Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][S:22][CH3:23])[CH:3]=1.Cl.I([O-])(=O)(=O)=[O:26].[Na+].[OH-].[Na+]>O.C(Cl)Cl>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][S:22]([CH3:23])=[O:26])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCSC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCS(C)=O
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To a stirred solution of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[2-(methylthio)ethoxy]benzamide (1.0 g, 2.28 mmoles) (prepared in Example 20) and 1.4N HCl solution (3.97 ml, 5.56 mmoles) in 15 ml of H2O at 0°-5°, was added sodium metaperiodate (0.625 g, 2.92 mmoles). The mixture, which soon began to darken, was stirred at 0°-5° to 2 hours. The mixture was then diluted to 50 ml and made alkaline (pH=12) with NaOH solution. Methylene chloride (50 ml) was added, the mixture was shaken well, and the layers were separated. The aqueous layer was extracted with 3 portions of methylene chloride and the combined organic solutions were dried (anhydrous MgSO4) and evaporated. A dark oil (0.96 g) which solidified upon standing was obtained. The crude product was flash chromatographed on silica, eluting with CH2Cl2 :CH3OH:NH4OH, 80:20:0.5. Appropriate fractions were combined and evaporated to give 0.80 g (77%) of the title compound as a yellow resin which crystallized upon standing, mp. 110°-114°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([F:18])[C:16]=1[F:17].C(=O)([O-])[O-].[K+].[K+].CC(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:12]=[C:11]([F:10])[C:16]([F:17])=[C:15]([F:18])[CH:14]=2)=[C:3]([F:9])[CH:4]=1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: Oc1ccc(Br)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Oc1ccc(-c2cc(F)c(F)c(F)c2)c(F)c1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
4-Bromo-3-fluorophenol (T-10; 5.00 g), 3,4,5-trifluorophenylboronic acid (5.07 g), potassium carbonate (10.9 g), Pd(Ph3P)2Cl2 (0.552 g), and 2-propanol were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 5 hours. The reaction mixture was cooled to 25° C., and then poured into water (100 ml) and toluene (100 ml) and mixed. Then, the mixture was allowed to stand to be separated into two layers of organic and aqueous layers, and the extraction to an organic layer was carried out. The obtained organic layer was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The product was further purified by recrystallization from a mixed solvent of heptane/Solmix A-11 and dried, whereby 4.79 g of 4-hydroxy-2,3′,4′,5′-tetrafluoro-1,1′-biphenyl (T-11) was obtained. The yield based on the compound (T-1) was 74%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C1(P(=[CH:33][C:34]([O:36][CH3:37])=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:37][O:36][C:34](=[O:35])/[CH:33]=[CH:7]/[C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(OC)c([N+](=O)[O-])c1
Yield: 25.7 %

Procedure:
A mixture of 4-methoxy-3-nitrobenzaldehyde (1.5 g, 8.2 mmol) and methyl (triphenylphosphoranylidene)acetate (4.4 g, 13 mmol) in tetrahydrofuran (30 mL) was heated at reflux overnight. The reaction mixture was cooled and evaporated under reduced pressure; the crude residue was purified by flash chromatography (acetone/hexane, 20/80) to afford 0.5 g of (E)-3-(4-methoxy-3-nitro-phenyl)-acrylic acid methyl ester.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][CH:9]=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)CC)C>ClCCCl.CC(O)C>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[C:3]3[CH:11]=[CH:10][CH:9]=[N:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: Clc1ncnc2ncccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3ncccc23)CC1
Yield: 90.8 %

Procedure:
To a solution of 4-chloropyrido[2,3-d]pyrimidine (0.72 g, 4.4 mmol) and 1-Boc piperazine (0.84 g, 4.5 mmol) in DCE (10 mL) and IPA (10 mL) was added triethylamine (4 mL). The mixture was refluxed for 4 hours. After cooling, the solvent was removed. The residue was subject to column chromatography by ethyl acetate to give 4-pyrido[2,3-d]pyrimidin-4-yl-piperazine-1-carboxylic acid tert-butyl ester (1.26 g, 92%). 1H NMR (CDCl3, 400 MHz) δ 9.07 (dd, J=4.30 Hz, J=1.98 Hz, 1H), 8.88 (s, 1H), 8.25 (dd, J=7.99 Hz, J=1.98 Hz, 1H), 7.41 (dd, J=8.18 Hz, J=3.74 Hz, 1H), 3.82 (m, 4H), 3.65 (m, 4H), 1.50 (s, 9H). MS (APCI+) [M+H]+316.
