Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:11])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)[CH2:13][CH3:14].[OH-].[K+]>C(O)C>[C:16]1([C:12]2[C:13]([CH3:14])=[CH:6][C:5]3[C:4](=[C:3]([O:2][CH3:1])[CH:10]=[CH:9][CH:8]=3)[N:11]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCC(=O)c1ccccc1
Reactant: COc1cccc(C=O)c1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc2cc(C)c(-c3ccccc3)nc12
Reaction time: 8 h
Yield: 0.1 %

Procedure:
15.3 g (101 mol) of 3-methoxy-2-aminobenzaldehyde and 14 ml (105 mol) of propiophenone are dissolved in 400 ml of ethanol. 1.4 g (25 mol) of potassium hydroxide are added to the reaction mixture and the latter is brought to 100° C. for 8 hours. After cooling the reaction medium, the latter is concentrated under vacuum and 200 ml of water are added. A yellow precipitate forms after a few minutes. The medium is filtered and the yellow precipitate is taken up in a mixture of 300 ml of ethyl ether and of 200 ml of a 1N hydrochloric acid solution. The aqueous phase is extracted with 2×100 ml of ethyl ether. Then, after addition of 300 ml of methylene chloride, 100 ml of a 3N sodium hydroxide solution are added to the aqueous phase. The latter is then extracted with 3×200 ml of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum. 21.2 g of 2-phenyl-3-methyl-8-methoxyquinoline are obtained in the form of a pale yellow solid; M.p.=105° C. (Yield: 85%)
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]3[O:36][N:35]=[C:34]([CH:37]([CH3:39])[CH3:38])[N:33]=3)[CH2:28][CH2:27]2)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:39][CH:37]([C:34]1[N:33]=[C:32]([N:29]2[CH2:28][CH2:27][CH:26]([CH2:25][O:24][C:21]3[CH:20]=[CH:19][C:18]([C:11]4[CH:12]=[CH:13][C:8]([C:6]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)=[O:7])=[CH:9][CH:10]=4)=[CH:23][CH:22]=3)[CH2:31][CH2:30]2)[O:36][N:35]=1)[CH3:38]
Reactant: CC(C)c1noc(N2CCC(COc3ccc(Br)cc3)CC2)n1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCCC1
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: [Na+]
Solvent: COCCOC
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(C(=O)N5CCCC5)cc4)cc3)CC2)n1
Yield: 4.2 %

