Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Na].[CH3:15][C:16]1([CH3:63])[CH2:21][CH:20]([N:22]([C:33]2[N:38]=[C:37]([N:39]([CH:50]3[CH2:55][C:54]([CH3:57])([CH3:56])[NH:53][C:52]([CH3:59])([CH3:58])[CH2:51]3)[CH:40]3[CH2:45][C:44]([CH3:47])([CH3:46])[NH:43][C:42]([CH3:49])([CH3:48])[CH2:41]3)[N:36]=[C:35](Cl)[N:34]=2)[CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[CH2:19][C:18]([CH3:62])([CH3:61])[NH:17]1>C1(C)C(C)=CC=CC=1>[CH3:58][C:52]1([CH3:59])[CH2:51][CH:50]([N:39]([C:37]2[N:38]=[C:33]([N:22]([CH:23]3[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]3)[CH:20]3[CH2:21][C:16]([CH3:15])([CH3:63])[NH:17][C:18]([CH3:62])([CH3:61])[CH2:19]3)[N:34]=[C:35]([S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:36]=2)[CH:40]2[CH2:41][C:42]([CH3:48])([CH3:49])[NH:43][C:44]([CH3:46])([CH3:47])[CH2:45]2)[CH2:55][C:54]([CH3:57])([CH3:56])[NH:53]1
Reactant: CCCCCCCCCCCCS
Reactant: CC1(C)CC(N(c2nc(Cl)nc(N(C3CC(C)(C)NC(C)(C)C3)C3CC(C)(C)NC(C)(C)C3)n2)C2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: [Na]
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCSc1nc(N(C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)nc(N(C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)n1

Procedure:
Following the procedure described in Example 11 and using 20.3 g (0.11 mol) of 1-dodecanthiol, 2.53 g (0.11 mol) of sodium and 70.25 g (0.1 mol) of 2,4-bis[N,N-bis(2,2,6,6-tetramethyl-4-piperidyl)amino]-6-chloro-1,3,5-triazine in 250 ml of xylene, the product of melting point 168°-170° C. is obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:14])[CH:8]=2)[N:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1.CO.N.C(Cl)Cl>>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[Cl:27])[CH2:20][NH:19][CH2:18][CH2:17][CH2:16][NH:15][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:14])[CH:8]=2)[N:3]=1
Reactant: NCCCNCc1ccc(Cl)c(Cl)c1
Reactant: COc1cc(Cl)nc2ccc(C)cc12
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc(NCCCNCc2ccc(Cl)c(Cl)c2)nc2ccc(C)cc12
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A mixture of 2-chloro-4-methoxy-6-methylquinoline (94 mg, 0.45 mmol) and N-(3-aminoprop-1-yl)-3,4-dichlorobenzylamine (0.21 g) was heated at 70° C. for 15 h, at 100° C. for 2 h, and then at 120° C. for 15 h. The resulting mixture was submitted to column chromatography (silica gel, MeOH:NH3:CH2Cl2 20:2:100) to give the title compound as a red film, (65 mg, 36%). δH (CDCl3) 1.72-1.89 (m, 3H+H2O), 2.42 (s, 3H), 2.74 (t, J=6.4, 2H), 3.53-3.65 (m, 2H), 3.71 (s, 2H), 3.94 (s, 3H), 5.06 (br, s, 1H), 5.87 (s, 1H), 7.12 (dd, J=8.2. 2.0, 1H), 7.28-7.36 (m, 2H), 7.40-7.48 (m, 2H), 7.72 (br, s, 1H): MS (ES+) 404 (MH+, 43%), 229 (100).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([CH2:16][OH:17])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]>C(Cl)Cl.O=[Mn]=O>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([CH:16]=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(-c2cccnc2CO)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1ncccc1-c1cccc([N+](=O)[O-])c1
Reaction time: 48 h
Yield: 96.4 %

