Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:44][CH2:45][C:46]([C:48]1[C:49](=[O:59])[N:50]([CH3:58])[C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:47].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[C:10]([NH:44][CH2:45][C:46]([C:48]1[C:49](=[O:59])[N:50]([CH3:58])[C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:47])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cn1c(=O)c(C(=O)CN)cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)c1cc2ccccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (S)-2-((tert-butoxycarbonyl)amino)-8-oxodecanoic acid (0.76 mmol, 1 eq; prepared as described in J. Med. Chem. 2008, 51(8), pp 2350-2353), EDC.HCl (1 eq), HOBT (1 eq) in DMF (0.2 M) was stirred at room temperature for 10 min. 3-(2-aminoacetyl)-1-methylquinolin-2(1 H)-one (1.1 eq) in DMF (3 eq) was subsequently added, followed by DIPEA (2.2 eq) and the mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM and washed with brine. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, Petroleum ether/EtOAc, from 10% EtOAc to 80% EtOAc), to give the title compound as an oil. MS (ES) C27H37N3O6 requires: 499.60, found: 500.
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=O.CC=C([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)CC.O.[CH:16]1C=CC=CC=1>>[CH3:1][C:3]1[CH:4]=[CH:11][CH:12]=[C:13]([CH3:16])[C:14]=1[NH2:10]
Reactant: CC=C(CC)N1CCCC1
Reactant: c1ccccc1
Reactant: C=CC=O
Solvent: O
Product: Cc1cccc(C)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
12.9 g (0.23 mole) of freshly distilled acrolein is added dropwise at room temperature to a solution of 27.8 g (0.2 mole) of N-(3-pent-2-enyl)-pyrrolidine in 50 ml of absolute benzene, with the temperature rising to a maximum of 50° C. After completion of the addition, the mixture is stirred for 2 hours at room temperature. It is subsequently boiled for 15 hours at about 110° C. bath temperature in a water-separator. The oil obtained after evaporating off the solvent is heated for 18 hours with 100 ml of abs. dioxane, 10.0 g of ammonia, 50.0 g of propylene and 5.0 g of palladium on charcoal (5%) at 120°-130° C. under a pressure of 47 bars (nitrogen). After the addition of 100 ml of ether, the catalyst is filtered off and washed three times with ether. The oil obtained after removal of the solvent by evaporation is distilled in vacuo. There is obtained 4.5 g (20% of theory) of 2,6-dimethylaniline, b.p. 103° C./ 18 Torr, and as byproducts 1.9 g (8% of theory) of 2,6-dimethyl-cyclohex-2-en-1-one, b.p. 62°-64° C./ 17 Torr, and 2.4 g (10% of theory) of 2,6-dimethyl-cyclohexanone.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38](B(O)O)[CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:25][CH2:26][CH2:27]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:4]=2[N:3]1[C:38]1[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=1
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(c3cccnc3)C(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.5 %

Procedure:
In a 15 mL reaction tube was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.212 mmol), pyridin-3-ylboronic acid (52 mg, 0.424 mmol), copper(II)acetate (58 mg, 0.318 mmol) and 5 Å molecular sieves (60 mg) in anhydrous dichloromethane (2 ml). To this was added anhydrous pyridine (34 μl, 0.424 mmol) and the resulting blue suspension stirred at room temperature under air for 24 hours. Further pyridine (1 mL) was added and the resulting deep blue solution stirred at room temperature for 24 hours. Further pyridin-3-ylboronic acid (52 mg, 0.424 mmol) and copper(II)acetate (58 mg, 0.318 mmol) were added and the mixture stirred at room temperature for 72 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 88:12 to 0:100) to give the desired product as an off-white solid (32 mg 28% yield). 1H-NMR (500 MHz, CDCl3) δ 8.50-8.80 (2H, br m), 7.71 (1H, d), 7.50 (1H, br s), 7.09-7.26 (7H, m), 6.92-7.02 (2H, d), 6.71 (1H, s), 5.00 (3H, s), 2.10-2.55 (4H, m), 1.92-2.05 (1H, m), 1.66-1.80 (1H, m), 1.00-1.45 (9H, br m). LCMS (Method A) RT=6.61 min, M+H+=549.09.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Li]CCCC.CCCC(C)C.C(NC(C)C)(C)C.[I:27]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([I:27])[C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: II
Reactant: Clc1ccc(Cl)nc1
Agent: [Li]CCCC
