Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[Cl:22].N([O-])=O.[Na+].[I-:27].[K+]>Cl.O.C(OCC)(=O)C>[C:18]([O:17][C:15]([NH:14][C@@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([I:27])=[C:3]([Cl:22])[CH:4]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: [I-]
Reactant: COC(=O)[C@H](Cc1ccc(N)c(Cl)c1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(I)c(Cl)c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
Methyl (2S)-3-(4-amino-3-chlorophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (3.00 g, 9.12 mmol) in aqueous hydrochloric acid solution (1.0 N, 100.0 mL) at 0° C. was treated with a solution of sodium nitrite (692 mg, 10.0 mmol) in water (10 mL). The solution was stirred at 0° C. for 30 minutes. A solution of potassium iodide (1.89 g, 11.4 mmol) in water (10 mL) was added and the solution stirred 30 minutes at rt and then 10 minutes at 35° C. The solution was diluted with ethyl acetate (200 mL), quenched with aqueous sodium thiosulfate solution (1.0 N, 500 mL), and the organic phase separated. The organic layer was washed with aqueous hydrochloric acid solution (1.0 N, 100 mL), brine (100 mL), and after drying over sodium sulfate was concentrated in vacuo. Purification by silica gel chromatography (10–40% ethyl acetate/hexanes) afforded product as a yellow solid (2.1 g, 53%). 1H NMR (400 MHz, CD3OD): δ 7.80 (d, J=8.0 Hz, 1H), 7.37 (s, 1H), 6.90 (d, J=8.2 Hz, 1H), 4.36–4.33 (m, 1H), 3.70 (s, 3H), 3.12–3.07 (m, 1H), 2.86–2.80 (m, 1H), 1.37 (s, 9H); LCMS found for C10H12ClINO2 (M+H)+: m/z=340.
Reaction SMILES: CS(O[C@@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([F:17])=[CH:11][C:12]=2[F:16])[CH2:7]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Li+]>CN(C=O)C>[N:18]([C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]([F:17])=[CH:11][C:12]=2[F:16])[CH2:7]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@@H]1CCc2c(F)cc(F)cc2C1
Agent: [Li+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CCc2c(F)cc(F)cc2C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate (54.0 g), prepared as in Example 7, and lithium azide (15.8 g, 0.322 mol) in 400 mL of DMF was stirred under argon at 50° C. for 16 hours. The reaction was quenched with 200 mL of water and the mixture extracted with 1 L of pentane. The extract was washed with 50 mL of water and dried over magnesium sulfate. Evaporation under reduced pressure at 35° C. gave crude (S)-2-azido-5,7-difluoro-1,2,3,4-tetrahydronaphthalene as a yellow oil residue (59.8 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]2[CH2:17][CH2:18][CH:12]1[C:13](=O)[CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:21]1[CH:26]=[N:25][CH:24]=[C:23]([CH3:27])[N:22]=1>>[CH3:27][C:23]1[N:22]=[C:21]([CH:13]2[CH:12]3[CH2:18][CH2:17][CH:15]([CH2:16][N:11]3[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:14]2)[CH:26]=[N:25][CH:24]=1
Reactant: O=C1CC2CCC1N(C(=O)OCc1ccccc1)C2
Reactant: Cc1cncc(I)n1
Product: Cc1cncc(C2CC3CCC2N(C(=O)OCc2ccccc2)C3)n1

Procedure:
The title compound (666 mg) was prepared from 2-benzyloxycarbonyl-2-azabicyclo[2.2.2]octan-6-one and 2-iodo-6-methylpyrazine as described in Example 3. The alcohol obtained was dehydrated using potassium hydride, iodomethane and carbon disulphide as described in Example 3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][NH:16][CH3:17].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C>[CH3:12][N:13]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1)[CH2:14][CH2:15][NH:16][CH3:17]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CNCCNC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CNCCN(C)c1ccc(C(F)(F)F)cc1
Yield: 21 %

