Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[C:16]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH:15]=[CH:14][C:13]=1[CH3:34])=S.CCN=C=NCCCN(C)C>CN(C=O)C>[NH:1]1[C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]=[C:9]1[NH:11][C:12]1[CH:17]=[C:16]([CH:15]=[CH:14][C:13]=1[CH3:34])[C:18]([N:20]1[CH2:21][CH2:22][CH:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[CH:30][CH:31]=2)[CH2:24][CH2:25]1)=[O:19]
Reactant: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1NC(=S)Nc1cnccc1N
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1Nc1nc2cnccc2[nH]1
Reaction time: 8 h

Procedure:
To a solution of 1-(4-aminopyridin-3-yl)-3-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)thiourea (281.2) in DMF continued from the prior step was added EDCI (0.12 g, 0.64 mmol). The mixture was stiffed at room temperature overnight. The DMF was removed under high vacuum and the residue was purified using prep.-TLC (5% MeOH in EtOAc) to yield 76 mg (56% for 3 steps) of a white powder. m/z (ES+) 437 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (br, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.08 (d, 1H), 7.78 (d, 2H), 7.53 (d, 2H), 7.29 (d, 2H), 7.05 (d, 1H), 4.65 (m, 1H), 3.91 (m, 1H), 3.17 (m, 1H), 3.04-3.72 (m, 2H), 2.36 (s, 3H), 1.97-1.60 (m, 4H).
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH:4]([C:8]1[CH:9]=[C:10](C2C=CC=CC=2)[CH:11]=[C:12](C(F)(F)F)[CH:13]=1)[C:5]([OH:7])=[O:6].[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)#[CH:26]>>[CH3:24][CH:2]([CH3:1])[CH2:3][CH:4]([C:8]1[CH:9]=[C:10]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:11]=[C:12]([C:26]#[C:25][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=2)[CH:13]=1)[C:5]([OH:7])=[O:6]
Reactant: CC(C)CC(C(=O)O)c1cc(-c2ccccc2)cc(C(F)(F)F)c1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Product: CC(C)CC(C(=O)O)c1cc(C#Cc2ccc(C(F)(F)F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from a Sonogashira coupling of 4-methyl-2-(5-trifluoromethyl-biphenyl-3-yl)pentanoic acid (intermediate compound 1g) with 1-ethynyl-4-trifluoromethyl-benzene under the conditions described in Example 10; 1H NMR (400 MHz, MeOD) δ ppm 0.86 (dd, J=6.60, 1.96 Hz, 6 H), 1.44 (dt, J=13.45, 6.72 Hz, 1 H), 1.62 (ddd, J=13.82, 7.09, 6.97 Hz, 1 H), 1.87-1.97 (m, 1 H), 3.70 (t, J=7.83 Hz, 1 H), 7.49 (d, J=1.47 Hz, 1 H), 7.57-7.73 (m, 9 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CCOC(C)=O.CCCCCC>[C:26]1([C:4]2[CH:3]=[C:2]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:25])[CH3:23])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Br)cc1C1=CCCCC1
Reactant: OB(O)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccccc2)cc1C1=CCCCC1
Yield: 85 %