Procedure:
To a stirred solution of [3-(3-nitrophenyl)-pyridin-2-yl]-methanol (69 mg, 0.30 mmol) (Agrawal, K. C. et al. J. Med. Chem. 1974, 17, 631-5) in dry CH2Cl2 (5 mL) was added activated MnO2 (90% purity, <10 micron, 251 mg, 2.89 mmol). The resulting heterogeneous mixture was stirred 2 d, at which point the black slurry was filtered through a cake of celite and washed with CH2Cl2 (3×15 mL). The combined washings were concentrated to afford 66 mg (96%) of 3-(3-nitrophenyl)-pyridine-2-carbaldehyde as a pale white solid, which was used in subsequent reactions without further purification. 1H NMR (CDCl3) δ 7.60-7.69 (m, 3H), 7.77 (dd, 1H, J=7.8, 1.5 Hz), 8.21-8.23 (m, 1H), 8.30-8.35 (m, 1H), 8.91 (dd, 1H, J=4.5, 1.5 Hz), 10.12 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[CH:8][C:7]=1[C:12]1[CH:43]=[CH:42][C:15]([C:16]([N:18]([C@@H:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]2)[C:19]2[N:20]=[CH:21][CH:22]=[C:23]3[CH:27]=[CH:26][N:25]([CH3:28])[C:24]=23)=[O:17])=[CH:14][CH:13]=1)=[O:5])C.[OH-].[Na+]>CO>[C:38]([O:37][C:35]([N:31]1[CH2:32][CH2:33][CH2:34][C@@H:29]([N:18]([C:19]2[N:20]=[CH:21][CH:22]=[C:23]3[CH:27]=[CH:26][N:25]([CH3:28])[C:24]=23)[C:16]([C:15]2[CH:42]=[CH:43][C:12]([C:7]3[CH:8]=[N:9][N:10]([CH3:11])[C:6]=3[C:4]([OH:5])=[O:3])=[CH:13][CH:14]=2)=[O:17])[CH2:30]1)=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: CCOC(=O)c1c(-c2ccc(C(=O)N(c3nccc4ccn(C)c34)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1ncc(-c2ccc(C(=O)N(c3nccc4ccn(C)c34)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound from Step 2 (R)-tert-butyl 3-(4-(5-(ethoxycarbonyl)-1-methyl-1H-pyrazol-4-yl)-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)benzamido)piperidine-1-carboxylate (0.2 g, 0.34 mmol) in MeOH (10 mL) was added aqueous NaOH (2 N, 1.5 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and the pH was adjusted with 1N HCl until pH 4. The acidified mixture was extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to deliver the title compound (0.18 g) as yellow oil which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[N:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:16][N:17]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3cc(Cl)cn4ccnc34)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1cc(Nc2ccc(N3CCNCC3)cn2)c2nccn2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.5 %

Procedure:
Compound 102a (1.75 g, 4.08 mmol) was suspended in 4.0 M HCl/dioxane (10 mL) and stirred at room temperature for 5 h. It was then concentrated under reduced pressure to afford 102b (1.2 g, 81%). MS: [M+H]+ 329.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:9]1[N:14]=[C:13]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=3[CH:19]=2)[CH:12]=[CH:11][N:10]=1>>[F:1][CH2:2][CH2:3][CH2:4][O:5][C:9]1[N:14]=[C:13]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:18]=3[CH:19]=2)[CH:12]=[CH:11][N:10]=1
Reactant: OCCCF
Reactant: COc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2cc(-c3ccnc(OCCCF)n3)sc2c1
Yield: 65.4 %

