Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30]Br)([CH3:25])([CH3:24])[CH3:23].[I-].[K+].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:22]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][N:18]1[CH2:19][CH2:20][O:21][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)[CH2:17]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCCCCCCCOc1ccc(C2CNCCO2)cc1
Reactant: CC(C)(C)OC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCOc1ccc(C2CN(CCCC(=O)OC(C)(C)C)CCO2)cc1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
2-(4-Octyloxy-phenyl)-morpholine (1.50 g; 5.2 mmol), 4-bromo-butyric acid tert-butyl ester (1.38 g; 6.2 mmol) (prepared according to C. Morin, M. Vidal Tetrahedron, 1992, 48(42), 9277), potassium iodide (1.03 g; 6.2 mmol), K2CO3 (1.42 g; 10.29 mmol), and CH3CN (15 mL) were mixed and heated under reflux for 2 hours. After cooling to RT the reaction mixture was concentrated in vacuo, dissolved in EtOAc, washed with 5% aqueous NaHCO3 solution, dried (Na2SO4) concentrated in vacuo and purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 4-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-butyric acid tert-butyl ester (1.90 g), TLC (SiO2 Rf. 0.20 EtOAc:hexanes 1:1)
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][S-:12].[Na+]>C1(C)C=CC=CC=1.CCOCC>[CH3:11][S:12][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: C[S-]
Reactant: O=Cc1ccc(F)cc1F
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CSc1cc(F)ccc1C=O
Temperature: 80 °C
Reaction time: 14 h
Yield: 75.3 %

Procedure:
A suspension of 2,4-difluorobenzaldehyde (16 mL, 146 mmol) and sodium thiomethoxide (14 g, 200 mmol) in toluene (200 mL) was stirred at 80° C. for 7 h and 14 h at room temperature. The reaction mixture was diluted with ether (300 mL), washed with water (100 mL), saturated aqueous NaHCO3 (100 mL) and brine (50 mL). The aqueous layers were combined and extracted with ether (2×100 mL). The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated to give a viscous oil. This viscous oil was dissolved in ether/hexanes (1:1, v/v) and slowly concentrated on under vacuum. The precipitated white solid was separated by filteration and dried to give 2-methylthio-4-fluorobenzaldehyde (18.7 g, 75% yield). 1HNMR (500 MHz, CDCl3) δ: 10.11 (1H, s), 7.78 (1H, dd, J=8.55, 6.11 Hz), 6.97 (1H, dd, J=10.07, 2.44 Hz), 6.91 (1H, td, J=8.54, 2.44 Hz), 2.45 (3H, s). MS calcd for C8H7FOS (M+H): 171.2. found: 171.6.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C@@H:9]([NH:14][C:15](=[O:29])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]3[CH2:28][CH2:27][CH2:26][O:25]3)=[CH:18][CH:17]=1)[CH2:8][CH2:7]2)[CH3:3].Br[CH2:31][CH2:32][CH:33]([CH3:37])[CH2:34][CH2:35]Br.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:37][CH:33]1[CH2:34][CH2:35][N:1]([C@@H:2]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][C@@H:9]([NH:14][C:15](=[O:29])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]4[CH2:28][CH2:27][CH2:26][O:25]4)=[CH:18][CH:17]=2)[CH2:8][CH2:7]3)[CH3:3])[CH2:31][CH2:32]1
Reactant: CC(CCBr)CCBr
Reactant: C[C@@H](N)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1CCN([C@H](C)c2ccc3c(c2)CC[C@H](NC(=O)c2ccc(OC[C@@H]4CCCO4)cc2)C3)CC1
Temperature: 40 °C

