Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]([OH:24])=O)=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N1C=CN=C1)(N1C=CN=C1)=O.[Na].[CH3:43][C:44]1(C)[O:49]C(=O)[CH2:47][C:46](=O)[O:45]1.[H-].[Na+]>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22](=[O:24])[CH2:43][C:44]([O:45][CH2:46][CH3:47])=[O:49])=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC(=O)C1=C(COCC(=O)O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)COCC1=C(C(=O)OCC)C(c2ccccc2Cl)C(C(=O)OC)=C(C)N1
Temperature: 0 °C
Reaction time: 2.25 h

Procedure:
A solution of 2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}acetic acid (4.24 g) in tetrahydrofuran (60 ml) was treated with ice-cooling with carbonyldiimidazole (1.70 g) and the mixture stirred at 0° C. for 2.25 hours. This solution was added dropwise over 10 minutes to a solution of the sodium salt of 2,2-dimethyl-1,3-dioxane-4,6-dione in dimethylformamide (prepared by stirring a mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (1.44 g) and sodium hydride (0.30 g; 80% dispersion in oil) in dimethylformamide (30 ml) with ice-cooling for 30 minutes) and the mixture stirred for 16 hours at room temperature and then evaporated. The residue was dissolved in dichloromethane, washed twice with 1M hydrochloric acid and water, dried (MgSO4), and evaporated. A solution of the residual oil (6 g) in ethanol (50 ml) was heated under reflux for 6 hours and evaporated. The residue was dissolved in diethyl ether, washed twice with 10% aqueous sodium carbonate and once with saturated aqueous sodium chloride, dried (MgSO4), and evaporated. The residue was purified by chromatography on silica (30 g) using hexane plus 5-15% v/v ethyl acetate as eluant. Appropriate fractions were combined and evaporated and the residue crystallised from ethanol to give the title compound (1.5 g), m.p. 88°-89° C. Found: C,58.18; H,5.73; N,2.85. C24H28ClNO8 requires: C,58.36; H,5.71; N,2.84%.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH:7]=[O:8])[CH2:4][O:3]1.[CH:10]([Mg]Br)=[CH2:11].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C.O>[CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH:7]([OH:8])[CH:10]=[CH2:11])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](C=O)O1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC(O)[C@H]1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 117.4 %

Procedure:
On a stirred solution of (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde (11.0 g, 0.063 mol, 75% assay, 94% ee) in THF (40 g) at 0° C. under nitrogen atmosphere, a vinyl magnesium bromide solution (1.0 M in THF, 88.7 ml, 0.0887 mol) was added over a period of 90 min. After 2 h stirring at 0° C., the temperature was raised to 10° C. and a saturated ammonium chloride solution (60 ml) was added dropwise in 30 min. The quenched reaction mixture at 20° C. was then diluted with ethyl acetate (100 ml) and demi water (50 ml) and the layers separated. The organic phase was further washed with demi water (50 ml). The organic phase was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to furnish 11.7 g of 1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)prop-2-en-1-ol as a light yellow oil. Spectroscopic data are conform to literature.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1.Br[CH2:24][C:25]#[N:26]>C1COCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH2:24][C:25]#[N:26])[C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CC#N)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
LHMDS (1.0 M solution in THF, 13.1 mL, 13.1 mmol) was added dropwise at −78° C. under nitrogen to a stirred solution of methyl 2-(4-chlorophenyl)acetate (2.20 g, 11.9 mmol) in THF (40 mL). The resulting solution was stirred at −78° C. for 1 hour. A solution of 2-bromoacetonitrile (2.50 g, 20.9 mmol) in THF (16 mL) was added dropwise. The reaction was stirred at −78° C. for 1 hour. The reaction was then warmed to room temperature and stirred overnight. The reaction was then quenched with 1N HCl. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexanes: EtOAc, 4:1) to give methyl 2-(4-chlorophenyl)-3-cyanopropanoate (2.60 g, 98%) as a white solid. A solution of EtMgBr in THF (1.0 M, 8.0 mL, 8.0 mmol) was added dropwise at room temperature to a stirred solution of this methyl 2-(4-chlorophenyl)-3-cyanopropanoate (0.894 g, 4.00 mmol) and Ti(i-PrO)4 (1.30 mL, 4.40 mmol) in Et2O (20 mL). After the mixture was stirred at room temperature for 1 hour, water (4 mL) was added, followed by DCM (100 mL). The resulting precipitate was filtered and washed with DCM. The combined filtrates were dried and concentrated. The residue was purified by column chromatography (hexanes:EtOAc, 1:1) to give 6-(4-chlorophenyl)-4-azaspiro[2.4]heptan-5-one (0.330 g, 37%) as a white solid. LCMS (APCI+) [M-Boc+H]+ 222.2; Rf: 2.44 min.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@@H:44]([CH2:54][S:55][C:56]6[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=6)[CH2:45][CH2:46][N:47]6[CH2:52][CH2:51][CH:50]([OH:53])[CH2:49][CH2:48]6)=[C:39]([S:62]([C:65]([F:68])([F:67])[F:66])(=[O:64])=[O:63])[CH:38]=5)(=[O:36])=[O:35])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=2)[C:5]([C:69]([OH:71])=O)=[C:4]1[CH3:72].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:94][CH:95]1[CH2:100][CH2:99][CH:98]([C:101]([O:103]C)=[O:102])[CH2:97][CH2:96]1.[OH-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:3]([CH2:2][CH3:1])[C:4]([CH3:72])=[C:5]([C:69]([NH:94][CH:95]3[CH2:100][CH2:99][CH:98]([C:101]([OH:103])=[O:102])[CH2:97][CH2:96]3)=[O:71])[C:6]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@H:44]([CH2:45][CH2:46][N:47]6[CH2:52][CH2:51][CH:50]([OH:53])[CH2:49][CH2:48]6)[CH2:54][S:55][C:56]6[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=6)=[C:39]([S:62]([C:65]([F:68])([F:66])[F:67])(=[O:63])=[O:64])[CH:38]=5)(=[O:35])=[O:36])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=2)=[CH:13][CH:12]=1
Reactant: CCn1c(C)c(C(=O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1
Reactant: COC(=O)C1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCn1c(C)c(C(=O)NC2CCC(C(=O)O)CC2)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.9 %

