Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].[ClH:10].[CH2:11](OC(OCC)C)[CH3:12]>C(O)C(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[ClH:10].[NH2:8][C:7]1[NH:6][C:4]([N:2]([CH3:3])[CH3:1])=[N:5][CH:11]([CH3:12])[N:9]=1
Reactant: CN(C)C(=N)N=C(N)N
Reactant: CCOC(C)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)CO
Product: CC1N=C(N)NC(N(C)C)=N1
Yield: 77.6 %

Procedure:
A mixture of 250.2 g of metformin hydrochloride, 213.6 g of acetaldehyde diethyl acetal and 12.5 g of toluene-4-sulfonic acid monohydrate in 500 ml of isobutanol is heated under reflux for 40 hours. Some of the solvent is removed by distillation. The mixture is cooled to 10°, and the white precipitate is separated off, giving 224.7 g (77.4%) of 4-amino-3,6-dihydro-2-dimethylamino-6-methyl-1,3,5-triazine hydrochloride.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:9](=[O:11])[NH:10][C:5]2=[N:4][CH:3]=1.BrC1N=C([NH:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)C(N)=NC=1.C(N1C=CN=C1)(N1C=CN=C1)=[O:36]>C1COCC1.CN(C=O)C>[CH:13]1([CH2:12][N:8]2[C:6]3[C:5](=[N:4][CH:3]=[C:2]([C:31]4[CH:32]=[CH:33][C:28]([C:27]([NH2:26])=[O:36])=[CH:29][CH:30]=4)[N:7]=3)[NH:10][C:9]2=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1ncc(Br)nc1NCC1CCCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=c1[nH]c2ncc(Br)nc2n1CC1CCCCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc(-c2cnc3[nH]c(=O)n(CC4CCCCC4)c3n2)cc1
Temperature: 120 °C
Yield: 89 %

Procedure:
6-Bromo-1-(cyclohexylmethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. 6-Bromo-N2-(cyclohexylmethyl)pyrazine-2,3-diamine (4.85 g, 17.01 mmol) was dissolved in THF (50 mL), 1,1′-carbonyldiimidazole (3.45 g, 21.26 mmol) was added, and the reaction solution was divided into 4 different vials. Each fraction was heated in a Biotage Emrys Optimizer microwave reactor at 120° C. for 30 min. The reacted fractions were combined and condensed under reduced pressure. The crude material was dissolved in minimal DMF and precipitated with deionized water while sonicating. The filtered product was dried in a vacuum oven at 60° C. over night to afford the title compound (4.72 g, 89%). MS (ESI) m/z 311.3 [M]+, 313.5 [M+2]+
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:52]([N:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN(C=O)C.C(OCC)C>[CH:52]([N:65]1[CH2:70][CH2:69][N:68]([C:12]([C@@H:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:67][CH2:66]1)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 85.4 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.300 g, 1.17 mmol, Example 1, Step B) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.408 mL, 2.34 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.444 g, 1.17 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid benzhydrylpiperazine (0.295 g, 1.17 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 40 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (50% EtOAc in hexanes) to provide 0.49 g (85%) of the pure titled compound as a white foam; mp 66-74° C. APCI-MS m/z 491.4 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[S:30][C:29]([NH2:31])=[N:28][N:27]=4)=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Br[CH2:33][C:34]([C:36]1[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=1)=O.C(OC(C)C)(C)C>C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[S:30][C:29]5=[N:31][C:34]([C:36]6[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=6)=[CH:33][N:28]5[N:27]=4)=[CH:22][CH:21]=3)[CH2:18][CH2:19]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: Nc1nnc(-c2ccc(C3CCN(C4CCCCC4)CC3)cc2)s1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: CCOC(=O)c1ccc(-c2cn3nc(-c4ccc(C5CCN(C6CCCCC6)CC5)cc4)sc3n2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 41.9 %

Procedure:
A mixture of 5-[4-(1-cyclohexyl-4-piperidyl)phenyl]-1,3,4-thiadiazol-2-amine trifluoroacetate (0.78 g) and ethyl 4-(bromoacetyl)benzoate (0.6 g) in ethanol (15 ml) was stirred for 5 hours at 80° C. After being cooled to room temperature, the reaction mixture was poured into isopropyl ether. The resulting precipitate was collected by filtration, washed with isopropyl ether and added to a solution of trifluoroacetic acid (1.5 ml) in xylene (15 ml). Then a mixture was stirred for 3 hours at 130° C. After being cooled to room temperature, the reaction mixture was poured into isopropyl ether. The resulting precipitate was collected by filtration and washed with isopropyl ether to give ethyl 4-[2-[4-(1-cyclohexyl-4-piperidyl)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoate trifluroacetate (0.45 g).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25]([OH:27])=O)(=[O:3])[NH2:2].[O:28]1[CH2:32][CH2:31][CH:30]([CH2:33][NH2:34])[CH2:29]1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:34][CH2:33][CH:30]4[CH2:31][CH2:32][O:28][CH2:29]4)=[O:27])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Reactant: NCC1CCOC1
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)NCC1CCOC1

Procedure:
2-Carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.05 g) was reacted with (tetrahydrofuran-3-yl)methanamine similar to as described in Example 2 to afford 6.2 mg of (±) 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(tetrahydrofuran-3-ylmethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 457 (M)+. 1H NMR (400 MHz, DMSO) δ 11.33 (t, J=5.4 Hz, 1H), 8.61 (d, J=8.5 Hz, 1H), 8.38 (s, 1H), 7.89 (s, 1H), 7.01 (d, J=10.6 Hz, 1H), 5.47 (s, 1H), 5.06-4.94 (m, 2H), 4.60-4.44 (m, 2H), 3.81-3.71 (m, 2H), 3.63 (dd, J=15.2, 7.7 Hz, 1H), 3.44 (dd, J=8.6, 5.9 Hz, 1H), 2.48-2.37 (m, 1H), 2.04-1.92 (m, 1H), 1.68-1.54 (m, 1H), 1.49 (s, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.C(OCC)(OCC)OCC.[CH:35]([NH2:38])([CH3:37])[CH3:36].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN(C=O)C.CC(O)=O>[CH:35]([NH:38][CH2:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([C:10]3[N:11]=[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[S:8][CH:9]=3)[C:13](=[O:24])[NH:14]2)=[CH:19][CH:18]=1)([CH3:37])[CH3:36]
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Reactant: CC(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Solvent: CN(C)C=O
Product: CC(C)NCc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde (step (a), 100 mg, 0.3 mmol), 1.5 mL AcOH, 1.5 mL of triethyl orthoformate, isopropylamine (0.5 mL), and 30 mL of DMF was stirred for 3 h. Gentle heating was be used to bring about a homogenous solution. After 3 h, NaBH(OAc)3 (0.5 g, Aldrich) was added and the reaction was stirred for 3 days at RT. The solution was concentrated in genevac overnight to remove DMF. The resulting solid was dissolved in a minimal amount of DMSO and purified by mass triggered HPLC to give a yellow solid after drying in genevac (TFA salt). MS m/z: 377.3 (M+1).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)=[O:5])C.[OH-].[Li+]>CO.O1CCOCC1.O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:11]=[CH:10][C:9]([C@@H:7]3[CH2:8][C@H:6]3[C:4]([OH:5])=[O:3])=[CH:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(-c2ccc(F)cc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(-c2ccc(F)cc2)nc1
Temperature: 70 °C

Procedure:
3.00 g (10.5 mmol) of trans-2-[6-(4-fluoro-phenyl)-pyridin-3-yl]-cyclopropanecarboxylic acid ethyl ester and 378 mg (15.8 mmol) of lithium hydroxide were dissolved in a mixture of 27 ml of methanol, 5 ml of dioxane and 3 ml of water, and the mixture was heated at 70° C. for 2 h. Subsequently, the mixture was evaporated to dryness, the residue was taken up in water and the pH was adjusted to 4 with acetic acid. The precipitate was isolated by filtration and purified by column chromatography (silica gel, dichloromethane/methanol, gradient from 98:2 to 95:5). Yield: 2.2 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:31]C(OC)=O)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](C4C=CC(=O)N(C)C=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[Mg][Br:38].[CH2:39]1[CH2:43][O:42]C[CH2:40]1>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[Br:38][C:20]1[CH:21]=[CH:22][C:17]([C@@H:15]([N:11]2[CH2:10][CH2:9][C@@:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)([CH2:31][C:43]3([OH:42])[CH2:40][CH2:39]3)[O:13][C:12]2=[O:14])[CH3:16])=[CH:18][CH:19]=1
Reactant: C[Mg]Br
Reactant: C1CCOC1
Reactant: COC(=O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)O1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC2(O)CC2)(c2ccc(F)cc2)OC1=O
Reaction time: 2 h
Yield: 2 %

Procedure:
To a solution of methyl 2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-ethyl)-2-oxo-1,3-oxazinan-6-yl)acetate (150 mg, 0.33 mmol), and tetraisopropoxytitanium (189 mg, 0.66 mmol) in THF (20 mL) was added 3.0 Methylmagnesium bromide (4 mL, 12 mmol) at rt under nitrogen. Then the mixture was stirred for 2 h. The reaction was quenched with aqueous NH4Cl solution, and the mixture was filtered. The filtrate was extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give the crude product, which was purified by preparative HPLC to give (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-((1-hydroxycyclopropyl)methyl)-1,3-oxazinan-2-one (2.51 mg, 2%). 1H NMR (CDCl3): 0.03 (m, 1H), 0.18 (m, 1H), 0.49 (m, 1H), 0.60 (m, 1H), 1.43 (m, 3H), 2.08 (s, 2H), 2.26 (m, 1H), 2.37 (m, 2H), 2.88 (m, 1H), 5.53 (m, 1H), 6.66 (d, 2H), 6.97 (t, 2H), 7.16 (m, 2H), 7.26 (m, 2H).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:29]([CH3:39])[S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:40]=[N+:41]=[N-:42].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:42][N:41]=[N:40][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[CH:24]=[C:25]([N:29]([CH3:39])[S:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)(=[O:32])=[O:31])[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(C)cc(N(C)S(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(N(C)S(=O)(=O)c3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-methyl-6-(N-benzenesulphonyl-methylamino)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:11])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:11]
Reactant: COC(=O)c1cc(NC(=O)CNC(=O)OC(C)(C)C)ccc1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(NC(=O)CN)ccc1O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The methyl 5-(2-(tert-butoxycarbonylamino)acetamido)-2-hydroxybenzoate (1.3 g, 4.0 mmol) was dissolved in CH2Cl2 (15 mL) and TFA (8 mL). The reaction was stirred (RT, 2.5 h) and then concentrated to afford methyl 5-(2-aminoacetamido)-2-hydroxybenzoate as a clear oil. [M+H]+=225.1. The oil was dissolved in CH2Cl2 (20 mL) and to this was added DHA (1.3 g, 4.0 mmol), EDCI (0.84 g, 4.4 mmol) and triethylamine (2.0 g, 20.0 mmol). The reaction was stirred (RT, 4 h) and then partitioned between CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were dried over MgSO4. The crude material was purified by silica chromatography (0-5% MeOH/CH2Cl2) to afford 0.9 g of methyl 5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoacetamido)-2-hydroxybenzoate as a tan solid. Mass calculated for C10H12N2O4=534.69. found: [M+H]+=535.4.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12](Cl)(=[O:16])[CH2:13][CH2:14][CH3:15]>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:12](=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(=O)Cl
Reactant: Nc1ccccc1C(F)(F)F
Product: CCCC(=O)Nc1ccccc1C(F)(F)F
Yield: 52.8 %

Procedure:
Using the procedure of Step A of Example 6, 32.2 g of o-trifluoromethylaniline and 23.44 g of butyryl chloride were reacted to obtain 24.4 g of N-(2-trifluoromethylphenyl)-butanamide melting at 76° C which was used as is for the next step.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[CH2:16][CH2:15][C@H:14]([NH:17]CC2C=CC=CC=2)[C@H:13]([O:25][CH3:26])[CH2:12]1.[H][H]>[Pd].CO>[OH2:25].[OH2:25].[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[CH2:16][CH2:15][C@H:14]([NH2:17])[C@H:13]([O:25][CH3:26])[CH2:12]1
Reactant: CO[C@@H]1CN(Cc2nc3ccccc3[nH]2)CC[C@@H]1NCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CN(Cc2nc3ccccc3[nH]2)CC[C@@H]1N
Product: O

Procedure:
A mixture of 18 parts of cis-1-(1H-benzimidazol-2-ylmethyl)-3-methoxy-N-(phenylmethyl)-4-piperidinamine and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (93:7 by volume), saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue solidified slowly and the solid product was suspended in 2,2'-oxybispropane. The product was filtered off and dried at the air, yielding 6 parts of cis-1-(1H-benzimidazol-2-ylmethyl)-3-methoxy-4-piperidinamine dihydrate:mp. 92.0° C. (intermediate 122).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:47][CH:48]([F:50])[F:49])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH2:34][CH2:35]N4CCC([C:42]([O:44]CC)=[O:43])CC4)[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.Cl.[CH3:52][C:53]1([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>>[CH:42]([OH:44])=[O:43].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:47][CH:48]([F:50])[F:49])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][N:56]4[CH2:57][CH2:58][C:53]([CH3:52])([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:54][CH2:55]4)[CH2:32][CH2:33]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CCOC(=O)C1CCN(CCN2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Reactant: CCOC(=O)C1(C)CCNCC1
Agent: Cl
Product: CCOC(=O)C1(C)CCN(CCN2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Product: O=CO

Procedure:
Using synthetic method analoguous to that of ethyl 1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]piperidine-4-carboxylate, the title compound was prepared from ethyl 4-methylpiperidine-4-carboxylate hydrochloride. LCMS (Method 24) [M+H]+=728.2, RT=1.87 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.2, 6.8 Hz), 8.69-8.68 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.22 (s, 2H), 4.06 (q, 2H, J=7.2 Hz), 2.67-2.60 (m, 2H), 2.44-2.38 (m, 8H), 2.09-2.04 (m, 2H), 1.97-1.93 (m, 2H), 1.42-1.41 (m, 2H), 1.16 (t, 3H, J=7.2 Hz), 1.10 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([O:13][CH3:14])=[C:5]([CH3:12])[C:6]=1[C:7]([O:9]CC)=O.Cl[C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[N:34]1([CH2:40][CH2:41][NH2:42])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(Cl)Cl>[CH3:14][O:13][C:4]1[S:3][C:2]2[NH:1][C:16](=[O:18])[N:42]([CH2:41][CH2:40][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[C:7](=[O:9])[C:6]=2[C:5]=1[CH3:12]
Reactant: NCCN1CCOCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(N)sc(OC)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1sc2[nH]c(=O)n(CCN3CCOCC3)c(=O)c2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.7 %

Procedure:
To a solution (30 mL) of ethyl 2-amino-5-methoxy-4-methylthiophene-3-carboxylate (1.0 g) in methylene chloride were added triphosgene (1.8 g) and triethylamine (3.0 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-morpholin-4-ylethanamine (1.8 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (15 mL), sodium methoxide (1.0 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.51 g, 34%).
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30]C=O)[C:28](=[O:33])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:36])=O.CCOCC>CO.CCOCC>[ClH:36].[C:1]([S:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH2:30])[C:28](=[O:33])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Solvent: CO
Solvent: CCOCC
Product: CC(=O)SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Product: Cl
Reaction time: 0.33 h
Yield: 88.7 %

Procedure:
A stirred suspension of diphenylmethyl 3-acetylthiomethyl-7β-formamidoceph-3-em-4-carboxylate (0.505 g) in methanol: ether (1:1, 3 ml) at 0° was treated over 10 min. with phosphorous oxychloride (0.468 g). The ice bath was removed and stirring continued for a further 20 min, when a clear solution resulted. The reaction was cooled to 0°, and a white crystalline precipitate appeared. Ether (15 ml) was added and the precipitate filtered off, washed with ether and dried in vacuo to give diphenylmethyl 3-acetylthiomethyl-7β-aminoceph-3-em-4-carboxylate hydrochloride (0.456 g, 89%) as white microcrystals; m.p. 155 -160° (d) [α]D - 91° (c 0.83 in DMSO), λmax (EtOH) 268 nm (ε 8,700)νmax. (Nujol) 1770 (β-lactam), 1720 (CO2R), 1702 cm.-1 (SCOCH3), τ (DMSO-d6) values include 2.60 (m; Ph), 3.02 (s, CHPh2), 7.66 (s, SCOCH3).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10](Cl)[CH:9]1C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27].[H-].[Na+].N1C2C(=CC=CC=2)C(=O)[C:31]1=O>O1CCCC1.C(O)(=O)C.O>[OH:27][C:20]1([CH2:31][CH:10]2[CH2:11][CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)[C:19]2[C:23](=[CH:24][CH:25]=[C:17]([F:16])[CH:18]=2)[NH:22][C:21]1=[O:26]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC1C(Cl)CCN1Cc1ccccc1
Agent: [H-]
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(F)cc2C1(O)CC1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
A solution of a magnesium compound is prepared, on the one hand, from 334 mmol of 1-benzyl-3-chloro-methylpyrrolidine, 334 mmol of magnesium and 300 ml of tetrahydrofuran (THF). On the other hand, a solution containing [lacuna] is prepared from 303 mmol of 5-fluoroisatin and 303 mmol of sodium hydride in 500 ml of THF. The solution containing the magnesium compound is added at 0° C. to the second solution containing the sodium anion of the isatin. The combined mixture is left for 3 hours at room temperature and then brought to reflux for 12 hours. The reaction mixture is then hydrolyzed while cold with 1 kg of ice and 500 ml of water containing 60 ml of glacial acetic acid. The expected product is then extracted with dichloromethane and obtained in the form of an oil, after drying, evaporation and purification by chromatography on a silica column, using a dichloromethane/methanol/aqueous ammonia (98/2/0.2) mixture as eluent.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C@H:12]3[NH:15][CH2:16][CH2:17][C@:6]4([C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)[C:5]=2[CH:4]=[C:3]([C:18](=[O:20])[CH3:19])[CH:2]=1.C(N(CC)CC)C.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[C:18]([C:3]1[CH:2]=[CH:1][C:14]2[CH2:13][C@H:12]3[N:15]([C:34]([CH2:33][C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[O:35])[CH2:16][CH2:17][C@@:6]4([C:5]=2[CH:4]=1)[C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)(=[O:20])[CH3:19]
Reactant: O=C(Cl)Cc1ccco1
Reactant: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)Cc1ccco1)CC3
Temperature: 25 °C
Yield: 90 %

Procedure:
To a mixture of 1.5 g, (-)-1-(morphinan-3-yl)ethanone, 1.7 g of triethylamine and 15 ml of methylene chloride at ice-bath temperature was added a solution of 1.3 g of 2-furyl acetyl chloride in 10 ml of methylene chloride over a period of 1 hour. After the mixture had been refluxed for 4 hours, it was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in 100 ml ether and the ether solution was washed with 1 N hydrochloric acid (2×15 ml) then with water and dried over magnesium sulfate. Removal of the solvent gave 1.9 g (90%) of crude (-)-3-acetyl-N-[(2-furylmethyl)carbonyl]morphinan. For analysis, a sample of this compound was distilled, bp 235°-245° (0.05 mm), [α]25D-160.43° (c 0.94, MeOH).