Solvent: CCCC(C)C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Clc1cc(I)c(Cl)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
A solution of 2,5-dichloropyridine (10 g, 67.57 mmol) in THF (17 mL) was added dropwise to a stirred solution of n-BuLi in isohexane (33.8 mL, 67.57 mmol) and diisopropylamine (9.63 mL, 67.57 mmol) in THF (68.0 mL) cooled to −78° C., over a period of 1 hour under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 30 minutes and then a solution of I2 (17.49 g, 68.92 mmol) in THF (17.0 mL) was added dropwise. The resulting solution was stirred at −78° C. for 1 hour and then quenched with water (75 mL) and allowed to warm to room temperature. The mixture was extracted with Et2O (3×100 mL) and the combined organic layers were dried over MgSO4, and then evaporated. The residue was triturated with CH2Cl2 to give a solid which was dried under vacuum to afford 2,5-dichloro-4-iodopyridine (9.72 g, 53% yield). The filtrate was evaporated and the residue purified by chromatography on silica, eluting with a gradient of 50-100% CH2Cl2 in isohexane. Fractions containing product were combined and evaporated and the residue triturated with MeOH to leave a second crop of 2,5-dichloro-4-iodopyridine (5.74 g, 31% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 7.85 (1H, s), 8.34 (1H, s).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:4]([CH:10]=[C:11](I)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:38]2[C:33](=[N:34][CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=2)[N:32]([S:48]([C:51]2[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][CH:52]=2)(=[O:50])=[O:49])[CH:31]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[F:1][C:2]1[C:3]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:4]([CH:10]=[C:11]([C:36]2[CH:37]=[C:38]3[C:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])=[CH:31][N:32]([S:48]([C:51]4[CH:52]=[CH:53][C:54]([CH3:57])=[CH:55][CH:56]=4)(=[O:50])=[O:49])[C:33]3=[N:34][CH:35]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CN(C)C(=O)c1cc(I)cc(F)c1NCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(NCc4ccncc4)c(C(=O)N(C)C)c3)cc12
Yield: 22.3 %

Procedure:
Crude 3-fluoro-5-iodo-N,N-dimethyl-2-[(pyridin-4-ylmethyl)-amino]-benzamide (˜1.63 mmol) from the previous step and 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (822 mg, 1.63), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1, 133 mg, 0.16 mmol), acetonitrile (8 ml) and 2 M aqueous sodium carbonate solution (4 ml) were placed in a microwave reactor and irradiated to 100° C. for 10 minutes. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel (0 to 100% [10% methanol in ethyl acetate] in hexanes) to afford 236 mg (22% for 2 steps) of 3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-2-[(pyridin-4-ylmethyl)-amino]-benzamide. MS: m/z 650.3 (M+H+).
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][O:5][C:6]1[C:11]([CH2:12]Br)=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21]>CS(C)=O>[CH3:4][O:5][C:6]1[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][C:1]#[N:2]
Reactant: COc1c(CBr)cccc1Oc1ccccc1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(CC#N)cccc1Oc1ccccc1F
Temperature: 25 °C
Yield: 79.2 %

Procedure:
Powdered sodium cyanide (2.5 g) was added to a solution of 2-fluorophenyl 2-methoxy-3-bromomethylphenyl ether (17.6 g) in dimethyl sulfoxide (50 ml) with stirring at room temperature, and the reaction mixture was treated in a similar manner to that of Example 5-(4) to give oily 2-[2-methoxy-3-(2-fluorophenoxy)phenyl]acetonitrile (10.4 g).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].Cl[CH2:9][CH:10]=O.C(=O)=O>N1C=CC=CC=1>[CH3:2][C:1]1[O:3][CH:9]=[CH:10][C:4]=1[C:5](=[O:7])[CH3:6]
Reactant: O=CCCl
Reactant: CC(=O)CC(C)=O
Agent: O=C=O
Solvent: c1ccncc1
Product: CC(=O)c1ccoc1C
Reaction time: 4.5 h

Procedure:
To 100.12 g acetylacetone, 44 g dolomite powder and 4 ml pyridine (5 mol%) are added as described in example 1, whereafter 174.4 g 45% aqueous chloracetaldehyde solution is added, with stirring. Stirring is continued at 70° C. for 4.5 hours, and then another hour at 75° C. The CO2 -volume generated is 10.8 liter at room temperature. Workup occurs as in example 1. A fraction is collected at temperatures from 59°-61° C. at 11 torr; it amounts to 93.56 corresponding to 75.5% of the theoretical.
