Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1.C(N(CC)CC)C.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][CH2:26][CH2:27]Br)[CH3:22]>CO>[CH2:21]([O:23][C:24]([CH2:25][CH2:26][CH2:27][NH:1][CH2:2][CH2:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1)=[O:29])[CH3:22]
Reactant: CCOC(=O)CCCBr
Reactant: NCCC1COc2ccccc2C1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)CCCNCCC1COc2ccccc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
17.7 g (0.1 mol) of 3-(2-aminoethyl)chroman are dissolved in 100 ml of methanol, and then 10.5 g (0.1 mol) of triethylamine and 19.5 g (0.1 mol) of 4-bromobutyric acid ethyl ester are added to the solution. The reaction mixture is stirred for 15 hours at room temperature and is then concentrated under a water-jet vacuum. The residue is taken up in diethyl ether and washed neutral with ice-water. The ethereal phase is dried over potassium carbonate and concentrated by evaporation. Oily N-(3-ethoxycarbonylpropyl)-N-[2-(chroman-3-yl)ethyl]-amine is thus obtained and can be used further in crude form.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[CH2:33]([NH2:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH2:33]([NH:35][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:23])([F:25])[F:24])[O:14][N:13]=2)=[CH:8][CH:7]=1)[CH3:34]
Reactant: CCN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 77.8 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 35 mg, 0.081 mmol), ethanamine-HCl (9.95 mg, 0.122 mmol), HATU (40.2 mg, 0.106 mmol), and 4-methylmorpholine (32.9 mg, 0.325 mmol) were added to DMF (1 mL). It was stirred for 1 h and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=13.3 min) to provide (R/S)-N-ethyl-2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (30 mg, 0.063 mmol, 77% yield): LCMS=458.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.46 (1 H, s), 8.11 (2 H, d, J=8.58 Hz), 7.51-7.72 (7 H, m), 5.09 (1 H, s), 3.24-3.30 (2 H, m), 1.14 (3 H, t, J=7.15 Hz); HPLC peak RT=7.9 min (Method A).
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH2:14]([C:16]1[O:17][C:18]([CH2:21][CH2:22][OH:23])=[CH:19][CH:20]=1)[CH3:15]>CN(C=O)C.C(OCC)C>[C:7]([Si:10]([O:23][CH2:22][CH2:21][C:18]1[O:17][C:16]([CH2:14][CH3:15])=[CH:20][CH:19]=1)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1ccc(CCO)o1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCc1ccc(CCO[Si](C)(C)C(C)(C)C)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
Imidazole (255 mg, 3.75 mmol) and TBSCl (414 mg, 2.75 mmol) were added to the solution of 245A (350 mg, 2.5 mmol) in DMF (4 mL). The mixture was stirred at rt for 15 hr and then 100 mg (0.66 mmol) of additional TBSCl was added to drive the reaction to completion. After stirring for an additional hour, the reaction mixture was diluted with diethylether (100 mL) and washed with water (20 mL), 1 N HCl (20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give 509 mg of compound 434A (80.3%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:12]>C1C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(O)nc1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(O)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 258.7 %

Procedure:
To a stirred solution of 6-hydroxynicotinic acid (2 g, 14.38 mmol) in benzene (32 mL) and MEOH (8 mL) was added dropwise TMSCHN2 (1.97 mL, 3.953 mmol) at 0° C., and the resulting mixture was stirred for 2 hr at room temp. The mixture was quenched by the addition of AcOH and concentrated in vacuo. The residue was suspended in water and the solid was collected. The crude solid was washed with Et2O, and dried in vacuo to give 1.566 g (71%) methyl 2-hydroxypyridine-5-carboxylate as a pale brown crystalline powder. IR (KBr) 1655, 1645, 1610, 1433, 1300, 1113, 777, 642 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 3.77 (s, 3H), 6.37 (d, J=9.8 Hz, 1H), 7.99 (dd, J=2.4, 9.8 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H); MS (FAB) m/z 154 (M++1); Anal. Calcd for C7H7NO3: C, 54.90; H, 4.61; N, 9.15. Found: C, 54.89; H, 4.60; N, 9.13.
