Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[CH:12]=[N:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:2]1.CC(C)([O-])C.[K+].[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1>O1CCCC1.O>[C:15]1([C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:13][CH:12]([CH2:42][C:41]2[CH:44]=[CH:45][C:38]([F:37])=[CH:39][CH:40]=2)[C:11]2[CH:27]=[CH:28][CH:29]=[CH:30][C:10]=2[C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:1][N:2]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C(=NC(c1ccccc1)c1ccccc1)c1ccccc1-c1noc2ccccc12
Reactant: Fc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(CC(N=C(c2ccccc2)c2ccccc2)c2ccccc2-c2noc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 2.23 g of 2-(1,2-benzisoxazol-3-yl)-benzaldehyde and 2.6 g of magnesium sulfate in 25 ml of methylene chloride was added 1.7 ml of diphenylmethanamine and the stirring continued overnight. The reaction was filtered through dicalite and the filtrate evaporated to give 3.9 g crude N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine as a gum which slowly solidified. A stirred solution of 0.75 g of N-[2-(1,2-benzisoxazol-3-yl)-benzylidene]-1,1-diphenylmethanamine in 15 ml tetrahydrofuran was cooled to -65° C. and 2.5 ml of a 1M solution of potassium tert-butoxide in tetrahydrofuran was added dropwise. The purple coloured solution was stirred for 5 min then 4-fluorobenzyl bromide was added rapidly and the reaction allowed to slowly warm to room temperature. The reaction was diluted with 25 ml of water then extracted with 100 ml then 50 ml of methylene chloride. The combined organic extracts were dried over sodium sulphate then evaporated to give 1.18 g of crude N-(diphenylmethylidene)-2-(1,2-Benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine which was not characterised due to instability. To a solution of 1.1 g of N-(diphenylmethylidene)-2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine in 20 ml of acetone was added 9 ml of 1 M hydrochloric acid. The solution was stirred overnight then evaporated and 15 ml of 4M sodium hydroxide solution added. The solution was extracted with 100 ml then 50 ml of methylene chloride. The organic extracts were dried and evaporated to an oil which was purified by flash chromatography eluting with a 19:1 mixture of methylene chloride-methanol to yield the pure amine free base which was dissolved in methanol and acidified with a solution of hydrogen chloride in methanol, evaporated and crystalised from methanol-ether to yield 0.18 g of 2-(1,2-benzisoxazol-3-yl)-a-(4-fluorobenzyl)-benzenemethanamine hydrochloride, melting at 238-241° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][OH:11])=[N:8][CH:9]=1.[Mn]([O-])(=O)(=O)=[O:15].[K+]>O>[F:13][C:2]([F:1])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:15])=[O:11])=[N:8][CH:9]=1
Reactant: OCc1ccc(OC(F)(F)F)cn1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(OC(F)(F)F)cn1
Reaction time: 0.5 h

Procedure:
A mixture of 3 g 5-trifluoromethoxy-2-pyridinemethanol is vigorously stirred in 120 mL water at 5° C. To this mixture is added in several portions 3.0 g potassium permanganate during which time the temperature rises to 25° C. After a further 30 minutes at 25° C., the mixture is filtered, the solid washed several times with water, the filtrate and washings combined and the pH adjusted to 5. The solution is concentrated to a small volume and extracted with ethyl acetate several times. The extract is washed, dried and concentrated to give 5-trifluoromethoxy-2-pyridinecarboxylic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[N:24]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[N:25]1>>[N:24]1([CH2:29][CH2:30][CH2:31][NH:32][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)[CH:10]=[N:11]3)=[N:16][CH:17]=2)[CH:28]=[CH:27][CH:26]=[N:25]1
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Reactant: NCCCn1cccn1
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)NCCCn4cccn4)cn3)c2O)cc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-(1H-pyrazol-1-yl)propan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.00-2.10 (m, 2H) 3.25-3.30 (m, 2H) 4.19 (t, J=6.95 Hz, 2H) 6.23 (t, J=2.02 Hz, 1H) 7.45 (d, J=1.77 Hz, 1H) 7.77 (d, J=1.52 Hz, 1H) 7.79 (d, J=8.59 Hz, 2H) 8.14 (d, J=7.33 Hz, 2H) 8.37-8.44 (m, 1H) 8.45-8.58 (m, 1H) 8.66 (br. s., 1H) 8.74 (t, J=5.31 Hz, 1H) 8.88-8.94 (m, 1H) 13.54 (br. s., 1H). MS m/z [M+H]+ 414.2.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH3:15]>>[CH3:10][C:4]1[CH:3]=[C:2]([O:1][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: CCCCBr
Reactant: Cc1cc(O)ccc1C=O
Product: CCCCOc1ccc(C=O)c(C)c1
Yield: 67.6 %