Reaction SMILES: N[C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1.C=O.[C:22]([BH3-])#[N:23].[Na+].[C:26](O)(=O)C>C(#N)C.C(OCC)C>[ClH:18].[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][C@@H:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][C@@H:2]1[N:23]([CH3:22])[CH3:26]
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Reactant: N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(Cl)c(Cl)c1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: CN(C)[C@H]1Cc2ccccc2[C@H]1Oc1ccc(Cl)c(Cl)c1
Product: Cl
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A solution of (±) cis 2-amino-1-(3,4dichlorophenoxy)indane (0.88 g, 3.0 mmol) in acetonitrile (40 ml) was treated with formaldehyde (2 ml of a 37% aqueous solution, 26 mmol) followed by sodium cyanoborohydride (0.38 g, 6.0 mmol). The mixture was stirred at room temperature for 6 days while maintaining the pH at 5-7 by the addition of glacial acetic acid. The reaction mixture was diluted with diethyl ether and washed with 1M sodium hydroxide followed by brine. The organic layer was dried over Na2 SO4 and concentrated in vacuo. Passage through a short column of neutral alumina eluting with 0.5-1% ethanol in chloroform afforded a colourless oil which was converted into the hydrochloride salt and recrystallised to give the title compound as a colourless solid (0.6 g), m.p. 219°-220° C. (from methanol/ethyl acetate/diethyl ether).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[NH:36]1[CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:25]([C:22]2[N:23]=[CH:24][C:19]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][CH:17]([CH3:18])[N:8]([C:6]5[CH:5]=[C:4]([N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)[N:3]=[C:2]([NH2:1])[N:7]=5)[CH2:9]4)=[CH:14][CH:13]=3)=[CH:20][CH:21]=2)=[O:26])[CH2:39][CH2:38][CH2:37]1
Reactant: C1CNC1
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CC1Cc2ccc(-c3ccc(C(=O)N4CCC4)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50B starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50B, Step 1) and azetidine hydrochloride (Aldrich, Cat. No. 414336). LCMS (M+H)+: m/z=499.2.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[N:3]1.Cl[S:17]([OH:20])(=O)=[O:18].[NH3:21]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[N:3]=2)=[CH:10][C:11]=1[S:17]([NH2:21])(=[O:20])=[O:18]
Reactant: O=S(=O)(O)Cl
Reactant: Cn1nc(-c2ccc(Cl)cc2)ccc1=O
Reactant: N
Product: Cn1nc(-c2ccc(Cl)c(S(N)(=O)=O)c2)ccc1=O

Procedure:
Similarly reaction of 2-methyl-6-(4-chlorophenyl)-3(2H)-pyridazinone with chlorosulfonic acid followed by ammonia according to the procedure of this Example gives 2-chloro-5-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)benzenesulfonamide.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=O)[CH:10]=[CH:9]2>>[Cl:3][C:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([CH3:5])[CH:7]=2)[N:12]=[C:11]([C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]#[N:20])[CH:10]=1
Reactant: Cc1ccc2nc(-c3ccccc3C(N)=O)ccc2c1
Reactant: O=S(Cl)Cl
Product: Cc1ccc2nc(-c3ccccc3C#N)cc(Cl)c2c1
Yield: 11 %

Procedure:
2.5 ml (34.2 mmol) of thionyl chloride were added to 1.28 g (4.88 mmol) of 2-(6-methylquinolin-2-yl)benzamide obtained in Reference Example 7 and the mixture was stirred. After heating the mixture under reflux for 3 hours, thionyl chloride was distilled off. The residue was dissolved in 100 ml of chloroform and poured into iced water. The organic layer was separated, neutralized with 150 ml of a saturated sodium bicarbonate solution, washed with a saturated sodium chloride solution and dried over magnesium sulfate followed by filtration. The resulting filtrate was concentrated and the concentrate was subjected to silica gel chromatography using a mixed solvent of hexane and ethyl acetate (10/1) to obtain 150 mg of 2-(4-chloro-6-methylquinolin-2-yl)benzonitrile.