Reaction SMILES: CNC(N[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=O.C1(C)C(O)=CC=CC=1.C(OC)(=O)/[CH:21]=[CH:22]\[C:23]([O:25][CH3:26])=[O:24].[CH3:30][N:31]1[CH2:37][C:35](=[O:36])[N:34]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:32]1=[O:33].C1(N2CC(=O)N(C)C2=O)CCCCC1>>[CH3:30][N:31]1[C:37](=[C:22]([CH3:21])[C:23]([O:25][CH3:26])=[O:24])[C:35](=[O:36])[N:34]([C:38]2([CH:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]3)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)[C:32]1=[O:33]
Reactant: CNC(=O)NC1CCCCC1
Reactant: CN1CC(=O)N(C2CCCCC2)C1=O
Reactant: COC(=O)/C=C\C(=O)OC
Agent: CN1C(=O)CN(C2CCCCC2)C1=O
Agent: Cc1ccccc1O
Product: COC(=O)C(C)=C1C(=O)N(C2(C3CCCCC3)CCCCC2)C(=O)N1C
Reaction time: 1 h

Procedure:
78 g of N-methyl-N'-cyclohexyl urea, 220 g of cresol and 72 g of dimethyl maleate were stirred at 185° C for one hour and then at 200° C for one hour. 15 g of methanol distilled over during this time. After fractional distillation, a main fraction boiling at 180°-185° C/0.08 Torr could be isolated. It consisted of an isomeric mixture of 1-methyl-3-cyclohexyl-hydantoin and 1-cyclohexyl-3-methylhydantoin but its exact composition could not be determined by gas chromatography.
Reaction SMILES: Br.[CH2:2]([O:4][N:5]=[C:6]([C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3].[Cl:18]CC(Cl)=O.[C:23]([O:26]CC)(=O)[CH3:24]>CN(C)C(=O)C>[CH2:2]([O:4][N:5]=[C:6]([C:12]1[N:13]=[C:14]([N:17]([Cl:18])[C:23]([CH3:24])=[O:26])[S:15][CH:16]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:3]
Reactant: CCON=C(C(=O)OCC)c1csc(N)n1
Reactant: O=C(Cl)CCl
Reactant: CCOC(C)=O
Agent: Br
Solvent: CC(=O)N(C)C
Product: CCON=C(C(=O)OCC)c1csc(N(Cl)C(C)=O)n1
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 2.43 g of ethyl α-ethoxyimino-2-aminothiazol-4-ylacetate hydrobromide in 25 ml of anhydrous N,N-dimethylacetamide is added 1.43 g of chloroacetyl chloride under cooling and stirring. The solution is stirred for 30 minutes under ice-cooling and then for 30 minutes at room temperature. To the reaction mixture is added 150 ml of ethyl acetate and the mixture is repeatedly washed with saturated aq. NaCl solution. The ethyl acetate layer is dried over anhydrous magnesium sulfate, and subjected to the distillation of the solvent under reduced pressure. To the residue is added water to precipitate solid material. The solid is collected by filtration and dried. The procedure gives 1.90 g of ethyl α-ethoxyimino-2-(chloroacetamino)thiazol-4-ylacetate.
Reaction SMILES: [F:1][C:2]([F:20])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15])[C:3]([F:6])([F:5])[F:4].[NH2:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH3:30])[N:23]=1>O1CCOCC1>[F:20][C:2]([F:1])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:17][C:18]([NH:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH3:30])[N:23]=1)=[O:19])(=[O:15])=[O:16])[C:3]([F:6])([F:5])[F:4]
Reactant: COc1nc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(F)(F)C(F)(F)F
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)(F)C(F)(F)F)n1
Temperature: 20 °C

Procedure:
3.2 g of 2-pentafluoroethoxyphenylsulfonyl isocyanate and 1.4 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine are stirred in 40 ml of dioxane for 3 hours at 90°-100° C. The solution is then cooled to 20° C., filtered, and concentrated to about 1/4 of its volume. After addition of ether, 3.3 g of N-(2-pentafluoroethoxyphenylsulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea crystallise from the residue. Melting point: 157°-159° C.
