Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.[CH2:6]([Si:8](Cl)([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].[OH:14][C@@H:15]([C@@H:17]1[C@@H:20]([C@@H:21]([CH3:40])[C:22]([C:24]2[S:28][C:27]3=[C:29]([C:32]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:33])[N:30]=[CH:31][N:26]3[CH:25]=2)=[O:23])[NH:19][C:18]1=[O:41])[CH3:16]>CN(C)C=O.C(OCC)(=O)C>[CH2:6]([Si:8]([CH2:11][CH3:12])([CH2:9][CH3:10])[O:14][C@@H:15]([C@@H:17]1[C@@H:20]([C@@H:21]([CH3:40])[C:22]([C:24]2[S:28][C:27]3=[C:29]([C:32]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:33])[N:30]=[CH:31][N:26]3[CH:25]=2)=[O:23])[NH:19][C:18]1=[O:41])[CH3:16])[CH3:7]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Imidazole (0.15 g) and 0.36 ml of triethylsilylchloride were added to a solution of 0.32 g of (3S,4R)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonyl imidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one in 3.2 ml of dimethylformamide under ice cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with 80 ml of ethyl acetate, and the diluted reaction mixture was washed three times with 20 ml of a 10% aqueous sodium chloride solution and was then washed with an a saturated aqueous sodium chloride solution and was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the resultant solid was suspended in 4 ml of a hexane:ethyl acetate=1:1 solution and was collected by filtration to give 0.33 g of (3S,4R)-3-[(1R)-1-(triethylsilyloxy)ethyl]-4-[(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1>>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([NH:24][C:1]([C:4]23[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]2)[CH2:8][CH2:9]3)=[O:3])=[CH:26][CH:27]=1)#[N:30]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 26.9 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-aminobenzonitrile (40.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-cyanophenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (17.6 mg).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][CH:9]([O:13][CH3:14])[CH2:10][NH:11][CH3:12].CC1OCCC1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].Cl>O>[CH2:25]([O:24][C:22](=[O:23])[N:11]([CH2:10][CH:9]([O:13][CH3:14])[O:8][CH3:7])[CH3:12])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCC(OC)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: O
Product: COC(CN(C)C(=O)OCc1ccccc1)OC
Temperature: 5 °C

Procedure:
K2CO3 (8.4 kg, 60 mol, 1.8 eq.) and H2O (49.3 kg, 2.6 volumes) were placed in the reaction vessel and stirred. N-methylaminoacetaldehyde dimethylacetal (6.5 kg, 54 mol, 1.6 eq) and MeTHF (20.2 kg, 2.9 volumes) were added. The resulting mixture was cooled to 5° C. Benzyl chloroformate (6.8 kg, 37.6 mol, 1.1 eq.) was added over a period of about 30 minutes, while maintaining the temperature below 10° C. The feed line was rinsed with MeTHF (4.3 kg). The mixture was then maintained at 5° C. and stirred for 1 hour. The layers were separated and the organic layer was washed with 1N HCl (14.3 kg, 11.7 mol, 1.4 volumes) and used directly in the next step.
