Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH:6]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:8])[CH3:7].[CH3:19][O:20][CH:21]([O:28][CH3:29])/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25].P(O)(O)([O-])=O.[Na+]>O1CCCC1.CCCCCC>[C:15]1([CH3:18])[CH:16]=[CH:17][C:12]([S:9]([C:6]([CH3:7])([CH3:8])[CH:22]([CH:21]([O:28][CH3:29])[O:20][CH3:19])[CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)C(C)C)cc1
Reactant: COC(=O)/C=C/C(OC)OC
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(C(OC)OC)C(C)(C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.25 h

Procedure:
3.4 ml of a 1.95 M of butyllithium per liter of hexane were added at -70° C. to a mixture of 1.24 g of p-tolyl isopropyl sulfone in 13 ml of tetrahydrofuran and after stirring the mixture for 15 minutes, a solution of 1 g of methyl (E) 4,4-dimethoxy-2-butenoate in 20 ml of tetrahydrofuran was slowly added thereto. The mixture was stirred at -20° C. for one hour and was then poured into an aqueous monosodium phosphate solution. The mixture was extracted with methylene chloride and the organic phase was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an ether-petroleum ether (b.p. =40° to 70° C.) mixture to obain 1.1 g of methyl 4-p-tolylsulfonyl-4-methyl-3-dimethoxymethyl-pentanoate melting at 110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH2:12][CH:11]([CH2:13][CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[N:10]([CH3:26])[C:9]2=[O:27])=[CH:5][CH:4]=1.[CH2:30]([O:32][C:33](=[O:46])[C:34]([O:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][C:39]=1[CH3:45])([CH3:36])[CH3:35])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:30]([O:32][C:33](=[O:46])[C:34]([O:37][C:38]1[CH:43]=[CH:42][C:41]([O:15][CH2:14][CH2:13][CH:11]2[CH2:12][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=3)[C:9](=[O:27])[N:10]2[CH3:26])=[CH:40][C:39]=1[CH3:45])([CH3:35])[CH3:36])[CH3:31]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: COc1ccc(CN2CC(CCOS(=O)(=O)c3ccc(C)cc3)N(C)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1C
Temperature: 65 °C
Yield: 92.4 %

Procedure:
To a mixture of toluene-4-sulfonic acid 2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester (0.100 g, 0.239 mmole) and 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (0.063 g, 0.262 mmole) in anhydrous DMF (2.0 mL), is added cesium carbonate (0.093 g, 0.287 mmole). After heating at 65° C. for about 16 hours, the reaction mixture is partitioned between ethyl acetate (5 ml) and 1.0 N HCl aq. (5 ml), the aqueous layer is extracted with more ethyl acetate (2×5 ml). The combined organic layer is washed with brine (3×5 ml). The organic layer is dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography using silica gel (0-40% acetone/hexane) produces a colorless oil (0.107 g, 91%). Mass [EI+] 485 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[OH:13][C@H:14]([CH3:27])[CH2:15][C:16]#[C:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+]>O>[C:1]([O:13][C@H:14]([CH3:27])[CH2:15][C:16]#[C:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: C[C@@H](O)CC#CCOCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)O[C@H](C)CC#CCOCc1ccccc1
Temperature: 60 °C
Yield: 98.2 %

Procedure:
Next, acetic anhydride (23.6 ml, 0.25 mole) and sulfuric acid (0.13 ml) were added to stirred 5-(R)-hydroxy-1-benzyloxy-2-hexyne (34 g, 0.17 mole), prepared above, at 25° C., and the reaction was heated to 60° C. for 20 hours. Water (100 ml) was added, followed by solid sodium bicarbonate (33 g, 0.40 mole) in portions. The reaction mixture was extracted with ethyl acetate (80 ml), the solvent dried (magnesium sulfate) and evaporated to afford 5-(R)-acetoxy-1-benzyloxy-2-hexyne (41.1 g, 99% yield) as a brown oil.
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH:12]=[C:13]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:8]2=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH:12]=[C:13]([CH2:14][C:15]([OH:17])=[O:16])[C:8]2=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCCc1ncc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 84 %

