Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([N:18]2[C:27]3[C:22](=[CH:23][C:24]([S:28](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:30])=[O:29])=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:43])=[CH:6][C:7]([F:17])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:9]=1)[CH3:2].[O:44]1[CH:48]=[CH:47][C:46]([NH2:49])=[N:45]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]1[C:5]([N:18]2[C:27]3[C:22](=[CH:23][C:24]([S:28]([NH:49][C:46]4[CH:47]=[CH:48][O:44][N:45]=4)(=[O:29])=[O:30])=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:43])=[CH:6][C:7]([F:17])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
A solution of perfluorophenyl 1-(5-ethoxy-2,3′-difluoro-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (398 mg, 0.638 mmol), isoxazol-3-amine (66.0 pdr, 0.894 mmol) and THF (6383 μl) was cooled in an ice-bath for 15 min, then lithium bis (trimethylsilyl)amide (1M in THF) (1596 μl, 1.596 mmol) was added dropwise. After 1.5 h, the mixture was diluted with 1N aq. HCl and EtOAc. The layers were separated, and the organic layer was washed with 1N aq. HCl. The aq. layers were combined and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 70% EtOAc in heptane, to provide 1-(5-ethoxy-2,3′-difluoro-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (270 mg, 81% yield) as light-yellow solid. m/z [M+H]+=524.0. NMR (400 MHz, DMSO-d6) δ ppm 0.97 (t, J=6.99 Hz, 2 H) 4.01-4.13 (m, 2 H) 6.42 (s, 1 H) 6.82 (d, J=9.68 Hz, 1 H) 6.88 (d, J=9.10 Hz, 1 H) 7.27-7.37 (m, 1 H) 7.43 (d, J=6.94 Hz, 1 H) 7.50-7.67 (m, 4 H) 7.86 (dd, J=8.95, 2.20 Hz, 1 H) 8.24 (d, J=9.59 Hz, 1 H) 8.37 (d, J=2.05 Hz, 1 H) 8.69 (s, 1 H) 11.66 (br. s., 1H).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:9]=2[O:10][CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:27]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:26][C:24]1[CH:23]=[CH:22][C:9]([O:10][CH:11]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:12]([O:14][CH3:15])=[O:13])=[C:8]([C:2]2([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(Oc1ccc(C)cc1C1(C)CCCCC1)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1ccc(CBr)cc1C1(C)CCCCC1)c1ccccc1
Yield: 21.3 %

Procedure:
To a solution of 0.780 g (2.21 mmol) of the product of Step A dissolved in 12 mL of CCl4 was added 0.394 g (2.21 mmol) of N-bromosuccinimide and 20 mg (catalytic amount) of AIBN. The mixture was stirred and refluxed under a N2 atmosphere for 6 hours. The mixture was then cooled, filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 7% ethyl acetate/hexane to afford 0.203 g (21%) of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:20])[C:13]=2[N+:17]([O-])=O)[C:8]1=[O:21])(=[O:3])[CH3:2].C(O)C.[Cl-].[NH4+].O>[Fe]>[C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:20])[C:13]=2[NH2:17])[C:8]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCn1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)OCCn1ccc2c(N)c(Cl)ccc2c1=O
Reaction time: 0.75 h

Procedure:
A round bottom flask was charged with 2-(6-chloro-5-nitro-1-oxoisoquinolin-2(1H)-yl)ethyl acetate (450.00 mg, 0.0014484 mol), ethanol (20 mL, 0.3 mol), and ammonium chloride (774.8 mg, 0.01448 mol) in water (10 mL, 0.6 mol) was added at 85° C., followed by iron (324 mg, 0.00579 mol) in two portions. The reaction was stirred at that temperature for 45 minutes and then poured onto methylene chloride (200 mL) and extracted. The solvent was removed under reduced pressure to afford the pure product as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-:3])=[O:2].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[C:13]([CH2:14][Br:15])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-:3])=[O:2]
Reactant: COC(=O)c1cccc(C)c1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(CBr)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Methyl 2-nitro-3-methylbenzoate (15.3 gm) was suspended in carbon tetrachloride (45 mL) along with N-bromosuccinimide (15 3 gm) and heated to reflux. 2,2'-Azobis(2-methylpropionitrile) (AIBN) (0.4 gm) was added to the refluxing solution in four equal portions over 48 hours. The reaction was cooled to room temperature, filtered, and concentrated. The residue consisted of a mixture of starting material, desired product, and dibrominated material which were difficult to separate and so were used in the next step without purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:22][N:23]([CH3:27])[C:24](Cl)=[O:25].C(OCC)(=O)C>ClCCl>[CH3:22][N:23]([CH3:27])[C:24]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)=[O:25]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)C(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of 500 mg (2.50 mmol) of tert-butyl 4-piperidinyl-carbamate in 20 mL of dichloromethane was added 522 μL (3.74 mmol) of triethylamine and 276 μL (3.00 mmol) of dimethylaminocarbonyl chloride and the mixture was stirred for 2 hours at room temperature. Then, the mixture was treated with ethyl acetate and the organic layer was washed with water and saturated saline solution, and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 636 mg (94%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:18]OS(C)(=O)=O)=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:24].[Na+]>CC(C)=O.C(OCC)C>[CH2:1]([O:8][C:9]1[C:10]([CH2:18][I:24])=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CS(=O)(=O)OCc1cc2c(cc1OCc1ccccc1)CCO2
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: ICc1cc2c(cc1OCc1ccccc1)CCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.1 %