Procedure:
The title compound (4 mg, 4%) was prepared as a yellow solid from [4-(1-pyrrolidinylcarbonyl)phenyl]boronic acid (44 mg, 0.2 mmol), 4-{[(4-bromophenyl)oxy]methyl}-1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]piperidine (prepared as in Example 24, Step 1, 76 mg, 0.2 mmol), Pd(PPh3)4 (50 mg, 0.04 mmol), 2M Na2CO3 (1 mL) and DME (1 mL) in a manner similar to Example 1, Step 1, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.58 (s, 4H), 7.53 (d, 2H, J=8.8 Hz), 6.96 (d, 2H, J=8.8 Hz), 4.26-4.16 (m, 2H), 3.88 (d, 2H, J=6.4 Hz), 3.70 (t, 2H, J=7.0 Hz), 3.52 (t, 2H, J=6.6 Hz), 3.18-3.08 (m, 2H), 2.99-2.84 (m, 1H), 2.15-1.85 (m, 7H), 1.57-1.40 (m, 2H), 1.29 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 475 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11](OS(C)(=O)=O)[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:38]([OH:41])[CH2:39][CH3:40]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:41][CH2:38][CH2:39][CH3:40])[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[CH:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: C#CCOc1ccc(CCN(OS(C)(=O)=O)C(=O)Cc2ccc(Cl)cc2)cc1OC
Reactant: CCCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#CCOc1ccc(CCNC(=O)C(OCCC)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-(4-chloro-phenyl)-N-mesyloxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-acetamide (452 mg, 1 mmol) in a mixture of 6 ml acetonitrile and 6 ml n-propanol during a period of 12 hours a solution of triethylamine (0.146 ml, 1.05 mmol) in 12 ml of acetonitrile is added dropwise. The mixture is stirred for 20 hours at room temperature. The solvent and excess n-propanol is removed under reduced pressure and the residue was diluted with ethyl acetate (30 ml), washed with water, 1N HCl, and brine, and dried with Na2SO4. After evaporation of the solvent the product is purified by flash chromatography (ethyl acetate:hexane, 1:2) to yield 2-(4-chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-propoxy-acetamide in form of an oil. 1H-NMR (300 MHz, CDCl3): 0.89(t, 3H, CH3), 1.58(q, 2H, CH2), 2.50(t, 1H, C≡CH), 2.79(t, 2H, CH2CH2), 3.35(t, 2H, OCH2), 3.52(dt, 2H, CH2CH2), 3.83(s, 3H, OCH3), 4.63(s, 1H, CHOH), 4.74(d, 2H, OCH2), 6.67-7.30(m, 8H, CH arom., NH).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N12CCCN=[C:15]1[CH2:14][CH2:13][CH2:12]CC2.[C:20](#N)C>O.O.[Cu](Cl)Cl>[CH3:12][C:13]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)([CH3:20])[C:14]#[CH:15]
Reactant: CC#N
Reactant: C1CCC2=NCCCN2CC1
Reactant: Oc1ccc(I)cc1
Agent: Cl[Cu]Cl
Solvent: O
Product: C#CC(C)(C)Oc1ccc(I)cc1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of 4-iodophenol (6.05 g, 27.5 mmol), in anhydrous acetonitrile (25 mL) cooled to 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 4.50 mL, 30.1 mmol). The solution was stirred for 10 minutes then the title B compound (2.56 g, 25 mmol) was added followed by copper(II) chloride dihydrate (5.1 mg, 0.030 mmol). The reaction mixture was stirred at 0° C. for five hours then concentrated in vacuo. The residue was partitioned between 200 mL of toluene and 40 mL of 1M aq HCl solution. The organic layer was washed with two-40 mL portions of 1M aq HCl solution, two-40 mL portions of 1M aq NaOH solution, brine then dried (magnesium sulfate) and concentrated in vacuo to give a pale yellow liquid. The crude material was purified by bulb-to-bulb distillation (100° C., 0.1 mm) to afford the title compound as a colorless liquid (5.65 g, 19.7 mmol, 79%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[OH:30])[N:10]=1.[OH-:31].[K+].[I-].[K+].Br[CH:36]([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38]>COCCOCCOC>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:42])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:36]([C:37]([O:39][CH2:40][CH3:41])=[O:31])[CH3:42])=[CH:25][C:24]=2[OH:30])[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:42])=[CH:17][C:16]=2[O:22][CH:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH3:42])[N:14]=1
Reactant: Oc1ccc(-c2nc(-c3ccc(O)cc3O)nc(-c3ccc(O)cc3O)n2)c(O)c1
Reactant: CCOC(=O)C(C)Br
Reactant: [OH-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOCCOC
Product: CCOC(=O)C(C)Oc1ccc(-c2nc(-c3ccc(OC(C)C(=O)OCC)cc3O)nc(-c3ccc(OC(C)C(=O)OCC)cc3OC(C)C(=O)OCC)n2)c(O)c1

Procedure:
A mixture of 15.0 g (0.037 mol) of 2,4,6-tris(2,4-dihydroxyphenyl)-1,3,5-triazine and 80 ml of diglyme (Fluka 99.5%) is admixed under nitrogen in succession with 9.2 g (0.139 mol) of pulverized KOH (Fluka, 85%), 0.3 g (0,002 mol of potassium iodide (Fluka, 99.5% ) and 29.5 g (0.163 mol) of ethyl 2-bromopropionate (Fluka, 98%).
Reaction SMILES: O[C@:2]12[CH2:19][CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:20])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=1.P(=O)(O)(O)O>O>[CH3:17][C@:16]12[CH2:18][CH:19]=[C:2]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:22])[CH2:4][CH2:5][C:6](=[O:21])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C:15]2=[O:20]
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: O=P(O)(O)O
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 7.5 h

