Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][C@H:16]([N:18]1[CH2:22][C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[O:20][C:19]1=[O:30])[CH3:17])=[O:5])[CH3:2].CI.[C:35](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:31]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[N:13]([CH3:35])[CH:12]=[C:11]2[CH2:15][C@H:16]([N:18]1[CH2:22][C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[O:20][C:19]1=[O:30])[CH3:17])=[O:5])[CH3:32]
Reactant: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)N3C[C@@H](c4cccc(Cl)c4)OC3=O)c[nH]c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCN(CC)C(=O)c1cccc2c(C[C@@H](C)N3C[C@@H](c4cccc(Cl)c4)OC3=O)cn(C)c12
Yield: 29.1 %

Procedure:
A solution of 3-{(2 R)-2-[(5R)-5-(3-chlorophenyl)-2-oxooxazolidin-3-yl]propyl}-1H-indole-7-carboxylic acid diethylamide (10 mg, 0.022 mmol), methyl iodide (21 μL, 0.33 mmol), potassium carbonate (90 mg, 0.66 mmol) in acetone (2 mL) is refluxed for 24 hours. After cooling, the insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by preparative TLC (silica gel, 0.5 mm, 20×20 cm, methanol/chloroform=1/30) to give 3-{(2R)-2-[(5R)-5-(3-chlorophenyl)-2-oxooxazolidin-3-yl]-propyl}-1-methyl-1H-indole-7-carboxylic acid diethylamide (3 mg). A solution of 3-{(2R)-2-[(5R)-5-(3-chlorophenyl)-2-oxooxazolidin-3-yl]-propyl}-1-methyl-1H-indole-7-carboxylic acid diethylamide (3 mg, 0.0064 mmol) and potassium hydroxide (0.6 g) in water (1 mL) and ethanol (1 mL) is stirred at 70° C. for 7 hours. After cooling, ethanol is removed by distillation, and water is added thereto. The mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (60, 2 g, a saturated ammonia solution in chloroform) to give 3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxyethyl-amino]propyl}-1-methyl-1H-indole-7-carboxylic acid diethylamide (2 mg, yield: 71%).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:12]2[CH:11]3[CH2:15][CH:7]([CH2:8][N:9]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:10]3)[C:6]=2[CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:14]=[CH:13][C:12]2[CH:11]3[CH2:15][CH:7]([CH2:8][N:9]([C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH2:10]3)[C:6]=2[CH:5]=1
Reactant: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])ccc12)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)C1CC2CN(C(=O)C(F)(F)F)C1
Yield: 94.5 %

Procedure:
Hydrogenation of 1-(4-nitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7), 3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (2.0 g, 6.66 mmol) under a H2 atmosphere (40 psi) and 10% Pd/C (200 mg) in MeOH over 1.5 hours, filtration through Celite and concentration affords a yellow oil (1.7 g). (TLC 50% EtOAc/hexanes Rf 0.27). 1H NMR (400 MHz, CDCl3) δ 6.99 (m, 1H), 6.64 (br s, 1H), 6.57 (m, 1H), 4.25 (m, 1H), 3.82 (m, 1H), 3.50 (m, 1H), 3.17-3.07 (m, 3H), 2.35 (m, 1H), 1.90 (d, J=10.8 Hz, 1H). GCMS m/e 270 (M+).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[C:11]([O:13][CH3:14])=[O:12].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:14][O:13][C:11]([C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[NH:1][S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22])=[O:12]
Reactant: COC(=O)c1c(C(F)(F)F)noc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Product: COC(=O)c1c(C(F)(F)F)noc1NS(=O)(=O)c1ccccc1
Yield: 85 %

Procedure:
N-(4-Methoxycarbonyl-3-trifluoromethyl-5-isoxazolyl)benzenesulfonamide was prepared as described in Example 25 from 5-amino-4-methoxycarbonyl-3-trifluoromethylisoxazole and benzenesulfonyl chloride in 85% yield. The crude product was purified by recrystallization from methanol/water to give a solid, m.p. 100°-101° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[C:14]([OH:15])=[C:13]([F:16])[C:12]([F:17])=[CH:11][C:7]=1[C:8](O)=[O:9]>C1C=CC=CC=1>[F:5][C:6]1[C:14]([OH:15])=[C:13]([F:16])[C:12]([F:17])=[CH:11][C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Solvent: c1ccccc1
Product: O=C(Cl)c1cc(F)c(F)c(O)c1F