Procedure:
The compound was synthesized as in Example 87.1, using 4-hydroxy-2-methylbenzaldehyde (54.4 mg, 0.40 mmol) in place of 4-hydroxybenzaldehyde and 1-bromobutane (77 μL, 0.80 mmol) in place of 1-iodo-(3,3,3-trifluoro)propane to give 2-methyl-4-butoxybenzaldehyde (52 mg, 68%). Used without further characterization.
Reaction SMILES: B(O)(O)O.O[CH:6]([CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[CH2:7][C:8](=[O:10])[CH3:9]>C1(C)C=CC=CC=1>[F:22][C:20]([F:21])([F:23])[C:17]1[CH:18]=[CH:19][C:14]([S:13][CH2:12][CH2:11][CH:6]=[CH:7][C:8](=[O:10])[CH3:9])=[CH:15][CH:16]=1
Reactant: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Agent: OB(O)O
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1ccc(C(F)(F)F)cc1
Temperature: 30 °C
Yield: 99.1 %

Procedure:
0.85 Gram of boric acid was added to 80 ml of toluene, and the resulting mixture was refluxed for 3 hours with stirring and then cooled to 30° C. A solution of 6.00 g of 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone in 20 ml of toluene was added thereto, and the resulting mixture was further refluxed for 8 hours with stirring. The refluxed mixture was washed three times with hot water and then dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 5.58 g of 6-(4-trifluoromethylphenylthio)-3-hexen-2-one (trans : cis =38.7 : 1) (purity: 99.3%). The yield was 98.4%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([OH:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[O:13])[CH:8]=[CH:9][C:2]1=2.[C:34](=O)([O:37]C)[O:35][CH3:36]>COCCOC.C(Cl)(Cl)Cl>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([OH:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][O:33][C:34]([O:35][CH3:36])=[O:37])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[O:13])[CH:8]=[CH:9][C:2]1=2
Reactant: Cc1cc(O)c(C(=O)CCc2ccc3occc3c2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Reactant: COC(=O)OC
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: COC(=O)OC[C@H]1O[C@@H](Oc2cc(C)cc(O)c2C(=O)CCc2ccc3occc3c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 40 °C
Reaction time: 24 h

Procedure:
3-(5-Benzo[b]furanyl)-2'-(β-D-glucopyranosyloxy)-6'-hydroxy-4'-methylpropiophenone (10 g) is dissolved in ethyleneglycol dimethyl ether (30 ml), and thereto are added dimethyl carbonate (100 ml), Novozyme 435 (2 g, manufactured by Novo Nordisk A/S, Denmark) and molecular sieves 4A powder (8 g), and the mixture is stirred at 40° C. for 24 hours, and stirred at room temperature for 14 hours. The reaction mixture is diluted with chloroform, and the insoluble materials are removed by filtration. The filtrate is concentrated to dryness, and the residue is dissolved in ethyl acetate. The mixture is washed successively with 10% aqueous hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure. The residue is recrystallized three times from ether-isopropyl ether-water to give 3-(5-benzo[b]-furanyl)-2'-(6-O-methoxycarbonyl-β-D-glucopyranosyloxy)-6'-hydroxy-4'-methylpropiophenone (7.9 g). The physicochemical properties of the compound are the same as those of the compound obtained in Example 18.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[S:42])[NH:18][C:19](=[O:41])[N:20]([CH2:22][CH2:23][O:24][C:25]4[C:26]([C:37]([O:39]C)=[O:38])=[C:27]([CH:34]=[CH:35][CH:36]=4)[O:28][CH2:29][C:30]([O:32]C)=[O:31])[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[C:30]([CH2:29][O:28][C:27]1[CH:34]=[CH:35][CH:36]=[C:25]([O:24][CH2:23][CH2:22][N:20]2[CH:21]=[C:16]([CH:6]3[C:7]4[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=4[CH:9]=[CH:10][C:11]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]3=4)[C:17](=[S:42])[NH:18][C:19]2=[O:41])[C:26]=1[C:37]([OH:39])=[O:38])([OH:32])=[O:31]
Reactant: COC(=O)COc1cccc(OCCn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)COc1cccc(OCCn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)c1C(=O)O
Temperature: 60 °C

