Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:10]([C:11](=[O:13])[CH3:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1.CCOCC>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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>[CH:27]1([NH:32][C:2]2[N:7]3[N:8]=[C:9]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[C:10]([C:11](=[O:13])[CH3:12])=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCCC1
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)cccc12
Temperature: 25 °C
Yield: 96.7 %

Procedure:
To a solution of 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone (2.7 g, 9.5 mmol) in toluene (50 mL) was added successively racemic-BINAP (378 mg, 0.6 mmol), cesium carbonate (4.7 g, 14.3 mmol), cyclopentylamine (4.7 mL, 47.5 mmol), and palladium (II) acetate (86 mg, 0.4 mmol). The resultant mixture was heated to 95° C. for 2.5 hours at which time the reaction was judged complete by thin layer chromatography. The solution was cooled to room temperature and ether was added. The organic layer was washed with water and brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 hexanes-ethyl acetate) provided 1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone (3.1 g, 95%) as a yellow solid. 1H NMR (CDCl3): δ 7.62 (d, 1 H), 7.55 (dd, 2 H), 7.40 (t, 1 H), 7.15 (t, 2 H), 6.10 (d, 1 H), 5.99 (d, 1 H), 3.94 (m, 1 H), 2.09 (s, 3 H), 2.12–2.04 (m, 2 H), 1.78–1.58 (m, 6 H); 13C NMR (CDCl3) δ 192.63, 163.28 (d, JCF=247.3 Hz), 154.89, 142.65, 142.38, 131.66 (d, JCF=8.3 Hz) 131.09, 130.03 (d, JCF=3.8 Hz), 115.33 (d, JCF=22.0 Hz), 111.32, 105.41, 91.97, 53.81, 33.21, 30.10, 23.96; 19F NMR (CDCl3) δ −112.70; MS m/z 338 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[F:10].[Br-:11]>>[F:10][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Br:1])[CH2:8][Br:11]
Reactant: OCc1ccc(Br)c(F)c1
Reactant: [Br-]
Product: Fc1cc(CBr)ccc1Br

Procedure:
The product from step A was converted to the bromide according to the procedure from example 5 (step A). 1H NMR (500 MHz, CDCl3) δ 7.54 (m, 1H), 7.19 (d, 1H), 7.08 (d, 1H), 4.43 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:8]=2[C:7]=1[OH:20])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)CCC>>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]2[N:13]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:8]=2[C:7]=1[OH:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(C(C)(C)C)sc2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Product: CCOC(=O)c1nc(-c2ccccc2)c2nc(C(C)(C)C)sc2c1O

Procedure:
The title compound was prepared from 4-bromo-2-tert-butyl-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester and tributylphenyl tin under conditions analogous to the experimental procedure found in example 169(a). MS (ESI+): m/z 412.0 (M+1).
Reaction SMILES: CO[C:3](=[O:38])[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].NC(CO)[CH2:41][OH:42]>>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([NH:5][CH:4]([CH2:3][OH:38])[CH2:41][OH:42])=[O:37]
Reactant: NC(CO)CO
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Product: O=C(NC(CO)CO)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Yield: 72 %

Procedure:
The title compound was prepared in analogy to Example 1, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and 2-amino-propane-1,3-diol (commercially available, CAS RN 534-03-2). The product was purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give the desired compound as a light brown foam (72%). MS (ESI): m/z=559.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:12])[CH2:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7]=1[CH2:8][OH:9].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3](=[O:12])[CH2:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7]=1[CH2:8][O:9][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=C(CO)C(C)(C)CCC1=O
Solvent: c1ccncc1
Product: CC(=O)OCC1=C(C)C(=O)CCC1(C)C
Temperature: 0 °C