Procedure:
A mixture of N-[(S)-6-((R)-1-aminoethyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (50 mg), 1,5-dibromo-3-methylpentane (31 mg), ethyldiisopropylamine (0.10 ml) and acetonitrile (1 ml) was heated to 40° C. for 8 hours. The cooled reaction mixture was concentrated and the residue was purified by preparative HPLC. The product was thus obtained with the molecular weight of 476.66 (C30H40N2O3); MS (ESI): 477 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:24]([O-:26])=[O:25])=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=2)[N:11]=1)=[O:8].C(=O)([O-])[O-].[K+].[K+].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C)C=O>[CH3:22][C:17]1[CH:16]=[C:15]([N:12]2[CH:13]=[CH:14][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:23]=[C:2]([N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[CH:3]=[CH:4][C:5]=3[N+:24]([O-:26])=[O:25])=[N:11]2)[CH:20]=[CH:19][C:18]=1[CH3:21]
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])n2)cc1C
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(N4CCCCC4)ccc3[N+](=O)[O-])n2)cc1C
Temperature: 110 °C
Reaction time: 4 h
Yield: 88.3 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 5-chloro-N-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-yl)-2-nitrobenzamide 4g (300 mg, 0.81 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), potassium carbonate (330 mg, 2.39 mmol, 3.00 equiv), and piperidine (200 mg, 2.35 mmol, 3.00 equiv). The resulting solution was stirred for 4 h at 110° C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 50 mL of ethyl acetate. The resulting mixture was washed with 2×30 mL of brine, dried over sodium sulfate, and concentrated under vacuum. This resulted in 300 mg (88%) of product as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([C:19]3([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:21][CH2:20]3)[N:13]=4)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39]>CN(C=O)C.C(Cl)Cl>[C:22]1([C:19]2([C:14]3[N:13]=[C:12]4[S:11][C:10]([C:6]5[CH:5]=[C:4]6[C:9](=[CH:8][CH:7]=5)[N:1]([CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:2]=[CH:3]6)=[N:18][C:17]4=[CH:16][CH:15]=3)[CH2:20][CH2:21]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)CCCBr
Reactant: c1ccc(C2(c3ccc4nc(-c5ccc6[nH]ccc6c5)sc4n3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CCCn1ccc2cc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(1H-Indol-5-yl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (80 mg, 0.218 mmol) was dissolved in DMF (1.1 mL) before cesium carbonate (156 mg, 0.479 mmol) was added and stirred at ambient temperature for 1 h; to the reaction mixture was added methyl 4-bromobutanoate (43 mg, 239 μmol) before it was stirred for 20 h at 80° C. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with water, washed 1 times with 50 mL of water, separated, dried over sodium sulfate, and concentrated via rotovap to give methyl 4-(5-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-1H-indol-1-yl)butanoate after flash chromatography. MS (ESI) m/z: Calculated: 467.2; Observed: 468.4 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[C:19](Cl)(=O)/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[N:4]1[C:3]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:16])[F:17])=[CH:14][C:2]=2[N:1]=[C:19]1/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: Nc1cc(C(F)(F)F)ccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 2-amino-N-(2-pyridyl)-4-trifluoromethylaniline and (E)-cinnamoyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 365.36; mp: 144.5-145.0° C.; 1H-NMR (CDCl3) δ: 8.82-8.79 (1H, m), 8.12-8.00 (3H, m), 7.57-7.49 (6H, m), 7.41-7.31 (3H, m), 7.11 (1H, d, J=16.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](Cl)=[O:11])=[CH:4][CH:3]=1.[CH3:13][CH2:14][O:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1)=[O:17].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([C:16]([O:15][CH2:14][CH3:13])=[O:17])=[CH:23][CH:22]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCC(=O)Cl)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)CCc2ccc(C)cc2)cc1

Procedure:
A solution of 15 g. of 3-(4-methylphenyl)propionyl chloride in 100 ml. of dichloromethane is created with stirring with a solution of 15 g. of benzocaine and 9.13 g. of triethylamine in 100 ml. of dichloromethane. The mixture is stirred overnight, then washed with 100 ml. each of 10% hydrochloric acid, water, and brine, then dried with magnesium sulfate, and evaporated to yield a solid. This solid is crystallized from 200 ml. of acetonitrile and dried in vacuo, giving 22.08 g. of the desired product, m.p. 154°-155° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:17])[C:8]([F:16])=[C:9]2[C:14]=1[N:13]=[C:12]([CH3:15])[CH:11]=[CH:10]2)=[O:4].O.[H][H]>C(O)(=O)C.[Pt]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:17])[C:8]([F:16])=[C:9]2[C:14]=1[NH:13][CH:12]([CH3:15])[CH2:11][CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(F)c(F)c2ccc(C)nc12
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(F)c(F)c2c1NC(C)CC2
Yield: 68.9 %