Procedure:
The title compound was prepared by the procedure of Example 28, step (a) using 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the Example 11, step (f), 19 mg, 0.038 mmol), and phenylboronic acid (5.1 mg, 0.042 mmol). Silica gel chromatography (5-10% EtOAc/hexane) afforded the title compound (16 mg, 85%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.79 (s, 1H), 8.42 (d, 1H, J=8.5 Hz), 7.78 (s, 1H), 7.59 (m, 2H), 7.52 (dd, 1H, J=8.5, 2.1 Hz), 7.44 (m, 2H), 7.41 (d, 1H, J=2.1 Hz), 7.33 (m, 1H), 5.97 (s, 2H), 5.91 (m, 1H), 3.67 (t, 2H, J=8.3 Hz), 2.26-2.36 (m, 4H), 1.75-1.93 (m, 4H), 0.98 (t, 2H, J=8.3 Hz), 0.01 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C29H34N4O2Si, 499.3 (M+H), found 498.8.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1.[C:15]([O:19][C:20](=[O:25])[NH:21][CH2:22][CH2:23][NH2:24])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[CH:4]([NH:24][CH2:23][CH2:22][NH:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)C(Br)c1cccc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(NCCNC(=O)OC(C)(C)C)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of (3-methoxy-phenyl)-acetic acid methyl ester (19.6 mmol) in CCl4 was added N-bromosuccinimide (19.6 mmol) and the reaction mixture was irradiated for 2 hours. The reaction mixture was then concentrated in vacuo to afford the intermediate bromo-(3-methoxy-phenyl)-acetic acid methyl ester. To a solution of bromo-(3-methoxy-phenyl)-acetic acid methyl ester in THF (30 mL) under an atmosphere of nitrogen was added a solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (20.6 mmol) in THF (20 mL) followed by K2CO3 (39.2 mmol, 2 equivalents). The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was partitioned between water (50 mL) and EtOAc (2×50 mL), the combined organics were dried (sodium sulfate) and concentrated in vacuo to afford an oil. The oil was purified by silica gel column chromatography using as eluent EtOAc:petrol (1:1) to give the title compound as an oil in 53% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35]C(N)=O>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][C@H:15]([CH3:35])[CH2:16][OH:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Product: Cc1ccc(C(=O)N[C@H](C)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (R)-(−)-2-amino-1-propanol for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.92 (m, 1H), 7.77 (s, 1H), 7.61 (q, 1H, J=8.0 Hz), 7.52 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 4.16 (q, 1H, J=6.4 Hz), 3.56 (m, 2H), 2.20 (s, 3H), 1.22 (d, 3H, J=6.0 Hz). ESHRMS m/z 464.1186 (M+H calculated for C22H21ClF2N3O4 requires 464.1183).
Reaction SMILES: [CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](F)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[S:13][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Cc1cc2c(s1)CN(C)CCC2O
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: Cc1cc2c(s1)CN(C)CCC2Oc1ccc(Cl)c(Cl)c1

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 23) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([O:19][C:20](=[O:22])[CH3:21])[CH:8]=[C:9]([CH:11](OC(OCC)=O)[CH3:12])[CH:10]=1)(=[O:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([O:19][C:20](=[O:22])[CH3:21])[CH:6]=1)[CH:11]=[CH2:12])(=[O:3])[CH3:2]
Reactant: CCOC(=O)OC(C)c1cc(OC(C)=O)cc(OC(C)=O)c1
Solvent: Cc1ccccc1
Product: C=Cc1cc(OC(C)=O)cc(OC(C)=O)c1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
20.0 g acetic acid 3-acetoxy-5-(1-ethoxycarbonyloxy-ethyl)-phenyl ester is dissolved in 92.5 ml toluene and the mixture is continuously conducted through a glass tube filled with ceramic packing at 475° C. After cooling the reaction mixture to room temperature the solvent is evaporated in vacuum and 12.8 g (90%) pure 3,5-diacetoxystyrene is isolated.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[CH:18][CH:17]=2)[N:6]1[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1[O:40][CH3:41].[OH-].[Na+]>O1CCOCC1>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:7]3[N:6]([C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=4[O:40][CH3:41])[CH:5]([CH2:4][C:3]([OH:42])=[O:2])[C:14]4[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=4)[N:8]=3)=[CH:17][CH:18]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CC1c2cccc(F)c2N=C(c2ccc(-c3cccc(OC)c3)cc2)N1c1cc(C(F)(F)F)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cccc(-c2ccc(C3=Nc4c(F)cccc4C(CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)cc2)c1

Procedure:
Starting from 459 mg (0.79 mmol) of the ester from Example 22A, reaction in analogy to general method [E] with 95.2 mg (2.38 mmol) of sodium hydroxide in 54 ml of dioxane results in 383 mg (86% of theory) of the target compound.
Reaction SMILES: C([NH:8][C@@H:9]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[CH:10]=[O:11])C1C=CC=CC=1.C(N[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)C=O)C1C=CC=CC=1.[ClH:39]>CO.[Pd]>[ClH:39].[OH:11][CH:10]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@@H:9]1[NH2:8]
Reactant: O=C[C@@H](NCc1ccccc1)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Pd]
Agent: Cl
Agent: O=C[C@H](NCc1ccccc1)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CO
Product: N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 45 °C
Reaction time: 8 h