Procedure:
A flame dried, N2 purged 1-liter, 3-neck round bottom flask equipped with an internal thermometer and mechanical stirrer was charged with 5-benzyloxy-6-(methanesulfonyloxymethyl)-2,3-dihydrobenzofuran (30.60 g, 0.10 moles) and anhydrous acetone (250 ml). The resultant solution was cooled to 0° C. and with efficient stirring sodium iodide (59.90 g, 0.40 moles) in acetone (150 ml) was added in one portion. The reaction mixture was stirred at room temperature for 72 hours and then suction filtered through a bed of celite. The filtrate was concentrated in vacuo to afford the crude product. This was dissolved in ethyl ether (400 ml) and water (200 ml), the layers partitioned, and separated. The organic phase was washed with saturated NaHS03 solution (2×200 ml) and water (1×200 ml), dried over MgSO4, suction filtered, and the filtrate concentrated in vacuo to yield 5-benzyloxy-6-iodomethyl-2,3-dihydrobenzofuran as a yellow solid (33.0 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[NH:21][C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NC(c2cccnc2)c2ccccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NC(c2cccnc2)c2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-1-(pyrid-3-yl)-1,2,3,4-tetrahydroisoquinoline-3-one (Example 5-D), the title compound was prepared as a solid having a melting point of 100-120° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:14]1[CH:18]=[C:17]([CH2:19][NH2:20])[N:16]=[CH:15]1.[Cl-].[Cl-].[Ca+2]>C1COCC1>[NH:14]1[CH:18]=[C:17]([CH2:19][NH:20][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:16]=[CH:15]1
Reactant: O=C(O)CCCCc1ccccc1
Reactant: NCc1c[nH]cn1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(CCCCc1ccccc1)NCc1c[nH]cn1
Reaction time: 0.5 h

Procedure:
8 mmol of N,N'-carbonyldiimidazole and 8 mmol of 5-phenylpentanoic acid are introduced successively into 10 ml of absolute THF and, after having stirred for 30 min, 8 mmol of (1H-imidazol-4-yl)methanamine are added to the mixture, moisture being excluded using CaCl2. At the end of 14 h, the solvent is removed by distilling under vacuum. The remaining oil is mixed with a small amount of water. The title compound is filtered under vacuum, dried and crystallized from ethanol/diethyl ether.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)=[C:6]([CH:28]([CH3:30])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)=[C:6]([CH:28]([CH3:30])[CH3:29])[N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1cccc(/C=C/c2c(C(C)C)nc(C(C)C)c(CO)c2-c2ccc(F)cc2)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cccc(CCc2c(C(C)C)nc(C(C)C)c(CO)c2-c2ccc(F)cc2)c1

