Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[N:3]=1.[C:32](Cl)(=[O:34])[CH3:33]>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:32](=[O:34])[CH3:33])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:6]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[N:5]=[C:4]([C:28]([F:31])([F:29])[F:30])[N:3]=1
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(Cl)c2-c2ccc(S(N)(=O)=O)cc2)cc1
Agent: CN(C)c1ccncc1
Product: CC(=O)NS(=O)(=O)c1ccc(-c2c(Cl)nc(C(F)(F)F)nc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 30 °C

Procedure:
A solution of 4-{4-chloro-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-5-yl}benzenesulfonamide (0.5 g, 1.01 mmol, prepared according to the procedure described in PCT/IB03/02879), DMAP (0.01 g) and acetyl chloride (0.5 g, 6.36 mmol) were stirred at 30° C. TLC confirmed the completion of the reaction after 4 hours of stirring under the same conditions. Subsequently the resulting mass was poured onto the ice, and the procedure described for example 14 was followed to afford the title compound (0.252 g, 46.41%, purity by HPLC 98.82%); m.p.: 230-235° C. 1H-NMR (DMSO-d6) δ: 1.87 (s, 3H), 3.17 (s, 3H), 7.51-7.53 (m, 2H), 7.66-7.67 (m, 2H), 7.8-7.82 (d, 2H), 7.9 (s, 1H), 7.99 (s, 1H), 12.14 (s, 1H, D2O exchangeable). IR (KBr) cm−1: 3150, 1720, and 1525. MS m/z: 533.7(M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH2:12][C:11]([CH3:15])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13](=[O:14])[CH:12]([C:31](=[O:32])[NH:30][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[C:11]([CH3:15])=[N:10]2)=[CH:7][CH:8]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1ccc(N2N=C(C)CC2=O)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(N2N=C(C)C(C(=O)Nc3ccc(F)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of 4.1 g of 1-(p-methoxyphenyl)-3-methyl-2-pyrazolin-5-one in 75 ml of benzene and 2.5 g of triethylamine is combined with 2.75 g of p-fluorophenylisocyanate while stirring at ambient temperature. After standing overnight, the mixture is evaporated, the residue taken up in 0.3 N hydrochloric acid, the resulting crystals collected, washed with water, dried, triturated with ethyl acetate and recrystallized from methanol to yield the 1-(p-methoxyphenyl)-3-methyl-4-(p-fluorophenylcarbamoyl)-2-pyrazolin-5-one of Formula II with R=OCH3, R'=H and R"=F, melting at 254°-256° (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].Cl.[CH2:15]([O:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH2:15]([O:22][NH:23][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NOCc1ccccc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A solution of 2-nitrobenzene-1-sulfonyl chloride (500 g, 2.26 mol) in pyridine (1500 mL) was added dropwise to a solution of O-benzylhydroxylamine hydrochloride (400 g, 2.51 mol) in pyridine (1500 mL) at 0° C. The reaction mixture was then stirred at 20° C. overnight. The mixture was concentrated in vacuum, diluted with DCM and washed with HCl (10%) three times. The combined organic layer was concentrated in vacuum and re-crystallized with DCM to afford N-(benzyloxy)-2-nitrobenzenesulfonamide (485 g, 62.6%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1.[NH:20]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[N:21]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)C.C1C=CC=CC=1>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=3)[C:25]([C:22]3[CH:23]=[CH:24][NH:20][N:21]=3)=[N:1][C:2]=2[CH:17]=1
Reactant: O=Cc1cc[nH]n1
Reactant: COc1ccc(Nc2ccc(CCO)cc2)c(N)c1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CCO
Solvent: c1ccccc1
Product: COc1ccc2c(c1)nc(-c1cc[nH]n1)n2-c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.1 %

