Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:10]([F:12])[F:11])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:35]=[CH:34][C:17]([CH2:18][NH:19][C:20]([C:22]2[S:26][C:25]([N:27]3[CH2:31][CH2:30][CH2:29][C:28]3=[O:32])=[N:24][C:23]=2[CH3:33])=[O:21])=[CH:16][CH:15]=1>>[F:11][CH:10]([F:12])[O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][CH:29]2[CH2:30][CH2:31][N:27]([C:25]3[S:26][C:22]([C:20]([NH:19][CH2:18][C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:35][CH:34]=4)=[O:21])=[C:23]([CH3:33])[N:24]=3)[C:28]2=[O:32])=[CH:4][CH:5]=1
Reactant: Cc1nc(N2CCCC2=O)sc1C(=O)NCc1ccc(F)cc1
Reactant: FC(F)Oc1ccc(CBr)cc1
Product: Cc1nc(N2CCC(Cc3ccc(OC(F)F)cc3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 31 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use 1-(bromomethyl)-4-(difluoromethoxy)benzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene to react with N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 31% yield: mp 143-145° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.34-7.22 (m, 2H), 7.16 (d, J=8.4 Hz, 2H), 7.06-6.93 (m, 4H), 6.45 (t, J=73.9 Hz, 1H), 6.08 (t, J=5.6 Hz, 1H), 4.51 (d, J=5.6 Hz, 2H), 4.09-3.99 (m, 1H), 3.91-3.78 (m, 1H), 3.25-3.12 (m, 1H), 3.05-2.94 (m, 1H), 2.83-2.73 (m, 1H), 2.59 (s, 3H), 2.32-2.18 (m, 1H), 1.98-1.81 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 174.7, 162.3, 162.2, 160.6, 155.4, 152.7, 149.9, 135.4, 133.8, 130.3, 129.6, 119.8, 115.6, 112.4, 45.9, 44.3, 43.3, 35.6, 24.2, 17.2; MS (ES+) m/z 490.3 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[C:31]([O:1][C@@H:2]([CH2:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:22])[O:9]2)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)COc3ccccc3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C1C[C@@H]2[C@@H](/C=C/[C@H](COc3ccccc3)OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1

Procedure:
Analogously to Example 1(a), 5 g of (1S,5R,6R,7R)-6-[(E)-(3R)-3-hydroxy-4-phenoxy-1-butenyl]-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one, 22 ml of pyridine, and 2.84 g of benzoyl chloride yield 6.1 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[C:23]([C:24]([OH:26])=O)=[CH:22][N:21]=[CH:20][CH:19]=3)[C:11]3[O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1.[CH2:28]([N:30](CC)CC)C.CN.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[C:23]([C:24]([NH:30][CH3:28])=[O:26])=[CH:22][N:21]=[CH:20][CH:19]=3)[C:11]3[O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1OCC2
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-ylamino]-nicotinic acid (75 mg, 0.19 mmol, 1 eq) in DMF (2 ml) was added triethylamine (30 μl, 0.21 mmol, 1.1 eq) followed by methylamine (1.17 ml, 3.89 mmol, 2 M solution in THF, 20 eq). To the suspension was added a solution of PyBrOP (100 mg, 0.21 mmol, 1.2 eq) in DMF (1 ml) dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo and the residue was triturated with ether (2×20 ml). The crude residue was purified by flash column chromatography (5% MeOH in CHCl3) to afford 4-[2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-ylamino]-N-methyl nicotinamide, i.e. compound of formula (44) (20 mg, 26%) as a white solid.
Reaction SMILES: [N:1]([CH:4]1[CH2:8][CH2:7][CH:6]([C:9](=O)[CH2:10][CH:11](OC)[O:12]C)[CH:5]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[N+:2]=[N-:3].[NH2:24]O.Cl>N1C=CC=CC=1>[N:1]([CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[CH:11][O:12][N:24]=2)[CH:5]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[N+:2]=[N-:3]
Reactant: COC(CC(=O)C1CCC(N=[N+]=[N-])C1c1ccc(F)cc1)OC
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: [N-]=[N+]=NC1CCC(c2ccon2)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
A solution of 130 mg (0.40 mmol) of 3-(SR)-azido-2-(SR)-(4-fluorophenyl)-1-(SR)-(3,3-dimethoxy-1-oxo-propyl)cyclopentane (from Example 97, Step C) in 3 mL of pyridine was treated with 150 mg (2.2 mmol) of hydroxylamine×HCl and stirred at rt for 3 h. The reaction mixture was partitioned between 50 mL of ether and 25 mL of 2.0N HCl and the layers were separated. The organic layer was washed with 25 mL of sat'd NaHCO3, 25 mL of sat'd NaCl, dried over MgSO4 and concentrated in vacuo. A mixture of the crude ketoxime and 200 mg of Amberlyst 15 H+ resin in 4 mL of acetone was heated at reflux for 2 h. The mixture was cooled, the resin filtered and the filtrate concentrated in vacuo. Flash chromatography on 7 g of silica gel using 10:1 v/v hexanes/ether as the eluant afforded 79 mg (72%) of the title compound.
Reaction SMILES: [OH:1][C@H:2]([C:21]1[S:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][C:13]([C:16](OCC)=[O:17])=[CH:12][CH:11]=1.[Li+].[BH4-].Cl.O>C1COCC1>[OH:1][C@H:2]([C:21]1[S:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:11]=[CH:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ccc([C@H]2CC(=O)N(C)[C@H]2[C@H](O)c2ccc(-c3ccccc3)s2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)C[C@H](c2ccc(CO)cc2)[C@@H]1[C@H](O)c1ccc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.6 %