Procedure:
A mixture of 4-bromobenzotrifluoride (3.0 g, 13.3 mmol), N,N′-dimethylethylenediamine (9.4 g, 0.11 mol), palladium acetate (60 mg, 0.27 mmol), BINAP (250 mg, 0.40 mmol) and sodium tert-butoxide (1.80 g, 18.7 mmol) in toluene (20 ml) was refluxed under a nitrogen atmosphere for 3 hours. Ethyl acetate and water were added to the reaction mixture, and the mixture was stirred for a while. The insoluble substances were removed by filtration through Celite, and the filtrate was then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=10/1) to afford N,N′-dimethyl-N-[4-(trifluoromethyl)phenyl]-1,2-ethylenediamine (650 mg, yield 21%) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:25](=[O:26])[CH2:24][O:23][CH3:22])=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCC(=O)Nc1ccc(NC(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 104 %

Procedure:
To a stirred solution of N-t-butoxycarbonyl-1,4-phenylene diamine (0.25 g) in dry tetrahydrofuran (20 ml) were added pyridine (0.12 ml) and methoxyacetyl chloride (0.15 g) and the reaction mixture was stirred for 1 hrs. The solution was diluted with ethyl acetate (50 ml), washed with a 3N solution of hydrochloric acid (30 ml) and brine (30 ml), dried and concentrated in vacuum to give the title compound (0.35 g). T.l.c. CH/EA acetate 1/1. Rf=0.33.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:11]([C:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1.CCOCC.CCCCCC>[CH2:20]([C:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:2]1[CH:1]=[CH:5][CH:4]=[CH:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C1=CCC=C1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: C1=CC(=C(Cc2ccccc2)Cc2ccccc2)C=C1
Temperature: 25 °C