Procedure:
To a solution of 20 mg (0.039 mmol) of biphenyl imidazolyl tert-butyl ester (the title compound of Example 17) in 0.5 mL of chloroform was added 0.25 mL of TFA, and the progress of the reaction was monitored by 1H NMR. The resulting solution was stirred at room temperature for 75 min. The mixture was quenched with methanol and concentrated in vacuo. The residue was dissolved in a minimum amount of methanol and triturated with dropwise addition of methylene chloride-ether-hexane to give 15 mg (84%) of the title compound of Example 18 as a solid: mp 148°-171° C. (decomposed); 1H NMR (CD3OD) δ 0.83 (t, J=7.25 Hz, 3H), 1.10-1.60 (m, 4H), 2.68-2.95 (m, 3H), 3.13-3.35 (m, 1H), 3.48-3.60 (m, 2H), 5.80-6.0 [m (with d at 5.87, J=7.66 Hz), 2H], 7.10 (br s, 4H), 7.40-7.75 (m, 5H); HRMS. calcd for M+H: 455.2195. Found: 455.2215.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[CH:7]12[CH2:13][CH:10]([CH:11]=[CH:12]1)[CH:9]([C:14](Cl)=[O:15])[CH:8]2[C:17](Cl)=[O:18]>C1COCC1>[C:2]([O:4][C:17]([CH:8]1[CH:9]([C:14]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:15])[CH:10]2[CH2:13][CH:7]1[CH:12]=[CH:11]2)=[O:18])([CH3:5])([CH3:3])[CH3:1]
Reactant: O=C(Cl)C1C2C=CC(C2)C1C(=O)Cl
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1C2C=CC(C2)C1C(=O)OC(C)(C)C

Procedure:
34 g (0.3 mol) of potassium t-butoxide was dissolved in 250 mL of THF in a round-bottom flask and then 22 g (0.1 mol) of 5-norbornene-2,3-dicarbonyl chloride was slowly added thereto at room temperature to be reacted at 45° C. for about 12 hours.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:43]1([C:49]2[N:50]=[C:51]([C:54]3([CH2:60][NH2:61])[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)[S:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[C:43]1([C:49]2[N:50]=[C:51]([C:54]3([CH2:60][NH:61][C:13](=[O:15])[C:12]4[CH:16]=[C:8]([C:5]5[N:4]=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=5)[CH:9]=[N:10][CH:11]=4)[CH2:55][CH2:56][O:57][CH2:58][CH2:59]3)[S:52][CH:53]=2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: O=C(NCC1(c2nc(-c3ccccc3)cs2)CCOCC1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 33.9 %