Procedure:
A mixture of 2-(4-{[2-amino-4-(methyloxy)phenyl]amino}phenyl)ethanol (step 2 of Example 71, 1.95 g, 7.56 mmol), pyrazol-3-carbaldehyde (726 mg, 7.56 mmol) in ethanol (45 ml) was heated at reflux temperature for 2 h. After cooling, the mixture was concentrated. A mixture of the residue, lead tetraacetate (4.61 g, 8.32 mmol) in benzene (50 ml) was stirred at room temperature for 16 h. The mixture was quenched with saturated NaHCO3 aqueous solution (150 ml). The whole was extracted with ethyl acetate (150 ml×4). The organic layer was washed with water (100 ml×5), brine (50 ml), dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with dichloromethane/methanol (gradient elution from 20:1 to 10:1) to afford 408 mg (16%) of the title compound as an amber solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][NH2:8].[C:9]([C:13]1[CH:22]=[CH:21][C:16]([CH2:17][N:18]=[C:19]=[S:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(OCC)(=O)C>[C:9]([C:13]1[CH:22]=[CH:21][C:16]([CH2:17][NH:18][C:19]([NH:8][CH2:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)=[S:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(CN=C=S)cc1
Reactant: Cn1cccc1CN
Solvent: CCOC(C)=O
Product: Cn1cccc1CNC(=S)NCc1ccc(C(C)(C)C)cc1
Reaction time: 12 h
Yield: 75.9 %

Procedure:
(1-methyl-1H-pyrrol-2-yl)methylamine (65 mg) and 4-t-butylbenzylisothiocyanate (120 mg) were dissolved in ethyl acetate (30 ml) and the solution was stirred for 12 hours. After the completion of the reaction, the resulting mixture was purified by column-chromatography (ethyl acetate/hexane=1/3) to yield the compound 17-2 (140 mg, 75%)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]([CH3:27])[C@@H:19]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.O>[CH2:11]([N:18]([CH3:27])[C@@H:19]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH:20]=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN(Cc1ccccc1)[C@H](CO)C1CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(Cc1ccccc1)[C@H](C=O)C1CCCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of oxalyl chloride (8.7 g, 68.5 mmol, 2.0 eq) in anhydrous dichloromethane (200 mL) was added drop-wise a solution of DMSO (10.7 g, 137 mmol, 4.0 eq) in anhydrous dichloromethane (20 mL) at −78° C. under nitrogen. After 1 hour, a solution of (S)-2-(benzyl(methyl)amino)-2-cyclopentylethanol (4) (8.0 g, 34.3 mmol, 1.0 eq) in anhydrous dichloromethane (30 mL) was added drop-wise at −78° C. The reaction mixture was allowed to stir for another 1 hour at −78° C. Then triethylamine (27.8 g, 274 mmol, 8.0 eq) was added drop-wise at −78° C. After the addition the reaction mixture was warmed to 0° C. under stirring. After 30 min at 0° C., water (250 mL) was added into the reaction solution and the organic phase was washed with brine, dried over sodium sulphate and concentrated in vacuo to give the product 5 as an oil (quant); LC-MS: m/z 232 [M+H+]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH:14]([CH2:21][C:22]2([CH3:27])[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:15]3=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C1(C)C=CC=CC=1.OS(O)(=O)=O>CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14]([CH2:21][C:22]2([CH3:27])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:15]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(CC2Cc3c(cccc3-c3ccc(C(C)(C)C)cc3)C2=O)CCCC1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1(CC2=Cc3cccc(-c4ccc(C(C)(C)C)cc4)c3C2)CCCC1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
19.5 g of crude 4-(4-tert-butyl-phenyl)-2-[(1-methylcyclopentyl)methyl]-indan-1-one (˜86% purity), 2.06 g (54.5 mmol) of NaBH4 and 52 ml of toluene are charged in a flask equipped with reflux condenser, dropping funnel and magnetic stirring bar. The mixture is warmed to 50° C. and 10 ml of methanol are slowly added with stirring and stirring is continued for 2.5 h to ensure a complete reaction. Excess NaBH4 is carefully hydrolyzed with approx. 30 ml of 2n H2SO4. The organic phase is separated and the water phase is washed with another 26 ml of toluene. The combined organic phases are twice extracted with 2n H2SO4 and dried over anhydrous MgSO4. Most of the solvent is removed in a vacuum and replaced by fresh toluene up to a total volume of 75 ml and 0.22 g of p-toluenesulfonic acid are added. The reaction flask is fitted with a water separator and the reaction mixture is heated to reflux for 1.5 h. The conversion can be monitored by TLC. Once the dehydration is complete, the solution is washed with a saturated NaHCO3 solution and dried over anhydrous MgSO4. The solvent is thoroughly removed in a vacuum and a brown oil is obtained. Purification of the indene is carried out via a column chromatography. Yield: 13.8 g (˜86%) of 7-(4-tert-Butyl-phenyl)-2-[(1-methylcyclopentyl)methyl]-1H-indene.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].C1N=C[N:36](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([NH2:36])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(N)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 78.8 %

Procedure:
3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy -phenyl)-propionamide was prepared by the procedure of Example 6 from 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.5 g, 1.1 mmol), CDI (0.19 g, 1.2 mmol) and NH4OH (0.1 ml, 1.2 mmol) in THF (30 ml) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionamide as white solid (0.40 g, 80%): mp 178–180° C.; 1HNMR (CDCl3): δ1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 2.26 (s, 3H, CH3CO), 3.03 (dd, J=5, 15 Hz, 1H, CH2), 3.70 (dd, J=10, 15 Hz, 1H, CH2), 4.09 (q, J=7.0 Hz, 2H, OCH2CH3), 5.38 (broad, 1H, NH2), 5.61 (broad, 1H, NH2), 5.76–5.83 (m, 1H, CHN), 6.83 (t, JH-F=7.5 Hz, 1H, CF2H), 7.06–7.14 (m, 3H, Ar), 7.46(d, J=7.5 Hz, 1H, Ar), 7.65 (t, J=7.5 Hz, 1H, Ar), 7.74 (d, J=7.5 Hz, 1H, Ar), 9.45 (s, 1H, NHCO). 13CNMR (DMSO-d6): δ 14.4, 24.2, 36.7, 50.0, 64.2, 93.9, 112.5, 113.2, 116.7, 116.7, 118.0, 119.4, 121.2, 125.9, 131.4, 135.8, 136.4, 137.6, 139.0, 149.7, 167.2, 168.2,169.2, 171.0; Anal Calcd for C22H21F2N3O6: C, 57.27; H, 4.59; N, 9.11. Found: C, 57.04; H, 4.41; N, 8.93.
Reaction SMILES: C(C1C=CC(C(=O)C(O)(C)C)=CC=1)(C)C.C(C1C=CC(C(=O)C(O)(C)C)=CC=1)CCCCCCCCCCC.[CH2:40]([O:42][C:43]([O:58][CH2:59]C)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:45])C.COC1C=CC=C(OC)C=1C(P(=O)CC(C)CC(C)(C)C)=O.OC(C)(C)C(C1C=CC=CC=1)=O>>[CH3:59][O:58][C:43]([O:42][CH3:40])([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:45]
Reactant: CCOC(OCC)(C(=O)c1ccccc1)c1ccccc1
Agent: CC(C)(O)C(=O)c1ccccc1
Agent: CC(C)c1ccc(C(=O)C(C)(C)O)cc1
Agent: CCCCCCCCCCCCc1ccc(C(=O)C(C)(C)O)cc1
Product: COC(OC)(C(=O)c1ccccc1)c1ccccc1

Procedure:
2-methyl-1-[4-(methyl thio)-phenyl]-2-morpholinopropanone-1; 1-(4-isopropylphenyl)-2-hydroxy-2-methylpropan-1-one; 1-(4-dodecyl-phenyl)-2-hydroxy-2-methylpropan-1-one; 4-(2-hydroxyethoxy)phenyl-2(2-hydroxy-2-propyl)-ketone; diethoxyphenyl acetophenone; 2,4,6 trimethylbenzoyl diphenylphosphone, a mixture of (2,6-dimethoxy benzoyl)-2,4,4 trimethylpentylphosphineoxide and 2-hydroxy-2-methyl-1-phenyl-propane-1-one, and mixtures thereof.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[OH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[NH:22][CH2:21][CH:20]([N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:19]2>C1COCC1>[CH2:25]([N:24]([CH2:28][CH2:29][CH3:30])[CH:20]1[CH2:19][C:18]2[C:23]3=[C:14]([O:13][C:1](=[O:2])[N:22]3[CH2:21]1)[CH:15]=[CH:16][CH:17]=2)[CH2:26][CH3:27]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCN(CCC)C1CNc2c(O)cccc2C1
Solvent: C1CCOC1
Product: CCCN(CCC)C1Cc2cccc3oc(=O)n(c23)C1
Reaction time: 0.08 h
Yield: 86.6 %

Procedure:
Carbonyldiimidazole (0.46 g, 2.8 mmol) was added to a stirred solution of 1,2,3,4-tetrahydro-8-hydroxy-N,N-dipropyl-3-quinolinamine (0.59 g, 2.4 mmol) in THF (10 mL). After 5 minutes, the solvent was removed and the residue was dissolved in ethyl acetate and chromatographed on silica gel using 5% ethyl acetate in hexane as the initial eluant to give 0.57 g of 5-(dipropylamino)-5,6-dihydro-2H,4H-oxazolo(5,4,3-ij)quinolin-2-one as an oil.
Reaction SMILES: [Cl-].[NH4+:2].[F:3][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7]>CO.O.[Fe]>[NH2:2][C:14]1[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[C:4]([F:3])[CH:15]=1
Reactant: [NH4+]
Reactant: CON(C)C(=O)c1ccccc1F
Agent: [Fe]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CON(C)C(=O)c1ccc(N)cc1F