Procedure:
(±)-(4R*,5R*)-5-[(1S*)Hydroxy(5-phenyl(2-thienyl))methyl]-4-(4-(ethoxycarbonyl)-phenyl)-1-methylpyrrolidin-2-one (0.046 g, 0.106 mmol) was dissolved in THF (1 mL) under Ar. A solution of LiBH4 (2M in THF, 0.10 mL, 0.21 mmol) was added and the resulting mixture was stirred at room temperature for 18 h. Additional LiBH4 solution (0.5 mL, 1.0 mmol) was added and the reaction was stirred for 24 h. The reaction was treated with a 1M HCl solution, followed by water and the resulting mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by HPLC to yield (±)-(4R*,5R*)-5-[(1S*)hydroxy(5-phenyl(2-thienyl))methyl]-4-[4-(hydroxymethyl)-phenyl]-1-methylpyrrolidin-2-one (9 mg, 20%) as a white solid: mp 205° C.; TLC (EtOAc)Rf 0.24.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:10]([C:22]3[N:27]=[C:26]([CH3:28])[N:25]=[C:24](SC)[N:23]=3)=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:31]>O1CCOCC1>[NH2:31][C:24]1[N:25]=[C:26]([CH3:28])[N:27]=[C:22]([C:10]2[C:11]([NH:13][C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[N:12][C:7]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:8][CH:9]=2)[N:23]=1
Reactant: N
Reactant: COc1ccc(Nc2nc(NC3CCCC3)ncc2-c2nc(C)nc(SC)n2)cn1
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(NC3CCCC3)ncc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Yield: 83.5 %