Reaction SMILES: ClC1C=CC(S(N)(=O)=O)=CC=1.[H-].[Na+].FC1C=C(F)C=CC=1[N+]([O-])=O.Cl.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][C:37]2[CH:42]=[C:41](F)[CH:40]=[CH:39][C:38]=2[N+:44]([O-:46])=[O:45])(=[O:35])=[O:34])=[CH:29][CH:28]=1.[CH3:47][N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>CN(C=O)C.C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][C:37]2[CH:42]=[C:41]([N:51]3[CH2:52][CH2:53][CH2:54][N:48]([CH3:47])[CH2:49][CH2:50]3)[CH:40]=[CH:39][C:38]=2[N+:44]([O-:46])=[O:45])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CN1CCCNCC1
Agent: Cl
Agent: NS(=O)(=O)c1ccc(Cl)cc1
Agent: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCCN(c2ccc([N+](=O)[O-])c(NS(=O)(=O)c3ccc(Cl)cc3)c2)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
4-chlorobenzene sulfonamide (3.5 g, 18.3 mmol) was added slowly to a suspension of sodium hydride (1.6 g, 55% suspension in mineral oil, 36.6 mmol) in anhydrous DMF (50 mL) under an atmosphere of nitrogen. The mixture was warmed to 40° C. for 1 hour and 2,4-difluoronitrobenzene (2 mL) was added dropwise. This mixture was stirred at 60° C. overnight. The cooled reaction mixture was poured into hydrochloric acid (1 N, 250 mL) and extracted with ethyl acetate (2×50 mL). The organic extracts were washed with water, dried over MgSO4 and evaporated to give a yellow solid. The product was re-crystallized from ethanol. Yield 2.4 g (40%). 1H NMR (400 MHz, CDCl3) δ 6.85 (m, 1 H), 7.48 (AB, J=8.3 Hz, 2 H), 7.56 (dd, J=10.01, 2.68 Hz, 1 H), 7.84 (AB, J=8.3 Hz, 2 H), 8.21 (dd, J=9.28, 5.61 Hz, 1 H), 10 (bs, 1 H). Calculated N 8.47%, C 43.58%, S 9.70%, H 2.44%; Found N 8.54%, C43.89%, S 10.10%, H 2.76%. 4-Chloro-N-[5-fluoro-2-nitrophenyl]benzenesulfonamide (1 g, 3 mmol) and N-methylhomopiperazine (0.4 mL) were heated together at 130° C. for 3 hours. The product was allowed to cool, dissolved in CH2Cl2 (50 mL) and washed with aqueous sodium bicarbonate. The organic phase was dried over MgSO4 and evaporated to give 1.05 g of a yellow solid which was re-crystallized from toluene. Yield 0.65 g (51%). 1H NMR (400 MHz, —CDCl3) δ 1.98 (q, J=5.62 Hz, 1H), 2.37 (s, 3 H), 2.52 (t, J=5.62 Hz, 2 H), 2.67 (t, J=5.12 Hz, 2 H), 3.55 (t, J=6.35 Hz, 2 H), 3.60 (t, J=5.12 Hz, 2 H), 6.34 (dd, J=9.77, 2.68 Hz, 1 H), 6.86 (d, J=2.68 Hz, 1 H), 7.43 (ab, J=8.79 Hz, 2 H), 7.79 (ab, J=8.79 Hz, 2 H), 8.01 (d, J=9.77 Hz, 1 H), 11.6 (br s, 1 H). Calculated N 13.19%, C 50.88%, H 4.98%; Found N 13.27%, C 50.99%, H 4.83%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([N:35]2[CH2:44][CH2:43][C@@H:42]3[C@H:37]([O:38][CH2:39][C:40](=[O:45])[NH:41]3)[CH2:36]2)[C:33]=1[Cl:34])[C:29]#[N:30].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Cl:34][C:33]1[C:32]([N:35]2[CH2:44][CH2:43][C@@H:42]3[C@H:37]([O:38][CH2:39][C:40](=[O:45])[NH:41]3)[CH2:36]2)=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[NH:25][C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1
Reactant: N#Cc1cc(N)c(Cl)c(N2CC[C@H]3NC(=O)CO[C@@H]3C2)c1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(C#N)cnc12
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@H]4NC(=O)CO[C@@H]4C3)c2Cl)nn2c(C#N)cnc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (33.5 mg, 0.098 mmol), (Intermediate 10), (+/−)-3-amino-4-chloro-5-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)benzonitrile (30 mg, 0.098 mmol), DPPF (3.8 mg, 6.85 mmol), Cs2CO3 (65.4 mg, 0.201 mmol), Xantphos (5.66 mg, 9.78 mmol), palladium(II)Acetate (6.83 mg, 0.029 mmol) and 1,4-dioxane (2 ml) were combined in a microwave vial. The vial was evacuated and backfilled with Nitrogen 3×. The reaction stirred at 100° C. for 3 hr. The reaction mixture cooled to 25° C., diluted with EtOAc and washed with brine and dried (Na2SO4). The solvents were removed and the material purified on silica gel 5% MeOH in DCM to afford (+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethyl (4 methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:11]=[C:12]([CH2:16][OH:17])[CH:13]=[CH:14][CH:15]=2)=[CH:2]1.O[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][O:17][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=2)=[CH:2]1
