=4.0 Hz, 11.0 Hz), 3.97 (1H, t, J=4.0 Hz), 3.93 (3H, s), 2.64-2.58 (1H, m), 2.18-2.15 (1H, m), 2.11-2.04 (1H, m), 1.97-1.91 (2H, m), 1.91-1.84 (2H, m), 1.22-1.02 (5H, m), 0.92 (9H, s).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([OH:23])=O)=[CH:16][CH:15]=[CH:14]3)[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].O=S(Cl)[Cl:26]>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([Cl:26])=[O:23])=[CH:16][CH:15]=[CH:14]3)[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: O=S(Cl)Cl
Reactant: NC(=O)c1cc(Oc2ccc3c(C(=O)O)cccc3c2)ccn1
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(Oc2ccc3c(C(=O)Cl)cccc3c2)ccn1
Temperature: 110 °C

Procedure:
A mixture of 6-(2-carbamoylpyridin-4-yloxy)-1-napthoic acid (Step a, 1.0 g, 3.2 mmol) and SOCl2 (600 μL, 8.1 mmol) in toluene (25 mL, Aldrich) was heated at 110° C. for 7 h. The resulting solution was concentrated under reduced pressure and azeotroped from toluene (3×10 mL) to provide the title compounds as a yellow solid. MS (ESI, pos. ion) m/z: 327.5 (M+1). Mass Calc'd for C17H11ClN2O3: 326.73.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:14])=[N:5][CH:6]=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2].Cl.NCC1C=C(C=C(OC)C=1)C(OC)=O>>[NH2:2][CH2:1][C:3]1[C:4]([CH3:14])=[N:5][CH:6]=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1cnc(C)c(C#N)c1
Agent: COC(=O)c1cc(CN)cc(OC)c1
Agent: Cl
Product: CCOC(=O)c1cnc(C)c(CN)c1

Procedure:
Ethyl 5-(aminomethyl)-6-methylnicotinate was prepared from ethyl 5-cyano-6-methylnicotinate in an analogous manner to Intermediate 2.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:5][C:6]([O-:8])=O.[K+].[Cl:14][C:15]1[CH:23]=[CH:22][C:18](C(O)=O)=[CH:17][CH:16]=1.S(Cl)(Cl)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.CN(C)C=O.C1(C)C=CC=CC=1.C(N(CC)CC)C>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:6](=[O:8])[CH2:5][C:4]([O:10][CH2:11][CH3:12])=[O:9])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (17 ml) and magnesium chloride (5.5 g) were added to a suspension of potassium ethyl malonate (8.2 g) in ethyl acetate (100 ml) under ice cooling, and the mixture was stirred for 18 hours while the temperature of the system was gradually raised to room temperature. On the other hand, a suspension composed of 4-chlorobenzoic acid (5.0 g), thionyl chloride (12 ml), N,N-dimethylformamide (one drop) and toluene (100 ml) was heated under reflux for 1 hour, and the reaction mixture was then concentrated. The resultant residue was dissolved in ethyl acetate, and the solution was added dropwise to the reaction mixture previously prepared under ice cooling. The resultant mixture was stirred for 18 hours while the temperature of the system was gradually raised to room temperature. A 10% aqueous solution of citric acid was added to the reaction mixture, and the mixture was stirred for 30 minutes to separate the resultant organic layer. The organic layer was washed with saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was isolated and purified by column chromatography on silica gel (chloroform) to obtain the title compound (6.4 g).
Reaction SMILES: [CH2:1]([CH:9]1[C:13]2[NH:14][C:15]([C:17]([O:19]CC)=[O:18])=[CH:16][C:12]=2[CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>>[CH2:1]([CH:9]1[C:13]2[NH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:12]=2[CH2:11][CH2:10]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc2c([nH]1)C(CCc1ccccc1)CC2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc2c([nH]1)C(CCc1ccccc1)CC2
Yield: 28.6 %

Procedure:
The title compound was synthesized from ethyl 6-phenethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (87.3 mg, 0.31 mmol) and NaOH according to General Procedure 7. The crude product was purified by preparative HPLC (50%-100% methanol/water with 1% formic acid and 1% acetonitrile) to afford 22.6 mg of 6-phenethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (27) in 29% yield. LCMS m/e 254 (M−H); 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.18-7.28 (m, 4H), 7.11-7.17 (m, 1H), 6.58 (s, 1H), 3.00-3.10 (m, 1H), 2.48-2.71 (m, 5H), 2.00-2.15 (m, 2H), 1.66-1.79 (m, 1H).
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[F:39][C:40]1[CH:41]=[C:42]([CH:47]=[C:48]([F:51])[C:49]=1F)[C:43]([O:45][CH3:46])=[O:44].N[C@H](C(O)=O)[C@@H](C)O>C(OCC)(=O)C.CS(C)=O>[C:16]([O:15][C:14]([N:13]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:25][N:24]([C:49]2[C:48]([F:51])=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][C:40]=2[F:39])[CH2:23]1)[C@@H:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:12])=[O:20])([CH3:18])([CH3:19])[CH3:17]
Reactant: COC(=O)c1cc(F)c(F)c(F)c1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: C[C@@H](O)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cc(F)c(N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)c(F)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 10 ml DMSO solution of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate was mixed with 1.3 g of potassium carbonate and 1.0 g of methyl 3,4,5-trifluorobenzoate and stirred overnight at 110° C. Thr reaction solution was mixed with ethyl acetate, washed with water and dried with anhydrous sodium sulfate. This was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (hexane-ethyl acetate) to obtain 2.1 g of methyl 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-3,5-difluorobenzoate as a colorless amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:27])=[CH:8][N:7]=1)=O.[Si]([N:36]=[C:37]=[O:38])(C)(C)C>C1COCC1.CC(O)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:11]2[C:6]([C:4]3[C:3]4[C:2](=[CH:31][CH:30]=[CH:29][CH:28]=4)[NH:1][C:37](=[O:38])[N:36]=3)=[N:7][CH:8]=[C:9]([Cl:27])[CH:10]=2)(=[O:15])=[O:14])=[CH:17][C:18]=1[C:23]([F:24])([F:25])[F:26]
Reactant: C[Si](C)(C)N=C=O
Reactant: Nc1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=c1nc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c2ccccc2[nH]1
Temperature: 65 °C