Procedure:
9α-Hydroxyandrostenedione (280 mg.; 302 mg. of 92.7% purity) is added to phosphoric acid (85%, 5 ml.) and stirred at 35°-48° for 7.5 hours. Water (10 ml.) is then added, the mixture stirred and filtered. The solids are air-dried at 25° for 10 hours to give androsta-4,9(11)-diene-3,17-dione, 254 mg. (90.7% weight yield, 96.2% chemical yield); m.p. 197°-201°. GC (Example 1) shows an androsta-4,9(11)-diene-3,17-dione/androsta-4,8-diene-3,17-dione ratio greater than 99 to 1.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH2:12])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[O:54][C:55]3[CH:65]=[CH:64][C:63]([C:66]4[CH:67]=[C:68]([CH:72]=[CH:73][CH:74]=4)[C:69](O)=[O:70])=[CH:62][C:56]=3[C:57]=2[C:58](=[O:61])[NH:59][CH3:60])=[CH:49][CH:48]=1>CN(C=O)C.CCOC(C)=O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([NH:12][C:69]([C:68]3[CH:67]=[C:66]([C:63]4[CH:64]=[CH:65][C:55]5[O:54][C:53]([C:50]6[CH:51]=[CH:52][C:47]([F:46])=[CH:48][CH:49]=6)=[C:57]([C:58]([NH:59][CH3:60])=[O:61])[C:56]=5[CH:62]=4)[CH:74]=[CH:73][CH:72]=3)=[O:70])[CH2:10][CH2:11]2)=[CH:7][CH:8]=1
Reactant: NC1(c2ccc(Cl)cc2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC4(c5ccc(Cl)cc5)CC4)c3)cc12
Reaction time: 1 h
Yield: 14.4 %

Procedure:
1-(4-chlorophenyl)cyclopropanamine hydrochloride (25 mg, 0.123 mmol) was added to a stirring solution of HATU (59 mg, 0.154 mmol), DIEA (54 μL, 0.308 mmol), and 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (40 mg, 0.103 mmol) in DMF (1 mL) at rt. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (8 mg, 14%). 1H NMR (500 MHz, DMSO-d6) d ppm 9.37 (1 H, s), 8.46-8.55 (1 H, m), 8.22 (1 H, s), 7.95-8.05 (2 H, m), 7.86-7.95 (3 H, m), 7.74-7.83 (2 H, m), 7.59 (1 H, t, J=7.63 Hz), 7.38-7.44 (2 H, m), 7.30-7.36 (2 H, m), 7.20-7.28 (2 H, m), 2.86 (3 H, d, J=4.58 Hz), 1.26-1.36 (4 H, m). LC-MS retention time: 1.92 min; m/z (MH+): 539. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=14.56 min, purity=99%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, Rt=13.20 min, purity=97%.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2].[CH3:51][C@@H:52]1[CH2:57][NH:56][CH2:55][C@H:54]([CH3:58])[NH:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:56]3[CH2:55][C@H:54]([CH3:58])[NH:53][C@H:52]([CH3:51])[CH2:57]3)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:46][CH2:47][O:48][CH2:49][CH2:50]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(C=O)c3)c2)c1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
N-[(6-Cyano-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (108 mg, 0.000161 mol) in DCM (4 mL) and (2R,6S)-2,6-dimethylpiperazine (26.7 mg, 0.00023 mol) were mixed with sodium triacetoxyborohydride (68.3 mg, 0.00032 mol) and AcOH (11.6 mg, 11 μL). This solution was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). The combined organic extracts were washed with sat. aq. NaCl, dried (Na2SO4) and concentrated to a glassy foam (122.9 mg). Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic layers were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a white solid [62.3 mg (51%)]. LC-MS m/z 769.7 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[NH:12][C:13](=[O:15])[CH3:14]>CO.CCO.C(O)(=O)C.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([NH:12][C:13](=[O:15])[CH3:14])[C:4]([CH3:11])=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1c(C)ccc([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)Nc1c(C)ccc(N)c1C
Temperature: 25 °C
Reaction time: 36 h
Yield: 19.3 %