Procedure:
A mixture of the product from step (vi) (0.073 g) and sodium hydroxide (1 g) in methanol (20 ml) and water (20 ml) was heated at 60° C. overnight. The mixture was acidified with 2M HCl and extracted with ethyl acetate. The extract was evaporated and the residue purified by reverse phase chromatography. Yield 0.04 g.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[F:12][CH:13]([CH2:15][C:16](Cl)=[S:17])[F:14]>ClCCl>[F:12][CH:13]([CH2:15][C:16]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[S:17])[F:14]
Reactant: CC(C)(C)O
Reactant: FC(F)CC(=S)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=S)CC(F)F
Yield: 48.6 %

Procedure:
To a stirred and ice cooled solution of t-butanol (1.2 equivalents) and pyridine (1.3 equivalents) in dichloromethane (5 parts by weight) is dropwise added difluoromethylthioacetyl chloride, and the mixture is stirred for 4 hours. The mixture is washed with water, dried and concentrated in vacuum. The residual liquid is distilled to give t-butyl difluoromethylthioacetate as an oil. Yield: 48.6%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[N:11]1([CH2:6][C:5]2[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N#Cc1cccc(C=O)c1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cccc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.2 %

Procedure:
To a stirred solution of of 3-cyanobenzaldehyde (15 g, 114.4 mmol) in THF (150 ml) was added pyrrolidine (9.76 g, 137.2 mmol, 1.2 eq.), acetic acid (8,24 g, 137.2 mmol, 1.2 eq.) and sodium triacetoxyborohydride (36.3 g, 171.6 mmol, 1.5 eq.). The resulting suspension was vigorously stirred at r.t. for 24 hrs. under Ar. 5% NaHCO3 was then added and the mixture stirred for a further 10-15 min. The mixture was then extracted with ethylacetate. The organic phase was washed with brine, then dried with Na2SO4. After removal of the solvent the yellow liquid was distilled over a Vigreux column to afford the title compound as a colorless liquid (19 g, 102 mmol, 89% yield). MS: m/e=186 (M+)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[NH:16]1[CH2:19][CH2:18][CH2:17]1>>[N:16]1([C:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[CH3:12])[C:2]([Cl:1])=[N:3][CH:4]=2)=[O:15])[CH2:19][CH2:18][CH2:17]1
Reactant: C1CNC1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CCC3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and azetidine by following the similar procedure as described for intermediate-11a.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23](O)=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:26]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH2:27][OH:28]>>[OH:28][NH:27][C:23](=[O:24])[CH2:22][C:20]1[CH:19]=[CH:18][C:17]2[C:11]3[N:12]([CH:26]=[C:9]([C:8]4[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=4)[N:10]=3)[CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1
Reactant: NO
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(CC(=O)O)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(CC(=O)NO)cc1OCC2