Procedure:
300 ml of thionyl chloride were added to a solution of 100.0 g (0.52 moles) of 2,4,5-trifluoro-3-hydroxybenzoic acid [(XXIII), X=X'=F] (prepared as described in Preparation 13) in 400 ml of benzene, and the mixture was heated under reflux for 3 hours. At the end of this time, the solvent and excess thionyl chloride were removed by distillation under reduced pressure, to give 2,4,5-trifluoro-3-hydroxybenzoyl chloride. The whole of this chloride was added dropwise to 1500 ml of 28% w/v aqueous ammonia, whilst stirring and ice-cooling, and the mixture was then stirred for a further 2 hours. At the end of this time, the mixture was allowed to stand at room temperature overnight, after which it was acidified by the addition of dilute aqueous hydrochloric acid. The reaction mixture was then extracted with ethyl acetate, and the extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 88.2 g of 2,4,5-trifluoro-3-hydroxybenzoyl amide as a colorless powder, melting at 153°-155° C.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:26]12([CH2:36][O:37][C:38]3[C:46]([Cl:47])=[CH:45][C:41]([C:42](O)=[O:43])=[C:40]([F:48])[CH:39]=3)[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2.CS(N)(=O)=O.[F:54][CH:55]1[CH2:58][N:57]([S:59]([NH2:62])(=[O:61])=[O:60])[CH2:56]1>>[C:26]12([CH2:36][O:37][C:38]3[C:46]([Cl:47])=[CH:45][C:41]([C:42]([NH:62][S:59]([N:57]4[CH2:58][CH:55]([F:54])[CH2:56]4)(=[O:61])=[O:60])=[O:43])=[C:40]([F:48])[CH:39]=3)[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: NS(=O)(=O)N1CC(F)C1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: O=C(NS(=O)(=O)N1CC(F)C1)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 50 step 5 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid and methanesulfonamide with 3-fluoroazetidine-1-sulfonamide, the title compound was obtained as colorless solid (0.15 g, 52%): 1H NMR (300 MHz, DMSO-d6) δ 12.02 (s, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.25 (d, J=12.4 Hz, 1H), 5.49-5.43 (m, 0.5H), 5.30-5.24 (m, 0.5H), 4.45-4.32 (m, 2H), 4.26-4.13 (m, 2H), 3.73 (s, 2H), 1.99 (br s, 3H), 1.75-1.64 (m, 12H); MS (ES+) m/z 475.1, 477.1 (M+1); MS (ES−) m/z 473.2, 475.2 (M−1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[C:21](=[O:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][C:13]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[CH:21]([OH:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][C:13]([C:24]([F:27])([F:25])[F:26])=[CH:12][CH:11]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2nc3cc(C(F)(F)F)ccc3c(NCc3ccccc3)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2nc3cc(C(F)(F)F)ccc3c(NCc3ccccc3)c21
Reaction time: 1 h

Procedure:
To a cooled solution of 3.5 g of 9-benzylamino-3,4-dihydro-6-trifluoromethylacridin-1(2H)-one in 60 ml of tetrahydrofuran was added 5 ml of 1M solution of lithium aluminum hydride in tetrahydrofuran. This was stirred for 1 hour at ice temperature.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[O:10]1[CH:16]2[CH:11]1[C:12]([CH3:29])([CH3:28])[O:13][C:14]1[CH:20]=[CH:19][C:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])=[CH:17][C:15]=12.O>CS(C)=O>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C@@H:16]1[C:15]2[CH:17]=[C:18]([S:21]([C:24]([F:25])([F:27])[F:26])(=[O:23])=[O:22])[CH:19]=[CH:20][C:14]=2[O:13][C:12]([CH3:28])([CH3:29])[C@H:11]1[OH:10]
Reactant: Oc1ccccn1
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2C2OC21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](n2ccccc2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.5 %