Procedure:
To a solution of BM-957 (100 mg, 0.09 mmol), EDCI (27 mg, 0.14 mmol) and HOBT (19 mg, 0.14 mmol) in DCM (2 mL) was added methyl 4-aminocyclohexanecarboxylate (44 mg, 0.28 mmol). The solution was stirred for 2 hours at room temperature until no BM-957 was observed by TLC. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 solution (50 mL), brine (50 mL) and dried over sodium sulfate. The solvent was removed in vacuo to give crude product which was used for next step without purification. The resulting residue was dissolved in H2O and MeOH (5 mL and 5 mL respectively) and followed by adding NaOH (76 mg, 1.9 mmol). The solution was stirred at room temperature for 20 h until no starting material was observed by TLC. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to give the pure product 10 (salt with TFA, 61 mg, yield 55% over two steps). The gradient ran from 60% of solvent A and 40% of solvent B to 20% of solvent A and 80% of solvent B in 40 min. MS (ESI): m/z 1191.17 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12](=[O:34])[C@H:13]([CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:14](CC1C=CC=CC=1)[CH3:15].[H][H]>[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12](=[O:34])[C@H:13]([CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[NH:14][CH3:15]
Reactant: [H][H]
Reactant: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Oc1ccc2ccccc2c1
Agent: [Pd]
Product: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Oc1ccc2ccccc2c1