Procedure:
A solution of 8.0 g (33.7 mmol) of 5,6-difluoro-2-methylquinoline-8-carboxylic acid methyl ester (Example 33) in 100 mL of glacial acetic acid is treated with 2.15 g of platinum on carbon (0.8 g of active catalyst+62.8% water) and then shaken in a hydrogen atmosphere at temperatures of 24° C. to 29° C. and pressures of 23.9 to 46.6 psi for 3 hours. The catalyst is removed by filtration and the solvent is removed in vacuo at 50° C. The residue is triturated with water (50 mL) and extracted with dichloromethane (2×200 mL). The combined organic layers are stirred with 5% sodium bicarbonate solution, washed with water, dried (MgSO4), filtered and evaporated in vacuo. The residue is chromatographed over flash grade silica gel (230-400 mesh) eluting with dichloromethane to give 5.6 g of the title compound as a light yellow oil. 1H NMR (400 MHz, CDCl3): 7.66 (bs, 1H), 7.49 (m, 1H), 3.82 (s, 3H), 3.46 (m, 1H), 2.88 (m, 1H), 2.67 (m, 1H), 1.97 (m, 1H), 1.27 (d, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[C:25]([NH2:39])=[CH:26][C:27]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][O:36][CH3:37])[CH2:30][CH2:29][C:28]=2[CH:38]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[Cl:21][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:39][C:25]2[C:24]([O:23][CH3:22])=[CH:38][C:28]3[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][O:36][CH3:37])[CH2:32][CH2:33][C:27]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Reactant: CN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: COCCN1CCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4N(C)S(C)(=O)=O)n3)c(OC)cc2CC1

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-methyl-methanesulfonamide (95 mg, 0.27 mmol), 8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (67 mg, 0.27 mmol), and 10-Camphorsulfonic acid (96 mg, 0.41 mmol) in Isopropyl alcohol (4 mL) and was heated in a microwave vial for 2 h at 120° C. Upon cooling, the mixture was treated with MP-Carbonate (2.69 mmol/g loading; 0.35 g, 0.941 mmol) for 1 h, was filtered and was concentrated in vacuo onto Celite. Chromatography (ISCO, 12 g silica gel, 40-80% EtOAc:Hex) afforded N-((1R,2R)-2-{5-Chloro-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-N-methyl-methanesulfonamide as a off white foam (99 mg, 65%). LCMS: 567 (M+H); 1H-NMR, CDCl3: 8.17 (s, 1H), 7.91 (s, 1H), 7.35 (s, 1H), 6.64 (s, 1H), 5.56 (s, 1H), 4.10 (m, 1H), 3.87 (s, 3H), 3.7 (m, 3H), 3.35 (s, 3H), 2.9 (m, 6H), 2.83 (s, 3H), 2.74 (s, 3H), 2.4 (m, 1H), 1.9 (m, 4H), 1.65 (m, 3H), 1.35 (m, 4H).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=3)[N:30]=2)=[CH:26][CH:25]=1.CN(C)C=O.[C:51]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=1)#[CH:52]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[N:54]1[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=1[C:51]#[C:52][C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:38][CH:37]=3)[N:30]=2)=[CH:26][CH:25]=1
Reactant: C#Cc1ccccn1
Reactant: NS(=O)(=O)c1ccc(Nc2nccc(-c3ccc(Br)s3)n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(Nc2nccc(-c3ccc(C#Cc4ccccn4)s3)n2)cc1
Temperature: 180 °C
Yield: 11.5 %