Procedure:
47 g (0.28 mole) of 2,4,4-trimethyl-3-hydroxymethylcyclohex-2-en-1-one (IIId) were refluxed with 26.54 g of pyridine and 28.6 g of acetic anhydride for 3 hours. After cooling, the mixture was poured onto 200 ml of ice water and was extracted five times with ether, the combined extracts were washed several times with saturated NaHCO3 solution and dried with sodium sulfate, and the solvent was distilled off under about 20 mbar.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([CH2:22][OH:23])=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:8]=1.S(OC)(O[CH3:28])(=O)=O>CN(C=O)C>[Br:3][C:4]1[C:5]([CH2:22][O:23][CH3:28])=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][CH2:10]2)[CH:8]=1
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c(CO)n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (57.7 mg, 60% in oil) was added to tert-butyl 4-[4-bromo-3-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate (200 mg) dissolved in degassed DMF (2 mL) under nitrogen. The resulting solution was stirred at room temperature for 10 minutes. Dimethyl sulfate (0.068 ml) was added and the resulting solution was stirred at 25° C. for 1 hour. The reaction mixture was quenched with water and diluted with ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with a saturated aqueous solution of brine, dried over magnesium sulfate and concentrated in presence of silica gel to afford the crude, which was purified by flash chromatography on silica gel eluting with 0 to 100% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-bromo-3-(methoxymethyl)pyrazol-1-yl]piperidine-1-carboxylate (180 mg). NMR Spectrum: (DMSOd6) 1.41 (s, 9H), 1.71 (dd, 1H), 1.76 (dd, 1H), 1.96 (bs, 1H), 1.98 (bs, 1H), 2.87 (bs, 2H), 3.22 (3H), 4.02 (bs, 2H), 4.28 (s, 2H), 4.29-4.36 (m, 1H), 8.04 (s, 1H).
Reaction SMILES: C([O:4][CH2:5][C:6]12[O:26][C:13]3([CH2:18][CH2:17][N:16]([CH2:19][N:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH2:21]4)[CH2:15][CH2:14]3)[CH2:12][CH:11]1[C:10](=[O:27])[CH2:9][CH:8]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:7]2)(=O)C.O.NN>C(O)C>[CH2:19]([N:16]1[CH2:17][CH2:18][C:13]2([CH2:12][CH:11]3[C:6]([CH2:5][OH:4])([CH2:7][CH:8]([C:28]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:29])[CH2:9][C:10]3=[O:27])[O:26]2)[CH2:14][CH2:15]1)[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH2:25]1
Reactant: CC(=O)OCC12CC(C(=O)OCc3ccccc3)CC(=O)C1CC1(CCN(CN3C=CN=CC3)CC1)O2
Agent: NN
Solvent: CCO
Solvent: O
Product: O=C(OCc1ccccc1)C1CC(=O)C2CC3(CCN(CN4C=CN=CC4)CC3)OC2(CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of the compound obtained in Step 5 (400 mg) in ethanol (8 ml) was added hydrazine monohydrate (0.38 ml) under cooling with ice. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the resulting residue was purified by silica gel chromatography (eluent; methylene chloride:methanol=50:1–25:1) to obtain the title compound (329 mg).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:38]2([CH3:39])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:37]2[CH2:36][CH2:35][C@@:34]2([CH3:40])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C@@H:21]([O:23][CH:24]([C:27]([O:29][CH:30]([CH3:33])[CH2:31][CH3:32])=[O:28])[CH2:25][CH3:26])[CH3:22])[CH2:12][C@@H:11]([O:41][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@:38]2([CH3:39])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:37]2[CH2:36][CH2:35][C@@:34]2([CH3:40])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C@@H:21]([O:23][CH:24]([C:27]([O:29][CH:30]([CH3:33])[CH2:31][CH3:32])=[O:28])[CH2:25][CH3:26])[CH3:22])[CH2:12][C@@H:11]([OH:41])[CH2:10]1
Reactant: CCC(C)OC(=O)C(CC)O[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(C)OC(=O)C(CC)O[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 65 °C
Reaction time: 17 h
Yield: 64.4 %

