Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:33][O:34][CH2:35][CH2:36][CH3:37])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([O:20]CC4C=CC([N+]([O-])=O)=CC=4)=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1.O1CCCC1.CO.C(O)(=O)C>[C].[Pd].O>[O:1]1[C:6]([C:7](=[N:33][O:34][CH2:35][CH2:36][CH3:37])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)C1=CSCCO1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)C1=CSCCO1
Yield: 51.3 %

Procedure:
4-Nitrobenzyl 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 6.7 g.), tetrahydrofuran (200 ml.), methanol (67 ml.), acetic acid (2 ml.), water (6 ml.) and 10% palladium-carbon (3.3 g.) were treated in a similar manner to that of Example 18-(2) to give 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-propoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.59 g.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:23]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:33]3[CH:34]=[CH:35][C:30]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:31][CH:32]=3)=[CH:18][CH:19]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(O)cc2)COC1(C)C
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(Oc3ccc(Oc4ccccc4)cc3)cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 7.5 %

Procedure:
To a solution of (S)-4-(4-Hydroxy-benzyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.250 g, 0.846 mmol), 4-Phenoxyphenyl-boronic acid (0.181 g, 0.846 mmol), and triethylamine (0.59 mL, 4.232 mmol) in anhydrous dichloromethane (DCM) (20.8 mL) at room temperature under an atmosphere of nitrogen was added copper (II) acetate (0.154 g, 0.846 mmol), and the resulting mixture was stirred at room temperature for about 60 hours. The reaction mixture was washed with 20 mL of water and 20 mL of DCM and filtered. The DCM layer was then extracted. The aqueous layer was re-extracted with DCM (2×15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvent was removed in vacuo to obtain the crude mixture, which was purified by of silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain the product (0.030 g, 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:27]=[N:26][CH:25]=[CH:24][N:23]=2)[CH2:21][O:20]1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:18][C:19]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)([OH:20])[CH3:21])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CC1(c2cnccn2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(C)(O)c2cnccn2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
To a solution of 8-chloro 2-methyl-2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indole (1.0 g, 4.54 mmol) in DMF (10 mL) was added sodium hydride (600 mg, 13.63 mmol). After stirring for 10 min at RT, 2-(2-methyl oxiranyl)pyrazine (804 mg, 5.9 mmol) was added dropwise at 0-10° C. and the reaction mixture was stirred at RT for 16 h. The reaction mixture was poured into ice water and extracted with EtOAc (3×150 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to afford crude product, which was crystallized in ether-hexane to yield a yellow solid product as the free base (1.2 g). 1H NMR (DMSO, Oxalate salt) d (ppm): 8.65 (s, 1H), 8.55 (s, 1H), 8.50 (d, 1H), 7.42 (s, 1H), 7.05 (d, 1H), 6.95 (d, 1H), 4.40 (m, 4H), 3.20 (m, 2H), 3.0 (m, 2H), 2.90 (s, 3H), 1.58 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:21][O:20]2)=[C:15]([OH:22])[CH:14]=1)(=[O:12])=[O:11].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:21][OH:20])=[C:15]([OH:22])[CH:14]=1)(=[O:12])=[O:11]
Reactant: C1COCCN1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C3CO3)c(O)c2)c(C)c1
Solvent: CCO
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(CO)N3CCOCC3)c(O)c2)c(C)c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a stirred solution of N-(2,4-dimethylphenyl)-3-hydroxy-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide (60 mg, 0.160 mmol) in ethanol (1 mL) at 25° C. was added morpholine (30.6 mg, 0.352 mmol) and the reaction mixture stirring at 50° C. for 12 hours. The reaction mixture was then concentrated in vacuo and purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give a single regioisomer of the desired product, 11.2 mg. LCMS [LCMS2] Rt 1.25 min, m/z (ES+) 463 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=1.Cl[CH2:17][CH:18]1[O:22][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]([CH:29]([CH3:31])[CH3:30])[CH2:19]1.C[O-].[Na+]>>[OH:1][C:2]1[C:7]([O:8][CH2:17][CH:18]2[O:22][CH:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:20]([CH:29]([CH3:31])[CH3:30])[CH2:19]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][C:12](=[O:15])[NH:13][N:14]=1
Reactant: O=C1CCC(c2cccc(O)c2O)=NN1
Reactant: CC(C)N1CC(CCl)OC1c1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: CC(C)N1CC(COc2cccc(C3=NNC(=O)CC3)c2O)OC1c1ccccc1