Procedure:
The title compound was prepared 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[2-(E)-(3-methylphenyl)ethenyl]pyridine (Example 41) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.18 (d, J=7 Hz, 4 H), 7.10 (m, 1 H), 6.97 (m, 1 H), 6.65 (m, 2 H), 4.36 (s, 2 H), 3.44 (sept, J =6.6 Hz, 1 H), 3.35 (d, J=6.6 Hz, 1 H), 2.57 (m, 4 H), 2.28 (s, 3 H), 1.35 (d, J=6.6 Hz, 6 H), 1.34 (d, J=6.6 Hz, 6 H), 1.20 (m, 1 H). FAB-MS: calculated for (C27H32FNO) 405, found 406 (M+H). Anal. Calcd for C27H32FNO: C, 79.96; H, 7.95; N, 3.45. Found: C, 79.30; H, 8.10; N, 3.36. mp 148-150° C. Rf=0.3 (20% ethyl acetate/hexane).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].O.[N-:19]=[N+]=[N-].[Na+]>CN(C=O)C>[NH2:19][C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1nc(-c2cccnc2)sc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc(-c2cccnc2)sc1N
Temperature: 75 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To a round bottom flask containing ethyl 5-bromo-2-(pyridin-3-yl)thiazole-4-carboxylate (2.5 g, 7.98 mmol) in DMF (26.6 ml)/water (13.3 ml) was carefully added sodium azide (2.59 g, 39.9 mmol) and stirred overnight at 75° C. The reaction was cooled to room temperature and poured into water which was extracted with ethyl acetate. The ethyl acetate layers were combined and washed with hexanes/water. The ethyl acetate extracts were dried (MgSO4), filtered and concentrated to dryness. The crude material was purified by silica gel column chromatography (0 to 75% ethylacetate/hexanes) to give the desired product as a white solid (0.6 g, 30%) 1H NMR (300 MHz, CDCl3) δ 8.98 (s, 1H), 8.63 (d, 1H), 8.19 (d, 1H), 7.45-7.32 (m, 1H), 6.3 (s, 2H), 4.46 (q, 2H), 1.43 (t, 3H). ESIMS m/z 251.1 (M+2).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3](O)[CH2:2]2.N12CCC(CC1)CC2O.[C:19]([OH:23])(=[O:22])[CH:20]=[CH2:21]>ClCCl.C(OCC)(=O)C>[C:19]([CH2:20][CH2:21][N+:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2)([O-:23])=[O:22]
Reactant: C=CC(=O)O
Reactant: OC1CN2CCC1CC2
Agent: OC1CC2CCN1CC2
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C([O-])CC[N+]12CCC(CC1)CC2
Yield: 86.3 %

Procedure:
1.91 grams of 3-quinuclidinol was added to a 100 mL round bottom flask containing a stir bar. 50 mL of dichloromethane was added to the flask and the mixture stirred to dissolve the quinuclidinol. 1.08 grams of acrylic acid was dissolved in 8 mL of dichloromethane in a test tube and then added dropwise to the solution of 3-quinuclidinol with stirring. The mixture was allowed to stir for 48 hours at room temperature during which time about half of the dichloromethane evaporated leaving a white slurry which was diluted with ethyl acetate and the solid collected in a medium porosity glass fritted funnel. The solid was washed with 30 mL of ethyl acetate and the resulting solid dried in a 85° C. drying oven to give 2.37 grams of a white solid. The structure was confirmed by positive mode electrospray mass spectrometry (M+H)=199.3 m/z and 1H NMR.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[N:3][CH:2]=1.N1C=CC(C(=O)CC(OCC)=O)=CC=1.[NH2:29][C:30]1[CH:34]([N:35]2[C:43](=[O:44])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]2=[O:45])[CH2:33][CH2:32][N:31]=1>>[O:11]=[C:9]1[N:31]2[CH2:32][CH2:33][CH:34]([N:35]3[C:43](=[O:44])[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]3=[O:45])[C:30]2=[N:29][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)=[CH:8]1
Reactant: NC1=NCCC1N1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: CCOC(=O)CC(=O)c1ccncc1
Product: O=C1c2ccccc2C(=O)N1C1CCn2c1nc(-c1ccncn1)cc2=O

Procedure:
By analogy with the method described in example 1 (step 1.3), using ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the method described in patent DE 2705582) in place of ethyl 3-(pyridin-4-yl)-3-oxopropionate and using 2-(2-amino-4,5-dihydro-3H-pyrrol-3-yl)-isoindole-1,3-dione, the compound was obtained as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[CH3:5].[CH3:27][C:28]1[C:33]([C:34](O)=[O:35])=[C:32]([CH3:37])[N:31]=[CH:30][N:29]=1>>[C:23]([Si:20]([CH3:21])([CH3:22])[O:19][C:16]1[CH:15]=[CH:14][C:13]([NH:12][CH:9]2[CH2:10][CH2:11][N:6]([C@H:4]([CH3:5])[CH2:3][CH2:2][NH:1][C:34]([C:33]3[C:28]([CH3:27])=[N:29][CH:30]=[N:31][C:32]=3[CH3:37])=[O:35])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1)([CH3:25])([CH3:24])[CH3:26]
Reactant: Cc1ncnc(C)c1C(=O)O
Reactant: C[C@H](CCN)N1CCC(Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2)CC1
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2)CC1