Reaction SMILES: S1C=CC(C(Cl)=O)=C1.S1C=CC(C([O:16][C:17]2[CH:26]=[C:25]3[C:20]([C:21](=[O:43])[C:22]([C:32]4[CH:37]=[CH:36][C:35]([C:38]([O:40]CC)=[O:39])=[CH:34][CH:33]=4)=[C:23]([C:27]4[CH:31]=[CH:30][S:29][CH:28]=4)[O:24]3)=[CH:19][CH:18]=2)=O)=C1>>[OH:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21](=[O:43])[C:22]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([OH:40])=[O:39])=[CH:34][CH:33]=3)=[C:23]([C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)[O:24]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1ccc(-c2c(-c3ccsc3)oc3cc(OC(=O)c4ccsc4)ccc3c2=O)cc1
Agent: O=C(Cl)c1ccsc1
Product: O=C(O)c1ccc(-c2c(-c3ccsc3)oc3cc(O)ccc3c2=O)cc1

Procedure:
Synthesis: Prepared following General Scheme 1, starting from Intermediate A-1a and thiophene-3-carbonyl chloride in step 1 using condition b) to 3-(4-(ethoxycarbonyl)phenyl)-4-oxo-2-(thiophen-3-yl)-4H-chromen-7-yl thiophene-3-carboxylate. Step 2 followed d) conditions. See Example 3 for detailed example.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=1.[CH:24]1([CH2:27][NH2:28])[CH2:26][CH2:25]1>>[ClH:12].[Cl:12][C:10]1[CH:11]=[C:2]([NH:28][CH2:27][CH:24]2[CH2:26][CH2:25]2)[CH:3]=[C:4]2[C:9]=1[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=1
Reactant: CC(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Br)cc32)cc1
Reactant: NCC1CC1
Product: CC(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(NCC4CC4)cc32)cc1
Product: Cl

Procedure:
Preparation takes place in analogy to the method described in example 25, starting from N-[4-(6-bromo-8-chloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-acetamide (example 24) and C-cyclopropyl-methylamine. The chromatography on silica gel was followed by a further purification on a preparative HPLC. The purified compound was dissolved in 1 N HCl, diluted with H2O and freeze dried.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:30][CH:29]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:27]([C:28]3[CH:33]=[CH:32][C:31]([O:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:30][CH:29]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CS(=O)(=O)Oc1ccc(N)cc1
Product: CS(=O)(=O)Oc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
Light brown solid. MS (ESI): 499.07 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chlorobenzenesulfonyl chloride and methanesulfonic acid 4-amino-phenyl ester (synthesis: S. Kobayashi, et al.; Synlett. 2000, p 883).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C[C@@H](OC)[C@H](F)[C@H]1C(O)=O)=O)(C)(C)C.[CH3:37][C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH2:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([O:14][CH3:15])[C@H:9]1[C:16](=[O:18])[NH:41][CH2:40][CH2:39][C:38]([CH3:43])([CH3:42])[CH3:37])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)CCN
Reactant: CO[C@H]1[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C[C@@H]1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CO[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)[C@H]1F
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1[C@@H](C(=O)NCCC(C)(C)C)N(C(=O)OC(C)(C)C)C[C@@H]1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,3S,4S)-4-fluoro-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R,3R,4R)-3-fluoro-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (300 mg, 1.14 mmol), 3,3-dimethylbutylamine (115 mg, 1.14 mmol) and HBTU (648 mg, 1.71 mmol) in CH2Cl2 (7 mL) was added DIPEA (0.60 mL, 3.42 mmol). The reaction mixture was stirred at RT under nitrogen atmosphere overnight and concentrated. The crude residue was taken-up in EtOAc, washed with 0.1 N HCl (×2), dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 6:4 in 40 min) to give (2S,3S,4S)-2-(3,3-dimethyl-butylcarbamoyl)-4-fluoro-3-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: Rf, TLC (EtOAc)=0.5; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.92 (m, 1H), 5.16 (dq, 1H), 4.29-4.37 (m, 1H), 4.15 (m, 1H), 3.72 (m, 1H), 3.39 (m, 1H), 3.35 (s, 3H), 3.08 (m, 2H), 1.32-1.40 (m, 11H), 0.90 (s, 9H) and (2R,3R,4R)-2-(3,3-dimethyl-butylcarbamoyl)-3-fluoro-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester: Rf, TLC (EtOAc)=0.6; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.90 (m, 1H), 5.05 (m, 1H), 4.20 (t, 1H), 4.02 (m, 1H), 3.70 (m, 1H), 3.39 (m, 1H), 3.33 (overlap with DMSO, m, 1H); 3.27 (s, 3H), 3.06 (m, 2H), 1.36-1.43 (m, 11H), 0.89 (s, 9H)