Procedure:
6-(2,3-Dihydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone was reacted with 5-chloromethyl-3-isopropyl-2-phenyloxazolidine in the presence of sodium methoxide to give 6-[2-hydroxy-3-(3-isopropyl-2-phenyl-5-oxazolidinylmethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:18]([CH2:19][C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[C:17]3[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=3[N:15]=2)[CH2:9][CH2:8]1>O1CCCC1>[O:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[CH2:19][N:18]1[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[N:15]=[C:14]1[NH:13][CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][N:4]=[C:1]=[S:3])[CH2:8][CH2:9]1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Reactant: S=C=S
Solvent: C1CCOC1
Product: S=C=NCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Reaction time: 8 h

Procedure:
To a stirred and cooled (-10° C.) mixture of 12.6 parts of carbon disulfide, 5.2 parts of N,N'-methanetetraylbis[cyclohexanamine] and 45 parts of tetrahydrofuran was added dropwise a solution of 8.5 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(2-furanylmethyl)-1H-benzimidazol-2-amine in 45 parts of tetrahydrofuran. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was evaporated and the residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 6.7 parts of 1-(2-furanylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine (intermediate 123).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[CH:17][N:18]=3)[CH:15]=2)=[O:8])=[CH:5][N:6]=1.[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)#[N:20]>C(#N)C>[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:2]2[S:3][C:4]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]4[N:14]([CH:16]=[CH:17][N:18]=4)[CH:15]=3)=[O:8])=[CH:5][N:6]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=C(Nc1ccc2nccn2c1)c1cnc(Br)s1
Solvent: CC#N
Product: N#Cc1ccc(CNc2ncc(C(=O)Nc3ccc4nccn4c3)s2)cc1
Temperature: 180 °C

Procedure:
To a solution of 2-bromo-N-(imidazo[1,2-a]pyridin-6-yl)thiazole-5-carboxamide (165 mg, 0.511 mmol) in acetonitrile (2553 μl) was added 4-cyanobenzylamine (67.5 mg, 0.511 mmol). The mixture was heated in a microwave (Biotage Initiator) at 180° C. for 30 minutes. The heating was repeated again after another equivalent of 4-cyanobenzylamine was added. The reaction mixture was purified by normal phase chromatography to provide the title compound.
Reaction SMILES: Cl.[C:2]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])(=[O:4])[NH2:3].[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([O:36][CH2:37][CH3:38])[C:34]=1[F:35])[CH:30]=O)[CH3:25].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[C:2]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[C:10]([NH:12][CH:13]1[CH2:14][CH2:15][N:16]([CH2:30][C:29]2[CH:32]=[C:33]([O:36][CH2:37][CH3:38])[C:34]([F:35])=[C:27]([O:26][CH2:24][CH3:25])[CH:28]=2)[CH2:17][CH2:18]1)=[O:11])(=[O:4])[NH2:3]
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Reactant: COc1cc(OCC(N)=O)cc(C(=O)NC2CCNCC2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC(N)=O)c3)CC2)cc(OCC)c1F

Procedure:
In analogy to the procedure described in example 50k), 3-carbamoylmethoxy-5-methoxy-N-piperidin-4-yl-benzamide hydrochloride was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 504.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:30][CH:31]=O)[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:33][C:34]1[C:39]([NH2:40])=[CH:38][CH:37]=[C:36]([N:41]2[CH2:45][CH2:44][C@@H:43]([N:46]3[CH2:50][CH2:49][CH2:48][C@@H:47]3[CH3:51])[CH2:42]2)[N:35]=1>>[CH2:1]([O:3][C:4]([C:6]1([CH2:30][CH2:31][NH:40][C:39]2[C:34]([CH3:33])=[N:35][C:36]([N:41]3[CH2:45][CH2:44][C@@H:43]([N:46]4[CH2:50][CH2:49][CH2:48][C@@H:47]4[CH3:51])[CH2:42]3)=[CH:37][CH:38]=2)[CH2:7][CH2:8][CH:9]([O:12][Si:13]([C:26]([CH3:29])([CH3:27])[CH3:28])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: CCOC(=O)C1(CC=O)CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Product: CCOC(=O)C1(CCNc2ccc(N3CC[C@@H](N4CCC[C@@H]4C)C3)nc2C)CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1