Procedure:
To a stirred solution of N-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide (48 mg, 0.097 mmol) in anhydrous THF (2 mL) and AcOH (400 L) was added TMSisocyanate (32 L, 0.22 mmol) and the resulting mixture was heated at 65° C. overnight. The crude reaction mixture was directly purified by HPLC to provide 4-Chloro-N-[5-chloro-2-(2-oxo-1,2-dihydro-quinazolin-4-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 10.50 (br s, 1H), 8.58 (d, J=2.4 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H), 7.80-7.76 (m, 1H), 7.65 (dd, J=8.4, 2.4 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.23-7.22 (m, 2H); Mass spectrum m/z: 515.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:11][S:12][C:13]2[NH:14][C:15]3[C:16]([N:21]=2)=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:11][S:12]([C:13]2[NH:14][C:15]3[C:16]([N:21]=2)=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:30])=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(C)cnc(CSc2nc3ncccc3[nH]2)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1c(C)cnc(CS(=O)c2nc3ncccc3[nH]2)c1C

Procedure:
0.4 Gram of 2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]imidazo[4,5-b]pyridine was dissolved in 40 ml of chloroform, then this solution was stirred under ice-cooling condition, 0.27 g of m-chloroperbenzoic acid (85%) was added thereto. The whole reaction mixture was stirred at the same temperature for 20 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, the residue thus obtained was washed with diethyl ether. Recrystallization from ethanol to yield 1.15 g of 2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]imidazo[4,5-b]pyridine in the form of light brown powdery crystals. Melting point: 169°-170° C.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[N:9][NH:10][CH:11]=1)=[O:5].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:26]([O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:10]1[CH:11]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:15][CH:14]=[CH:13][C:12]=2[F:16])[CH:8]=[N:9]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCOc1ccccc1CBr
Reactant: O=C(Nc1cn[nH]c1)c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccccc1Cn1cc(NC(=O)c2c(F)cccc2F)cn1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
2,6-Difluoro-N-1H-pyrazol-4-ylbenzamide (for a preparation see intermediate 2, 45 mg, 0.20 mmol), 1-(bromomethyl)-2-(butyloxy)benzene (for a preparation see intermediate 4, 56 mg, 0.23 mmol) and potassium carbonate (42 mg, 0.30 mmol) were weighed into a vial with a stirrer. DMF (0.5 ml) was added, the vial was capped and the mixture was stirred at ambient temperature for 26 h. The reaction mixture was filtered, washing with MeOH to give a total volume of 1 ml. This solution was purified by MDAP Sunfire C18 column (Method B) using acetonitrile-water with a formic acid modifier. The solvent was removed to give the title compound (25 mg) as a colourless gum; LCMS (System 4): MH+=386, tRET=3.02 min.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.C1(C#C)C=CC=CC=1.[C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)#N>C(#N)C1C=CC=CC=1>[C:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)#[C:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C#CCCCCCC
Reactant: N#Cc1ccncc1
Solvent: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CCCCCCC#Cc1ccncc1
Reaction time: 21 h
Yield: 80 %

Procedure:
The procedure was identical to Example 2, with the exception that 1-octyne (0.590 ml; 0.441 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 4-cyanopyridine (0.208 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 21 h at room temperature showed the presence of 1.60 mmol (80% yield) of 4-(1-octynyl)pyridine and no remaining 4-cyanopyridine in the reaction mixture.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+]>>[CH2:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][C:16]2[CH:17]=[CH:18][C:13]([C@@H:4]([NH:5][C:6]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7])[C:3]([OH:33])=[O:2])=[CH:14][CH:15]=2)=[CH:21][CH:22]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(Oc2ccc(Cc3ccccc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(Oc2ccc(Cc3ccccc3)cc2)cc1
Yield: 99 %

Procedure:
The title compound was prepared from the product from step 2 (1.3 g, 2.2 mmol) and NaOH (0.2 g, 4.4 mmol) using the Step 7 procedure of example 1 with 99% yield (1.0 g). 1HNMR (CDCl3) δ 1.43 (s, 9H), 3.86 (s, 2H), 4.71 (br, 1H), 4.93 (br, 1H), 5.76 (br, 1H), 6.75 (m, 4H), 7.02 (d, J=6.8 Hz, 2H), 7.13 (m, 3H), 7.23 (m, 4H), MS m/z 432 (M−1).