Procedure:
A glass microwave reaction vessel was charged with N2-cyclopentyl-N4-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidine-2,4-diamine (36 mg, 0.085 mmol), ammonia (0.5 mL, 23.11 mmol) and dioxane (2 mL). The reaction mixture was stirred and heated in an oil bath at 100° C. for 24 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with EtOAc to give 5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-N2-cyclopentyl-N4-(6-methoxypyridin-3-yl)pyrimidine-2,4-diamine (28 mg, 0.071 mmol, 84% yield). 1H NMR (300 MHz, CDCl3) δ 11.99 (s, 1H); 9.21 (s, 1H); 8.29-8.56 (m, 1H); 8.19 (s, 1H); 6.76 (d, J=8.92 Hz, 1H); 5.26 (s, 3H); 4.25 (s, 1H); 3.95 (s, 3H); 2.49 (s, 3H); 2.04 (s, 2H); 1.34-1.87 (m, 6H). m/z (ESI, +ve ion) 394.1 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18]([OH:20])=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:44][C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][C:46]=1[CH:52]1[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]1>ClCCl>[Cl:44][C:45]1[CH:51]=[CH:50][C:48]([NH:49][C:18](=[O:20])[CH2:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:8][CH:9]=2)=[CH:47][C:46]=1[CH:52]1[CH2:53][CH2:54][N:55]([CH3:58])[CH2:56][CH2:57]1
Reactant: O=C(O)Cc1ccc(-c2ccncc2)c2ccccc12
Reactant: CN1CCC(c2cc(N)ccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CN1CCC(c2cc(NC(=O)Cc3ccc(-c4ccncc4)c4ccccc34)ccc2Cl)CC1
Reaction time: 0.5 h
Yield: 7.1 %

Procedure:
To a solution of 4 -(pyridin-4-yl)napth-1-ylacetic acid (D2, 260 mg, 1.0 mmol) in dichloromethane was added 1-hydroxybenzotriazole hydrate (153 mg, 1.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (200 mg, 1.0 mnmol) and the mixture stirred for 0.5 h. To the mixture was added dropwise a solution of 4-chloro-3-(1-methylpiperidin-4-yl)aniline (D7, 200 mg, 0.90 mmol) in dichloromethane (3 ml) and stirring continued for 48 h. Purification of the crude by flash chromatography gave the title compound as a white solid (30 mg, 7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:10][C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:11]
Reactant: COC(OC)N(C)C
Reactant: COc1ccccc1C(C)=O
Product: COc1ccccc1C(=O)C=CN(C)C

Procedure:
A mixture of o-methoxyacetophenone and dimethylformamide dimethylacetal is reacted as described in Example 51 to give the product of the Example.
Reaction SMILES: [CH2:1]([N:7]1[C:12](=[O:13])[CH:11]2[CH:9]([C:10]2([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[CH2:14][C:15]([F:18])([F:17])[F:16])[C:8]1=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Fe]>[CH2:1]([N:7]1[C:8](=[O:28])[CH:9]2[CH:11]([C:10]2([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=2)[CH2:14][C:15]([F:16])([F:17])[F:18])[C:12]1=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1C(=O)C2C(C1=O)C2(CC(F)(F)F)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CCCCCCN1C(=O)C2C(C1=O)C2(CC(F)(F)F)c1cccc(N)c1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
3-Hexyl-6-(3-nitrophenyl)-6-(2,2,2-trifluoroethyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (Preparation 103, 178 mg, 0.45 mmol) was dissolved in ethanol (15 ml). Iron powder (225 mg, 4.0 mmol) was added at room temperature followed by calcium chloride (50 mg, 0.45 mmol), dissolved in water (2 ml). The vigorously stirred mixture was heated under reflux for 2 h then cooled to room temperature and filtered through a pad of silica. The solvent was removed in vacuo and the filtrate was dissolved in dichloromethane and filtered through a Whatman anotop 10 plus™ cartridge. The organic mixture was concentrated in vacuo to give the product as a brown gum (170 mg, 100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(Br)cc2)CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a solution of 1-benzyl-4-(4-bromophenyl)piperidin-4-ol (3.0 g) in toluene (20 mL) was added p-toluenesulfonic acid monohydrate (1.98 g) at room temperature. The reaction mixture was stirred at 130° C. for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate solution at 0° C., and the mixture was extracted with ethyl acetate-THF. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.80 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH:12]2[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:6][C:5]([N:15]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][N:3]=1.Cl>C1COCC1>[NH2:15][C:5]1[CH:6]=[C:7]([NH:8][S:9]([CH:12]2[CH2:14][CH2:13]2)(=[O:11])=[O:10])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: O=S(=O)(Nc1cc(N=C(c2ccccc2)c2ccccc2)cnc1Cl)C1CC1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cnc(Cl)c(NS(=O)(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2-chloro-5-(diphenylmethyleneamino)pyridin-3-yl)cyclopropanesulfonamide (0.300 g, 0.728 mmol) in THF (5 mL) was added hydrochloric acid, In (1.092 mL, 1.092 mmol). The reaction was stirred at rt in closed system. After 30 min, LC/MS showed no sign of starting materials with desired product mass as the major peak. The reaction mixture was partitioned between EtOAc and sat. NaHCO3. The aqueous layer was extracted with more EtOAc (2×10 mL). The combined organic layer were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 3% MeOH in DCM) to afford the desired product as a yellow solid (170 mg). MS (ESI pos. ion) m/z: 248.0. 1H NMR (300 MHz, CDCL3) δ ppm 1.04 (d, J=6.58 Hz, 2H) 1.13-1.32 (m, 2H) 2.51 (t, J=4.60 Hz, 1H) 3.85 (br. s., 2H) 6.63 (br. s., 1H) 7.35 (s, 1H) 7.68 (s, 1H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)(=[O:5])=[O:4])[CH3:2].[CH2:11]([N:16]([CH2:20][CH2:21][CH3:22])[C:17](Cl)=[O:18])[CH2:12][CH2:13][CH2:14][CH3:15].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:16]([CH2:20][CH2:21][CH3:22])[C:17]([N:8]1[CH:9]=[N:10][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:7]1)=[O:18])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCN(CCC)C(=O)Cl
Reactant: CCS(=O)(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCN(CCC)C(=O)n1cnc(S(=O)(=O)CC)n1