Procedure:
The crude mixture of N-benzyl-2-amino-2-deoxy-D-mannose and N-benzyl-2-amino-2-deoxy-D-glucose obtained according to example 2A was suspended in methanol (20-100 mL), and the pH was adjusted to approximately 1-2 with HCl (10-40 mL 2M HCl and additional 2-8 mL conc. HCl). 10% Pd on charcoal (0.4-1.6 g) was added and the reaction mixture was stirred at r.t. or at 45° C. under H2-atmosphere (up to 5 bar) until all the starting material was consumed. The reaction mixture was filtered through Celite® and washed with 20-50 mL of methanol:water (2:1). The solvents were evaporated until approx. 20-40 mL of volume remained. The crystallization of glucosamine hydrochloride was initiated by adding methanol (40-80 mL) to the aqueous sugar solution and kept at 0-5° C. for overnight. The crystals were separated by filtration and washed with cold methanol. Methanol from the mother liquor was evaporated, and to the remaining aqueous solution 20-80 mL isopropanol was added. The solution was kept at 0-5° C. overnight, the crystals formed were filtered, washed with cold isopropanol and dried: 3.9 g of D-mannosamine hydrochloride was isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7].[Br:14]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(OCC)(=O)C>[Br:14][CH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc(C)c(OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CBr)c(OC)c1
Yield: 89 %

Procedure:
A mixture of methyl 3-methoxy-4-methylbenzoate (10.0 g, 55.5 mmol), N-bromosuccinimide (10.7 g, 60.9 mmol), 2,2′-azobis(isobutyronitrile) (1.6 mg) and ethyl acetate (200 ml) was heated under reflux overnight. The solvent was evaporated under reduced pressure, and hexane was added to the residue. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (9:1-7:3, v/v) to give the title compound (12.8 g, 92%) as a colorless oil.
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3cc(F)ccc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2cc(F)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(6-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (403 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (355 mg, 93%) as a white solid.
Reaction SMILES: [CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:17][C:18]1[CH:28]=[CH:27][C:21]([CH2:22][NH:23][C:24]([NH2:26])=[O:25])=[CH:20][CH:19]=1>>[CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([NH:26][C:24]([NH:23][CH2:22][C:21]2[CH:27]=[CH:28][C:18]([F:17])=[CH:19][CH:20]=2)=[O:25])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)N(C1CCCCC1)C1CCCCC1
Reactant: NC(=O)NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)NC(=O)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in General Procedure 1 using dicyclohexyl carbamoyl chloride and 4-fluorobenzyl urea.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](Br)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:22]2[CH2:23][CH2:24][N:19]([C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=3)[CH2:20][CH2:21]2)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Reactant: Brc1cnc(Cc2ccccc2)c2ccccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1ccc(N2CCN(c3cnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Temperature: 80 °C
Reaction time: 0.03 h
Yield: 25 %

Procedure:
In a 40 mL vial 120 mg (0.40 mmol) 1-benzyl-4-bromo-isoquinoline (see above), 160 mg (0.84 mmol) 6-piperazin-1-yl-nicotinonitrile, 40 mg (0.04 mmol) tris(dibenzylideneaceton)dipalladium(0), and 60 mg (±)-(1,1′-binaphthalene-2-2′diyl)bis(diphenylphosphine) are added to 5 mL dioxane. After flushing the vial with nitrogen for 5 min, the reaction mixture is stirred for 2 min followed by the addition of 150 mg (1.55 mmol) sodium tert-butoxide. After flushing with nitrogen for 5 min, the vial is sealed and heated at 80° C. for 12 h. After cooling, the mixture is loaded onto a silica column directly and purified. The eluent containing the correct mass is concentrated in vacuo and the resulting residue is purified by reversed phase HPLC using a Varian Prostar system equipped with a Waters xTerra column (50×100 mm) and a solvent gradient of 0.1% NH3 in water/0.1% NH3 in acetonitrile (0→100%). Pure fractions are pooled and evaporated to give 40 mg (0.10 mmol, 25% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[N:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[OH:33].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:7]=2)[CH:21]=[CH:20][C:19]=1[OH:33]
Reactant: Clc1cncc(NCc2cccnc2)n1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(-c2cncc(NCc3cccnc3)n2)ccc1O
Yield: 100.5 %

Procedure:
A mixture of 6-chloro-N-(pyridin-3-ylmethyl)pyrazin-2-amine (49 mg, 0.22 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (52 mg, 0.20 mmol), (PPh3)4Pd (23 mg, 0.020 mmol) and a Na2CO3 solution (0.22 mmol of a 2 M solution) in toluene (10 ml) was heated under reflux overnight. After removal of the solvents, the residue was dissolved in CH2Cl2 (150 ml), dried (Na2SO4), filtered and the CH2Cl2 removed in vacuo. The residue was purified by column chromatography, eluting with a n-hexane:ethyl acetate gradient mixture to obtain the desired product (62 mg, 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[C:11]([CH3:18])[N:10]=[N:9]1.F[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[CH:17]=2)=[C:11]([CH3:18])[N:10]=[N:9]1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1c[nH]cn1
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-n2cnc(-c3c(C)nnn3-c3ccccc3F)c2)cc1
Temperature: 120 °C
Yield: 1.8 %