Procedure:
The title compound was synthesized in essentially the same manner using the procedures as set forth in Step 1 of Example 1, by condensing 4-(tert-butyl-diphenyl-silanyloxy)-1-(2-oxo-ethyl)-cyclohexanecarboxylic acid ethyl ester (100 mg, 0.22 mmol) and 2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine to obtain 132 mg of a crude solid, which was used in the next reaction without further purification.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:2]=1[CH:3]1[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH:4]1[CH2:5][O:6]2.[H-].[Na+].[CH:21](I)([CH3:23])[CH3:22].Cl>CN(C=O)C.O>[CH:21]([O:11][C:9]1[CH:8]=[C:7]2[C:2]([CH:3]3[O:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[CH:4]3[CH2:5][O:6]2)=[CH:1][CH:10]=1)([CH3:23])[CH3:22]
Reactant: Oc1ccc2c(c1)OCC1c3ccccc3OC21
Reactant: CC(C)I
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1)OCC1c3ccccc3OC21
Yield: 50.6 %

Procedure:
Compound 6a,11a-Dihydro-6H-benzo[4,5]furo[3,2-c]chromen-3-ol (100 mg, 0.42 mmol) was dissolved in DMF (5 ml) and NaH (10 mg, 0.42 mmol) was added to the solution at room temperature, followed by isopropyl iodide (149 mg, 0.84 mmol). The reaction mixture was stirred at room temperature to 6 hours and poured into iced water and neutralized with 10% HCl to get the white precipitate. Precipitate were washed with water and purified by silica gel column chromatography using hexane-chloroform as the eluent to give 3-isopropoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]chromene (60 mg, 51%) as white solid.
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:14][C@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12]2)=[CH:7][CH:6]=1>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:10]1[CH:9]=[C:8]([C@H:11]2[CH2:12][C@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:14]2)[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: II
Reactant: COc1ccc([C@H]2C[C@H](C(=O)OC)C2)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COc1ccc([C@H]2C[C@H](C(=O)OC)C2)cc1I
Reaction time: 4 h