Reaction SMILES: [CH3:1][C:2]([CH3:51])([CH3:50])[C:3](=[O:49])[CH2:4][O:5][C:6]([C:8]1([C:39]([O:41]CC2C=CC=CC=2)=[O:40])[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[C:28]([F:38])[CH:27]=4)[O:23][N:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7].C(OCC)(=O)C.O1CCCC1>[Pd].C([O-])([O-])=O.[Ca+2].C(O)C>[CH3:1][C:2]([CH3:51])([CH3:50])[C:3](=[O:49])[CH2:4][O:5][C:6]([C:8]1([C:39]([OH:41])=[O:40])[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[C:28]([F:38])[CH:27]=4)[O:23][N:22]=3)=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: CC(C)(C)C(=O)COC(=O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)C(=O)COC(=O)C1(C(=O)O)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 25 °C

Procedure:
2 g of 1-{4-[5-(2-fluorobiphenyl-4-yl)[1,2,4]oxadiazol-3-yl]benzyl}piperidine-4,4-dicarboxylic acid benzyl ester 3,3-dimethyl-2-oxobutyl ester are added into round bottomed flask containing a solvent mixture of ethyl acetate/tetrahydrofuran [1/0.5] and stirred at room temperature to get a clear solution. Then 40 mL of ethanol are added followed by 0.6 g Pd/CaCO3. The mixture is stirred under hydrogen gas. After 30 mins 0.2 g of Pd/CaCO3 are added to the above reaction mixture and stirring under hydrogen is continued. Once the reaction gets completed 4 g of silica gel are added and the mixture stirred at RT for 10 mins, cooled to 0-5° C. and stirred for 20-30 mins. The slurry is filtered and washed with 40 mL ethyl acetate. The product along with Pd/CaCO3 on the funnel was leached with 200 mL, then 250 mL of a dichloromethane/methanol [2:1] mixture at RT and filtered. The product containing filtrate is concentrated and dried under vacuum at 35-40° C. to yield 1-{4-[5-(2-fluorobiphenyl-4-yl)[1,2,4]oxadiazol-3-yl]benzyl}-piperidine-4,4-dicarboxylic acid (3,3-dimethyl-2-oxobutyl)ester (62).
Reaction SMILES: [Na+].[CH3:2][Si:3]([CH3:17])([CH3:16])[CH2:4][CH2:5][O:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]([O-:15])=O)[N:10]=[CH:9]1.[N:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH2:30])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CCN=C=NCCCN(C)C.CN(C=O)C>CN(C1C=CN=CC=1)C.CCOC(C)=O>[N:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH:30][C:13]([C:11]2[N:10]=[CH:9][N:8]([CH2:7][O:6][CH2:5][CH2:4][Si:3]([CH3:2])([CH3:17])[CH3:16])[CH:12]=2)=[O:15])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccccc1N1CCCCC1
Reactant: C[Si](C)(C)CCOCn1cnc(C(=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc(C(=O)Nc2ccccc2N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
A flask was charged with 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylate sodium salt (70 mg, 0.26 mmol) (as prepared in the previous step), 2-piperidin-1-yl-phenylamine (36 mg, 0.20 mmol), EDCI (60 g, 0.31 mmol), DMAP (25 mg, 0.20 mmol), and DMF (1 mL) and stirred for 3 h at RT. The reaction was diluted with EtOAc (10 mL) and washed with brine (2×10 mL), and the organic layer was dried over Na2SO4 and then concentrated. The title compound was eluted from a 5-g SPE cartridge (silica) with 30% EtOAc/hexane to give 80 mg (97%) of a white solid. Mass spectrum (ESI, m/z): Calcd. for C21H32N4O2Si, 401.2 (M+H), found 401.1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Si:32]([O:39][C@@H:40]1[CH2:44][CH2:43][C@@H:42]([OH:45])[CH2:41]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].[C:46]1([C:52]2[CH:57]=[CH:56][C:55](O)=[CH:54][CH:53]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1COCC1>[C:46]1([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:51]=[CH:50][C:49]([O:45][C@H:42]2[CH2:43][CH2:44][C@@H:40]([O:39][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:41]2)=[CH:48][CH:47]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@H](O)C1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](Oc2ccc(-c3ccccc3)cc2)C1