Procedure:
Using general procedure E, [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-amine (see EXAMPLE 233) (940 mg, 2.5 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (490 mg, 3.2 mmol) afforded 4,6-dimethyl-pyrimidine-5-carboxylic acid ((R)-3-{4-[4-(tert-butyl-dimethyl-silanyloxy)-phenylamino]-piperidin-1-yl}-butyl)-amide as a peach solid (790 mg, 62%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH:23](=O)[C:24]1[O:28][CH:27]=[CH:26][CH:25]=1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:23][C:24]4[O:28][CH:27]=[CH:26][CH:25]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccco1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccco4)c23)c1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 144 mg (1.5 mmol) of furfural to form 4-(3-chloro-phenylamino)-3-[(fur-2-yl)-methyleneamino]-1H-pyrazolo[3,4-d]-pyrimidine. Reduction of the above intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H and analogous working-up yield 4-(3-chloro-phenylamino-3-[(fur-2-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100) 8.4; MS (M)+=340.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([CH3:26])=[C:21]([CH:25]=3)[C:22]([OH:24])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)O.[CH3:32]O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([CH3:26])=[C:21]([CH:25]=3)[C:22]([O:24][CH3:32])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CO
Reactant: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)ccc1C
Temperature: 25 °C
Yield: 90 %

Procedure:
To a stiffed mixture of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylbenzoic acid (compound 39.3, 1.392 g, 4.00 mmol, 1.00 equiv) in methanol (50 mL) was added sulfuric acid (784 mg, 7.99 mmol, 2.00 equiv), dropwise. The resulting mixture was heated to reflux overnight in an oil bath. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The residue was diluted with 20 mL of EtOAc and was washed with 1×100 mL of saturated sodium bicarbonate(aq) followed by 1×100 mL of brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield 1.303 g (90%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:20])([C:16](OC)=[O:17])[C:12](OC)=[O:13].[BH4-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:20])([CH2:16][OH:17])[CH2:12][OH:13]
Reactant: COC(=O)C(C)(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(CO)(CO)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.9 %

Procedure:
To a stirred solution of dimethyl 2-(2-fluoro-4-nitrophenyl)-2-methylmalonate (1.0 g, 3.50 mmol, 1.0 eq) in methanol (20 mL) was added NaBH4 (0.67 gm, 17.63 mmol, 5.0 eq) at 0° C. and stirred at RT for 16 h. The mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was vaporated under reduced pressure. The crude product obtained was purified by CC using EtOAc/PE (2:3) to get 2-(2-fluoro-4-nitrophenyl)-2-methylpropane-1,3-diol (400 mg, 50%; TLC system: EtOAc/PE (1:1), Rf: 0.3).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[CH:22][NH:23]2>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: NCC1CCN(C(=O)OCc2ccccc2)C1
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncnc3[nH]cnc23)C1

Procedure:
EXAMPLE 102 was prepared from 3-aminomethyl-pyrrolidine-1-carboxylic acid benzyl ester (EXAMPLE 79, Step 3) and 6-chloro-9H-purine: MS (m+1)=353.4.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:24][C:25]1([CH3:33])[CH2:30][C:29](=[O:31])[CH2:28][C:27](=[O:32])[CH2:26]1.CC(C)(O)C#N>ClCCl>[CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([CH:28]2[C:29](=[O:31])[CH2:30][C:25]([CH3:33])([CH3:24])[CH2:26][C:27]2=[O:32])=[O:10])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)(=[O:4])=[O:3]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Agent: CC(C)(O)C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)C(C(=O)c2ccc(S(C)(=O)=O)cc2[N+](=O)[O-])C(=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.8 %

Procedure:
A solution of 4-methylsulphonyl-2-nitrobenzoyl chloride (9.62 g) in dry dichloromethane (50 ml) was added to a stirred solution of triethylamine (5.6 ml) and 5,5-dimethylcyclohexane-1,3-dione (5 g) in dry dichloromethane (70 ml) during 30 minutes and the reaction mixture stirred at ambient temperature for 4 hours. Triethylamine (15.3 ml) and acetone cyanohydrin (0.5 ml) were added successively and the reaction mixture stirred at ambient temperature for 18 hours. The reaction mixture was washed successively with 2N hydrochloric acid (2×50 ml) and water (2×50 ml), dried over magnesium sulphate and evaporated under reduced pressure to give a yellow glass which was recrystallised from methanol (20 ml) to give 2-(4-methylsulphonyl-2-nitrobenzoyl)-5,5-dimethylcyclohexane-1,3-dione (6.4 g), m.p. 156.5°-158° C., as a yellow crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:32])[CH3:33])[N:28]=[CH:29][N:30]=2)[N:19]=4)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Agent: O=[Pt]
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(C3CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 63652.9 %

Procedure:
A mixture of 4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (89 mg, 0.19 mmol) in IMS (10 mL) was treated with platinum oxide (10 mg), the reaction mixture degassed and stirred at RT under an atmosphere of hydrogen for 72 h. Further platinum oxide (10 mg) was added and stirring continued at RT for 18 h before the filtering through Celite® and concentrating in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 5% methanol in DCM) to give 4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (58 g, 64%). LCMS RT=2.72, [M+H]+=480