Procedure:
2-[2-(3-Fluoropropoxy)pyrimidine-4-yl]-6-methoxybenzothiophene (1-32, 75 mg, 65%) was prepared in the same manner as in Example 31 as a pale yellow solid using 3-fluoro-1-propanol (40 mL, 0.54 mmol), sodium hydride (NaH, 22 mg, 0.54 mmol) and 2-(2-chloropyrimidine-4-yl)-6-methoxybenzothiophene (105a, 100 mg, 0.36 mmol) obtained in Preparation Example 19.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16].C(O)(C(F)(F)F)=O>ClCCl>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:14][C:15]([OH:17])=[O:16])=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-(2-tert-butyl-2-oxoethyl)benzoate obtained by carrying out reaction of ethyl 4-hydroxybenzoate with tert-butyl bromoacetate in the same manner as in Reference Example 23 (1) was dissolved in dichloromethane, mixed with TFA at room temperature and stirred overnight at room temperature. By evaporating the solvent, [4-(ethoxycarbonyl)phenoxy]acetic acid was obtained as a white solid. EN: 223.
Reaction SMILES: [OH:1][C@H:2]1[CH2:11][C:10]2([CH2:14][CH2:13][CH2:12]2)[CH2:9][C:8]2[N:7]=[C:6]([CH:15]([CH3:17])[CH3:16])[C:5]([CH:18]=[O:19])=[C:4]([I:20])[C:3]1=2.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C@@H:18]([OH:19])[C:5]2[C:6]([CH:15]([CH3:17])[CH3:16])=[N:7][C:8]3[CH2:9][C:10]4([CH2:12][CH2:13][CH2:14]4)[CH2:11][C@H:2]([OH:1])[C:3]=3[C:4]=2[I:20])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O)CC1(CCC1)C2
Product: CC(C)c1nc2c(c(I)c1[C@H](O)c1ccc(C(C)(C)C)cc1)[C@@H](O)CC1(CCC1)C2

Procedure:
Obtained by starting from (S)-5′-hydroxy-4′-iodo-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carbaldehyde and 4-tert.-butylphenylmagnesium bromide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([NH:14][CH3:15])=[N:7][C:6]=1[N:16]1[CH2:21][CH2:20][CH:19]([C:22]([F:25])([F:24])[F:23])[CH2:18][CH2:17]1)[CH3:2]>[Pd].CCO>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH:14][CH3:15])=[N:7][C:6]=1[N:16]1[CH2:21][CH2:20][CH:19]([C:22]([F:24])([F:25])[F:23])[CH2:18][CH2:17]1)[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(NC)nc1N1CCC(C(F)(F)F)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(N)c(NC)nc1N1CCC(C(F)(F)F)CC1
Reaction time: 6 h

Procedure:
A mixture of 6-methylamino-5-nitro-2-(4-trifluoromethyl-piperidinyl)-nicotinic acid ethylester (6.0 g, 15.9 mmol), Pd/C (800 mg) and EtOH (100 mL) is stirred under 60 psi H2-atmosphere for 6 h. The mixture is filtered, and the filtrate is concentrated. HPLC Rt=1.13 min (method A). MS m/z: 347 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[CH:13][N+:14]([O-])=O)=[CH:4]1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][NH2:14])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C=C[N+](=O)[O-])c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1cc(CCN)c2ccccc21
Yield: 98.9 %

Procedure:
Using analogous reaction conditions and workup as described in Example 1, 1-ethyl-3-(2-nitro-vinyl)-1H-indole (4.8 g, 22.018 mmol) in dry THF (25 mL) was reacted with LAH (4.17 g, 110.091 mmol) in dry THF (25 mL). The resulting mixture was refluxed for 16 hours under nitrogen atmosphere to afford 4.1 g of the product (98% yield).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:20][C:21]([NH:23][C@H:24]([C:40](O)=[O:41])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:58]([O:65][C:66]([NH:68][CH2:69][CH2:70][CH2:71][CH2:72][C@@H:73]([C:75]([OH:77])=[O:76])[NH2:74])=[O:67])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>>[C:1]([O:18][CH:19]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:20][C:21]([NH:23][C@H:24]([C:40]([NH:74][C@H:73]([C:75]([OH:77])=[O:76])[CH2:72][CH2:71][CH2:70][CH2:69][NH:68][C:66]([O:65][CH2:58][C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)=[O:67])=[O:41])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Yield: 67.8 %