Procedure:
A mixture of 4.83 g. 3-ethylsulphonyl-1,2,4-triazole, 6.0 g. N-n-pentyl-N-propylcarbamoyl chloride, 40 ml. dry tetrahydrofuran and 6 ml. dry triethylamine was refluxed under anhydrous conditions for 24 hours. The cooled reaction mixture was filtered. The filtrate was distilled under reduced pressure to give 1-(N-n-pentyl-N-propylcarbamoyl)-3-ethylsulphonyl-1,2,4-triazole as a residual oil, nD25 1.4967. (96.5% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[I-:12].[Na+].O>CC(C)=O>[I:12][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(CI)cc1
Yield: 95 %

Procedure:
A suspension of 1-chloromethyl-4-nitro-benzene (10 g, 58.3 mmol) and sodium iodide in acetone (150 ml) was refluxed for 1 h. Water was added until complete dissolution and the mixture extracted with ethyl acetate (4×100 ml). The combined organic layers were extracted with brine, dried over sodium sulfate and concentrated in vacuo yielding 13.9 g (95%) 1-Iodomethyl-4-nitro-benzene as beige crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:19][CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Ic1ccc(OC2CCCCO2)cc1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc(OC2CCCCO2)cc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
A mixture of 4-benzyloxy-1H-pyridin-2-one (7.04 g, 35.0 mmols), 2-[(4-iodophenyl)oxy]tetrahydropyran (13.6 g, 44.8 mmols), cuprous iodide (2.1 g, 11.2 mmols), potassium carbonate (10.3 g, 73.5 mmols) and N,N-dimethylformamide (200 mL) was stirred overnight at 150° C. The reaction liquid was cooled to room temperature, into which water (1.2 L) was poured, and the formed insoluble matter was recovered by filtration. Chloroform (300 mL) was added to the insoluble matter, followed by another filtration. The filtered organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, ethyl acetate was added to the resulting residue. The precipitate was recovered by filtration and dried to provide the title compound (7.6 g, 58%).
Reaction SMILES: [C:1]([C:5]1[CH:40]=[CH:39][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[C:23](C)[N:22]=3)[CH2:13][C@@:12]2([CH2:35][CH:36]([CH3:38])[CH3:37])[C:28]([O:30]C(C)(C)C)=[O:29])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:41](O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)[C@@H:14]([C:21]3[C:26]([CH3:41])=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:35][CH:36]([CH3:37])[CH3:38])[C:28]([OH:30])=[O:29])=[O:10])=[CH:39][CH:40]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cncc([C@H]2C[C@@](CC(C)C)(C(=O)OC(C)(C)C)N(C(=O)c3ccc(C(C)(C)C)cc3)[C@H]2c2nccs2)n1
Product: Cc1nccnc1[C@H]1C[C@@](CC(C)C)(C(=O)O)N(C(=O)c2ccc(C(C)(C)C)cc2)[C@H]1c1nccs1