Procedure:
To a stirred solution of compound 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid (100 mg, 0.4 mmol) in dry DMF (5 mL) were added HATU (180 mg, 0.46 mmol) followed by hydrochloride salt of (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (120 mg, 0.4 mmol) and NMM (0.12 mL, 1.1 mmol) at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for further 10 h. The reaction mixture was diluted with EtOAc. The organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 50-60% EtOAc in petroleum ether) to get pure product N-((4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methyl)-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide (70 mg, yield 37%): 1H NMR (400 MHz, CDCl3) δ 9.43 (d, J=2 Hz, 1H), 9.21 (br s, 1H), 8.76 (br s, 1H), 7.87 (d, J=7 Hz, 2H), 7.75 (br s, 1H), 7.53 (s, 1H), 7.41-7.32 (m, 3H), 3.99-3.95 (m, 2H), 3.79-3.74 (m, 2H), 2.35-2.32 (m, 2H), 2.07-2.03 (m, 2H). MS (ESI) m/z: Calculated for C24H20F3N5O3S: 515.12. found: 516.0 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][N:9]([C@@H:16]2[CH2:18][C@H:17]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)C(=O)C(F)(F)F)[CH2:4][CH2:3]1.[CH:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:19]1([C@@H:17]2[CH2:18][C@H:16]2[NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([NH:1][CH2:25][C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)[CH2:7][CH2:6]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N[C@H]1CC[C@H](CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(O)c1ccc(CN[C@H]2CC[C@H](CN[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-((trans-4-aminocyclohexyl)methyl)-2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamide (100 mg, 0.294 mmol) in 1,2-dichloroethane (3 mL) was added 4-formylbenzoic acid (48.5 mg, 0.323 mmol). The reaction mixture was refluxed for 2 minutes, then cooled down to room temperature. Sodium triacetoxyborohydride (187 mg, 0.881 mmol) was added. The reaction mixture was stirred 1 hour at room temperature. The reaction mixture was evaporated, and dissolved in 1 mL of water and 2 mL of methanol. The reaction mixture was injected on preparatory HPLC (5 to 40% AcCN: H2O with 0.1% formic acid modifier). The fractions were collected and evaporated. The resulting oil was dissolved in 6 ml of EtOH and 3 ml of 1 M NaOH. The reaction mixture was stirred for 20 minutes then it was evaporated. The resulting product was injected on preparatory HPLC (2 to 20% AcCN: H2O with 0.1% formic acid modifier). The fractions were collected and evaporated. 1 mL of 1 M HCl was added to each fraction and product was evaporated. 4-(((trans-4-(((trans-2-Phenylcyclopropyl)amino)methyl)cyclohexyl)amino)methyl)benzoic acid (60 mg, 0.151 mmol, 51.3% yield) was isolated as white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.68-13.69 (m, 1H), 9.23-9.66 (m, 4H), 7.99 (d, J=8.34 Hz, 2H), 7.72 (d, J=8.34 Hz, 2H), 7.28-7.35 (m, 2H), 7.11-7.26 (m, 3H), 4.24 (br. s., 2H), 2.79-3.09 (m, 4H), 2.58 (ddd, J=3.54, 6.38, 10.04 Hz, 1H), 2.20 (d, J=10.36 Hz, 2H), 1.96 (d, J=11.12 Hz, 2H), 1.65-1.85 (m, 1H), 1.54-1.66 (m, 1H), 1.46 (q, J=12.38 Hz, 2H), 1.18-1.34 (m, 1H), 1.03 (q, J=12.04 Hz, 2H); LC-MS Rt=0.56 min; MS (ESI): 379.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[C:4]([C:10]([CH3:14])([CH3:13])[CH2:11]Cl)[CH:3]=1.Cl.N1C=CC=CC=1.N1C2C(=CC=CC=2)C=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:14][C:10]([CH3:11])([CH3:13])[C:4]=2[CH:3]=1
Reactant: COc1ccc(Br)cc1C(C)(C)CCl
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: c1ccncc1
Product: CC1(C)COc2ccc(Br)cc21
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A mixture of 4-bromo-2-(2-chloro-1,1-dimethyl-ethyl)-1-methoxy-benzene (65 g, 0.234 mol), pyridine hydrochloride (121.8 g, 1.054 mol) and quinoline (110.67 mL, 0.936 mol) was refluxed at 164° C.–167° C. under argon for 5 hrs. After cooling to room temperature the reaction mixture was treated with ice-cold 6N HCl and extracted twice with ether. The organic layers were combined, dried (Mg2SO4), filtered and evaporated. The residue was purified on silica gel (10% ethyl acetate in hexane) to give 52 g of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (98%). 1H NMR (300 MHz; CDCl3): δ 1.32 (s, 6 H), 4.23 (s, 2 H), 6.67 (d, J=8.1 Hz, 1 H), 7.19 (m, 2 H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:21])([F:20])[C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1.Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[CH3:33][N:32]1[C:25]2[N:26]([C:27](=[O:29])[N:28]=[C:23]([O:19][CH2:18][C:15]3[CH:16]=[CH:17][C:12]([O:11][C:9]4[CH:8]=[CH:7][N:6]=[C:5]([C:4]([F:3])([F:20])[F:21])[CH:10]=4)=[CH:13][CH:14]=3)[CH:24]=2)[CH2:30][CH2:31]1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Agent: [H-]
Agent: [Na+]
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccnc(C(F)(F)F)c3)cc1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (4.85 mg, 0.121 mmol), (4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol (35 mg, 0.130 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (24.13 mg, 0.130 mmol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:13][CH:12]([OH:14])[CH2:11][CH:10]1[CH:15]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:16][CH:17]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:8].C(N([CH2:45][CH3:46])CC)C.[CH3:47][C@@H:48]([C@@H:55]1[C@@:59]2([CH3:77])[CH2:60][CH2:61][CH:62]3[C@@:67]4([CH3:76])[CH2:68][CH2:69][CH:70]([O:72][C:73](Cl)=[O:74])[CH2:71][C:66]4=[CH:65][CH2:64][CH:63]3[CH:58]2[CH2:57][CH2:56]1)CCCC(C)C.CO.C(Cl)(Cl)Cl>ClCCl>[CH3:76][C:67]12[CH2:68][CH2:69][CH:70]([O:72][C:73](=[O:74])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:9]3[CH2:13][CH:12]([OH:14])[CH2:11][CH:10]3[CH:15]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:16][CH:17]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[O:8])[CH2:71][C:66]1=[CH:65][CH2:64][CH:63]1[CH:62]2[CH2:61][CH2:60][C:59]2([CH3:77])[CH:58]1[CH2:57][CH2:56][CH:55]2[CH2:48][CH2:47][CH2:2][CH2:3][CH2:4][CH2:5][CH2:45][CH3:46]
Reactant: CCN(CC)CC
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCC1CCC2C3CC=C4CC(OC(=O)NCCCCCC(=O)N5CC(O)CC5C(OC(c5ccc(OC)cc5)c5ccc(OC)cc5)c5ccccc5)CCC4(C)C3CCC12C
Temperature: 0 °C
Reaction time: 2 h
Yield: 187 %