Procedure:
Starting from N-hydroxysuccinimide ester of Nα -(3-hexadecanoyloxyoctadecanoyl)-Nε -benzyloxycarbonyl-L-lysine (3 g) prepared by the method described in Example 20 (1), and Nε -benzyloxycarbonyl-L-lysine (2.24 g), Nα -[Nα -(3-hexadecanoyloxyoctadecanoyl)-Nε -benzyloxycarbonyl-L-lysyl]-Nε -benzyloxycarbonyl-L-lysine (2.7 g) was obtained as crystals according to a similar manner to that of Example 16 (2).
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[H-].[Na+].Cl[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1>CN(C=O)C>[CH3:47][S:44]([C:41]1[CH:42]=[CH:43][C:38]([CH2:37][O:1][C:2]2[C:11]3[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)[N:8]4[CH2:21][CH2:22][N:23]=[C:7]4[C:6]=3[CH:5]=[CH:4][C:3]=2[O:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[CH:39][CH:40]=1)(=[O:45])=[O:46]
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: O=C(NC1=Nc2c(ccc(OCCCN3CCOCC3)c2O)C2=NCCN12)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(COc2c(OCCCN3CCOCC3)ccc3c2N=C(NC(=O)c2cccnc2)N2CCN=C32)cc1
Reaction time: 16 h
Yield: 70.3 %

Procedure:
N-[7-Hydroxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide (Intermediate H, 0.09 g, 0.20 mmol) was suspended in DMF (2.0 mL) and NaH (0.02 g, 0.30 mmol, 60%) were added. After 20 min at rt 1-(chloromethyl)-4-(methylsulfonyl)benzene (0.06 g, 0.30 mmol) was added and the mixture was stirred at it for 16 h. The DMF was evaporated under reduced pressure and the residue triturated with a mixture of −10% MeOH in CH2Cl2 (4 mL). The mixture was vacuum filtered and the solids were washed well with CH2Cl2. The filtrate was concentrated under reduced pressure, and the residue purified via silica gel chromatography (0-6% MeOH/CH2Cl2). The fractions were combined, and the solvent was evaporated under reduced pressure. Drying under high vacuum gave the title compound (0.087 g, 70%): TLC (5% MeOH/CH2Cl2): Rf=0.47; HPLC MS RT=0.55 min, [M+Na]+=641; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.21-2.35 (2H, m), 3.05-3.17 (2H, m), 3.22 (3H, s), 3.31 (2H, m), 3.42-3.52 (2H, m), 3.60-3.72 (2H, m), 3.94-4.04 (2H, m), 4.29 (2H, m), 4.39 (2H, t), 4.56 (2H, m), 5.37 (2H, s), 7.52 (1H, d), 7.72 (1H, dd), 7.85 (2H, d), 8.01 (2H, d), 8.10 (1H, d), 8.66 (1H, d), 8.89 (1H, dd), 9.43 (1H, s).
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[Si:18]([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:1]1([O:9][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1CCCCCCC1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)OC1=CCCCCCC1
Reaction time: 15 h
Yield: 92.7 %