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1, to afford the title compound as a solid.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.[F:18][C:19]([F:30])([F:29])[C:20]1[O:21][C:22]([CH2:27][Br:28])=[CH:23][C:24]=1[CH2:25][OH:26]>CCOCC>[F:30][C:19]([F:18])([F:29])[C:20]1[O:21][C:22]([CH2:27][Br:28])=[CH:23][C:24]=1[CH2:25][O:26][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: OCc1cc(CBr)oc1C(F)(F)F
Reactant: C1=COCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCOCC
Product: FC(F)(F)c1oc(CBr)cc1COC1CCCCO1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
2.82 ml of dihydropyran and 250 mg of toluenesulfonic acid were added to 4 g of the product of Stage D in 80 ml of ether and the mixture was stirred for 3 hours at 20° C. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica (eluent: 9/1 hexane/ethyl acetate) to obtain 4.8 g of the expected product.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.Cl[C:10]1[N:15]2[N:16]=[C:17]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=3)[N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.C>CC(O)(C)C>[OH:8][CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:10]2[N:15]3[N:16]=[C:17]([NH:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=4)[N:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)[CH2:3]1
Reactant: NC1CCCC(O)C1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1cccnc1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2cccc(NC3CCCC(O)C3)n2n1)c1cccnc1
Temperature: 200 °C
Reaction time: 0.08 h

Procedure:
3-amino-cyclohexanol (Betapharma, 67.33 mg; 0.58 mmol; 2.0 eq.) was added to a mixture of N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 80 mg; 0.29 mmol; 1.0 eq.), DIEA (76 mg; 0.58 mmol; 2.0 eq.) and activated Charcoal (8 mg) in tBuOH (0.8 mL). The reaction mixture was heated at 200° C. for 2×30 min under microwave irradiation. After this time, it was filtered on a celite pad and the cake was washed with ACN. The filtrate was directly purified by RP-HPLC (Starting with 15% ACN in water for 5 min, then up to 30% in 10 min.). The title compound was isolated after lyophilisation as a white powder (51 mg, 49%). HPLC, Rt: 2.14 min. (purity 98.0%). LC/MS, M+(ESI): 353.0, M−(ESI): 351.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[NH:48]1[CH2:53][CH2:52][CH2:51][CH:50]([C:54]([OH:57])([CH3:56])[CH3:55])[CH2:49]1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:48]2[CH2:53][CH2:52][CH2:51][CH:50]([C:54]([OH:57])([CH3:56])[CH3:55])[CH2:49]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: CC(C)(O)C1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2oncc2C(=O)N2CCCC(C(C)(C)O)C2)cc1
Reaction time: 2 h
Yield: 54.8 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10 mg, 0.05 mmol), TBTU (19 mg, 0.06 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.10 mmol, 2 equ) in DMF (0.3 mL) was added to 2-piperidin-3-ylpropan-2-ol hydrochloride (9 mg, 0.05 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (9 mg). MS (ESI, pos. ion) m/z calcd for C19H24N2O3: 328.1787, found 328.1787.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([OH:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>C(Cl)Cl>[Br:1][CH2:2][C:3]([O:24][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C(Cl)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOC(=O)CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromoacetylchloride (52.11 grams) is added dropwise into a stirred solution of 89.27 grams of octadecanol and 50 ml of triethylamine in 400 ml of methylene chloride at 25°-30° C. After stirring the reaction mixture at room temperature overnight under N2, the mixture is filtered and the filtrate is concentrated under reduced pressure. Purification by liquid chromatography affords octadecyl bromoacetate as a white solid, mp 37°-40° C.