Procedure:
N-(2,6-dimethyl-3-nitro-phenyl)acetamide (12 g, 58 mmol, 1.0 eq) was dissolved in a mixture of MeOH (60 mL), EtOH (30 mL) and acetic acid (60 mL). Pd/C (1.6 g, 10%) was added and the reaction stirred at room temperature under H2 for 36 h. The catalyst was removed by filtration through celite and the filtrate collected. Water was added and the pH adjusted to pH 8 by addition of aqueous NaHCO3. The solution was concentrated in vacuo to remove methanol and ethanol. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried (Na2SO4) filtered and evaporated in vacuo. The crude product was purified by column chromatography (EtOAc:petroleum ether, 1:10 to 1:1) to give the title compound as a yellow solid (2 g, 19%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8]Br)=[CH:4][C:3]=1[N+:12]([O-])=O.[CH2:15]([C:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:28]([O-])([O-])=[O:29].[K+].[K+].Cl>>[CH2:15]([C:22]1[CH2:27][CH2:26][N:25]([CH2:8][CH2:7][O:6][C:5]2[CH:10]=[CH:11][C:2]3=[N:1][C:28](=[O:29])[N:12]=[C:3]3[CH:4]=2)[CH2:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: C1=C(Cc2ccccc2)CCNC1
Reactant: Nc1ccc(OCCBr)cc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Product: O=C1N=c2ccc(OCCN3CC=C(Cc4ccccc4)CC3)cc2=N1

Procedure:
The title compound was prepared from (4-amino-3-nitrophenoxy)ethyl bromide (1.31 g, 5.0 mmol), 4-benzyl-1,2,5,6-tetrahydropyridine (870 mg, 5.02 mmol), K2CO3 (700 g) and KI (80 mg) in three steps as a slightly grey powder, mp. 202-3° C. 1H NMR (DMSO-d6): 1.952 (bs, 2H), 2.50-2.56 (m, 4H), 2.686 (t, 2H, J=6), 2.973 (bs, 2H), 3.241 (s, 2H), 3.988 (t, 2H, J=6), 5.381 (s, 1H), 6.48-6.50 (m, 2H), 6.768 (d, 1H, J=9), 7.14-7.30 (m, 5H). The hydrochloride, mp. 256-7° C. Analysis, Calcd. for (C21H24ClN3O2 +0.2 HCl): C 64.44, H 6.12, N 10.61; Found: C 64.15, H 6.20, N 10.68.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[NH:17][C:18]4[C:24]([NH:25][C:26](=O)[C:27]5[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=5)=[CH:23][C:22]([C:37]([F:40])([F:39])[F:38])=[CH:21][C:19]=4[N:20]=3)[C@H:12]([CH3:41])[CH2:11]2)=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.B.C1COCC1>C1COCC1.CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[N:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[NH:17][C:18]3[C:24]([NH:25][CH2:26][C:27]4[CH:28]=[C:29]([F:35])[C:30]([F:34])=[C:31]([F:33])[CH:32]=4)=[CH:23][C:22]([C:37]([F:39])([F:38])[F:40])=[CH:21][C:19]=3[N:20]=2)[C@H:12]([CH3:41])[CH2:11]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(NC(=O)c3cc(F)c(F)c(F)c3)c2[nH]1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(NCc3cc(F)c(F)c(F)c3)c2[nH]1
Temperature: 0 °C

Procedure:
To a solution of N-{2-[(2R)-4-(3-chloro-5-hydroxymethyl-pyridin-2-yl)-2-methyl-piperazin-1-yl]-6-trifluoromethyl-3H-benzoimidazol-4-yl}-3,4,5-trifluoro-benzamide (120 mg, 0.2 mmol, Example 170c) in THF (1 mL) was added BH3.THF (0.6 mL, 0.6 mmol, Aldrich) dropwise with stirring at 0° C. The mixture was heated at reflux for 5 h, cooled to room temperature and diluted with 1:1 mixture of MeOH and 1N NaOH (2 mL). The mixture was stirred at room temperature for 30 min and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 5% MeOH/CH2Cl2 to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 586 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:14][C:15](=[O:20])[CH2:16][C:17](=[O:19])[CH3:18].Cl>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=[C:16]([C:15](=[O:20])[CH3:14])[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)C(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)C(C)=O