Procedure:
105 mg of 2-hydroxypyridine were added to a suspension of 48 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in anhydrous dimethyl sulfoxide, and the resulting mixture was stirred at room temperature for 15 minutes. At the end of this time, 309 mg of 3,4-epoxy-3,4-dihydro-2,2-dimethyl-6-trifluoromethylsulfonyl-2H-1-benzopyran (prepared as described in Preparation 8) were added under an atmosphere of nitrogen and at room temperature to the mixture. The mixture was then stirred at room temperature for 24 hours, after which it was poured into water and extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order; it was then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of ethyl acetate and cyclohexane as the eluent, to afford 95 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([OH:19])=O)[CH2:11]2)[CH:3]=1.CCN(C(C)C)C(C)C.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:19])[CH2:11]2)[CH:3]=1
Reactant: NCc1ccccc1
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)O)CC[C@H]2C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Temperature: 0 °C
Yield: 105.5 %

Procedure:
To a suspension of (3S,6R)-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (2.2 g, 7.73 mmol) in CH2Cl2 (30 mL) at room temperature was added Hunig's base (1.75 mL, 10.04 mmol, 1.3 equiv) and benzylamine (1.01 mL, 9.27 mmol, 1.2 equiv), and the resulting mixture was chilled in an ice bath. To this stirred solution was added HATU (3.23 g, 8.50 mmol, 1.1 equiv) in one portion, and the resulting suspension was stirred in the ice bath for 30 minutes. LCMS showed conversion complete. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. Silica gel column chromatography using a gradient elution of 1% EtOAc in CHCl3 to 40% EtOAc in CHCl3 afforded the title compound (3.05 g) as a gum. LC-MS (ES) m/z=374 [M+H]+.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C@H:5](O)[C:6]([O:8][CH3:9])=[O:7].Cl.O1CCOCC1.S(Cl)([Cl:20])=O>N1C=CC=CC=1>[ClH:20].[NH2:2][CH2:3][CH2:4][C@@H:5]([Cl:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)[C@@H](O)CCN
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cl)CCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
To methyl (S)-4-amino-2-hydroxybutyrate hydrochloride (170.1 mg; 133.5 mg when calculated as methyl (S)-4-amino-2-hydroxybutyrate) was added 3 ml of 4 N HCl/dioxane, followed by further addition of 189.1 mg of thionyl chloride. The mixture was stirred at room temperature for 1 hour. Thereafter, 2.5 mg of pyridine was added, and the mixture was further stirred at 50° C. for 6 hours. After confirmation of disappearance of the starting material by TLC, the solvent was distilled off under reduced pressure to give 191.6 mg of methyl (R)-4-amino-2-chlorobutyrate hydrochloride (yield quantitative, optical purity 93.9% ee). The analysis of the optical purity was carried out by derivatizing into (R)-3-chloro-2-pyrrolidinone with sodium hydrogen carbonate, followed by high performance liquid chromatography using a chiral column (Chiralcel OB-H (Daicel)).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=1>>[Cl:24][C:23]1[C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ncccc1Cl
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Product: Cc1onc(-c2ccccc2)c1-c1cn2cccc(Cl)c2n1
Yield: 76 %

Procedure:
As described for Example 1, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-3-chloropyridine instead of 2-aminopyridine, to the title compound (117 mg, 76%) which was obtained as a yellow foam. MS: m/e=310.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([P:9]([Cl:11])Cl)[CH:5]=[CH:6][C:7]=1[CH3:8].P(Cl)(Cl)Cl>[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1[CH:3]=[C:4]([P:9]([Cl:11])[C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(P(Cl)Cl)cc1C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClP(Cl)Cl
Product: Cc1ccc(P(Cl)c2ccc(C)c(C)c2)cc1C
Temperature: 120 °C
Reaction time: 5 h
Yield: 56.7 %

Procedure:
A mixture of 3,4-dimethylphenyl phosphonous dichloride (37.6 g) and freshly prepared anhydrous zinc chloride (1.96 g) was heated at 280°-320° C. in a distillation apparatus which incorporated a heated fractionating head, maintained at 120° C. The reaction was carried out under a reduced pressure of approximately 200 mmHg for a period of 5 hours. Phosphorus trichloride (12.4 g) was evolved during the reaction and was trapped out using liquid nitrogen. The reaction mixture was then fractionally distilled under reduced pressure by increasing the vacuum. Unreacted starting material was distilled off, as a colourless liquid, at 70°-125° C. at 0.05 mmHg pressure. Product bis(3,4-dimethylphenyl) phosphinous monochloride, was then distilled, as a colourless liquid, at 130°-155° C. and a pressure of 0.05 mmHg. The product weighed 12.5 g, equivalent to a yield of 56.7% based on a conversion of 87.8%. It has a melting point of 36°-38° C.
Reaction SMILES: Cl.C([NH:5][C:6]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:25])[CH:12]=2)[N:7]=1)(=O)C>[Fe]>[NH2:5][C:6]1[CH:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:25])[CH:12]=2)[N:7]=1
Reactant: CC(=O)Nc1cc(-c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2n1
Agent: [Fe]
Agent: Cl
Product: Nc1ccc(-c2cc(N)nc3ccc(Cl)cc23)cc1