Procedure:
15.2 g of ammonium chloride and 8 g of iron powder were added to a suspension of 10.84 g of 2-fluoro-N-methoxy-N-methylbenzamide in 60 ml of methanol and 30 ml of water, and the reaction liquid was heated under reflux for 3 hours. The reaction liquid was filtered through Celite, and the solvent was evaporated away under reduced pressure. The resulting residue was diluted with ethyl acetate, washed with water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1 to 1/2 to obtain the entitled compound as a brown oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:35])[CH:3]=1.Cl.[NH2:37][OH:38].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:37]\[OH:38])=[C:4]([CH3:35])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CCN(S(C)(=O)=O)CC3)cc2)c2ccc(Cl)cc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3CCN(S(C)(=O)=O)CC3)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-3-(4-chloro-2-methylphenyl)-1-(2-methyl-pyridin-4-yl)-3-(4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)propan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white solid, MS (ESI+): m/z=526.3 ([M+H]+).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[NH2:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([N:51]2[C:55]([NH:56][C:57]([NH:59][C:60]3[CH:65]=[CH:64][C:63]([O:66][C:67]4[CH:72]=[CH:71][N:70]=[CH:69][CH:68]=4)=[CH:62][CH:61]=3)=[O:58])=[CH:54][C:53]([C:73]([CH3:76])([CH3:75])[CH3:74])=[N:52]2)=[CH:47][CH:46]=1>C1COCC1.C(#N)C>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10](=[O:12])[NH:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([N:51]2[C:55]([NH:56][C:57]([NH:59][C:60]3[CH:65]=[CH:64][C:63]([O:66][C:67]4[CH:68]=[CH:69][N:70]=[CH:71][CH:72]=4)=[CH:62][CH:61]=3)=[O:58])=[CH:54][C:53]([C:73]([CH3:76])([CH3:75])[CH3:74])=[N:52]2)=[CH:47][CH:46]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(CN)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)NCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.7 %

Procedure:
To a solution of N-Boc-glycine (260 mg, 1.48 mmol), EDCI (283 mg, 148 mmol) and HOBT (200 mg, 1.48 mmol) in THF/acetonitrile (50:50, 5 mL) was added N,N-diisopropylethylamine (380 mg, 2.96 mmol), and the resulting reaction mixture was stirred at room temperature for 1 h. Then, 1-[2-(4-aminomethyl-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea (450 mg, 0.99 mmol) was added to the solution and the reaction mixture was stirred at 50° C. for 18 h. The reaction mixture was cooled to room temperature, concentrated at reduced pressure, and the residue was dissolved in EtOAc (20 mL). The solution was washed with water and brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by preparative TLC (50:50 hexanes/EtOAc) to give 65 mg (11%) of the desired product. 1H-NMR (DMSO-d6) 8.68 (s, 1H), 8.42 (d, J=6.3 Hz, 2H), 7.98 (s, 1H), 7.82 (b, 1H), 7.61 (d, J=6.9 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.08 (d, J=6.6 Hz, 2H), 6.80 (d, J=6.3 Hz, 2H), 6.46 (s, 1H), 4.48 (d, J=6.0 Hz, 2H), 3.78 (d, J=5.7 Hz, 2H), 1.35 (s, 9H), 1.30 (s, 9H); MS LC-MS [M+H]+=614, RT=2.89 min.
Reaction SMILES: Br[C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH:14]([CH3:17])[CH2:15][CH3:16])[N:5]=2.[CH3:24][O-:25].[Na+]>CO>[CH3:17][CH:14]([CH2:15][CH3:16])[CH2:13][O:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([O:25][CH3:24])[N:3]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:8]([NH2:11])[N:7]=1
Reactant: C[O-]
Reactant: CCC(C)COc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Na+]
Solvent: CO
Product: CCC(C)COc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1