Procedure:
Following the procedures of Example 316, 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetic acid and hydroxylamine were reacted to give 352. M/z 369.1, calc. 368.16. 1H NMR (400 MHz, DMSO) δ 10.69 (s, 1H), 8.88 (s, 1H), 8.32 (d, J=8.2, 1H), 7.92 (d, J=2.9, 2H), 7.04 (d, J=8.2, 1H), 6.97 (s, 1H), 5.95-5.81 (m, 1H), 4.50 (d, J=5.7, 4H), 3.29 (s, 2H), 1.48 (d, J=6.6, 6H)
Reaction SMILES: [CH3:1][CH:2]([CH2:8][N+]([O-])=O)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C[O-].[Na+].[O:15]=[O+][O-]>CO>[CH3:1][CH:2]([CH:8]=[O:15])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(C)C[N+](=O)[O-]
Reactant: O=[O+][O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(C)C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of methyl 3-methyl-4-nitrobutanoate (96 g, 0.596 m) in methanol (30 ml) is added dropwise to a solution of sodium methoxide (34.5 g, 0.638 m) in methanol (1 l) at room temperature under nitrogen. The resulting mixture is stirred for 1 hr., cooled to -78° C. and treated with one equivalent of ozone. The reaction mixture is then allowed to warm to room temperature and most of the solvent is removed in vacuo. The residue is filtered and the filtrate is treated with ether (500 ml). The organic phase is washed with water (3×200 ml), dried (Na2SO4) and the solvent is removed in vacuo to give the crude product, methyl 3-methyl-4-oxo-butanoate (86.3 g). This material is used directly in the next step.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([CH2:14][C:15](Cl)=[O:16])=[O:13])[CH3:10]>C(Cl)Cl>[CH2:1]([NH:8][C:15]([CH2:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A mixture of benzylamine (43.24 g) and methylene chloride (300 ml) is cooled with ice-water, and a solution of ethoxycarbonylacetyl chloride (29.63 g) in methylene chloride (150 ml) is added dropwise thereto. The mixture is stirred at the same temperature for 2 hours. The mixture is filtered to remove precipitates (benzylamine hydrochloride). The filtrate is washed with 2% hydrochloric acid and a saturated sodium chloride solution, dried and then evaporated to remove the solvent. The residue is recrystallized from a mixture of ether and n-hexane, whereby ethyl (N-benzylcarbamoyl)acetate (42.15 g) is obtained as colorless needles. Yield: 96.8%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[F:17][C:18]([F:25])([F:24])[CH2:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:20]([CH2:19][C:18]([F:25])([F:24])[F:17])(=[O:22])=[O:21])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2cncc(NS(=O)(=O)CC(F)(F)F)c2)cc1Cl
Yield: 27.5 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, 1 eq) in anhydrous pyridine (500 μl) was added 2,2,2-trifluoro-ethanesulfonyl chloride (10.6 μl, 96 μmol, 1.1 eq). The product was purified by preparative TLC, the plate was eluted with dichloromethane/methanol 95/5, to give N-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)-2,2,2-trifluoroethanesulfonamide (9 mg, >95% purity, yield: 27.6%). The isolated product was lyophilized and identified by LC-MS (system 1) and NMR (system 3): ESI-MS m/z: 376 [M+H]+, retention time=2.10 min, 1H NMR (500 MHz, DMSO-d6) δ ppm 4.75 (q, J=9.66 Hz, 2H) 7.87-7.91 (m, 2H) 8.11-8.14 (m, 1H) 8.14 (s, 1H) 8.46 (d, J=2.44 Hz, 1H) 8.74 (d, J=1.83 Hz, 1H) 10.94 (br. s., 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH2:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[I:20][C:21]1[CH:22]=[CH:23][C:24]([NH2:30])=[C:25]([CH:29]=1)[C:26](O)=[O:27]>>[CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:18][C:26](=[O:27])[C:25]1[CH:29]=[C:21]([I:20])[CH:22]=[CH:23][C:24]=1[NH2:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc(I)cc1C(=O)O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(I)ccc1N
Yield: 74.6 %