Procedure:
Into a 100 ml Kjeldahl flask purged thoroughly with nitrogen, equipped with a dropping funnel and a magnetic stirrer, were introduced cyclopentadiene 2.40 g (36.2 mmol) which had been subjected to cracking, and dehydrated tetrahydrofuran 50 ml. With cooling in an ice bath, 1.57 mol/L n-hexane solution of n-butyllithium, 24.3 ml (38.1 mmol), was dropwise added to the solution by means of the dropping funnel. The resulting slurry was stirred all night at room temperature. With the flask cooled in an ice bath, a solution of dibenzyl ketone 9.16 g (43.6 mmol) in 20 ml of dehydrated tetrahydrofuran, was dropwise added into the flask by means of the dropping funnel. The resulting slurry was stirred all night at room temperature. After addition of a saturated aqueous solution of ammonium chloride 50 ml and ether 50 ml, the organic phase was recovered with a separatory funnel. The water phase was extracted with ether 30 ml. The organic phase was washed twice with water 50 ml and once with a saturated salt solution 50 ml, and dried over magnesium sulfate. The solution was filtered to remove the magnesium sulfate, and the solvent of the filtrate was distilled away to obtain a solid. The residue was subjected to column chromatography to obtain an objective brown oil in 1.10 g (12%) yield. The 1H NMR spectrum and the FD-MS spectrum as measured with respect to the brown oil are given below:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[NH:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)=[O:12])[CH2:5]2.C(N(CC)C(C)C)(C)C.[C:35](Cl)(=[O:37])[CH3:36]>CN(C)C=O>[C:35]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[NH:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)=[O:12])[CH2:5]2)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(NC(C)=O)cc3C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide (0.035 g, 0.103 mmol) in dimethylformamide (0.7 mL) was treated with N,N-diisopropylethylamine (0.018 mL, 0.103 mmol) followed by acetyl chloride (0.011 g, 0.134 mmol) and the reaction solution was stirred at room temperature for 16 hours. The reaction was concentrated and purified by reverse-phase HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.97 (s, 1H), 8.52 (s, 1H), 8.25 (t, J=5.7 Hz, 1H), 7.74-7.78 (m, 2H), 7.65-7.67 (m, 1H), 7.62-7.67 (m, 2H), 7.43 (dd, J=8.2, 1.9 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 4.71-4.76 (m, 4H), 3.16-3.21 (m, 2H), 2.04 (s, 3H), 1.46-1.59 (m, 2H), 0.89 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 381 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:8]([O:6][CH2:5][CH2:4][CH2:3][OH:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: OCCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: OCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (5.6 g, 0.14 mole) in tetrahydrofuran (350 ml) is added 1,3-propanediol (15 ml, 0.21 mol). The gummy suspension is stirred at room temperature for 0.5 hour and tetra n-butylammonium iodide (0.54 g) is added followed by benzyl bromide (16.6 ml, 0.14 mole). The mixture is stirred at room temperature for 62 hours. The solvent is evaporated and the residue purified by flash chromatography over silica gel using 1:4 ethylacetate/hexane as eluent to obtain 3-benzyloxypropan-1-ol as a clear oil; 1H NMR (CDCl3): δ7.3 (m, 5H), 4.5 (s,2H), 3.78 (t,8 Hz,2H), 3.65 (t,8 Hz,2H), 1.87 (quintet,8 Hz,2H).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([O:11]C)=O)=[C:7]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:6]=[C:5]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH3:28])[CH2:23][CH2:22]2)[N:4]=1)#[N:2]>[Pd].CCO.Cl>[CH2:27]([N:24]1[CH2:23][CH2:22][N:21]([C:5]2[N:6]=[C:7]([NH:13][C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[C:8]3[C:9](=[O:11])[NH:2][CH2:1][C:3]=3[N:4]=2)[CH2:26][CH2:25]1)[CH3:28]
Reactant: CCN1CCN(c2nc(C#N)c(C(=O)OC)c(Nc3cccc(C)c3)n2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCN1CCN(c2nc3c(c(Nc4cccc(C)c4)n2)C(=O)NC3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
A mixture of methyl 4-cyano-2-(4-ethylpiperazin-1-yl)-6-(m-tolylamino)pyrimidine-5-carboxylate (49.8 mg, 0.131 mmol) and palladium on carbon (10.1 mg) in EtOH (3 mL) and 1N HCl (3 mL) was stirred at RT for 2 h under a hydrogen atmosphere. The insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was treated with saturated aq NaHCO3 and EtOAc for 3 h. The mixture was extracted with EtOAc. The organic layers were washed with aq NaHCO3, water, and brine, were dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography twice (SiO2, EtOAc then DM1020 EtOAc/MeOH=20/1) to give the title compound as a white solid (19.8 mg, 43%). 1H NMR (500 MHz, CDCl3) δ ppm 1.19 (br s, 3H), 2.36 (s, 3H), 2.5 (br s, 6H), 4.08 (br s, 4H), 4.23 (s, 2H), 5.50 (s, 1H), 6.91-6.92 (m, 1H), 7.22-7.26 (m, 1H), 7.49-7.54 (m, 2H), 8.44 (s, 1H). [M+H] calc'd for C19H25N6O, 353. found, 353.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.[C:8]([Si:12]([CH3:33])([CH3:32])[O:13][CH:14]1[C:22]2[C:17](=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[Br:7][C:5]1[CH:6]=[C:2]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[CH2:16][CH2:15][CH:14]3[O:13][Si:12]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:32])[CH3:33])[S:3][CH:4]=1
Reactant: Brc1csc(Br)c1
Reactant: CC1(C)OB(c2cccc3c2CCC3O[Si](C)(C)C(C)(C)C)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC1CCc2c(-c3cc(Br)cs3)cccc21

Procedure:
Prepared using General Procedure 1. A 2 mL microwave vial was charged with 2,4-dibromothiophene (15 mg, 0.06 mmol), tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane IND INT-8 (23 mg, 0.06 mmol), potassium carbonate (26 mg, 0.18 mmol) and 3:1 mixture of DME/H2O (2 mL). The reaction mixture was degassed by bubbling N2 through the stirred solution for 10 min. Pd(PPh3)4 (5 mg, 0.004 mmol) was added and the solution degassed for an additional 2 min. The vial was subjected to microwave irradiation at 70° C. for 30 min or until starting material consumed. The resulting ((4-(4-bromothiophen-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilane THIO INT-4 was carried onto the next experiment without workup and purification. LCMS-ESI (m/z) calculated for C19H25BrOSSi: 408.1; no M+ found, tR=6.50 min (Method 1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([NH:11][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]([C:22](Cl)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([C:22]([C:17]3[C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2CN(C(=O)c3ccccc3-c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.2 %