Procedure:
To a solution of cyclooctanone (40.0 g, 316 mmol) in 200 mL of anhydrous DMF were added triethylamine (TEA, 93.0 mL, 666 mmol) and chlorotrimethylsilane (84.0 mL, 666 mmol). The reaction was heated to reflux. After 15 h, the reaction was quenched with 20 mL of H2O and the DMF was removed on a rotary evaporator. The residue was diluted with hexanes (300 mL), washed with H2O (3×100 mL) and brine (1×50 mL), and dried over MgSO4. Distillation under reduced pressure (20 torr) yielded 58.1 g (93%) of the desired product as a colorless oil, bp 108° C. (20 torr) (lit. 106° C. at 25 torr). Nakamura, et al. J. Am. Chem. Soc. (1976) 98, 2346-2348. IR: 2926, 2851, 1661 cm−1. 1H NMR (CDCl3, 300 MHz): δ 0.20 (s, 9H), 1.39-1.58 (m, 8H), 2.02 (m, 2H), 2.19 (m, 2H), 4.75 (t, 1H, J=9.0 Hz). (Lit: 1H NMR (CDCl3, 600 MHz): δ 0.16 (s, 9H), 1.46 (m, 4H), 1.49 (m, 2H), 1.55 (m, 2H), 1.97 (m, 2H), 2.14 (m, 2H), 4.70 (t, 1H, J=8.0 Hz) (Frimer et al. J. Org. Chem. (2000) 65, 1807-1817.) 13C NMR (CDCl3, 75 MHz): δ 0.4, 25.5, 26.3, 26.4, 27.8, 30.9, 31.0, 105.41, 152.99. (Lit: 13C NMR (CDCl3, 150 MHz): δ 0.45, 25.52, 26.36, 26.40, 27.83, 30.98, 31.05, 105.45, 153.05) Frimer et al. (2000) supra) FAB-HRMS: Calcd. for C11H23OSi+ [M+H]+: 199.1518. found 199.1520.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH:6]=[C:5]([C:13]([O:15]C)=[O:14])[CH:4]=[CH:3]1.[OH-].[Li+].[CH3:19]O>O>[CH3:19][C:6]1[N:7]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[C:2](=[O:1])[CH:3]=[CH:4][C:5]=1[C:13]([OH:15])=[O:14]
Reactant: CO
Reactant: COC(=O)c1ccc(=O)n(-c2nccs2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)O)ccc(=O)n1-c1nccs1
Temperature: 75 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
After 680 mg (2.88 mmol) of methyl 6-oxo-1-(2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylate was dissolved in 12 mL of methanol and 4 mL of water, 207 mg (8.64 mmol) of lithium hydroxide was added to the solution. Afterward, the resulting reaction solution was stirred at about 75° C. for 5 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo, and aqueous HCl was then added to the reaction solution to titrate until pH 2 was reached. The resulting solid compound was filtrated to obtain a target compound (Actual yield: 466 mg, Percent yield: 73%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH:9]1([NH:15][C:16]2[C:21]([CH:22]=O)=[CH:20][N:19]=[C:18]3[N:24]([CH2:27][CH3:28])[N:25]=[CH:26][C:17]=23)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C(O)C>[CH:9]1([NH:15][C:16]2[C:21]([CH:22]=[N:2][OH:3])=[CH:20][N:19]=[C:18]3[N:24]([CH2:27][CH3:28])[N:25]=[CH:26][C:17]=23)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C=O)cnc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCn1ncc2c(NC3CCCCC3)c(C=NO)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydroxylamine hydrochloride (0.255 gm, 0.0036 mole) and sodium acetate (0.301 gm, 0.0036 mole) were added to a stirred solution of 4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (0.250 gm, 0.0009 mole) (example 7) in ethanol. The reaction mixture was allowed to stir at room temperature for about 2 h. Ethanol was removed under reduced pressure and residue was poured in water. The title compound was then filtered and washed with water twice and finally with hexane.
Reaction SMILES: [CH3:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](O)=[O:4].S(Cl)([Cl:15])=O>CN(C=O)C>[CH3:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([Cl:15])=[O:4]
Reactant: CC(=Cc1ccccc1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=Cc1ccccc1)C(=O)Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
α-methylcinnamic acid (45 g) and thionyl chloride (50 g) was stirred at 20-30° C. After 5 min, 0.3 ml of DMF was added and kept stirring at 20-30° C. for 1 hour to give crude of α-methylcinnamoyl chloride (solution A)
Reaction SMILES: [OH:1][CH:2]1[O:6][C@H:5]2[CH2:7][C:8]([CH:10]=[O:11])=[CH:9][C@H:4]2[CH2:3]1.[CH:12]1(O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH:12]1([O:1][CH:2]2[O:6][C@H:5]3[CH2:7][C:8]([CH:10]=[O:11])=[CH:9][C@H:4]3[CH2:3]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=CC1=C[C@H]2CC(O)O[C@H]2C1
Reactant: OC1CCCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: O=CC1=C[C@H]2CC(OC3CCCCC3)O[C@H]2C1
Temperature: 25 °C