Procedure:
A 10 mL glass microwave reaction vessel with stir bar contained palladium acetate (5 mg, 22 μmol), tri-o-tolylphosphine (13 mg, 44 μmol), and 4-[4-(5-bromo-thiophen-2-yl)-pyrimidin-2-ylamino]-benzenesulfonamide (80 mg, 200 μmol). Anhydrous dimethylformamide (DMF) (3.5 mL), 2-ethynylpyridine (46 mg, 450 μmol), and triethylamine (50 μL) is added to the reaction vessel. The reaction vessel is sealed and heated to 180° C. for 660 seconds in a microwave reactor (Emrys Microwave Reactor, personal Chemistry AB, Uppsala, Sweden). The reaction is filtered through celite, concentrated, redissolved in dimethylsulfoxide (DMSO), and purified by reverse phase (RP) HPLC to obtain 10 mg of the title compound. LC/MS data (Condition A; molecular ion and retention time): m/z 434 (M+H); 2.52 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][C@H:13]3[C@H:8]([CH2:9][N:10]([CH3:16])[CH2:11][CH2:12]3)[C:6]=2[CH:7]=1.[CH2:17](O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH2:18][CH2:17][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:15][CH2:14][C@H:13]4[C@H:8]([CH2:9][N:10]([CH3:16])[CH2:11][CH2:12]4)[C:6]=3[CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CC[C@H]2COc3ccc(O)cc3[C@H]2C1
Reactant: OCCc1ccccc1
Product: CN1CC[C@H]2COc3ccc(OCCc4ccccc4)cc3[C@H]2C1

Procedure:
A mixture of 0.2 g (±)-[4aR*,10bS*]-1,3,4,4a,5,10b-hexahydro-9-hydroxy-2-methyl-2H-[1]benzopyrano[4,3-c]pyridine (m.p. of HCl salt 268°-269° ), 0.215 ml phenethyl alcohol and 0.3 g dicyclohexylcarboddiimide is heated under nitrogen for 18 hours at 130°. The cooled reaction mixture is flash chromatographed with CH2Cl2 /methanol (20:1) to yield the title compound; m.p. HCl salt 204°.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([F:33])[CH:39]=3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: OB(O)c1cccc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(F)c1)N1CCN(C2CCCC2)CC1
Yield: 46 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 3-fluorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow solid (46%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][O:6][N:7]=[C:8]([C:24](=O)[CH2:25]Br)[C:9]([NH:11][CH:12]1[C:22](=[O:23])[N:14]2[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]12)=[O:10]>C(O)C>[NH2:1][C:2]1[S:3][CH:25]=[C:24]([C:8](=[N:7][O:6][CH3:5])[C:9]([NH:11][CH:12]2[C:22](=[O:23])[N:14]3[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[N:4]=1
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: NC(N)=S
Solvent: CCO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
Thiourea (8.4 mg.) was added to a solution of 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 42 mg.) in ethanol (6 ml.) and stirred at room temperature for an hour and at 50° C. for 30 minutes. After removing ethanol from the reaction mixture in vacuo, water (5 ml.) was added to the residue and adjusted to pH 4.0 with 6N-hydrochloric acid. The precipitates were collected by filtration and dried to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 8 mg.). The filtrate was subjected to column chromatography on nonionic, adsorption resin "Diaion HP-20" (trademark: manufactured by Mitsubishi Chemical Industries Ltd., 5 ml.), washed with chilled water (5 ml.) and eluted with 20% aqueous isopropyl alcohol. The eluate was adjusted to pH 6.5 with 1N aqueous sodium hydroxide under ice-cooling, and concentrated in vacuo. The residue was lyophilized to give sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 15 mg.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16](=O)[NH:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=O)[CH2:14][N:13]([CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:39]>>[CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[N:39]=2)[CH2:14][N:13]([CH2:29][C:30]([F:31])([F:33])[F:32])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: [NH4+]
Reactant: COC(=O)NC(C(=O)N1CN(CC(F)(F)F)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CN(CC(F)(F)F)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 1 h