Reaction SMILES: C(N(CC)CC)C.Cl[Si:9]([CH3:12])([CH3:11])[CH3:10].[NH2:13][C:14]1[N:19]2[N:20]=[CH:21][CH:22]=[C:18]2[N:17]=[C:16]([CH2:23][CH2:24][CH:25]([OH:27])[CH3:26])[CH:15]=1.C([O-])(O)=O.[Na+]>C1COCC1>[NH2:13][C:14]1[N:19]2[N:20]=[CH:21][CH:22]=[C:18]2[N:17]=[C:16]([CH2:23][CH2:24][CH:25]([O:27][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH3:26])[CH:15]=1
Reactant: CC(O)CCc1cc(N)n2nccc2n1
Reactant: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CCc1cc(N)n2nccc2n1)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Triethylamine (400 μl) and chlorotrimethylsilane (680 μl ) were added to 5 ml of a THF solution containing 500 mg of the crystals obtained in step (6), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, a saturated aqueous NaHCO3 solution was added and the reaction mixture was extracted with dichloromethane. The organic layer was collected, washed with water and a saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. n-Hexane was added to the residue. The crystals precipitated were collected by filtration to provide 520 mg of 7-amino-5-(3-trimethylsilyloxybutyl) pyrazolo[1,5-a]pyrimidine as colorless crystals.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl[C:28]1[O:29][C:30]2[C:31]([N:36]=1)=[N:32][CH:33]=[CH:34][CH:35]=2.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[CH2:19]([N:18]([C:28]1[O:29][C:30]2[C:31]([N:36]=1)=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: Clc1nc2ncccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1nc2ncccc2o1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2-chloro[1,3]oxazolo[4,5-b]pyridine as starting materials and by an operation similar to that of Example 303-3 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure to give the title compound.
Reaction SMILES: C(OC([NH:8][C:9]1[S:10][C:11]2[S:17](=[O:19])(=[O:18])[CH2:16][C:15]3[C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:21][N:22]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:14]=3[C:12]=2[N:13]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[NH2:8][C:9]1[S:10][C:11]2[S:17](=[O:19])(=[O:18])[CH2:16][C:15]3[C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:21][N:22]([CH:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[C:14]=3[C:12]=2[N:13]=1
Reactant: CCOC(=O)c1nn(C2CCOCC2)c2c1CS(=O)(=O)c1sc(NC(=O)OC(C)(C)C)nc1-2
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1nn(C2CCOCC2)c2c1CS(=O)(=O)c1sc(N)nc1-2

Procedure:
To a fine suspension of ethyl 7-[(tert-butoxycarbonyl)amino]-1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyrazolo[3′,4′:4,5]thiopyrano[3,2-d][1,3]thiazole-3-carboxylate 5,5-dioxide (182 mg; 0.37 mmol; 1.00 eq.) in DCM (540 μl) is added TFA (180 μl; 2.34 mmol; 6.40 eq.). The mixture is stirred at rt overnight after which water is added to the reaction mixture. The precipitate is washed with water then dried under vacuum to afford the title compound as an off-white powder. 1H NMR (DMSO) δ 8.34 (bs, 2H), 5.61-5.43 (m, 1H), 4.91 (s, 2H), 4.33 (q, J=7.1 Hz, 2H), 4.12-3.93 (m, 2H), 3.52-3.35 (m, 2H), 3.20-1.87 (m, 4H), 1.33 (t, J=7.1 Hz, 3H). HPLC (max plot) 95.1%; Rt 2.28 min. MS (ESI+): 398.7.
Reaction SMILES: [CH:1]1([N:6]([CH2:19][C:20]#[CH:21])[C@@H:7]2[CH2:11][CH2:10][N:9]([C:12](OC(C)(C)C)=O)[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.ClC1[C:25]2[CH:32]=[CH:31][NH:30][C:26]=2[N:27]=[CH:28][N:29]=1.CCN(C(C)C)C(C)C>>[CH:1]1([N:6]([CH2:19][C:20]#[CH:21])[C@@H:7]2[CH2:11][CH2:10][N:9]([C:12]3[C:25]4[CH:32]=[CH:31][NH:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CCN(C1CCCC1)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCN(C1CCCC1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1

Procedure:
(R)-tert-butyl 3-(cyclopentyl(prop-2-ynyl)amino)pyrrolidine-1-carboxylate (80 mg, 0.27 mmol) was stirred with HCl (in MeOH, 6N, 1 mL) at ambient temperature for 2 h, and then concentrated under reduced pressure. The residue was dissolved in EtOH (3 mL) and treated with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (42 mg, 0.27 mmol) in the presence of DIPEA (53 mg, 0.41 mmol) at the refluxing temperature for overnight. The volatiles were removed and the residue was purified by preparative HPLC to give the title compound. MS (m/z): 310 (M+H)+.
Reaction SMILES: S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(O)=O)N=1)CC2)=O.[C:39]([C:41]1[C:42]([C:46]2[CH:47]=[CH:48][C:49]([OH:92])=[C:50]([CH:91]=2)[CH2:51][C:52]2[S:56][C:55]([N:57]3[CH2:66][CH2:65][C:64]4[C:59](=[C:60]([C:67](=[O:86])/[N:68]=[C:69]5/[S:70][C:71]6[CH:85]=[CH:84][CH:83]=[CH:82][C:72]=6[N:73]/5COCC[Si](C)(C)C)[CH:61]=[CH:62][CH:63]=4)[CH2:58]3)=[N:54][C:53]=2[C:87]([O:89]C)=[O:88])=[CH:43][S:44][CH:45]=1)#[N:40]>>[S:70]1[C:71]2[CH:85]=[CH:84][CH:83]=[CH:82][C:72]=2[N:73]=[C:69]1[NH:68][C:67]([C:60]1[CH:61]=[CH:62][CH:63]=[C:64]2[C:59]=1[CH2:58][N:57]([C:55]1[S:56][C:52]([CH2:51][C:50]3[CH:91]=[C:46]([C:42]4[C:41]([C:39]#[N:40])=[CH:45][S:44][CH:43]=4)[CH:47]=[CH:48][C:49]=3[OH:92])=[C:53]([C:87]([OH:89])=[O:88])[N:54]=1)[CH2:66][CH2:65]2)=[O:86]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1Cc1cc(-c2cscc2C#N)ccc1O
Agent: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(-c3ccc(CO)cc3)s1)CC2
Product: N#Cc1cscc1-c1ccc(O)c(Cc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)c1

Procedure:
The title compound 60 was prepared in a similar manner to the synthesis of compound 34 by substituting compound 34D with compound 60A: 1H NMR (DMSO-d6): δ 9.92 (s, 1H), 8.55 (d, J=3.07 Hz, 1H), 8.00 (d, J=7.98 Hz, 1H), 7.77 (d, J=8.29 Hz, 1H), 7.63-7.66 (m, 2H), 7.29-7.48 (m, 6H), 6.90 (d, J=8.29 Hz, 1H), 4.79 (s, 2H), 4.34 (s, 2H), 3.66 (d, J=5.98 Hz, 2H), 2.99 (t, J=5.83 Hz, 2H). ESI (+)/MS: 650 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][N:40]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:24]=[N:25][N:26]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][N:40]=2)[CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: Cc1ccc(CCl)nc1
Agent: Cl
Product: COc1ccc(N(Cc2cnn(Cc3ccc(C)cn3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 81.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.94 g) and 2-chloromethyl-5-methylpyridine hydrochloride (0.71 g) as starting materials, 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-({1-[(5-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.94 g) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:11]2[N:10]3[C:14](=[O:22])[O:15][C@H:16]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[C@H:9]3[CH2:8][C:7]=2[CH:6]=1)=[O:4].[N-:23]=[N+:24]=[N-:25].[Na+].CC(C)=O>O1CCCC1.C(Cl)Cl.CO.CO.C(OCC)(=O)C>[N:23]([CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:11]2[N:10]3[C:14](=[O:22])[O:15][C@H:16]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[C@H:9]3[CH2:8][C:7]=2[CH:6]=1)=[O:4])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)NC[C@H]1OC(=O)N2c3ccc(C(=O)CCl)cc3C[C@H]12
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1OC(=O)N2c3ccc(C(=O)CN=[N+]=[N-])cc3C[C@H]12

Procedure:
A mixture of (+/-)-(1S,9aS),(1R,9aR) N-[(7-chloroacetyl-9,9a-dihydro-3-oxo-1H,3H-oxazolo[3,4-a]indol-1-yl)methyl]acetamide (EXAMPLE 46, 43 mg) and sodium azide (82 mg) are stirred in aqueous tetrahydrofuran (66%) for 3 days. Acetone (1 ml) is added and the mixture was heated in an oil bath (38°-50°) for 8 hours then concentrated to an aqueous layer and extracted with ethylacetate (6×2 ml). The combined organic layers are dried over magnesium sulfate and concentrated to provide the product as as an oil. The oil is taken up in methylene chloride/methanol and then placed on a 1000μ silica preprative plate and developed in methanol/ethylacetate (10/90, 2×) to give the title compound as an oil, NMR (CDCl3, 300 MHz) 7.79, 7.43, 6.45, 4.63, 4.53, 3.75, 3.38, 3.14 and 2.08 δ; IR (CHCl3) 2100, 1760, 1670 and 1360 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:5][NH:6][C:7]1[C:8]2[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:9]=2[N:10]=[C:11]([CH2:13]Cl)[N:12]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31].C(OCC)(=O)C>CN(C=O)C.O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:5][NH:6][C:7]1[C:8]2[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:9]=2[N:10]=[C:11]([CH2:13][NH:27][CH2:28][CH2:29][CH2:30][OH:31])[N:12]=1
Reactant: NCCCO
Reactant: CCCc1nn(C)c2c(NCc3ccc(OC)c(Cl)c3)nc(CCl)nc12
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nn(C)c2c(NCc3ccc(OC)c(Cl)c3)nc(CNCCCO)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2 g of 7-(3-chloro-4-methoxybenzylamino)-5-chloromethyl-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine in 10 ml of DMF is treated with 5 ml of 3-aminopropanol and stirred at room temperature for two hours. It is then diluted with water and extracted with ethyl acetate. The oily product obtained after customary work-up is dissolved in alcoholic HCl and treated with ethyl acetate until turbidity. The precipitated crystals are filtered off with suction and recrystallized from isopropanol/ethyl acetate. 3.1 g of 7-(3-chloro-4-methoxybenzylamino)-5-(3-hydroxypropylaminomethyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidine are obtained in the form of its dihydrochloride.
Reaction SMILES: C(OC1C=C(CC(OCC)=O)C=C(F)C=1)C1C=CC=CC=1.[CH2:22]([O:29][C:30]1[CH:31]=[C:32]([C:37]2([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:42][CH2:41]O[CH2:39][CH2:38]2)[CH:33]=[C:34]([F:36])[CH:35]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ClCCOCCCl>>[CH2:22]([O:29][C:30]1[CH:31]=[C:32]([C:37]2([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:38][CH2:39][CH2:41][CH2:42]2)[CH:33]=[C:34]([F:36])[CH:35]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C1(c2cc(F)cc(OCc3ccccc3)c2)CCOCC1
Agent: CCOC(=O)Cc1cc(F)cc(OCc2ccccc2)c1
Solvent: ClCCOCCCl
Product: CCOC(=O)C1(c2cc(F)cc(OCc3ccccc3)c2)CCCC1

Procedure:
The titled compound was prepared from ethyl 3-benzyloxy-5-fluorophenylacetate according to the preparation of ethyl 4-(3-benzyloxy-5-fluorophenyl)-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate except substituting 1,4-dibromobutane for bis-(2-chloroethyl) ether.
Reaction SMILES: C[C:2]1(C)[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH:10]([CH:12]=[CH2:13])=[O:11]>>[O:8]=[C:5]1[CH2:4][CH2:3][CH2:2][CH2:7][CH:6]1[CH2:13][CH2:12][CH:10]=[O:11]
Reactant: C=CC=O
Reactant: CC1(C)CCC(=O)CC1
Product: O=CCCC1CCCCC1=O

Procedure:
The title compound 1 was prepared in the following way. ##STR18## Isobutyraldohyde was alkylated with methyl vinyl ketone via its pyrrolidine enamine, cyclized in acid, and then hydrogenated to give 4,4-dimethylcyclohexanone (2). Ketone 2 was alkylated with acrolein via its morpholline enamine then hydrolyzed to give 3-(2-oxocyclohexyl)propanal (3). Crude 3 was then purified through its diketal, cyclized in 7 N hydrochloric acid, and esterified to give 7,7-dimethylbicyclo(3.3.1)nonan-9-one-2-yl pivalate (4). Kettalization of 4 followed by alkaline hydrolysis, CrO,--pyridine oxidation, and alkylation with iodomethane and potassium t-butoxide yielded 3,3,7,7-tetramothyl-9,9-ethylenedioxybicyclo(3.3.1)nonan2one (5). When various attempts of Wolff-Kishner reduction failed, 5 was reduced to alcohol with lithium--ammonia then mesylated to give 3,3,7,7-tetramethyl-9,9-ethylenedioxybicyclo(3.3.1)nonan-2-exo-yl methanesulfonae (6). Lithium--ammonia reduction of 6 followed by acid hydrolysis afforded the title compound 1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14][C:15]#[N:16].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>C(O)C.C(OCC)(=O)C>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[C:2]([CH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH2:14][CH2:15][NH:16][CH2:19][CH2:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])#[N:1]
Reactant: C=CC(=O)OCC
Reactant: COc1cc(CC#N)c(CCN)cc1OC
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNCCc1cc(OC)c(OC)cc1CC#N
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.3 %

Procedure:
A mixture of [2-(2-aminoethyl)-4,5-dimethoxyphenyl]acetonitrile (6.5 g, 29.5 mmol) and ethyl acrylate (3.9 ml, 36 mmol, 1.2 eq.) in 120 mL of ethanol is stirred for 20 hours at ambient temperature. The reaction mixture is subjected to drying in vacuo; then the crude reaction mixture is taken up in a mixture of ethyl acetate (133 mL) and ethanol (13 mL) and is heated at reflux in the presence of oxalic acid (2.52 g, 28 mmol, 0.95 eq.). Precipitation from the mixture occurs during contact at reflux. After returning to ambient temperature, the mixture is filtered and washed with 19 ml of ethyl acetate to obtain a white powder (9 g) corresponding to the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].[OH-].