Procedure:
Referring to scheme 2, compound 5 (13.3 g, 25 mmol) was dissolved in anhydrous dichloromethane (100 mL) and cooled to 0° C. To the solution were added triethylamine (7.5 g, 10 mL, 75 mmol) and cholesteryl chloroformate (11.24 g, 25 mmol) successively. The reaction temperature was brought to ambient temperature and stirred further for 2 h. The completion of the reaction was ascertained by TLC (10% MeOH/CHCl3). The reaction mixture was evaporated under the vacuum to afford the crude product. Compound 6 (22.1 g, 93%) was obtained as a white foamy solid after column chromatography over silica gel.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:13])[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:27][CH2:28][CH:29]([OH:31])[CH3:30]>C1(C)C=CC=CC=1>[CH3:13][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][C:4]1[CH:3]=[CH:2][N:27]([CH2:28][CH:29]([OH:31])[CH3:30])[C:5]=12
Reactant: Cc1cccc2c1CC(CC=O)C2=O
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc2c1Cc1ccn(CC(C)O)c1-2
Reaction time: 0.75 h
Yield: 27.5 %

Procedure:
A solution of 1.9 g of (RS)-2-(2-oxoethyl)-4-methyl-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator, A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 0.63 g (28%) of (RS)-1-(5-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol was obtained as a white solid which was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][C:30]#[N:31])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32].Cl.C(N(CC)CC)C.[N-:41]=[N+:42]=[N-:43].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][C:30]3[NH:43][N:42]=[N:41][N:31]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(F)ccc1-c1nc(NCCC#N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(NCCc2nnn[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 45.4 %

Procedure:
A suspension of the product of Example 206 (200 mg, 0.46 mmol), triethylamine hydrochloride (630 mg, 4.6 mmol) and NaN3 (299 mg, 4.6 mmol) in toluene (20 mL) was heated to toluene reflux for 60 h. Preparative HPLC afforded the title compound 100 mg (45%). LC-MS: 479.0 (WM+, m/z), 1.82 (Rt, min).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][N:9]=[C:8]2[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][S:19][C:20](=[N:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25])SC.C(N(CC)CC)C>C(#N)C>[CH3:18][S:19][C:20]([N:10]1[CH2:11][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9]1)=[N:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)(=[O:25])=[O:26]
Reactant: c1ccc(C2CNN=C2c2cccnc2)cc1
Reactant: CSC(=NS(=O)(=O)c1ccc(Cl)cc1)SC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSC(=NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2cccnc2)=N1
Yield: 34.5 %

Procedure:
Part C: Crude 4-phenyl-3-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole (9.81 g, 0.044 mol), [(4-chlorophenyl)sulfonyl]dithioimidocarbonic acid dimethyl ester (12.99 gram, 0.044 mol) and triethylamine (47 mL) are successively dissolved in acetonitrile. The resulting mixture is heated at reflux for 70 hours. The resulting mixture is allowed to attain room temperature and concentrated in vacuo. The residue is dissolved in dichloromethane. The organic layer is washed with water, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatographic purification (eluant: methanol/dichloromethane=5/95 (v/v)) gives N-((4-chlorophenyl)sulfonyl)-4-phenyl-3-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester (7.15 gram, 35% yield). ESI-MS (MH+) 471.
Reaction SMILES: CS(O[CH2:6][C:7]([F:19])([F:18])[CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.CN(C=O)C.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K]>O>[CH2:11]([O:10][CH2:9][CH2:8][C:7]([F:19])([F:18])[CH2:6][N:29]1[C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]2[C:25]1=[O:35])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)OCC(F)(F)CCOCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC(F)(F)CCOCc1ccccc1
Temperature: 120 °C

Procedure:
The compound 1-methanesulfonyloxy-2,2-difluoro-4-benzyloxybutane (21.8 g, 74.1 mM), dry DMF (100 mL), and potassium phthalimide (15.26 g, 10% excess) are stirred and heated under nitrogen, at 120° C. for 5 days. Following the addition of water (500 mL), the mixture is extracted with ether. The organic phase is washed with 1N CCl followed by water (twice), dried (Na2SO4) and concentrated to a volume of about 100 mL. Upon addition of petroleum ether, crystallization occurs. After chilling for 3 hours at 5° C., beige crystals of the compound N-(4-benzyloxy-2,2-difluorobutyl)phthalimide are obtained, filtered and washed with petroleum ether: 18 g (70%).
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].O.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:7]O.[Na].[OH-].[Na+].[CH3:16][CH2:17][O:18][CH2:19][CH2:20][OH:21]>>[CH2:17]([O:18][CH2:12][CH2:11][O:10][C:6](=[O:9])/[CH:7]=[CH:2]/[CH3:3])[CH3:16].[CH2:17]([O:18][CH2:19][CH2:20][O:21][C:11](=[O:10])[CH2:12][CH:1]=[CH2:2])[CH3:16]
Reactant: CCOC(=O)CO
Reactant: CCOCCO
Reactant: C=CCCl
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: C/C=C/C(=O)OCCOCC
Product: C=CCC(=O)OCCOCC
Yield: 12 %
Yield: 80 %

Procedure:
In a manner similar to Example 1, 76.5 g of allyl chloride is reacted over a period of 4 hours, in the presence of 5 ml of Ni(CO)4, at 1.2 at. CO pressure and at a pH of 10.0, at 60° C., in 200 grams of ethyl glycol containing 0.14 wt.-% of H2O, with 1.12 moles of 20.4% sodium ethyl glycolate in ethyl glycol containing 0.31 wt.-% of NaOH. The distillate contains, according to gas chromatographic analysis (Hewlett-Packard, DC 200 silicone oil, length 4 m), 105 g of crotonic acid-2-ethoxyethylester (yield 80%) and 16 g of vinyl acetic acid-2-ethoxyethylester (yield 12%).
Reaction SMILES: [CH:1]1(OC(=O)[C@@H](NC(OCC2C=CC=CC=2)=O)COC(C)(C)C)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:27]([O:31][C:32]([NH:34][C@@H:35]([CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[C:36]([OH:38])=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[CH:1]1([O:37][C:36](=[O:38])[C@@H:35]([NH:34][C:32]([O:31][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:33])[CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)OC1CCCC1)C1CCCCC1

Procedure:
This was prepared in the same manner as (S)-2-benzyloxycarbonylamino-3-tert-butoxy-propionic acid cyclopentyl ester (Method A, Stage 1) but from (S)-tert-butoxycarbonylamino-cyclohexyl acetic acid. 1H NMR (300 MHz, CDCl3), δ: 1.00-1.40 (10H, m, CH×10), 1.45 (9H, s, C(CH3)3), 1.60-2.00 (8H, m, 4×CH2), 4.15 (1H, m, CH), 5.05 (1H, d, NH, J=7.6 Hz), 5.25 (1H, m, CH).
Reaction SMILES: Cl.N1CCCC[C:3]1=[O:8].CC[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>ClCCl.C(Cl)(Cl)Cl>[O:8]=[C:3]1[CH2:13][CH2:12][N:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:15]1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Reactant: O=C1CCCCN1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(=O)CC1
Reaction time: 0.25 h

Procedure:
To a solution of a piperidone hydrochloride (1 eq) in dichloromethane was added Et3N (2.1 eq) at 0° C. and the reaction mixture was stirred for 15 min. A solution ethyl chloroformate (1.1 eq) in chloroform was added at 0° C. and reaction was continued at room temperature for 3 h Reaction was quenched with water and extracted with ethyl acetate, organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired ethyl 4-oxopiperidine-1-carboxylate.
Reaction SMILES: [C:1]([NH2:6])([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[C:1]([NH:6][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)N
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CCC(C)(C)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of tert-amylamine (2.0 g, 23.3 mmol) in tetrahydrofuran (15 mL) was added 1,3-propane sultone (2.76 g, 22.2 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid product was collected by filtration, washed with acetone (2×25 mL), and dried in vacuo, to afford compound DG (3.3 g, 73%): 1H NMR (D2O, 500 MHz) 8 ppm 3.04 (t, 2H, J=7.8 Hz), 2.89 (t, 2H, J=7.8 Hz), 2.87 (t, 2H, J=7.3 Hz), 1.97 (m, 2H), 1.55 (m, 2H), 1.18 (s, 6H), 0.82 (t, 6H, J=7.3 Hz). 13C NMR (D2O, 125 MHz) 8 ppm 60.42, 48.17, 39.88, 30.81, 22.23, 21.98, 7.25. ES-MS 208 (M−1).