Procedure:
A methanolic solution of Nα-benzyl-Nδ-Boc-Nα-methylornithinyl 2-naphthyl ether (D) was reduced with hydrogen, over 5% palladium-on-carbon, to afford titled product: 1H NMR (400 MHz, CDCl3) δ1.44 (s, 9H), 1.63 (m, 2H), 1.95 (m, 2H), 2.53 (s, 3H), 2.95 (m, 1H), 3.09 (m, 2H), 4.01 (dd, J=10.7; 6.7 Hz, 1H), 4.12 (dd, J=10.5; 4.4 Hz, 1H), 7.19 (m, 2H), 7.35 (t, J=9.1 Hz, 1H), 7.45 (t, J=8.9 Hz, 1H), and 7.75 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:20])([CH3:19])[O:6][C@@H:7]([CH3:18])[C:8](O[Si](C(C)(C)C)(C)C)=[O:9])([CH3:4])[CH3:3].C(Cl)(=O)C([Cl:24])=O>CN(C)C=O.C(Cl)Cl>[CH3:1][C:2]([Si:5]([CH3:20])([CH3:19])[O:6][C@@H:7]([CH3:18])[C:8]([Cl:24])=[O:9])([CH3:4])[CH3:3]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)O[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a solution of 41.0 g (0.13 mol) of 2-(1,1-dimethylethyl)dimethylsilyl (2S)-2-((1,1-dimethylethyl)dimethylsilyloxy)propanoate (7) and five drops of N,N-dimethylformamide in methylene chloride at 0° C. was added 70.8 mL (0.14 mol) of a 2.0M solution of oxalyl chloride in methylene chloride over a 30 minute period. The cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 18 hours. The solvent and excess oxalyl chloride were removed by rotary evaporation resulting in a yellow liquid. Purification by vacuum distillation afforded 25.6 g (88%) of (2S)-2-((1,1 -dimethylethyl)dimethylsilyloxy)propanoyl chloride (8) as a clear liquid: bp 42°-45° C. (1.5 mm Hg); 1H NMR (CDCl3) δ0.0920 (s, 3 H), 0.118 (s, 3 H), 0.909 (s, 9 H), 1.50 (d, J=6.7 Hz, 3 H), 4.49 (q, J=6.7 Hz, 1 H); 13C NMR (CDCl3) δ176.6, 76.0, 25.7, 25.6, 25.3, 20.9, 18.1, -1.57, -5.04, -5.28.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[O:3][C:2]=1[C:10]1[C:11]([NH2:27])=[N:12][CH:13]=[C:14]([C:16]2[CH:17]=NN(C3CCNCC3)[CH:20]=2)[CH:15]=1.[CH3:28][O:29][C:30]1C=C(B2OC(C)(C)C(C)(C)O2)C=[CH:32][C:31]=1[OH:45]>>[NH2:27][C:11]1[N:12]=[CH:13][C:14]([C:16]2[CH:20]=[CH:32][C:31]([OH:45])=[C:30]([O:29][CH3:28])[CH:17]=2)=[CH:15][C:10]=1[C:2]1[O:3][C:4]2[C:9]([N:1]=1)=[CH:8][CH:7]=[CH:6][N:5]=2
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cccnc2o1
Product: COc1cc(-c2cnc(N)c(-c3nc4cccnc4o3)c2)ccc1O
Yield: 101.6 %

Procedure:
Using the procedure described in the starting material portion of Example 41, 5-bromo-3-oxazolo[5,4-b]pyridin-2-yl-pyridin-2-amine (1 g, Example 9 starting material) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (902 mg) were reacted to afford 4-(6-amino-5-oxazolo[5,4-b]pyridin-2-yl-3-pyridyl)-2-methoxy-phenol (940 mg) as a solid. NMR Spectrum: (DMSOd6) 3.89 (s, 3H), 6.87 (d, 1H), 7.11 (dd, 1H), 7.25 (d, 1H), 7.53 (dd, 1H), 7.74 (bs, 2H), 8.29 (dd, 1H), 8.39 (dd, 1H), 8.44 (d, 1H), 8.57 (d, 1H), 9.11 (bs, 1H); Mass spectrum: M+H+ 335.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7](Cl)=[O:8].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:8]
Reactant: C1COCCN1
Reactant: Cc1oncc1C(=O)Cl
Product: Cc1oncc1C(=O)N1CCOCC1

Procedure:
of melting point 42° to 44° C., prepared from 5-methyl-4-isoxazolecarboxylic acid chloride and morpholine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:59])[N:7]([C@H:25]1[CH2:29][CH2:28][N:27]([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([O:40][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:38]=3)[CH:33]=[CH:32][CH:31]=2)[C:26]1=[O:58])[CH2:8][CH2:9][C:10]1[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([F:24])[CH:17]=2)[CH:12]=[N:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6](=[O:59])[N:7]([CH2:8][CH2:9][C:10]1[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([F:24])[CH:17]=2)[CH:12]=[N:13][CH:14]=1)[C@H:25]1[CH2:29][CH2:28][N:27]([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([OH:40])[CH:38]=3)[CH:33]=[CH:32][CH:31]=2)[C:26]1=[O:58])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1cncn1Cc1ccc(C#N)c(F)c1)[C@H]1CCN(c2cccc3ccc(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)cc23)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCc1cncn1Cc1ccc(C#N)c(F)c1)[C@H]1CCN(c2cccc3ccc(O)cc23)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (S)-{1-[7-(tert-butyldiphenylsilyloxy)naphthalen-1-yl]-2-oxo-pyrrolidin-3-yl}-{2-[3-(4-cyano-3-fluorobenzyl)-3H-imidazol-4-yl]ethyl}carbamic acid tert-butyl ester, as described above in Step I, (500 mg, 0.619 mmol) in ThF (5 mL) was added TBAF (0.68 mL of a 1 M solution in THF, 0.68 mmol), dropwise. The mixture was stirred at ambient temperature for 30 min, then concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with CHCl3—2% MeOH—0.2% NH4OH to yield the desired phenol as a white foam.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1.Cl[CH2:33][C:34]1[CH:43]=[C:42]([O:44][CH3:45])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]=1[O:46][CH3:47]>>[CH3:47][O:46][C:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:42]([O:44][CH3:45])=[CH:43][C:34]=1[CH2:33][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCCc3ccccc3)cc2)C(O)C1
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCCc3ccccc3)cc2)c(OC)c2ccccc12