Procedure:
The mixture containing 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(1-ethyl-1-methylpropoxycarbonylmethoxy)pregna-5,7-diene from Example 23(2) (5.59 g), a 1M tetrahydrofuran solution of tetra-n-butylammonium fluoride (79.5 ml, 79.5 ml) and acetic acid (2 ml) were mixed and stirred at an external temperature of 65° C. for 17 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed sequentially with aqueous potassium bisulfate, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After evaporation under reduced pressure to remove the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate:ethanol=5:5:0.3) to give the titled compound (2.43 g, 57% for 2 steps) as a pale yellow foam.
Reaction SMILES: C1(C2N=C(NC(C3C=CN4C(=O)C(/C=C/C(O)=O)=C(N5CCCC(O)C5)N=C4C=3)=O)SC=2)CCC1.[CH:36]1([C:40]2[N:41]=[C:42]([NH:45][C:46]([C:48]3[CH:71]=[CH:70][N:51]4[C:52](=[O:69])[C:53](/[CH:63]=[CH:64]/[C:65]([O:67]C)=[O:66])=[C:54]([N:56]5[CH2:61][CH2:60][N:59]([CH3:62])[CH2:58][CH2:57]5)[N:55]=[C:50]4[CH:49]=3)=[O:47])[S:43][CH:44]=2)[CH2:39][CH2:38][CH2:37]1>>[CH:36]1([C:40]2[N:41]=[C:42]([NH:45][C:46]([C:48]3[CH:71]=[CH:70][N:51]4[C:52](=[O:69])[C:53](/[CH:63]=[CH:64]/[C:65]([OH:67])=[O:66])=[C:54]([N:56]5[CH2:57][CH2:58][N:59]([CH3:62])[CH2:60][CH2:61]5)[N:55]=[C:50]4[CH:49]=3)=[O:47])[S:43][CH:44]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: COC(=O)/C=C/c1c(N2CCN(C)CC2)nc2cc(C(=O)Nc3nc(C4CCC4)cs3)ccn2c1=O
Agent: O=C(O)/C=C/c1c(N2CCCC(O)C2)nc2cc(C(=O)Nc3nc(C4CCC4)cs3)ccn2c1=O
Product: CN1CCN(c2nc3cc(C(=O)Nc4nc(C5CCC5)cs4)ccn3c(=O)c2/C=C/C(=O)O)CC1
Yield: 58.2 %

Procedure:
Reactions were performed in the same manner as in Example 7, (H) by using methyl (E)-3-[8-{[(4-cyclobutyl-1,3-thiazol-2-yl)amino]carbonyl}-2-(4-methylpiperazino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-2-propenoate (24.7 mg, 0.049 mmol) to obtain 14.1 mg (59%) of the title compound in yellow color.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13]COC)[CH:5]=[C:4]([O:17]COC)[C:3]=1[C:21](=[O:39])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30]COC)=[C:26]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:25]=1.Cl.CO>CO>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:11])[CH3:12])=[C:6]([OH:13])[CH:5]=[C:4]([OH:17])[C:3]=1[C:21](=[O:39])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:25]=1
Reactant: COCOc1ccc(CCC(=O)c2c(OCOC)cc(OCOC)c(CCC(C)C)c2O)cc1CCC(C)C
Agent: Cl
Solvent: CO
Product: CC(C)CCc1cc(CCC(=O)c2c(O)cc(O)c(CCC(C)C)c2O)ccc1O
Temperature: 0 °C
Yield: 72.3 %