Procedure:
{1-[5-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-3-(2,2,2-trifluoro-ethyl)-imidazolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (148 mg, <257 mmol) was dissolved in m-xylenes (4.0 mL) and heated at 135° C. Solid ammonium acetate (150 mg, 1.9 mmol) was added and the reaction was stirred at 135° C. After 60 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product {1-[4-(4-Bromo-phenyl)-1′-(2,2,2-trifluoro-ethyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (15.1 mg) as the TFA salt: LCMS-ESI+: calc'd for C21H25BrF3N5O3: 532.3 (M+); Found: 532.1/534.2 (M+).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=2[F:20])[CH2:7][C@@H:6]1[CH3:21])=[O:4].[I:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[NH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[Cl:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:25]3[C:26]4=[N:27][CH:28]=[CH:29][CH:30]=[C:31]4[C:23]([I:22])=[N:24]3)[C@@H:6]([CH3:21])[CH2:7]2)=[C:12]([F:20])[CH:13]=1
Reactant: Ic1n[nH]c2ncccc12
Reactant: COc1cc(N2CCN(C(=O)CCl)[C@@H](C)C2)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(I)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
A mixture of 2-Chloro-1-[(S)-4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-ethanone (1.37 g, 4.08 mmol, 1 eq), 3-Iodo-1H-pyrazolo[3,4-b]pyridine (1.0 g, 4.08 mmol, 1 eq), potassium carbonate (2.26 g, 16.4 mmol, 4 eq), and DMF (15 ml) was stirred overnight at 90° C. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous NaHCO3, and concentrated in vacuo. The crude product was purified by flash chromatography to provide 1-[(S)-4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-(3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanone (2.2 g).
Reaction SMILES: C(O)(=O)C.[C:5]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[OH:21])(=[NH:7])[NH2:6].C[O-].[Na+].[CH2:25]([O:32][C:33](=[CH:36]N(C)C)[CH:34]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH2:25]([O:32][C:33]1[CH:34]=[N:7][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[OH:21])=[N:6][CH:36]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)C=C(C=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)N)C(O)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(OCc3ccccc3)cn2)C(O)C1
Temperature: 25 °C
Yield: 27.5 %

Procedure:
A solution of 372 mg (1 mmol) of tert-butyl (3RS,4RS)-4-carbamimidoyl-3-hydroxy-piperidine-1-carboxylate acetate in 10 ml of methanol was treated with 1 ml of 1N sodium methylate solution and stirred at room temperature. Subsequently,205 mg (1 mmol) of 2-benzyloxy-3-dimethylamino-acrolein (EPA 0 477 901) were added thereto and the solution was heated to reflux for 18 hours. For the working-up, the reaction mixture was evaporated under reduced pressure and the residue was taken up in 20 ml of methylene chloride and washed with 5 ml of water. The organic phase was separated, dried over sodium sulphate and finally evaporated under reduced pressure. For purification, the residue was chromatographed on silica gel using a 1:4 mixture of methylene chloride and ethyl acetate as the eluent. There were obtained 106 mg (27% of theory) of tert-butyl (3RS,4RS)-4-(5-benzyloxy-pyrimidin-2-yl)-3-hydroxy-piperidine-1-carboxylate as a colourless oil; MS: 386 (M+H)+.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[C:24]([C:32](O)=O)[N:23]=2)=[CH:18][C:17]=1[CH3:35]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[N:25]=[C:24]([C:32]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=4)[N:14]=3)[N:23]=2)=[CH:18][C:17]=1[CH3:35]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(C(=O)O)n2)ccc1Cl
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3nc(-c4cccc(S(N)(=O)=O)c4)no3)n2)ccc1Cl

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.16 g, 0.74 mmol) and 4-(4-chloro-3-methyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.7) (0.16 g, 0.50 mmol) according to the general procedure V. Obtained as a white solid (0.046 g, 19%). MS (ISP) 496.2 [(M+H)+]; mp 246° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1[Cl:13].CO[C:17](OC)([N:19]([CH3:21])[CH3:20])[CH3:18]>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:10]=[C:17]([N:19]([CH3:21])[CH3:20])[CH3:18])=[O:9])=[CH:6][C:5]=1[Cl:13]
Reactant: COC(C)(OC)N(C)C
Reactant: COC(=O)c1ccc(C(N)=O)cc1Cl
Product: COC(=O)c1ccc(C(=O)N=C(C)N(C)C)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of 2-chloro-terephthalamic acid methyl ester of Step A (1.02 g, 4.8 mmol) and N,N-dimethylacetamide dimethyl acetal (3.5 mL, 23.9 mmol) was heated at 90° C. for 30 minutes under nitrogen. The solution was cooled, and excess reagent was removed under high vacuum to provide a brown oil which was used as such in the next step.