Procedure:
To a solution of 8-bromo-2-[(2-methylbutyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (284 mg) in dry MeOH (2.54 mL) was added sodium methoxide solution (0.416 mL, 30% wt. MeOH) and the mixture was stirred at reflux for 1 h. The reaction was allowed to cool and was concentrated in vacuo. The resulting residue was dissolved in EtOAc (15 mL) and was poured into saturated ammonium chloride solution (15 mL). The organics were separated, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as an orange foam (199 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=O)[CH3:12])=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:8][CH2:9][N:10]=[C:11]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(=O)NCCc1ccc(F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2ccc(F)cc21

Procedure:
In close analogy to the procedure described above, N-[2-(4-fluoro-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:30][OH:31])[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:34]I.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:30][O:31][CH3:34])[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2noc(-c3cc4c(CO)nccc4o3)n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1nccc2oc(-c3nc(COC4CCN(C(=O)OC(C)(C)C)CC4)no3)cc12
Reaction time: 1.5 h

Procedure:
To a stirred solution of 4-[5-(4-hydroxymethylfuro[3,2-c]pyridine-2-yl)-[1,2,4]oxadiazole-3-ylmethoxy]piperidine-1-carboxylic acid tert-butyl ester (Example 24, 50 mg, 116 μmol) in THF was added sodium hydride (60% dispersion in mineral oil, 6 mg, 150 μmol). After effervescence had ceased, MeI (10 μL, 161 μmol) was added. After 90 min, the mixture was poured into H2O and extracted with EtOAc. The organic layer was separated, washed with brine, dried and concentrated. Purification via column chromatography afforded the title compound: RT=3.54 min; m/z (ES+)=445.1 [M+H]+.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[N+:6]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)([O-:8])=[O:7]>C(OCC)(=O)C>[C:1]([NH:5][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)N
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
tert-Butyl amine (14.6 g, 0.200 mole) was stirred in ethyl acetate (150 mL, purified by washing with 5% sodium carbonate solution, saturated sodium chloride solution, drying over anhydrous magnesium sulfate, and filtering through fluted filter paper) and cooled to 5° C. with an ice bath. 4-nitrobenzoyl chloride (18.6 g, 0.100 mole) in purified ethyl acetate (75 mL) was added dropwise at such a rate to maintain the temperature below 10° C. The ice bath was removed upon complete addition of benzoyl chloride solution and the reaction stirred for 4 hours. The reaction mixture was then filtered on a Buchner funnel, the filtrate washed three times with 5 % HCl, once with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered through fluted filter paper, and the solvent stripped off leaving white crystalline product. The product was dried in a vacuum oven at 24 mm and 45° C. for 14 hours. This procedure produced 17.13 g of crystals of N-tert-butyl-4-nitrobenzamide (CPI1020) (77% yield), mp 162-163° C. Proton nuclear magnetic resonance (89.55 MHz in CDCl3) showed absorptions at 8.257 ppm (d, 8.8 Hz, 2H; 3,5-aryl H); 7.878 ppm (d, 8.8 Hz, 2H; 2,6-aryl H); 6.097 ppm (bs, 1H; N--H); 1.500 ppm (s, 9H; tert-butyl H).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]([F:19])([F:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.S(=O)(=O)(O)O>C(O)(=O)C.IN1C(=O)CCC1=O>[I:1][C:13]1[CH:12]=[C:11]([C:10]([F:18])([F:19])[F:9])[CH:16]=[CH:15][C:14]=1[OH:17]
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Oc1ccc(C(F)(F)F)cc1I
Temperature: 0 °C
Yield: 242.7 %

Procedure:
N-iodosuccinimide (69.5 g, 0.309 moles) was suspended in acetic acid (257 mL) and cooled to 0° C. 4-Trifluoromethylphenol (50.0 g, 0.310 moles) was added followed by sulphuric acid (5.44 mL) dropwise over 5 minutes. The orange-brown suspension was stirred whist warming slowly to room temperature over 18 hours. A further portion of N-iodosuccinimide (2.5 g, 0.011 moles) was added and the mixture was stirred at room temperature for 24 hours. The reaction was quenched by adding water (150 mL) and extracted with dichloromethane (2×100 mL). The combined organics were washed with a saturated aqueous solution of sodium metabisulphite (2×50 mL) and then with saturated aqueous sodium chloride solution (50 mL). The organics were dried over anhydrous magnesium sulphate, filtered and the solvents removed in vacuo to give the crude title product as a light yellow oil. This batch was combined with the products from two further identical reactions and purified by distillation in vacuo. The product was collected boiling at approximately 45° C. at 2 mBar to give the title compound as a pink-orange semi-solid (216 g).