Procedure:
A mixture of 1-(2-fluorophenyl)-5-(1H-imidazol-4-yl)-4-methyl-1H-1,2,3-triazole (290 mg, 1.19 mmol), methyl 4-fluorobenzoate (184 mg, 1.19 mmol) and potassium carbonate (330 mg, 2.38 mmol) in DMF (6.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 2 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (8 mg, 2%) as an off white solid. MS: m/e=378.3 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[C:34]1[CH:35]=[C:36]([C:40]2[CH:45]=[C:44]([NH:46][CH:47]([CH3:49])[CH3:48])[N:43]=[C:42]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=3)[CH:41]=2)[CH:37]=[N:38][CH:39]=1>COCCOC.C(Cl)Cl.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.Cl[Pd]Cl.[Fe+2]>[CH:47]([NH:46][C:44]1[N:43]=[C:42]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)[CH:41]=[C:40]([C:36]2[CH:37]=[N:38][CH:39]=[C:34]([C:15]3[CH:14]=[CH:13][C:12]([C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]4)=[O:11])=[CH:17][CH:16]=3)[CH:35]=2)[CH:45]=1)([CH3:49])[CH3:48]
Reactant: CC(C)N1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CC(C)Nc1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)Nc1cc(-c2cncc(-c3ccc(C(=O)N4CCN(C(C)C)CC4)cc3)c2)cc(-c2ccccn2)n1

Procedure:
To a solution of (4-Isopropyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (Intermediate B4) (1.2 eq, 0.162 mmol, 58 mg) and 2M Na2CO3 (2.0 eq, 0.262 mmol, 0.13 ml) in DME (1 ml) are added (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-isopropyl-amine (Ex. 2.46; step1) (1 eq, 0.131 mmol, 50 mg) and [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with DCM (0.1 eq, 0.0131 mmol, 9.6 mg). The reaction mixture is heated using microwave radiation at 90° C. for 3 hours. The reaction mixture is dissolved in DCM and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The residue is purified by reverse phase chromatography (Isolute™ C18, 0-20% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH and 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 521.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][C@@H:5]([CH:7]2[CH2:9][N@@:8]2[S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[O:4][C:3]1=[O:22].[CH3:23][C:24]1([CH3:38])[CH2:29][N:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[C:27](=[O:37])[CH2:26][NH:25]1>C1(C)C=CC=CC=1>[CH3:23][C:24]1([CH3:38])[CH2:29][N:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[C:27](=[O:37])[CH2:26][N:25]1[CH2:9][C@H:7]([NH:8][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C@@H:5]1[CH2:6][C@@H:2]([CH3:1])[C:3](=[O:22])[O:4]1
Reactant: Cc1ccccc1N1CC(C)(C)NCC1=O
Reactant: C[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: C[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: Cc1ccccc1N1CC(C)(C)N(C[C@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])[C@@H]2C[C@@H](C)C(=O)O2)CC1=O
Yield: 103 %

Procedure:
A solution of 590 mg of (3R,5S)-3-methyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (76g) (1.8 mmol) and 512 mg of 5,5-dimethyl-1-(2-methylphenyl)piperazin-2-one obtained in Example (51d) (2.35 mmol) in toluene (18 ml) was stirred at 110° C. for two hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/acetone=4/1-3/1) to obtain 1.01 g of the title compound (yield: quant.).
Reaction SMILES: [FH:1].[Cl-].[Cl-].[Cl-].[Cl-].[Cl-].[Cl-].[C:8]1([CH3:15])[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1>>[F-:1].[F-:1].[F-:1].[F-:1].[F-:1].[F-:1].[C:8]1([CH3:15])[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1
Reactant: F
Agent: [Cl-]
Solvent: Cc1cccc(C)c1
Product: [F-]

Procedure:
After having charged an autoclave according to example 3 under the same pressure conditions also specified in example 3 with 125 kg of hydrogen fluoride, a quantity of 84 kg of m-xylene-hexachloride and of 90 kg of hydrogen fluoride are fed in per hour (molar proportion 1:16.7). The reaction components are preheated to 125°C. The reaction temperature is 130°C in the first autoclave and 120°C in the second. m-xylenehexafluoride is obtained at a yield rate of 93.5 % of the theoretical yield, calculated on the m-xylenehexachloride initially used.