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(4-phenyl-butoxy)-phenyl]-piperidine-1-carboxylate [Example 122(b)] with 2-chloromethyl-1,4-dimethoxy-naphthalene [J.Org.Chem. (1983),48(19),3265-3268] there was obtained tert-butyl (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-[4-(4-phenyl-butoxy)-phenyl]-piperidine-1-carboxylate as a colourless, viscous oil; MS: 626 (M+H)+.
Reaction SMILES: [Li].N.[O:3]1[C@H:5]2[C:6](=[O:32])[CH:7]=[C:8]3[C@:29]([CH3:30])([C@@H:4]12)[C@@H:28]1[C@H:11]([C@H:12]2[C@:25]([CH3:31])([CH2:26][CH2:27]1)[C@@H:15]([C@H:16]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)[CH3:17])[CH2:14][CH2:13]2)[CH:10]=[CH:9]3.C=CC(=C)C.[Cl-].[NH4+]>CCOCC>[OH:3][C@@H:4]1[C@@:29]2([CH3:30])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH3:17])[CH2:7][C@@H:6]([OH:32])[CH2:5]1
Reactant: C[C@@H](OC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C=CC(=C)C
Solvent: CCOCC
Product: C[C@@H](OC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
0.316 g (45 mg-atom) of lithium are added to 150 ml of dry liquid ammonia at -31° C. to -33° C. After stirring for 15 minutes in an argon atmosphere, the resulting dark blue mixture is treated dropwise within 45 minutes with a solution of 3.23 g (7.8 mmol) of (20R)-1α,2α-epoxy-20-[(tetrahydro-2H-pyran-2-yl)oxy]-pregna-4,6-dien-3-one in 180 ml of ether. The blue mixture is stirred at the aforementioned temperature for 15 minutes in an argon atmosphere and 0.15 ml of isoprene is added. The resulting pink mixture is treated with 2.845 g (53 mmol) of ammonium chloride in portions and then with 0.0527 g (7.6 mg-atom) of lithium. As soon as the lithium has dissolved, 0.4065 g (7.6 mmol) of ammonium chloride and subsequently a further 0.0527 g (7.6 mg-atom) of lithium are added. This procedure, i.e. the addition of 7.6 mmol of ammonium chloride followed by 7.6 mg-atom of lithium, is repeated a further fourteen times, for which a total of 5.691 g (106 mmol) of ammonium chloride and 0.7378 g (106 mg-atom) of lithium are required. After the lithium of the last addition has dissolved, 10.0 g (180 mmol) of ammonium chloride and 200 ml of ether are added, and ammonia is evaporated with stirring. The resulting suspension is diluted at 0° C. with 200 ml of water and extracted with ethyl acetate. The extract is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated at 40° C./11 Torr. Chromatography of the residue on 65 g of silica gel with hexane/ether (1:1) gives 2.52 g (78%) of uniform (20R)-1α,3β-dihydroxy-20-[(tetrahydro-2H-pyran-2-yl)oxy]-pregn-5-ene of melting point 122°-124° C.; [α]D25 =-42° (c=1.0 in chloroform). By acidic hydrolysis there is obtained (20R)-1α,3β,20-trihydroxy-pregn-5-ene of melting point 235°-237° C.; [α]D25 =43° (c=0.5 in methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CO.O1CCOCC1.ClCCCl>[ClH:1].[NH2:31][CH:27]1[CH2:28][CH2:29][CH2:30][N:25]([CH2:23][CH2:22][C:19]2[CH:20]=[CH:21][C:2]([Cl:1])=[C:3]([CH:18]=2)[C:4]([NH:6][CH2:7][C:8]23[CH2:9][CH:10]4[CH2:11][CH:12]([CH2:13][CH:14]([CH2:16]4)[CH2:15]2)[CH2:17]3)=[O:5])[CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: O=CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Solvent: C1COCCO1
Product: NC1CCCN(CCc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 50.5 %