Procedure:
Then, 7.00 g of 1-[2-hydroxy-4,6-bis(methoxymethoxy)-3-isopentylphenyl]-3-(3-isopentyl-4-methoxymethoxyphenyl)-1-propanone was dissolved in 17.5 ml of methanol, and 52.0 ml of a hydrochloric acid/methanol reagent was added to the solution and the mixture was refluxed for 30 minutes. The reaction liquid was poured into ice water and extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous solution of sodium chloride in sequence and dried with anhydrous sodium sulfate. The solvent was removed by distillation and the obtained residue was recrystallized from chloroform to obtain 3.84 g (yield=72.4%) of 1-(2,4,6-trihydroxy-3-isopentylphenyl)-3-(4-hydroxy-3-isopentylphenyl)-1-propanone.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:44])[C:18]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([O:28][C:29](=[O:43])[NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:24][CH2:23]2)=[O:19])=[O:12])=[C:5]([CH3:45])[CH:4]=1.CS(C)=O.C(N(CC)C(C)C)(C)C.O>C(Cl)Cl>[CH:2]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:44])[C:18]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([O:28][C:29](=[O:43])[NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:26][CH2:27]2)=[O:19])=[O:12])=[C:5]([CH3:45])[CH:4]=1)=[O:1]
Reactant: Cc1cc(NC(=O)CCCCN(C)C(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1CO
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)CCCCN(C)C(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-hydroxymethyl-2,5-dimethylphenylcarbamoyl)butyl]methylcarbamoyl}ethyl)piperidin-4-yl ester (0.460 g, 0.748 mmol) and dimethyl sulfoxide (0.531 mL, 7.48 mmol) in DCM (2.58 mL) at 0° C. was added N,N-diisopropylethylamine (0.65 mL, 3.7 mmol). Sulfur trioxide-pyridine complex (0.357 g, 2.24 mmol) was added and the resulting mixture was stirred at 0° C. for 1 h. Water (3 mL) was added and the layers were separated. The organic layer was dried over sodium sulfate and filtered to give the title compound in a DCM solution, which was used immediately in the next reaction.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]3[N:22]=[C:21]([CH3:23])[N:20]([C:24]4[N:29]=[CH:28][N:27]=[C:26]([NH2:30])[N:25]=4)[C:19]=3[CH:31]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[NH2:30][C:26]1[N:27]=[CH:28][N:29]=[C:24]([N:20]2[C:19]3[CH:31]=[C:15]([C:14]#[C:13][C:8]4([CH2:7][OH:6])[CH2:9][CH2:10][CH2:11][CH2:12]4)[CH:16]=[CH:17][C:18]=3[N:22]=[C:21]2[CH3:23])[N:25]=1
Reactant: Cc1nc2ccc(C#CC3(C(C)(C)O[SiH2]C(C)(C)C)CCCC3)cc2n1-c1ncnc(N)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2ccc(C#CC3(CO)CCCC3)cc2n1-c1ncnc(N)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-{6-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopentylethynyl]-2-methyl-benzoimidazol-1-yl}-[1,3,5]triazin-2-ylamine (6-e) (80 mg, 0.17 mmol) was dissolved in THF (100 mL), TBAF (113 mg, 0.43 mmol) was added. The resulting mixture was stirred at room temperature for 12 h. Water (5 mL) was added, extracted with EtOAc. The organic phase was concentrated, purified via prep-TLC separation to afford the title target (27.5 mg, 47%): 1H NMR (400 MHz, DMSO) delta 1.55-1.76 (m, 8H), 2.86 (s, 3H), 3.40 (d, J=4.8 Hz, 2H), 4.96 (t, J=4.8 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.90-8.10 (m, 2H), 8.30 (t, J=0.8 Hz, 1H), 8.63 (s, 1H). LCMS: m/z=+349.1 (M+H)+.
Reaction SMILES: C([O:3][C:4]([CH2:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]2[CH:18]=[N:19][CH:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1)=[O:5])C>C(O)C.[OH-].[Na+]>[C:4]([CH2:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]2[CH:18]=[N:19][CH:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CSCCCCc1cccc2cncn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CSCCCCc1cccc2cncn12

Procedure:
5-[4-(Ethoxycarbonylmethylthio)butyl]imidazo[1,5-a]pyridine (4.4 g) in 30 ml of ethanol and 61 ml of 1.0N sodium hydroxide is heated under reflux for 3 hours. The ethanol is evaporated, the aqueous is extracted with ethyl acetate (20 ml) and the pH adjusted to 5. The resulting oil is crystallized from ethanol to yield 5-[4-(carboxymethylthio)butyl]imidazo[1,5-a]pyridine, m.p. 124°-126°.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:23]=[CH:22][O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:8]1)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+].CCOC(C)=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[N:24]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:23]=[CH:22][O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:8]1)=[N+:25]=[N-:26]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(-c3ccon3)cc2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(-c3ccon3)cc2)C(=O)O1
Temperature: 60 °C

Procedure:
[(5R)-3-(4-Isoxazol-3-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl methanesulfonate (Intermediate 7,400 mg, 1.18 mmol), sodium azide (99 mg, 1.53 mmol), 18 crown-6 (23.6 mg, 0.089 mmol) and tetrabutylammonium iodide (28.2 mg, 0.076 mmol) were combined in DMF (5 ml) and heated to 60° C. for 4 hours. EtOAc (20 ml) was added and the organic layers were washed with brine (3×20 ml), dried over Na2SO4 and concentrated under vacuum to yield (5R)-5-(azidomethyl)-3-(4-isoxazol-3-ylphenyl)-1,3-oxazolidin-2-one. (5R)-5-(Azidomethyl)-3-(4-isoxazol-3-ylphenyl)-1,3-oxazolidin-2-one (300 mg, 1.045 mmol) was added to CH2Cl2:MeOH:THF:H2O 10:10:10:2 and then polystyrene triphenylphosphine resin (2650 mg, 4.18 mmol) was added. The reaction was allowed to stir overnight and then the resin was filtered and washed multiple times with dichloromethane and methanol. The filtrate was concentrated in vacuo and then dissolved in dichloromethane (10 ml) followed by addition of 2N HCl in ether (0.5 ml). The precipitate was collected and washed with ether (2×20 ml) and then dried under vacuum to yield the title product (300 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]1.[CH:19]1[C:32]2[CH:31]([C:33]([Cl:35])=[O:34])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][CH:20]=1.Cl>CC(C)=O>[ClH:35].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:33]([CH:31]2[C:32]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[O:24][C:25]3[C:30]2=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:34])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCCO)CC1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Agent: Cl
Solvent: CC(C)=O
Product: COc1ccccc1N1CCN(CCCOC(=O)C2c3ccccc3Oc3ccccc32)CC1
Temperature: 60 °C
Yield: 70.5 %