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (0.195 g, 0.742 mmol) in 5 mL of dry THF was treated at 0° C. with diethylazodicarboxylate (0.117 mL, 0.742 mmol) and stirred for 20 min. A solution of (1R*,3R*)-3-(tert-butyldimethylsilanyloxy)cyclopentanol (0.146 g, 0.675 mmol) and 4-phenyl phenol (0.126 g, 0.0.724 mmol) in 5 mL of dry THF was added to the solution, and the mixture was stirred at room temperature overnight. The solution was concentrated under vacuum and purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 6:1, Rf0.66). 1H-NMR (200.15 MHz, CDCl3): δ 7.58–7.29 (m, 7H); 6.93 (d, 2H, J=8.92), 4.76–4.65 (m, 1H), 4.32–4.21 (m, 1H), 2.38 (qn, 1H, J=7.0), 2.04–1.94 (m, 2H), 1.87–1.78 (m, 3H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([C:29]3[N:30]=[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]4[CH:37]=3)[CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C)C=O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:40][N:39]=[N:38][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[CH:25]=[C:26]([C:29]3[N:30]=[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]4[CH:37]=3)[CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2ccc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-butyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][O:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:31](O)=[O:32])=[N:27][NH:28]2)=[CH:24][CH:23]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:31]([C:26]1[C:25]2[C:29](=[CH:30][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[NH:28][N:27]=1)=[O:32]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: COc1ccc2c(C(=O)O)n[nH]c2c1
Product: COc1ccc2c(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)n[nH]c2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 6-methoxy-1H-indazole-3-carboxylic acid. MS: 434.3 (M+H).
Reaction SMILES: [C:1]([CH:4]1[CH:17]2[CH2:18][CH:6]([CH:7]3[CH:16]2[C:15]2[CH2:19][CH:8]3[CH:9]3[C:14]=2[CH:13]2[CH2:20][CH:10]3[CH2:11][CH2:12]2)[CH2:5]1)([OH:3])=[O:2].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1.C(OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:2][C:1]([CH:4]1[CH:17]2[CH2:18][CH:6]([CH:7]3[CH:16]2[C:15]2[CH2:19][CH:8]3[CH:9]3[C:14]=2[CH:13]2[CH2:20][CH:10]3[CH2:11][CH2:12]2)[CH2:5]1)=[O:3]
Reactant: C1=COCCC1
Reactant: O=C(O)C1CC2CC1C1C3=C4C5CCC(C5)C4C(C3)C21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(OC1CCCCO1)C1CC2CC1C1C3=C4C5CCC(C5)C4C(C3)C21
Yield: 72.6 %

Procedure:
Next, 2.1 g of the 12-carboxyhexacyclo[6.6.1.13,6.110,13.02,7.09,14]heptadecene and 1.71 g of 3,4-dihydro-2H-pyran were dissolved in 50 ml of tetrahydrofuran, into which 0.03 g of p-toluenesulfonic acid were added. The resultant mixture was reacted at room temperature for 2 hours. The reaction mixture was diluted with 100 ml of ethyl ether, followed by the successive washing with a 3% aqueous solution of Na2CO3, 3% aqueous solution of sodium chloride, and water. An organic layer was dried over MgSO4. The ethyl ether and unreacted 3,4-dihydro-2H-pyran were distilled off under reduced pressure by an evaporator, whereby 2 g of 12-tetrahydropyranyloxycarbonylhexacyclo[6.6.1.13,6.110,13.02,7.09,14]heptadecene were obtained as a viscous liquid.