Procedure:
Partially purified residue containing lactol 7 from a procedure in accordance with Example 3E (6.24 g, 12.5% detected by NMR, 40.5 mmol, 1 eq.) was dissolved in CH2Cl2 (90 ml) and stirred at room temperature. Cyclohexanol (14.2 g, 14.9 ml, 3.5 eq.) was added via syringe and Amberlyst 15 (825 mg) and MgSO4 (16.83 g) were added as solids. The reaction mixture was stirred at r.t. for 36 h. The reaction mixture was filtered through a sinter funnel and the solids washed with CH2Cl2 (2×30 ml). The filtrate was concentrated under reduced pressure and the excess cyclohexanol was removed by distillation at 65° C. under high vacuum. The residue was purified by column chromatography (silica), eluting with petrol/EtOAc (10:1), to give the cyclohexyl acetal 50, (as an approximately 1.5:1 mixture of diastereoisomers, 6.10 g, 64% from lactol 7) as a yellow solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1>>[OH:36][CH:34]1[CH2:35][N:32]([C:2]2[CH:3]=[C:4]([C:8]3[N:9]=[C:10]4[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]4=[N:12][CH:13]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:33]1
Reactant: OC1CNC1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(I)c3)nc12
Agent: Cl
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(N4CC(O)C4)c3)nc12

Procedure:
1-[2-[3-(3-Hydroxy-azetidin-1-yl)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared starting from 1-[2-(3-iodo-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one and azetidin-3-ol hydrogen chloride following the same procedure of RO5364753. M+H=481.
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[CH:21]2>>[CH2:1]([C:3]1([C:21]2[C:20]3[C:24](=[C:16]([O:15][CH3:14])[CH:17]=[CH:18][CH:19]=3)[NH:23][CH:22]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(O)CCc2cc(F)ccc21
Reactant: COc1cccc2cc[nH]c12
Product: CCC1(c2c[nH]c3c(OC)cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 1-ethyl-5-fluoro-indan-1-ol and 7-methoxyindole, the title compound is prepared as in example 1. 123 mg (59%). LC-MS m/z 310.2 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[CH3:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][NH:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[N:24]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:33]1[CH:34]=[CH:35][N:31]([C:28]2[CH:29]=[CH:30][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[S:21][CH:22]=3)=[CH:26][CH:27]=2)[C:32]1=[O:36])[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: Cc1nc(-c2ccc(-n3cc[nH]c3=O)cc2)cs1
Product: Cc1nc(-c2ccc(-n3ccn([C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)c3=O)cc2)cs1

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 1-[4-(2-methyl-4-thiazolyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2-methyl-4-thiazolyl)phenyl]-2(1H,3H)-imidazolone (Compound 30).
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](Cl)=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:15]12([NH2:25])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.N1C=CC=CC=1>O>[C:15]12([NH:25][C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[N:2]=[CH:3][CH:4]=[CH:5]4)=[O:13])[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]3)[CH2:16]1)[CH2:24]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)c1ccc2ncccc2c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1ccc2ncccc2c1
Yield: 10.8 %

Procedure:
Prepared from 6-quinolinecarbonyl chloride hydrochloride (1.51 g, 10 mmol), 1-adamantanamine (1.73 g, 10 mmol), pyridine (5 mL), and water (200 mL) yielding 330 mg (11%) of (42):