Procedure:
Silver sulfate (0.671 g, 2.15 mmol) and iodine (0.11 mL, 2.15 mmol) were added successively to a solution of methyl trans-3-(4-methoxyphenyl)cyclobutanecarboxylate (0.474 g, 2.15 mmol) in MeOH (10.8 mL) at 25° C. and the reaction was stirred vigorously for 4 h. After this time the reaction mixture was filtered through a plug of Celite®. The filtrate was diluted with EtOAc (50 mL), washed with water (2×10 mL), aq. Na2SO3 (2×10 mL), and brine (10 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/imin, 100% hexanes for 144 mL, gradient to 20% EtOAc in hexanes over 2394 mL) to afford methyl trans-3-(3-iodo-4-methoxyphenyl)cyclobutanecarboxylate, as a colorless oil. Rf=0.54 (20% EtOAc/hexanes). LCMS calc.=347.01. found=347.02 (M+H)+. 1H NMR (500 MHz, CHCl3): δ 7.58 (d, J=2.2 Hz, 1H); 7.08 (dd, J=8.4, 2.2 Hz, 1H); 6.69 (d, J=8.4 Hz, 1H); 3.76 (s, 3H); 3.67 (s, 3H); 3.65-3.54 (m, 1H); 3.07-3.00 (m, 1H); 2.61-2.55 (m, 2H); 2.32-2.25 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([NH:10][CH2:11][CH2:12][OH:13])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Cl[C:15]1[C:28]2[C:19](=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[CH:23][CH:22]=[N:21]3)[N:18]=[C:17]([CH3:29])[CH:16]=1>C1COCC1>[C:6]([O:5][C:3](=[O:4])[NH:10][CH2:11][CH2:12][O:13][C:15]1[C:28]2[C:19](=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[CH:23][CH:22]=[N:21]3)[N:18]=[C:17]([CH3:29])[CH:16]=1)([CH3:7])([CH3:8])[CH3:9]
Reactant: Cc1cc(Cl)c2ccc3cccnc3c2n1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(OCCNC(=O)OC(C)(C)C)c2ccc3cccnc3c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.3 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 0.87 g, 21.8 mmol) in THF (15 mL) a solution of N-Boc-2-hydroxyethylamine (1.75 g, 21.8 mmol) in anhydrous THF (5 mL) was slowly added. The mixture was stirred at room temperature for 20 minutes and a solution of 4-chloro-2-methyl-[1,10]phenanthroline (1.00 g, 4.4 mmol) in anhydrous THF (20 mL) was slowly added. The reaction mixture was refluxed for 18 hours and the solvent was removed in a rotary evaporator. The residue was treated with methylene choride (100 mL) and saturated NaHCO3 (100 mL) and transferred to a separatory funnel. The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was washed with hexane and purified by flash chromatography (SiO2, MeOH/DCM, 1:40) to afford the pure product as a pale solid (0.72 g, 46%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][Mg]Br>C(OCC)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([CH3:15])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
To a solution of 1-Boc-4-piperidone (10.0 g, 50.0 mmol) in diethyl ether (100 mL) at 0° C. was added methylmagnesium bromide (3.0 M in Et2O, 22.3 mL, 67.0 mmol) maintaining the temperature below +10° C. The reaction mixture was allowed to warm to RT over 1 h. The reaction was quenched by addition of sat. aq. NH4Cl solution, then the mixture was extracted with diethyl ether (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, to give the title compound (6.76 g, 62%). 1H NMR (400 MHz, CDCl3): 1.26 (3H, s), 1.45 (9H, s), 1.48-1.62 (4H, m), 3.15-3.32 (2H, m), 3.70 (2H, d, J 12.5).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:38])[N:23]([C:27]2[C:32]([CH3:33])=[CH:31][C:30]([N+:34]([O-])=O)=[CH:29][C:28]=2[CH3:37])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C1COCC1.[Pd]>[NH2:34][C:30]1[CH:31]=[C:32]([CH3:33])[C:27]([N:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:22]2=[O:38])=[C:28]([CH3:37])[CH:29]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(N)cc(C)c1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O

Procedure:
970 mg (1.84 mmol) of the compound from Example 54A are dissolved in 20 ml of THF. 200 mg of palladium on carbon are then added, and the mixture is hydrogenated at RT in a hydrogen atmosphere under atmospheric pressure. The mixture is then filtered through kieselguhr, the filter cake is washed three times with THF and the filtrate is freed from the solvent. The reaction product (1.00 g) is reacted further without further purification.
Reaction SMILES: C(C1C=CC(S([N:14]2[C:18]3=[N:19][CH:20]=[C:21]([NH:23][NH2:24])[N:22]=[C:17]3[CH:16]=[CH:15]2)(=O)=O)=CC=1)(C)(C)C.CCN(C(C)C)C(C)C.[CH3:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[C:41](Cl)=O.O=S(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CO>[CH3:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[C:41]1[N:22]2[C:17]3[CH:16]=[CH:15][NH:14][C:18]=3[N:19]=[CH:20][C:21]2=[N:23][N:24]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: CC1CCCCC1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1CCCCC1c1nnc2cnc3[nH]ccc3n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
To a solution of 5-(4-tert-butylphenylsulfonyl)-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine (0.40 g, 1.2 mmol, Preparation #3) and DIEA (0.20 mL, 1.2 mmol) in 1,4-dioxane (12 mL) at about 0° C. was added 2-methylcyclohexanecarbonyl chloride (0.19 g, 1.2 mmol, Preparation #4). After the complete addition, the ice bath was removed and the reaction was allowed to warm to ambient temperature. After about 1 h, SOCl2 (0.42 mL, 5.8 mmol) was added and the reaction was heated at about 90° C. for about 1 h. The reaction was allowed to cool to ambient temperature and then 2 M aqueous Na2CO3 (2N, 11.6 mL, 23.2 mmol) and MeOH (12 mL) were added. The reaction was heated at about 90° C. for about 3 days. The reaction was concentrated under reduced pressure and then partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (40 mL). The organic layer was separated and dried over anhydrous Na2SO4, filtered and the solvent was concentrated under reduced pressure. The residue was purified over silica gel (12 g) using EtOAc as the eluent and then further purified by RP-HPLC (Table 2, Method b). The combined product-containing fractions were concentrated under reduced pressure to remove the MeCN and the resulting precipitate was collected by vacuum filtration to afford 1-(2-methylcyclohexyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine as a white solid (0.10 g, 35%): LC/MS (Table 2, Method a) Rt=1.84 min; MS m/z: 256 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:18])[CH:5]1[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6]1.O>CC(O)C.[C].[Pd]>[ClH:1].[ClH:1].[CH3:3][N:4]([CH3:18])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: CN(C)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CN(C)C1CCNCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 158.3 %