Procedure:
A solution of 3.8 g of 3-[4-(2-methoxyphenyl)-piperazin-1-yl]-1-hydroxy-propane in 40 ml of acetone is added dropwise at 20° C. to a stirred solution of 4.9 g of xanthene-9-carbonyl chloride in 30 ml of acetone. The reaction mixture is refluxed for 30 minutes, allowed to cool to 60° C., and then ethanolic hydrochloric acid is added to the mixture until no more crystalline substance separates. The reaction mixture is cooled to 0° C., the separated crude substance is filtered off, and the crude substance is recrystallized from 20 ml of a 1:2 mixture of water and ethanol. 5.3 g (73%) of 3-[4-(2-methoxyphenyl)-piperazin-1-yl]-1-(xanthene-9-carbonyloxy)-propane hydrochloride are obtained; m.p.: 193°-195° C.
Reaction SMILES: [Cl:1][C:2]1C(Cl)=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH:23](O)[CH2:24][OH:25])=[C:10]1[C:27]([O:29][CH2:30][CH3:31])=[O:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51]([Cl:55])(Cl)(Cl)Cl>O>[Cl:1][C:2]1[C:51]([Cl:55])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH:23]2[CH2:24][O:25]2)=[C:10]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C1=C(COCC(O)CO)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CCOC(=O)C1=C(COCC2CO2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl

Procedure:
A solution of 1- {[4-(2.3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-2,3-dihydroxypropane (4.74 g) (see Example 20) and triphenylphosphine (2.62 g) in carbon tetrachloride (60 ml) was heated under reflux for 4 hours and then diluted with dichloroaethane and water. The layers were separated and the aqueous layer was extracted into dichloromethane. The combined organic layers were washed with water, dried over Na2SO4 and evaporated. The residue was purified by chromatography on SiO2 (80 g) using toluene plus 0-20% ethyl acetate as the eluant. Appropriate fractions were combined and evaporated and the residue triturated with diisopropyl ether. The resulting solid was collected, washed with diisopropyl ether and dried to give the title compound (1.40 g), m.p. 103°-104° C.
Reaction SMILES: [NH2:1][CH:2]([C:5]1([C:8]([O:10]CC)=O)[CH2:7][CH2:6]1)[C:3]#[N:4].N.[H][H]>[Ni]>[NH2:1][CH:2]1[C:5]2([CH2:7][CH2:6]2)[C:8](=[O:10])[NH:4][CH2:3]1
Reactant: CCOC(=O)C1(C(N)C#N)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: NC1CNC(=O)C12CC2
Yield: 92.3 %

Procedure:
An autoclave was charged with 1.0 g of 1-(1-amino-1-cyanomethyl)-1-ethoxycarbonylcyclopropane, 0.4 ml of Raney nickel and 4.0 ml of ammonia-saturated ethanol, and the contents were stirred at 80° C. for 4 hours in an atmosphere of hydrogen under a pressure of 20 kg/cm2. After completion of the reaction, the catalyst was removed by filtration and the resulting filtrate was concentrated under a reduced pressure to obtain 692 mg (92%) of the title compound in the form of colorless crystals. The thus obtained product was recrystallized from ethyl acetate and diethyl ether and used as a sample for analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1
Reactant: COC(=O)c1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C)c(Cc2ccc(C(=O)O)c(-c3ccccc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
Methyl 4-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-phenylbenzoate (84 mg, 0.1926 mmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (5 ml) and 1,4-dioxane (5 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (20 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (45 mg, 0.1800 mmol, 93%).