Procedure:
Prepared according to the method described in Example 66c from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.094 g, Example 66b), 3-piperidinyl-carbamic acid, 1,1-dimethylethyl ester (0.109 g), sodium triacetoxyborohydride (0.081 g) and 1,2-dichloroethane (2 ml). After work-up, the residue was purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane then by HPLC eluting with a gradient of 0-2% ethanol in dichloromethane. The white powder obtained was dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) was added. The mixture was stirred for 14 h at room temperature. Solvents were then removed under reduced pressure and the product obtained was triturated with diethyl ether to afford the title compound as a white powder (0.032 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH:18]=2)C#N)[CH:5]=[CH:4][CH:3]=1.[CH:19](O)=[O:20]>[Ni]>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:15][C:14]([CH:19]=[O:20])=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: Cc1cccc(CCOc2cccc(C#N)c2)n1
Agent: [Ni]
Product: Cc1cccc(CCOc2ccc(C=O)cc2)n1

Procedure:
A mixture of 5-[2-(6-methyl-2-pyridyl)ethoxy]benzonitrile (9.62 g), Raney nickel alloy (10.0 g) and 75% formic acid (150 ml) was heated under reflux for 1 hour. The reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with water, alkalinized with 4N-KOH, and extracted with ethyl ether. The ethyl ether layer was washed with water and dried (MgSO4) and the solvent was distilled off. The residue was recrystallized from ethyl etherhexane to give 4-[2-(6-methyl-2-pyridyl)ethoxy]benzaldehyde.
Reaction SMILES: [OH:1][CH:2]([CH2:5][NH2:6])[CH2:3][NH2:4].[ClH:7].[NH2:8][C:9](N)=N.CC(O)C>CC#N>[ClH:7].[NH:8]=[C:9]1[NH:6][CH2:5][CH:2]([OH:1])[CH2:3][NH:4]1
Reactant: NCC(O)CN
Reactant: N=C(N)N
Agent: Cl
Solvent: CC#N
Solvent: CC(C)O
Product: N=C1NCC(O)CN1
Temperature: 140 °C

Procedure:
A mixture of 2-hydroxy -1,3-diaminopropane (9.80 g, 108 mmol) and guanidine hydrochloride (10.4 g, 108 mmol) in a 100 mL RBF was heated at 140° C. under nitrogen for 5 h. The reaction mixture, while under vigorous stirring, was let cooled to 100° C. whereby a mixture of iPrOH (5 mL) and CH3CN (5 mL) were added, resulting in the formation of a slurry. After cooled to room temperature, the mixture was filtered and the solid was washed with additional CH3CN (total 30 mL). The solid was further dried under vacuum to yield a white solid. 1H NMR (400 MHz, D2O): 4.21 (m, 1 H), 3.34 (dt, J 15.2, 2.8, 2H), 3.22 (dt, J 15.2, 2.8).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][C:6]([C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:7][CH:8]=2)[N:3]=1.C([O-])=O.[NH4+]>[Pd].CO>[CH3:13][O:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:14]3[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:7][CH:8]=2)[N:3]=[CH:2][CH:11]=1
Reactant: COc1cc(Cl)nc2cc(-c3ncccc3C(F)(F)F)ccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccnc2cc(-c3ncccc3C(F)(F)F)ccc12

Procedure:
Stir a mixture of 2-chloro-4-methoxy-7-[3-(trifluoromethyl)pyridin-2-yl]quinoline (111 mg), ammonium formate (190 mg), 10% palladium on carbon (30 mg) in methanol (10 mL) at room temperature for 2 hours. Cool, filter through Celite and evaporate to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.[CH2:24]([NH:26][CH3:27])[CH3:25]>>[Cl:23][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:26]([CH2:24][CH3:25])[CH3:27])[C:11]([C:12]#[N:13])=[C:10]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=1
Reactant: CCNC
Reactant: CC(C)c1cccc(-c2c(C#N)c(Cl)nc3ccc(Cl)cc23)c1
Product: CCN(C)c1nc2ccc(Cl)cc2c(-c2cccc(C(C)C)c2)c1C#N

Procedure:
The title compound was prepared in analogy to example 98 step E from 2,6-dichloro-4-(3-isopropyl-phenyl)-quinoline-3-carbonitrile (prepared as described in example 98 step D) and ethyl-methyl-amine. Light yellow oil. MS (ESI): 364.2 (M+H)+.