Procedure:
After adding 10% palladium-carbon (2.0 g) to a solution of the crude 4-dimethylamino-1-benzylpiperidine dihydrochloride (30.0 g) in 2-propanol (300 ml)-water (300 ml), the mixture was stirred for 22 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered and washed with 2-propanol. The filtrate was then concentrated. The obtained crystals were suspended in ethanol (50 ml). They were then diluted with diethyl ether (50 ml). The crystals were subsequently filtered and washed with methanol (10 ml). They were then subjected to aeration drying to provide the title compound (16.4 g) as colorless crystals.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[N:9]([CH:10]2[CH2:16][C@H:15]3[N:17]([CH2:18][CH2:19][C:20]4([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:25][CH2:24][CH2:23][NH:22][CH2:21]4)[C@H:12]([CH2:13][CH2:14]3)[CH2:11]2)[C:8]2[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=2[N:6]=1.CCN(CC)CC.[CH3:43][C:44]([CH3:49])([CH3:48])[C:45](Cl)=[O:46]>C(Cl)Cl>[CH3:43][C:44]([CH3:49])([CH3:48])[C:45]([N:22]1[CH2:23][CH2:24][O:25][C:20]([CH2:19][CH2:18][N:17]2[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[CH2:16][CH:10]([N:9]2[C:8]4[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=4[N:6]=[C:5]2[CH3:4])[CH2:11]3)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21]1)=[O:46]
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CNCCO1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CN(C(=O)C(C)(C)C)CCO1
Reaction time: 24 h
Yield: 107.7 %

Procedure:
To a solution of 2-methyl-1-{(1R,5S)-8-[2-(2-phenylmorpholin-2-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole trihyrdochloride (65 mg, 0.11 mmol) and Et3N (0.08 mL, 0.55 mmol in 1 mL CH2Cl2 was added trimethylacetyl chloride (0.02 mL, 0.17 mmol), and the reaction was stirred for 24 h. After washing with saturated aqueous NaHCO3, the organic phase was isolated, dried (Na2SO4), concentrated and chromatographed (5% (2M NH3/MeOH) in CHCl3) to afford 1-((1R,5S)-8-{2-[4-(2,2-dimethylpropanoyl)-2-phenylmorpholin-2-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (61 mg, quant.) as a film: 1H NMR (400 MHz, CDCl3), δ 7.68 (m, 1H), 7.45-7.40 (m, 2H), 7.38-7.27 (m, 3H), 7.19-7.11 (m, 2H), 4.77-4.63 (m, 2H), 3.76-3.54 (m, 4H), 3.40-3.20 (m, 3H), 2.59 (s, 3H), 2.48-2.36 (m, 2H), 2.15-1.85 (m, 8H), 1.69-1.59 (m, 2H), 1.19 (s, 9H); ESI-MS 515 (M+H).