Procedure:
1.8 ml of concentrated hydrochloric acid were added dropwise to a suspension of 0.59 g of 2-acetylamino-6-chloro-4-(4-nitrophenyl)quinoline and 0.29 g of iron powder, and then the reaction mixture was heated under reflux for 4 hours and filtered while hot. The solvent was removed by distillation, an MPLC was carried out on an MPRC cartridge with a mixture of 10 parts by volume of dichloromethane and 1 part by volume of methanol, and the substance was obtained as a yellow viscous oil.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])C1C=CC=CC=1>[Pd].C(O)C.Cl>[OH:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][P:14](=[O:21])([O:15][CH2:16][CH3:17])[O:18][CH2:19][CH3:20]
Reactant: CCOP(=O)(COCCCOCc1ccccc1)OCC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOP(=O)(COCCCO)OCC
Reaction time: 6 h
Yield: 86.2 %

Procedure:
10% Palladium on charcoal (4.5 g) was added to a solution of diethyl 3-benzyloxypropoxymethylphosphonate (14.6 g, 46 mmol) in ethanol (250 ml) and 5M hydrochloric acid (4 ml) and the reaction stirred under an atmosphere of hydrogen for 6 h. The catalyst was removed by filtration through a glass-fibre paper and the ethanol evaporated under reduced pressure. The residue was then dissolved in chloroform, dried (MgSO4), filtered and reduced in vacuo to give diethyl 3-hydroxypropoxymethylphosphonate as a colourless oil (8.97 g, 86%); νmax (film) 3419, 2935, 1241, 1029 cm-1); δH (CDCl3) 1.46(6H, t, J7.1 Hz, (CH3CH2O)2), 83(2H, m, CH2CH2CH2), 3.73-3.79(5H, m, CH2CH2CH2 and OH (D2O exchangeable)), 3.81(2H, d, J7.9 Hz, CH2P), 4.18(4 H, m, (CH3CH2O)2).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38]2)[C:31]2[N:36]=[N:35][NH:34][C:32]=2[N:33]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[S:52]([CH3:55])(=[O:54])=[O:53]>>[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:42])([F:43])[CH2:38]2)[C:31]2[C:32](=[N:34][N:35]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[S:52]([CH3:55])(=[O:54])=[O:53])[N:36]=2)[N:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)Nc1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CS(=O)(=O)c1ccccc1CBr
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(C)(C)Nc1nc(N2CCC(F)(F)C2)c2nn(Cc3ccccc3S(C)(=O)=O)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from tert-Butyl-[7-(3,3-difluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine and 1-(bromomethyl)-2-(methylsulfonyl)benzene. MS (m/e): 466.4 (MH+)
Reaction SMILES: C[Al](C)C.C[Al](C)C.C1N2CCN(CC2)C1.Cl.[F:18][C:19]([F:30])([F:29])[CH2:20][S:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[NH2:31][C:32]1[N:37]=[C:36]([N:38]([CH3:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:35]=[C:34]([C:46]2[N:50]=[C:49]([C:51](OCC)=[O:52])[O:48][N:47]=2)[N:33]=1>C1COCC1>[CH3:45][N:38]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:36]1[N:37]=[C:32]([NH2:31])[N:33]=[C:34]([C:46]2[N:50]=[C:49]([C:51]([N:26]3[CH2:27][CH2:28][CH:23]([CH2:22][S:21][CH2:20][C:19]([F:29])([F:18])[F:30])[CH2:24][CH2:25]3)=[O:52])[O:48][N:47]=2)[N:35]=1
Reactant: FC(F)(F)CSCC1CCNCC1
Reactant: CCOC(=O)c1nc(-c2nc(N)nc(N(C)c3ccccc3)n2)no1
Agent: C1CN2CCN1CC2
Agent: C[Al](C)C
Agent: Cl
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(C(=O)N3CCC(CSCC(F)(F)F)CC3)n2)n1
Reaction time: 2 h
Yield: 11 %