Reactant: OCc1cccc(-c2csc3ccccc23)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)CCc1ccc(OCc2cccc(-c3csc4ccccc34)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
To a solution of [3-(1-benzothiophen-3-yl)phenyl]methanol (0.70 g, 2.91 mmol), methyl 3-(4-hydroxyphenyl)propanoate (0.58 g, 3.22 mmol) and tributylphosphine (0.95 mL, 3.81 mmol) in anhydrous tetrahydrofuran (40 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.96 g, 3.80 mmol) by small portions, and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with diethyl ether (40 mL). The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:5) to give the title compound (1.0 g, yield 85%) as a colorless oil. MS: m/z 403 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]=C=O)NC3CCCCC3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)[C:52]([OH:54])=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:52]([NH:6][CH:7]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:8]3)=[O:54])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCc1nc2ccc(N(CCCCCC=C=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Product: CCCCCCN(C(=O)NC1CCCCC1)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylamino-carbonyl-n-hexylamino)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])C1C=CC=CC=1>O1CCCC1>[OH:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13]
Reactant: CON(C)C(=O)c1cccc(OCc2ccccc2)c1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cccc(O)c1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a solution of 100 g (0.37 mol) B1 in 750 ml tetrahydrofuran 10 g Pd/C (10%) were added and the mixture was hydrogenated at atmospheric pressure for 2 hours. The catalyst was filtered off and the filtrate was evaporated to yield 66.0 g B2 (98%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.CO.C([O:13][C@@H:14]1[C@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@:17]([CH2:46][O:47][S:48]([C:51]2[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][CH:52]=2)(=[O:50])=[O:49])([CH2:27][O:28][Si:29]([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:16][C@H:15]1[N:58]1[CH:65]=[C:64]([CH3:66])[C:62](=[O:63])[NH:61][C:59]1=[O:60])(=O)C>C(O)(=O)C>[CH2:20]([O:19][C@@H:18]1[C@@:17]([CH2:46][O:47][S:48]([C:51]2[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][CH:52]=2)(=[O:49])=[O:50])([CH2:27][O:28][Si:29]([C:42]([CH3:44])([CH3:43])[CH3:45])([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:16][C@@H:15]([N:58]2[CH:65]=[C:64]([CH3:66])[C:62](=[O:63])[NH:61][C:59]2=[O:60])[C@@H:14]1[OH:13])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)O[C@H]1[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(COS(=O)(=O)c2ccc(C)cc2)[C@H]1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@]2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@@H]2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 91.9 %

Procedure:
Potassium carbonate (12.75 mg, 0.0923 mmol) and water (0.5 ml) were added, under cooling with ice, to a methyl alcohol solution (4 ml) of Compound 35 (250 mg, 0.308 mmol), and the mixture was stirred for 22 hours at room temperature. Under cooling with ice, acetic acid was added to the reaction mixture to neutralize it, whereafter the solvent was distilled off under reduced pressure. After water was added to the residue, the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and then the resulting crude product was purified by silica gel column chromatography (AcOEt-hexane, 3:2) to obtain a white powder, Compound 36 (216.7 mg, 0.283 mmol, 92%). mp. 74-77° C. [α]D23 +5.15° (c=1.23, CHCl3). IR ν max (KBr): 3048, 2934, 1695, 1363, 1181, 1108, 977, 819, 704 cm−1.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([OH:23])=[O:22].O.O.O.[OH-].[Na+:29]>O>[CH3:1][C:2]1([CH3:24])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([O-:23])=[O:22].[Na+:29]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)[O-]

Procedure:
A suspension of 2.418 kg (6 mols) of ampicillin trihydrate in 15 liters of water was admixed with 300 ml of 2N sodium hydroxide, and the sodium ampicillin was isolated as a snow-white powder by lyophilization in the same manner and under the exact same conditions as in Example 1. The product was storage-stable and showed an active substance content of 91.5% in the microbiological test and 92.7% in the iodometric test.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13]2)=[CH:4][CH:3]=1.[Li]CCCC.[C:25]([N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1COCC1>[CH3:18][C:14]1([CH3:19])[CH2:15][CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([C:35]3([OH:38])[CH2:34][CH2:33][N:32]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:37][CH2:36]3)=[CH:3][CH:4]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC1(C)CCCN(CCCOc2ccc(I)cc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCCN(CCCOc2ccc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-{3-[(4-iodophenyl)oxy]propyl}-3,3-dimethylpiperidine (for example as prepared for Intermediate 2) (3 g, 8.02 mmol) in anhydrous THF (30 ml) was cooled to −78° C. under nitrogen and treated with nBuLi (1.6M solution in hexanes, 6.02 ml, 9.63 mmol), after 0.5 h, a solution of N-Boc-4-oxopiperidine (commercially available, for example from Aldrich) (1.99 g, 10 mmol) in THF (10 ml) was added dropwise. The mixture was allowed to warm up to room temperature and was stirred overnight. The mixture was quenched with ammonium chloride solution and extracted with EtOAc, dried over magnesium sulphate, filtered and concentrated. The resulting residue was purified by FlashMaster II chromatography using a 100 g cartridge, eluting with 100% cyclohexane for 5 minutes, 100% cyclohexane to 100% EtOAc over 15 minutes, 100% EtOAc to 100% DCM in 5 minutes and 100% DCM to 30% MeOH (containing 1% of triethylamine) in DCM over 40 minutes then held constant for 5 min, monitoring at 254 nm to afford the title compound (1.25 g). LCMS RT=2.48 min, ES+ve m/z 447 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCOCC1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N)ccc1OCCN1CCOCC1

Procedure:
Prepared analogously to Example 3.1.b. from 4-[2-(2-methoxy-4-nitrophenoxy)ethyl]morpholine. Yield: 0.23 g (85.8% of theory); C13H20N2O3 (M=252.31); calc.: molecular ion peak (M+H)+: 253; found: molecular ion peak (M+H)+: 253; Rf value: 0.5 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: C(N1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([B:16]([OH:18])[OH:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(C)C.BrC1C=CC(N2CC[CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)CC2)=CC=1>>[O:35]1[CH2:36][CH2:37][N:32]([CH:29]2[CH2:5][CH2:6][N:7]([C:10]3[CH:11]=[CH:12][C:13]([B:16]([OH:17])[OH:18])=[CH:14][CH:15]=3)[CH2:8][CH2:9]2)[CH2:33][CH2:34]1
Reactant: Brc1ccc(N2CCC(N3CCOCC3)CC2)cc1
Reactant: CC(C)N1CCN(c2ccc(B(O)O)cc2)CC1
Product: OB(O)c1ccc(N2CCC(N3CCOCC3)CC2)cc1
Yield: 40 %

Procedure:
The title compound was synthesized according to the synthesis of 4-(4-isopropylpiperazin-1-yl)phenylboronic acid, except substituting 4-(1-(4-bromophenyl)piperidin-4-yl)morpholine (250 mg, 0.77 mmol). The aqueous layer was washed with EtOAc and concentrated. The residue was triturated with THF and the filtrate was concentrated to give the title compound as a yellow solid (87 mg, 40%). 1H NMR (400 MHz, MeOD) δ 7.58 (br s, 2H), 6.93 (d, J=7.5 Hz, 2H), 3.85-3.82 (m, 2H), 3.72 (br s, 4H), 2.72 (t, J=12.3 Hz, 2H), 2.63 (br s, 4H), 2.40-2.34 (m, 1H), 2.01-1.98 (m, 2H), 1.62-1.54 (m, 2H); MS ESI 291.1 [M+H]+, calcd for [C15H23BN2O3+H]+ 291.18.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[N:14]=1.Cl.[CH3:21][CH2:22][O:23]CC>CN(C)C(=O)C>[Br:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:22](=[O:23])[CH3:21])[N:14]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCOCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(=O)N(C)C
Solvent: CCCCCC
Product: CC(=O)c1cccc(Br)n1
Reaction time: 0.5 h
Yield: 28 %

Procedure:
12.5 mL of a solution of n-BuLi 1.6 M in hexane (20 mmol) are added at −78° C. to a solution of 4.70 g 2,6-dibromopyridine 20 (20 mmol) in 100 mL anhydrous ether. The reaction medium is left in the cold for 30 min. 2 mL N,N-dimethylacetamide are added cold (−78° C.) for 1 h, then allowed to reach the ambient temperature. The reaction medium is neutralized with 25 mL of an aqueous HCl 1M solution. The aqueous phase is extracted with Et2O (3×20 mL). The combined organic phases are washed with brine (3×20 mL), dried on MgSO4, filtered, then evaporated under vacuum. The raw product is recrystallized in an Et2O/n-C5H12 (1/2) mixture. 1.18 g of an orange solid is obtained, i.e. a 28% yield.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11](OCC)=[O:12])[CH2:9][N:8]([S:16]([CH3:19])(=[O:18])=[O:17])[CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O>[OH:3][CH2:4][CH:6]1[CH2:7][N:8]([S:16]([CH3:19])(=[O:18])=[O:17])[CH2:9][CH:10]1[CH2:11][OH:12]
Reactant: CCOC(=O)C1CN(S(C)(=O)=O)CC1C(=O)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N1CC(CO)C(CO)C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of (3RS,4RS)-1-methanesulfonyl-pyrrolidine-3,4-dicarboxylic acid diethyl ester (1.13 g, 3.85 mmol) in THF (40 ml) was slowly added a 1 M solution of LiAlH4 in THF (11.55 ml. 11.55 mmol) at 0° C. The mixture was stirred for 1.5 h at 0° C. Water (0.44 ml), 1 M aqueous NaOH (0.44 ml) and water (1.31 ml) were added subsequently at 0° C. MgSO4 was added and filtered. The solid was washed with EtOAc (4×). The filtrate was evaporated to leave a colorless solid that was washed with hot dichloromethane to give ([3RS,4RS]-4-hydroxymethyl-1-methanesulfonyl-pyrrolidin-3-yl)-methanol as a colorless solid, MS: 268 (M+OAc)−.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:16])[C@@H:13]([CH2:17]Br)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:16])[C@@H:13]([CH2:17][NH:22][CH:19]2[CH2:21][CH2:20]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1C[C@H](CBr)[C@H](F)C1
Reactant: NC1CC1
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1C[C@H](CNC2CC2)[C@H](F)C1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
(3S,4S)-1-Benzyloxycarbonyl-3-bromomethyl-4-fluoropyrrolidine (415 mg), cyclopropylamine (0.91 mL) and acetonitrile (3 mL) were mixed together. The mixture was stirred at 80° C. for 6 hours and was subsequently concentrated under reduced pressure. To the resulting residue, cyclopropylamine (4.55 mL) was added and the mixture was again stirred at 80° C. for 6 hours and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL), washed with saturated brine (2×5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane:ethyl acetate=2:1) to give (3S,4S)-1-benzyloxycarbonyl-3-cyclopropylaminomethyl-4-fluoropyrrolidine as a pale brown oil (239 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[O:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1.[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)nc1
Reactant: NCCC1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC2CCOCC2)ccc1Oc1ccc(C(N)=O)nc1
Reaction time: 8 h

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyridine-2-carboxamide (Ex 391, Part A) (0.600 g, 2.20 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.285 g, 2.20 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (11.0 mL), cap and stir overnight. Add NaBH4 (0.0833 g, 2.20 mmol) and stir until the gasses stop evolving. Filter the reaction mixture, then concentrate it. Purify by chromatography eluting with 5% to 30% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes to give 5-(2-methoxy-4-{[2-(tetrahydropyran-4-yl)ethylamino]methyl}phenoxy)pyridine-2-carboxamide. (0.6103 g, 71.9%). Dissolve the compound in dichloromethane:methanol (3.2 mL) and add 1 equivalent of 0.50 M methanesulfonic acid in dichloromethane. Stir the solution for a short time before concentrating to give the title compound (0.775 g): TOF MS ES+ 386.2 (M+H)+, HRMS calcd for C21H28N3O4 386.2080 (M+H)+, found 386.2078, time 0.39 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=9.3 min, 100% purity.