Procedure:
3,8-Diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester (Intermediate 1, 300 mg, 1.42 mmol), biphenyl-2-carbonyl chloride (429 mg, 1.98 mmol) and tri-ethyl amine (0.6 mL, 3.95 mmol) were dissolved into DCM (5 mL) and stirred at room temperature for 18 h. The reaction mixture was diluted with DCM (25 mL) and washed with 1N NaOH (10 mL) and water (2×20 mL). The organic layers were combined, dried, filtered and concentrated under reduced pressure to yield 8-(Biphenyl-2-carbonyl)-3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester (380 mg, 68.6%). MS (ESI) mass calcd. for C24H28N2O3, 392.49; m/z found, 293.2 [M+H]+ (mass without Boc group). 1H NMR (CDCl3): 7.57-7.30 (m, 9H), 4.60-4.35 (m, 0.5H), 4.17-3.98 (m, 0.5H), 3.90-3.71 (m, 1H), 3.60-3.25 (m, 3H), 3.22-2.66 (m, 2H), 2.54-2.38 (m, 0.5H), 2.37-2.22 (m, 0.5H), 2.10-1.92 (m, 0.5H), 1.85-1.56 (m, 1.5H), 1.55-1.27 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11][CH3:12])=[CH:9][C:8]([CH3:13])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:14][C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1.C(Cl)(=O)C(Cl)=O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[C:10]([S:11][CH3:12])=[CH:9][C:8]([CH3:13])=[CH:7][C:3]=1[C:4]([NH:14][C:15]1[N:19]([CH3:20])[N:18]=[N:17][N:16]=1)=[O:5]
Reactant: Cn1nnnc1N
Reactant: CSc1cc(C)cc(C(=O)O)c1Cl
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: CSc1cc(C)cc(C(=O)Nc2nnnn2C)c1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
500 mg (2.31 mmol) of 2-chloro-5-methyl-3-(methylthio)benzoic acid and 320 mg (3.23 mmol) of 5-amino-1-methyltetrazole and a catalytic amount of 4-(dimethylamino)pyridine were dissolved in 10 ml of pyridine. 410 mg (3.23 mmol) of oxalyl chloride were then carefully added dropwise. After ten minutes, the mixture was stirred at 80° C. for 4 h. To bring the reaction to completion, another 137 mg (1.08 mmol) of oxalyl chloride were added at RT and the mixture was stirred at 80° C. for another 4 h. For work-up, the contents were cooled to RT and freed of the solvent on a rotary evaporator, and the residue was dissolved in dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate solution and the organic phase was then freed of the solvent. The residue was purified chromatographically, giving 495 mg of 2-chloro-5-methyl-3-methylthio-N-(1-methyltetrazol-5-yl)benzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([F:30])[CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:32]\[OH:33])=[C:4]([F:30])[CH:3]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2F)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(S(C)(=O)=O)cc2)c2ccc(Cl)cc2F)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-(3-(4-chloro-2-fluorophenyl)-3-(4-(methylsulfonyl)-phenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI+): m/z=463.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH:13]1([CH2:16][CH2:17]O)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:13]1([CH2:16][CH2:17][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH2:15][CH2:14]1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: OCCC1CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCCc2cc(OCCC3CC3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a suspension of 6-hydroxy-3,4-dihydro-1(2H)-naphthalenone (1.0 g, 6.0 mmol), 2-cyclopropylethanol (640 mg, 7.0 mmol) and triphenylphosphine (3.25 g, 12 mmol) in THF (100 mL) was added DEAD (2.13 g, 12 mmol) at 0° C. The reaction was stirred at rt overnight. The solution was concentrated and purified by silica gel chromatography (PE:EtOAc=12:1) to give 470 mg (33%) of the title compound as a red oil. 1H NMR (300 MHz, CDCl3): δ 0.13-0.15 (2H, m), 0.50-0.52 (2H, m), 0.86-0.93 (1H, m), 1.68-1.74 (2H, m), 2.11-2.15 (2H, m), 2.64 (2H, t, J=6.3 Hz), 2.93 (2H, t, J=6.0 Hz), 4.10 (2H, t, J=6.6 Hz), 6.73 (1H, s), 6.83 (1H, dd, J=2.4, 8.7 Hz), 8.02 (1H, d, J=8.7 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]#[N:13])=[C:6]([O:14][CH3:15])[CH:5]=1.Cl.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([CH2:12][NH2:13])=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COC(=O)c1cc(OC)c(C#N)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(OC)c(CN)c(OC)c1
Reaction time: 5 h