[K+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C(O)C>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccccc1C(=O)Nc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A 9.1 g (0.04 mol) portion of 3'-hydroxy-2-methylbenzanilide was dissolved in a solution of 2.3 g (0.041 mol) of potassium hydroxide in 50 ml of ethanol, and 5.1 g (0.04 mol) of benzylchloride was added dropwise to the above solution with stirring at room temperature. After the addition, the reaction mixture was warmed and refluxed for 3 hours. The reaction mixture was poured into 200 ml of water and the precipitated product was filtered and washed with water and dried. The product was recrystallized from 90% methanol to obtain 7.5 g (60.5%) of white needles having a melting point of 114°-115° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[C:10]([CH3:22])[CH:9]=2)=[O:5])C.CO.[OH-].[K+]>O>[C:17]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[CH3:22])[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:15][C:14]2=[O:16])(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(=O)c1cc2c(=O)cc(C(=O)OCC)[nH]c2cc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(=O)c1cc2c(=O)cc(C(=O)O)[nH]c2cc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2 g of 6-butyryl-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid ethyl ester are heated under reflux for 4 hours together with 20 ml of methanol, 1.2 g of potassium hydroxide and 0.5 ml of water. The reaction mixture is concentrated to dryness by evaporation and taken up in water. The solution is acidified to pH 1 with 2N hydrochloric acid and filtered with suction. The product obtained by filtering with suction is thoroughly washed with water, resuspended in water, thoroughly triturated and stirred at room temperature for 5 hours, then filtered with suction, washed with water, and recrystallised twice from methanol. In this manner 6-butyryl-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid having a melting point of 255°-258° is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH2:49][CH3:50])=[CH:44][CH:43]=2)(OC)[C:11]2[CH:16]=[C:15]([OH:17])[C:14]([C:18]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[CH:32][CH:31]=3)([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=3)OC)=[CH:13][C:12]=2[OH:39])=[CH:6][CH:5]=1)[CH3:2]>[N+](C1C=CC=CC=1)([O-])=O>[CH2:37]([O:36][C:33]1[CH:34]=[CH:35][C:30]2[C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=3)=[C:14]3[C:15](=[CH:16][C:11]4[C:12]([O:39][C:43]5[C:42]([C:10]=4[C:7]4[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=4)=[CH:47][CH:46]=[C:45]([O:48][CH2:49][CH3:50])[CH:44]=5)=[CH:13]3)[O:17][C:31]=2[CH:32]=1)[CH3:38]
Reactant: CCOc1ccc(C(OC)(c2ccc(OCC)cc2)c2cc(O)c(C(OC)(c3ccc(OCC)cc3)c3ccc(OCC)cc3)cc2O)cc1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCOc1ccc(C2=c3cc4c(cc3Oc3cc(OCC)ccc32)=C(c2ccc(OCC)cc2)c2ccc(OCC)cc2O4)cc1
Temperature: 195 °C

Procedure:
Synthesis of the precursor 2,5-Bis-[bis-(4-ethoxy-phenyl)-methoxy-methyl]-benzene-1,4-diol: This compound is prepared in an analogous manner as described in example 9. From 10.16 g of 1,4-bis-(1-ethoxy-ethoxy)-benzene (40 mmol) and bis-(4-ethoxy-phenyl)-methanone (21.6 g, 80 mmol) 17.95 g (66%) of the product is obtained. b) A flask is charged with 2,5-Bis-[bis-(4-ethoxy-phenyl)-methoxy-methyl]-benzene-1,4-diol (16.97 g, 25 mmol) and nitrobenzene (30 ml) and heated at 195° C. (bath temperature) for two hours. The dark violet coloured mixture is then allowed to cool to ambient temperature. The product is then filtered off, and washed for three times with nitrobenzene (ca. 7 ml each time) and three times with toluene (ca. 8 ml each time) and finally dried in vacuum to give the product as deep violet crystals, 6.03 g (39%). The DSC of this material shows a mp. of 302° C. The structure of the material was confirmed by X-ray crystallography; space group: P-1; a=7.483(6); b=8.710(7); c=12.618(7); α=91.22(5) β=92.43(5) γ=110.35(5).