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.FF.B(F)(F)F.CCOCC>C(#N)C>[CH2:9]1[CH:10]2[CH:5]([CH2:4][CH2:3][CH2:2][CH2:1]2)[CH2:6][CH2:7][CH2:8]1
Reactant: C1CC[C@H]2CCCC[C@H]2C1
Agent: FB(F)F
Agent: FF
Solvent: CCOCC
Solvent: CC#N
Product: C1CCC2CCCCC2C1
Temperature: 82 °C
Yield: 31.3 %

Procedure:
Using a similar procedure to that described above (Method 2), cis-decalin (2.2 g, 16 mmol), elemental fluorine (65 mmol), boron trifluoride etherate (2.3 g, 16 mmol), and anhydrous acetonitrile (120 cm3) gave, after heating (82° C.) and the work-up as detailed above, a crude product mixture which was distilled to give decalin (0.7 g, 5 mmol); bp 55° C./10 mmHg. The brown solid which remained gave, after recrystallisation, N-(trans-9-decalyl)acetamide (0.8 g, 49%, 67% conv.) as a white solid; mp 183-184° C. (from acetonitrile) (Found C, 73.6; H, 10.9; N, 7.3. C12H21NO requires: C, 73.8; H, 10.9; N, 7.2%); δH (400 MHz) 0.85-1.68 (18 H, m), 2.57 (1 H, s), 2.62 (1 H, s), 4.89 (1 H, br s, NH); δC (101 MHz) 21.6 (s, CH2), 24.6 (s, CH3), 26.1 (s, CH2), 28.6 (s, CH2), 34.4 (s, CH2), 45.2 (s, CH), 55.9 (CNHCO), 169.2 (s, CO); m/z (EI+) 195 (M+, 1%), 152 (18), 136 (100), 121 (141).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:13]([Br:14])=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]([N:20]([CH2:58][CH2:59][CH3:60])[CH2:21][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[N:38](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)=[N:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C>[C:1]1([CH2:7][CH2:8][N:9]2[C:13]([Br:14])=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]([N:20]([CH2:58][CH2:59][CH3:60])[CH2:21][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)=[N:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)c1nn(CCc2ccccc2)c(Br)c1C(=O)OCC
Solvent: CCO
Product: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1nn(CCc2ccccc2)c(Br)c1C(=O)OCC
Yield: 87.7 %

Procedure:
356 mg of N-[1-(2-phenylethyl)-4-ethoxycarbonyl-5-bromopyrazol-3-yl]-N-[(2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl]-n-propylamine were dissolved in 5 ml of ethanol and heated under reflux for 2 hours, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (n-hexane-ethyl acetate=2:1→ethyl acetate) to obtain 224 mg of the intended compound as a pale yellow, amorphous solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[H][H].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC1CCN(Cc2ccccc2)CC1

Procedure:
To a solution of N-benzyl-4-hydroxy-piperidine (19.2 g) in dry tetrahydrofuran (100 ml), sodium hydride (2.4 g, 0.1 mole) was added and the mixture was refluxed until evolution of hydrogen ceased (1 hour). A solution of ethyl bromoacetate (18.4 g) in dry tetrahydrofuran (20 ml) was added and the mixture was refluxed for 3 hours. After standing over night, the solvent was removed in vacuo and the residue was extracted with light petroleum. The extract was concentrated to a sirup which was distilled at 0.1 mm Hg to give (A) as a colourless oil with b.p. 140°-145° C.
Reaction SMILES: [CH2:1]([N:8]([C@@H:12]([CH3:15])[CH2:13]O)[CH2:9][C:10]#[N:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.C1(P([C:34]2[CH:39]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[OH:41]>C(Cl)Cl>[C:39]([NH:11][C@@H:10]1[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:12]([CH3:15])[CH2:13]1)(=[O:41])[CH3:34]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@@H](CO)N(CC#N)Cc1ccccc1
Reactant: CO
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)N[C@H]1C[C@H](C)N(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a stirred solution of 132.23 g (0.647 mol) of (S)-2-(N-Benzyl-N-cyanomethylamino)-1-propanol, from step 1b, in 500 mL of methylene chloride and 94 mL of anhydrous carbon tetrachloride under nitrogen and anhydrous conditions and at room temperature was added 170 g (0.648 mol) of triphenylphosphine. The mixture was stirred at room temperature, but soon the exothermic reaction raised the temperature to reflux temperature. The reaction was stirred for 22 hours, another 8.5 g (0.032 mol) of triphenylphosphine was added, and the reaction was stirred another 2.5 hours. Methanol was added to destroy the excess triphenylphosphine, and the mixture concentrated to dryness. The solid was triturated with ether and hexane, which were filtered and concentrated. The oil was redissolved in ether, hexane added, filtered, concentrated and chromatographed over a short silica gel column, eluting with 1:4 ethyl acetate:hexane to afford after removal of the solvent 112.31 g (77.9% yield) of the title product as a colorless liquid. MS M/Z: 223, 225 (M+H). NMR (CDCl3) d: 1.35 (3H, d, J=6 Hz), 3.21 (1H, sextet, J=6 Hz), 3.48 (2H, s), 3.52 (2H, s), 3.57 (1H, dd, J=6, J=12 Hz), 3.68 (1H, dd, J=5, J=12 Hz), 7.35 (5H, m).