Procedure:
30 G. of 4-cyano-3,5-dimethoxy-benzoic acid methyl ester and 1500 ml. of methanol and 150 ml. of 1N hydrochloric acid is hydrogenated in the presence of 10 g. of palladium-on carbon 10% at room temperature and under atmospheric pressure. In about 5 hours, 2 moles of hydrogen are taken up. The solution is freed of the catalyst by filtration, evaporated to dryness and the residue is taken up in a little water. The solution is thereafter filtered, saturated with solid potassium carbonate and shaken with benzene. From the shaken benzene mixture, is obtained 4-(aminomethyl)-3,5-dimethoxy-benzoic acid methyl ester, which after recrystallization from high boiling petroleum ether has a m.p. of 81°-83°.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23](O)=[O:24])[CH:21]=4)[CH:15]=3)[N:10]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+:33]>>[F:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]([NH2:33])=[O:24])[CH:21]=4)[CH:15]=3)[N:10]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(O)Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Agent: [Cl-]
Product: NC(=O)Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Yield: 75 %

Procedure:
Following the procedure of Example 144, 2-(4-(3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetic acid and ammonium chloride were reacted to give 60 mg (75%) of 2-(4-(3-(6-Fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)-1H-pyrazol-1-yl)acetamide. ESI MS m/z 422.2 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[CH2:7][S:8][C:9]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:10]=1[C:11]([O:13]C)=O.O.Cl>CN(C)C=O>[OH:13][C:11]1[C:10]2[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:9]=2[S:8][C:7]=1[C:6]1[CH:23]=[CH:24][CH:25]=[C:4]([CH3:3])[CH:5]=1
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1SCc1cccc(C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2sc3ccc(C(F)(F)F)cc3c2O)c1
Temperature: 75 °C
Reaction time: 0.75 h

Procedure:
To a slurry of sodium hydride (50% dispersion in mineral oil) (253 mg, 5.27 mmol) in N,N-dimethylformamide (3 ml) at 75° C. under a nitrogen atmosphere was added a solution of methyl 2-(m-methylbenzylthio)-5-trifluoromethylbenzoate (885 mg, 2.60 mmol) in N,N-dimethylformamide (12 ml). Gas evolution was observed during the 20 minute addition period. After stirring an additional 45 minutes at 75° C., water (70 ml) was added, and the aqueous mixture was brought to pH5-6 at room temperature with 2N hydrochloric acid. Extraction of the mixture with diethyl ether followed by washing the combined extracts with water and evaporation gave a residue that was chromatographed on a column of silica gel (Merck 7734, packed as a slurry in 15:1 hexane-ether). Elution with 15:1 hexane-ether containing 1% acetic acid and evaporation of the appropriate fractions afforded the product as a white crystalline solid; yield 450 mg (56%); m/z 308 (M+.); m.p. 124°-126°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC([C@]2(C)Cc3cc(Cl)ncc3O2)CC1
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC([C@@]2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from (S)-4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridine following a procedure analogous to that described for Intermediate 10. LC (method 4): tR=1.02 min; Mass spectrum (ESI+): m/z=478 [M+H]+.