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[N:7]=1)#[N:5]>CO>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:8]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[C:6]([C:4](=[NH:5])[O:2][CH3:1])=[N:7]1
Reactant: C[O-]
Reactant: N#Cc1nn(Cc2ccccc2F)c2ncccc12
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1nn(Cc2ccccc2F)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
30.37 g (562 mmol) of sodium methoxide are dissolved in 1.5 l of methanol, and 36.45 g (144.5 mmol) of 3-cyano-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (from example 2 D) are added. The solution obtained after stirring at room temperature for 2 hours is employed directly for the next stage.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][C@H:16]([CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)[O:15][C:14]2=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[N:10][NH:11][CH:12]=1.[H-].[Na+].I[CH3:28]>CN(C)C=O.O.CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][C@H:16]([CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)[O:15][C:14]2=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[N:10][N:11]([CH3:28])[CH:12]=1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2c[nH]nn2)c(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(-c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)nn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(5R)-3-[3-Fluoro-4-(1H-1,2,3-triazol-4-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 7, 1.7 g, 5.2 mmol) was stirred in N,N-dimethylformamide at 0° C. Sodium hydride (0.40 g, 10 mol) was added and the mixture was stirred for 30 minutes. Iodomethane (0.88 g, 6.2 mmol) was added and the reaction was stirred for three days, slowly warming to room temperature. The mixture was diluted with water and extracted using ethyl acetate. The organic layer was washed with water, dried (magnesium sulfate) and concentrated under vacuum. The residue was recrystallized using ethyl acetate to give a mixture of products (0.42 g) as beige solid. The solid was dissolved in dimethylsulfoxide (5 ml), acetonitrile (12 ml) and water (1 ml) and the isomers were separated using Gilson HPLC.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[N:12][CH:13]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>O1CCOCC1.O.C(OCC)(=O)C.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>[Cl:14][C:11]1[N:10]=[CH:9][C:8]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[F:15])=[CH:13][N:12]=1
Reactant: OB(O)c1ccccc1F
Reactant: Clc1ncc(Br)cn1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccccc1-c1cnc(Cl)nc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (2.06 g, 1.79 mmol, 0.1 eq) and caesium carbonate (17.4 g, 53.69 mmol, 2.0 eq) were added under an argon atmosphere to a stirred solution of 5-bromo-2-chloropyrimidine (2.5 g, 17.86 mmol, 1 eq) and (2-fluorophenyl)boronic acid (3.45 g, 17.86 mmol, 1.0 eq) in 1,4-dioxane/water (30 mL, 4:1) at room temperature. The mixture was heated to 90° C., stirred for 3 h and then cooled to room temperature. The mixture was diluted with ethyl acetate (10 mL), washed with water, and dried over sodium sulfate. The solvents were removed in vacuo and the residue was purified by column chromatography [silica gel 100-200 mesh, ethyl acetate/petrolether 1:19]. Yield: 2.0 g (53% of theory)