Procedure:
Bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct (225 mg, 0.88 mmol) was added to 4-{[(2,2,2-trifluoroethyl)sulfanyl]methyl}piperidine hydrochloride (Intermediate 267, 219 mg, 0.88 mmol) in dry THF (6 mL) in a sealed tube at room temperature. The reaction mixture was stirred at 40 C for 2 h. Ethyl 3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazole-5-carboxylate (prepared in an analogous manner to Example 73, 200 mg, 0.58 mmol) was added at 40 C. The reaction was heated at 80 C for 2 h before being concentrated under vacuum. The residue was taken up in DMSO (6 mL) and the inorganic residue was filtered off. The filtrate was purified by preparative HPLC, Method C, to provide two batches of the title compound (batch 1: 33 mg, 11%). Some impure product was recovered from the preparative HPLC purification, this material was concentrated, diluted with water (50 mL), acidified with a 1N aq. solution of HCl (to pH 4) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL) and dried over magnesium sulfate. This crude material was then purified by preparative HPLC, Method C, to provide the title compound (Batch 2: 83 mg, 28%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]1=[O:14].[Cl:15][C:16]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:17]=1[CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[Br-].[Na+].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[Cl:15][C:16]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:17]=1[CH2:18][N:19]1[CH2:20][CH2:21][N:22]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH:11]=[C:10]([CH3:12])[C:9](=[O:13])[NH:8][C:7]2=[O:14])[CH2:23][CH2:24]1
Reactant: Cc1cn(CCCCCl)c(=O)[nH]c1=O
Reactant: Clc1ccc(CN2CCNCC2)c(Cl)c1
Agent: [Br-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(CCCCN2CCN(Cc3ccc(Cl)cc3Cl)CC2)c(=O)[nH]c1=O
Yield: 33.4 %

Procedure:
1-(4-Chlorobutyl)-5-methyl-1H-pyrimidine-2,4-dione (0.69 mmol, 0.15 g), 1-(2,4-dichlorobenzyl)piperazine (0.62 mmol, 0.15 g), sodium bromide (3.46 mmol, 0.36 g) and diisopropylethylamine (6.92 mmol, 0.89 g) were heated in N-methylpyrrolidinone (0.6 ml) at 120° C. for 5 hours. The reaction mixture was then allowed to cool, the suspension was filtered with suction, and the filtrate was concentrated. The residue was then then taken up in ethyl acetate and washed with saturated brine. The organic layer was dried, filtered to remove the desiccant and evaporated in vacuo. The resulting residue was purified by chromatography on silica gel (eluent: methyl tert-butyl ether/methanol (0-100%), resulting in 88.0 mg of the title compound.
Reaction SMILES: C([Mg]Br)(C)C.CN(C)[CH:8]=[O:9].O.[Br:12][C:13]1[C:14]([CH3:20])=[CH:15][C:16](I)=[N:17][CH:18]=1>O1CCCC1>[Br:12][C:13]1[C:14]([CH3:20])=[CH:15][C:16]([CH:8]=[O:9])=[N:17][CH:18]=1
Reactant: Cc1cc(I)ncc1Br
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C=O)ncc1Br
Temperature: -15 °C
Reaction time: 1 h

Procedure:
In an oven-dried flask the compound obtained in Step A (4.67 g) was dissolved in tetrahydrofuran (22 ml). The solution was cooled to −15° C., then isopropyl magnesium bromide (17.2 ml, 15% solution in THF) was added dropwise at a rate to keep the internal temperature between −15° C. to −10° C. The reaction was stirred at this temperature for 1 hour, then anhydrous dimethylformamide (1.8 ml) was added at a rate to keep the internal temperature below 0° C. The reaction was stirred at this temperature for 1 hour, then poured into water and extracted with diethyl ether. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude title aldehyde product (2.4 g, brown solid) was used as such in the next step.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].CCN(C(C)C)C(C)C>>[CH3:30][S:31]([N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@H]3CCNC3)cnc21
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@H]3CCN(S(C)(=O)=O)C3)cnc21

Procedure:
((S)-1-Methanesulfonyl-pyrrolidin-3-yl)-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from (S)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and methanesulfonyl chloride, using DIPEA as base and following the general synthetic procedures described in the above Examples.