Procedure:
(2S)-(2-Amino-5-iodo-benzoyl-amino)-3-biphenyl-4-yl-propionic acid methyl ester (1.53 g, 80%) was prepared from (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 4.1 mmol), 5-iodo-2-amino-benzoic acid (1.23 g, 4.9 mmol) as described in general procedure A.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O[BH-](O[C:37](=O)[CH3:38])OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:2]([N:1]1[CH:10]=[C:9]([CH3:8])[N:11]=[C:37]1[CH2:38][N:11]([CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26])[CH:3]=[CH2:4]
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCn1cc(C)nc1CN(CCCCN1C(=O)c2ccccc2C1=O)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a solution of the above aldehyde (268 mg, 1.773 mmol) and 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindol-1,3-dione (743 mg, 2.13 mmol) in CH2Cl2 (17 mL) was added sodium triacetoxyborohydride (752 mg, 3.55 mmol). The reaction mixture was stirred at room temperature overnight. Then it was extracted with saturated NaHCO3 (3×20 mL). The organic layer was dried (MgSO4), filtered, concentrated, and dried in vacuo to afford a yellow foam. Purification by flash column chromatography on silica gel using 10% CH3OH/ethyl acetate afforded the product as a pale yellow foam (263 mg, 31%). 1H NMR (CDCl3) (as a mixture of regio-isomers) δ 1.52-1.60 (m, total 4H), 1.89-2.11 (m, total 8H), 2.56-2.66 (m, total 4H), 2.55 (t, 2H, J=7.5 Hz), 3.76 (d, 2H, J=6.0 Hz), 3.99 (t, 1H, J=6.0 Hz), 4.84-4.90 (m, total 1H) 4.93 and 4.96 (s, total 1H), 5.03-5.06 (m, total 2H), 5.83-5.87 (m, 1H), 6.43 (s, 1H), 6.99 (dd, 1H, J=3.0 Hz), 7.27 (d, 1H, J=6.0 Hz), 7.68-7.70 (m, 2H), 7.80-7.82 (m, 2H), 8.39 (d, 1H, J=3.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[N:25]=[C:26]([C:29]([OH:33])([C:31]#[CH:32])[CH3:30])[S:27][CH:28]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:32]#[C:31][C:29]([C:26]4[S:27][CH:28]=[C:24]([CH3:23])[N:25]=4)([OH:33])[CH3:30])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: COCCNc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Reactant: C#CC(C)(O)c1nc(C)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COCCNc1nc2ccc(C#CC(C)(O)c3nc(C)cs3)cc2n1-c1ccnc(N)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
A mixture of 1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-1,3-benzodiazol-2-amine (150 mg, 0.37 mmol), 2-(4-methyl-1,3-thiazol-2-yl)but-3-yn-2-ol (137.6 mg, 0.82 mmol), bis(triphenylphosphine)palladium(II) dichloride (150 mg, 0.21 mmol) and triethylamine (0.7 mL) in dimethylsulfoxide (1 mL) under nitrogen in a 10-mL sealed tube was stirred for 1 hr at 70° C. The reaction mixture was cooled to room temperature then purified on a silica gel column (dichloromethane/methanol, 8:1) to give 19.6 mg (11%) of 4-[1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-1,3-benzodiazol-6-yl]-2-(4-methyl-1,3-thiazol-2-yl)but-3-yn-2-ol as yellow oil: 1H NMR (300 MHz, DMSO) delta 8.40 (d, J=5.4 Hz, 2H), 8.22 (t, J=5.0 Hz 1H), 7.49 (s, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.16 (t, J=10.5 Hz, 2H), 6.91 (d, J=5.4 Hz, 1H), 6.89 (s, 1H), 6.86 (s, 1H), 3.62-3.59 (m, 4H), 3.32 (d, J=12.3 Hz, 3H), 2.35 (s, 3H), 1.85 (s, 3H); LC-MS: m/z=+450 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][NH:26][CH2:25][CH:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]2)=[CH:18][CH:17]=1)[CH3:15].C(N(CC)CC)C>ClCCl>[CH2:14]([C:16]1[CH:17]=[CH:18][C:19]([CH:22]2[CH2:27][N:26]([C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[CH2:25][CH:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]2)=[CH:20][CH:21]=1)[CH3:15]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C1CNCC(c2ccc(CC)cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., 1.93 g (9.57 mmol) of 4-nitrophenyl chloroformate were added slowly to 2.5 g (9.57 mmol) of ethyl 5-(4-ethylphenyl)piperidine-3-carboxylate, the compound from Example 17A, and 1.94 g (19.1 mmol) of triethylamine in 292 ml of dichloromethane. The mixture was stirred at RT for 2 h. For workup, the reaction mixture was washed first with saturated aqueous sodium hydrogencarbonate solution, then with water. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by means of preparative HPLC. Yield: 2.66 g (64% of theory)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10](Br)[C:11]#[CH:12].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:9][CH2:12][C:11]#[CH:10])[C:2]=1[F:1]
Reactant: Oc1cccc(F)c1F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCOc1cccc(F)c1F

Procedure:
115.0 g (0.88 mol) of 2,3-difluorophenol are refluxed for 3 h together with 118.2 ml (17.7 mol) of propargyl bromide (80% soln. in toluene) and 146.6 g (138.2 mol) of potassium carbonate in 1.6 l of ethyl methyl ketone. The batch is filtered, and the filter residue is washed with MTBE. The filtrate is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:MTBE=3:1).