Procedure:
A solution containing 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 1.00 g of 2,4-pentanedione in 10 ml of tetrahydrofuran was saturated with gaseous hydrogen chloride. After standing over night at 5° C. the product was filtered and washed with ether. Yield 1.2 g (50%), m.p. 175°-178° C.
Reaction SMILES: [S:1]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=O)[CH2:4][S:3][CH2:2]1.Cl.[C:12]1([C:18]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[C:21](=[O:27])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[C:28]1([C:18]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:26]3[CH:22]([CH2:23][N:24]([C:8](=[O:10])[CH2:7][C:5]4[CH2:4][S:3][CH2:2][S:1][CH:6]=4)[CH2:25]3)[C:21](=[O:27])[CH2:20][CH2:19]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)CC1=CSCSC1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)CC3=CSCSC3)CC12
Reaction time: 0.33 h
Yield: 61.8 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-(1,3-dithiin-5-yl)acetic acid (1.23 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 20 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred for 16 hours at 20° C. The reaction mixture is washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile (80 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[2-(1,3-dithiin-5-yl)acetyl]-4-perhydroisoindolone (1.94 g) melting at 211° C. is obtained.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42](C(O)=O)([CH3:44])[CH3:43])=[CH:33][C:32]=2[CH3:49])=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=1)(=O)C.C(O[C:61]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)=[O:62])C1C=CC=CC=1.C(N1CCNCC1)C1C=CC=CC=1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:61]([N:63]4[CH2:64][CH2:65][NH:66][CH2:67][CH2:68]4)=[O:62])([CH3:43])[CH3:44])=[CH:33][C:32]=3[CH3:49])=[C:28]([CH:50]([CH3:52])[CH3:51])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: c1ccc(CN2CCNCC2)cc1
Product: Cc1cc(CCCC(=O)NC(C)(C)C(=O)N2CCNCC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 99 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(benzyloxycarbonyl)piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-benzylpiperazine, respectively.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]=[C:5](NC)[CH3:6].N1C=CC=CC=1.[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.C1C[O:29]CC1>>[CH3:1][O:2][C:3](=[O:9])[CH:4]([C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([Br:16])=[CH:18][CH:19]=1)[C:5](=[O:29])[CH3:6]
Reactant: C1CCOC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CNC(C)=CC(=O)OC
Solvent: c1ccncc1
Product: COC(=O)C(C(C)=O)C(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 3-methylamino-but-2-enoic acid methyl ester (5.0 g, 39.1 mmol) in THF (100 mL) was added pyridine (3.7 mL, 47 mmol). The mixture was cooled to 0° C., and 4-bromobenzoyl chloride (8.55 g, 39.1 mmol) in THF (30 mL) was added dropwise over 2 minutes. The reaction was warmed to room temperature over 1 hour and stirred overnight. Aqueous workup provided the title compound.
Reaction SMILES: O1C2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([NH2:17])[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7][CH2:6]2)OCC1.ClC1N2N=CC=C2N=C(C2CC[N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])CC2)C=1.ClC1N2N=CC=C2N=C(C2CCC3(OCCO3)CC2)C=1>>[NH2:17][C:15]1[N:14]2[N:18]=[CH:19][CH:20]=[C:13]2[N:12]=[C:11]([CH:8]2[CH2:7][CH2:6][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:10][CH2:9]2)[CH:16]=1
Reactant: Nc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)n3nccc3n2)CC1
Agent: Clc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N)n3nccc3n2)CC1

Procedure:
tert-Butyl 4-(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate was synthesized in a manner similar to the synthesis of 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-amine, but tert-butyl 4-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate substituted for 7-chloro-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidine.