Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][OH:23])=[CH:16][CH:15]=1.O.Cl>C(O)C>[OH:23][CH2:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([OH:24])=[O:4])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CCCO)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccccc1COc1ccc(CCCO)cc1
Yield: 86.8 %

Procedure:
A stirring solution of 127.1 g of potassium hydroxide in 500 ml of 95% ethanol was treated portionwise over several minutes with 59.4 g of 2-[[4-(3-hydroxypropyl)phenoxy]methyl]benzoic acid methyl ester. The resulting solution was allowed to reflux overnight with continued stirring. The product solution was poured into 900 ml of water and the solution was acidified to below pH 2 with approximately 200 ml of concentrated hydrochloric acid. The resulting suspension was transferred to a separatory funnel and was partitioned against a total of 1000 ml of ethyl acetate. The primary aqueous phase was discarded and the organic phase was washed with several 500 ml aliquots of water until the pH of the final aqueous phase was neutral. The dried (Na2SO4) organic phase was concentrated in vacuo to a solid which was recrystallized from ethanol/water to give 49.13 g of 2-[[4-(3-hydroxypropyl)phenoxy]methyl]benzoic acid, m.p. 139-140° C.
Reaction SMILES: [I:1]I.[OH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([S:12][CH3:13])[N:5]=1>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[OH:3][C:4]1[C:11]([I:1])=[CH:10][C:7]([C:8]#[N:9])=[C:6]([S:12][CH3:13])[N:5]=1
Reactant: II
Reactant: CSc1nc(O)ccc1C#N
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CSc1nc(O)c(I)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
6 g (1.6 eq) of silver sulfate and 4.58 g (1.5 eq) of iodine are added successively to a solution of 2 g (12 mmol) of 6-hydroxy-2-(methylthio)nicotinonitrile in 200 ml of ethanol. The reaction medium is stirred at room temperature for 2 hours. The solid is filtered and the residue rinsed thoroughly with methanol. The filtrate is evaporated and then taken up in ethyl acetate. The organic phase is washed with water three times, dried on magnesium sulfate and evaporated to yield 3.18 g (90%) of 6-hydroxy-5-iodo-2-(methylthio)nicotinonitrile in the form of a yellow powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([OH:8])[CH:7]=1.O.O.[Sn](Cl)Cl.C[CH2:19][OH:20].C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[NH:9][C:19](=[O:20])[O:8][C:6]=2[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1O
Reactant: CCO
Agent: Cl[Sn]Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(F)c(Br)cc2o1
Temperature: 70 °C
Yield: 71.6 %

Procedure:
To a 100 mL of round bottom flask was added 5-bromo-4-fluoro-2-nitrophenol (0.98 g, 4.15 mmol), tin(II) chloride dihydrate (4.73 g, 20.76 mmol) and 5 mL of EtOH. The reaction mixture was heated to 70° C. for 30 minutes. The reaction mixture was concentrated and washed with saturated NaHCO3 solution, and extracted with DCM (100 mL×3), and concentrated providing the crude product. 1,1′-Carbonyldiimidazole (808 mg, 4983 mmol) was added to the crude product in 20 mL of THF. The reaction mixture was heated at reflux overnight. The reaction mixture was concentrated and purified with silica gel column chromatography, eluting with 0-30% EtOAc/hexane to give 6-bromo-5-fluorobenzo[d]oxazol-2(3H)-one (690 mg, 71.6% yield). MS m/z: 232 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O)=[CH:11][CH:10]=1.O.P(Br)(Br)[Br:30]>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][Br:30])=[CH:11][CH:10]=1
Reactant: BrP(Br)Br
Reactant: OCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Fc1cccc(-c2ccc(OCCCCCCCCCCCBr)cc2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 120.5 %

Procedure:
First, 8 g of 2,3-difluoro-4'-(11-hydroxyundecyl)oxybiphenyl and 100 ml of carbon tetrachloride were placed in a 200 ml flask. A solution in which 2.3 g of phosphorus tribromide was dissolved in 50 ml of carbon tetrachloride was added dropwise to the reaction mixture under ice water cooling, and the resultant reaction mixture was stirred at room temperature for 3 hours and under reflux for 2 hours. The reaction mixture was poured into water, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/hexane=1/9) and recrystallized from hexane to obtain 4.5 g of 2,3-difluoro-4'-(11-bromoundecyl)oxybiphenyl (Y: 47.8%). The compound thus obtained had a purity of 95.3% by GC.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.[H-].[Na+].[CH3:22][CH:23]1[CH2:27][C:26]2[CH:28]=[C:29]([CH2:32][CH2:33][O:34]S(C3C=CC(C)=CC=3)(=O)=O)[CH:30]=[CH:31][C:25]=2[O:24]1>O>[CH3:22][CH:23]1[CH2:27][C:26]2[CH:28]=[C:29]([CH2:32][CH2:33][O:34][C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=3[NH:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH:30]=[CH:31][C:25]=2[O:24]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CC(C)O3)cc1
Reactant: CON(C)C(=O)Nc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)Nc1ccccc1OCCc1ccc2c(c1)CC(C)O2
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
2.0 g of 1-(3-hydroxyphenyl)-3-methoxy-3-methylurea was dissolved into 20 ml of dried N,N-dimethylformamide, and 0.4 g of 60% sodium hydride was added thereto. After the mixture was stirred for 30 minutes, 3.3 g of 2-(2,3-dihydro-2-methyl-5-benzofuranyl)ethyl-p-toluene sulfonate was added dropwise thereto under cooling with ice. After the mixture was stirred at room temperature for 5 hours, it was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/2) as a developer to obtain 3.3 g of Compound No. 49 shown in Table 3.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:5].O.NN>C(O)C.[Ni]>[CH3:16][N:2]([CH3:1])[CH2:3][CH:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:5]
Reactant: CC(CN(C)C)Nc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(CN(C)C)Nc1ccc(N)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of N1,N1-Dimethyl-N2-(4-nitro-phenyl)-propane-1,2-diamine (446 mg, 2 mmol) in absolute ethanol (20 mL) was added hydrazine monohydrate (0.78 mL, 8 equiv.) followed by the addition of a small portion of Raney nickel. The reaction mixture was heated to 50° C. with stirring for 2 h at which point all gas evolution had ceased. The reaction mixture was filtered through celite to remove the Raney nickel. The filtrate was concentrated under reduced pressure to give the N-(2-Dimethylamino-1-methyl-ethyl)-benzene-1,4-diamine as a brown oil. This material was carried on in subsequent steps without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=C)=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4].I([O-])(=O)(=O)=[O:25].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[O:25])=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4]
Reactant: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1C=O
Reaction time: 0.03 h
Yield: 96.2 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinyl-pyrimidine-4-carboxylic acid methyl ester (0.500 g, 1.5 mmol) was dissolved in THF (3 mL) and water (3 mL). Osmium tetroxide (4 mg, 0.015 mmol) was added and the reaction mixture was stirred for 2 min. Sodium periodate (0.63 g, 3 mmol) was then added over a period of 2 min. The reaction mixture was stirred for 16 h at ambient temperature then poured into water (150 mL) and extracted with dichloromethane thrice. The combined organic layers were dried, filtered and concentrated to afford the title compound (490 mg, 98% yield) in sufficient purity for subsequent reactions. An analytical sample was obtained by reverse phase chromatography: 1H NMR (CDCl3) δ 10.31 (s, 1H), 8.72 (br s, 1H), 7.77 (dd, 1H), 7.23 (m, 1H), 6.03 (br s, 1H), 4.06 (s, 3H), 4.01 (d, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][N:13]2[C:17](=[O:18])[N:16]([CH2:19][C@H:20]([OH:25])[C:21]([F:24])([F:23])[F:22])[C:15]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:14]2)[CH:3]=1.[Cl:33][C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>>[Cl:33][C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][N:13]2[C:17](=[O:18])[N:16]([CH2:19][C@H:20]([OH:25])[C:21]([F:22])([F:24])[F:23])[C:15]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:14]2)[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Reactant: OB(O)c1cccc(Cl)c1Cl
Product: COC(=O)c1ccc(-c2cccc(Cl)c2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O

Procedure:
Analogously to the preparation of Example 75, 455 mg (0.85 mmol) of the compound from Example 105A were reacted with 244 mg (1.28 mmol) of 2,3-dichlorophenylboronic acid. This gave 347 mg (57% of theory) of the target compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:18]S(C)=O>>[CH:1]1[C:10]2[C:5](=[C:6]([C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CS(C)=O
Reactant: CCOC(=O)C(C)c1cccc2cnccc12
Product: CCOC(=O)C(C)(C)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 248 using ethyl 2-(5-isoquinolinyl)propanoate instead of ethyl 5-isoquinolinylacetate. MS (ESI+) m/z 244 (M+H)+; MS (ESI−) m/z 242 (M−H)−; 1H NMR (DMSO, 300 MHz) rotamers δ 0.98, 1.08 (t, J 7.1, 3H), 1.67 (s, 6H), 4.58 (q, J 7.1, 1H), 7.53 (m, 1H), 7.82 (m, 1H), 7.97 (m, 1H), 8.05 (m, 1H), 8.55, 8.50 (d, J 6.1, 1H), 9.33 (s, 1H).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21](CC2C=CC(OC)=CC=2)CC2C=CC(OC)=CC=2)[N:15]=1.[F:40][C:41]1[CH:42]=[C:43]([NH2:49])[CH:44]=[N:45][C:46]=1[O:47][CH3:48]>>[NH2:21][C:16]1[N:17]=[C:18]([CH3:20])[N:19]=[C:14]([C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[N:7][C:2]=2[NH:49][C:43]2[CH:44]=[N:45][C:46]([O:47][CH3:48])=[C:41]([F:40])[CH:42]=2)[N:15]=1
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccc(-c4cccnc4)nc3F)n2)cc1
Product: COc1ncc(Nc2nc(-c3cccnc3)ccc2-c2nc(C)nc(N)n2)cc1F

Procedure:
The title compound was prepared in an analogous manner to that described in Example 254 using 4-(6-fluoro-2,3′-bipyridin-5-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and 5-fluoro-6-methoxypyridin-3-amine (Anichem), and was isolated as an orange amorphous solid (5.7%). m/z (ESI, +ve ion) 405.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.03 (1H, s); 9.27 (1H, d, J=2.0 Hz); 8.91 (1H, d, J=8.2 Hz); 8.67 (1H, dd, J=4.8, 1.5 Hz); 8.55 (1H, d, J=2.2 Hz); 8.39-8.43 (1H, m); 8.36 (1H, dd, J=12.7, 2.3 Hz); 7.93 (1H, br. s.); 7.79 (1H, br. s.); 7.62 (1H, d, J=8.2 Hz); 7.57 (1H, dd, J=7.9, 4.8 Hz); 3.96 (3H, s); 2.45 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[C:3]=1[CH3:10].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: Cc1c(Br)cccc1CBr
Reactant: c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1c(Br)cccc1Cn1ncc2ccccc21
Temperature: 80 °C
Reaction time: 18.25 h

Procedure:
A mixture of 1-bromo-3-(bromomethyl)-2-methylbenzene (prepared according to the procedures reported in US Pat. Appl. 2006/0173183, 250 mg, 0.947 mmol), 1H-indazole (112 mg, 0.947 mmol) and potassium carbonate (131 mg, 0.947 mmol) in acetonitrile (5 mL) was heated with stirring at 80° C. After 18.25 h, the mixture was cooled to rt, diluted with water and extracted three times with EtOAc. The combined organic layers were dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 95:5 to 65:35 hexane-EtOAc) to provide 1-(3-bromo-2-methylbenzyl)-1H-indazole as an oil which crystallized on standing (Intermediate 31-1, 74 mg, 26%). 1H NMR (400 MHz, chloroform-d) δ 8.06 (1 H, d, J=0.9 Hz), 7.76 (1 H, dt, J=8.1, 1.0 Hz), 7.48 (1 H, d, J=7.9 Hz), 7.30-7.37 (1 H, m), 7.26-7.30 (1 H, m), 7.16 (1 H, ddd, J=8.0, 6.8, 1.0 Hz), 6.93 (1 H, t, J=7.8 Hz), 6.70 (1 H, d, J=7.7 Hz), 5.61 (2 H, s), 2.45 (3 H, s). Mass spectrum m/z 301, 303 (M+H)+. Also obtained was 2-(3-bromo-2-methylbenzyl)-2H-indazole as a pale yellow gum (Intermediate 31-2, 164 mg, 58%). 1H NMR (400 MHz, chloroform-d) δ 7.68-7.76 (2 H, m), 7.54-7.63 (2 H, m), 7.28 (1 H, ddd, J=8.2, 7.2, 1.1 Hz), 6.97-7.10 (3 H, m), 5.63 (2 H, s), 2.37 (3 H, s). Mass spectrum m/z 301, 303 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].[C:12](/[CH:14]=[C:15](/[O-])\[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:13].[Na+].FC(F)(F)C(O)=O>O1CCOCC1>[NH2:13][C:12]1[N:5]([CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:2]=2[F:1])[N:6]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=1
Reactant: CCOC(=O)/C([O-])=C\C#N
Reactant: NNCc1cccc(F)c1F
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(N)n(Cc2cccc(F)c2F)n1

Procedure:
Preparation takes place in analogy to that described in Example 7 A from 1.50 g (9.48 mmol) of 1-(2,3-difluorobenzyl)hydrazine from Example 2 A, 1.55 g (9.48 mmol) of sodium (1E)-1-cyano-3-ethoxy-3-oxo-1-propen-2-olate from Example 6 A, 1.73 g (1.17 ml; 15.18 mmol) of trifluoroacetic acid and 40 ml of dioxane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]([OH:19])[CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:6][C:7]=1[F:8].[C:20]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])#[CH:21]>>[F:15][C:14]([F:17])([F:16])[C:13]([NH:12][CH2:11][CH2:10][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:21]#[C:20][C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH:3]=1)[OH:19])=[O:18]
Reactant: C#CC(O)(CCC)CCC
Reactant: O=C(NCCC(O)c1ccc(F)c(Br)c1)C(F)(F)F
Product: CCCC(O)(C#Cc1cc(C(O)CCNC(=O)C(F)(F)F)ccc1F)CCC

Procedure:
N-(3-(3-bromo-4-fluorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide was coupled with alkynol 20 to give 2,2,2-trifluoro-N-(3-(4-fluoro-3-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-3-hydroxypropyl)acetamide as a pale yellow oil. Yield (1.37 g, 78%): 1H NMR (400 MHz, DMSO-d6) δ 9.31 (t, J=5.0 Hz, 1H), 7.37 (dd, J=6.8, 2.0 Hz, 1H), 7.34-7.30 (m, 1H), 7.18 (t, J=9.0 Hz, 1H), 5.41 (d, J=4.8 Hz, 1H), 5.19 (s, 1H), 4.58-4.54 (m, 1H), 3.28-3.16 (m, 2H), 1.82-1.69 (m, 2H), 1.63-1.41 (m, 8H), 0.89 (t, J=7.2 Hz, 6H).
Reaction SMILES: C([O:4][C@H:5]1[C:31](=O)[CH2:30][C@@:29]2([CH3:33])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:28]2[C@H:27]([O:34]C(=O)C)[CH2:26][C@@:25]2([CH3:38])[C@H:11]3[CH2:12][C@@H:13]3[O:18][C@@:17]4([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]4)[C@@H:15]([CH3:16])[C@@H:14]32)[CH2:6]1)(=O)C.C[O-:40].[Na+]>CO.C1COCC1>[CH3:16][C@@H:15]1[C@:17]2([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]2)[O:18][C@H:13]2[CH2:12][C@@H:11]3[C@@:25]([CH3:38])([C@@H:14]12)[C:26](=[O:40])[C@@H:27]([OH:34])[C@H:28]1[C@H:10]3[CH2:9][CH2:8][C@@H:7]2[C@:29]1([CH3:33])[CH2:30][CH2:31][C@H:5]([OH:4])[CH2:6]2
Reactant: CC(=O)O[C@@H]1C[C@@H]2CC[C@@H]3[C@H]([C@H](OC(C)=O)C[C@]4(C)[C@@H]5[C@H](C[C@@H]34)O[C@]3(CC[C@@H](C)CO3)[C@H]5C)[C@@]2(C)CC1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@H](O)C(=O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α,11α,25R)-3,11-di(acetoxy)spirostan-2-one was saponified with sodium methoxide in methanol and THF to give the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C@H:15]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.O1CCCC1.[Pd]>[OH:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C@@H:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][C@H:15]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:11][CH:10]=1
Reactant: CN1CC[C@@H](Oc2ccc(OCc3ccccc3)cc2)[C@H](c2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CC[C@@H](Oc2ccc(O)cc2)[C@H](c2ccccc2)C1

Procedure:
A solution of 8.59 g of trans-4-(4-benzyloxyphenoxy)-1-methyl-3-phenylpiperidine in a mixture of 100 ml of absolute ethanol and 50 ml of tetrahydrofuran is hydrogenated overnight over 5% palladium-on-carbon at room temperature under 45 pounds per square inch of hydrogen. The catalyst is filtered and washed with ethanol and ether. The filtrate is concentrated in vacuo to a nearly colorless, partially solidified foam. Trituration of the foam with ether followed by recrystallization from 270 ml of chloroform gives product as a colorless solid, mps 169.5° C., 170°-172° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[C:4](=[O:12])[CH2:3]1.[CH3:14][CH:15](O)[CH:16]=[CH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:14]([CH:3]1[C:2]([CH3:13])([CH3:1])[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[C:4]1=[O:12])[CH:15]=[CH:16][CH3:17]
Reactant: Cc1ccc2c(c1)C(=O)CC2(C)C
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1C(=O)c2cc(C)ccc2C1(C)C
Yield: 51 %

Procedure:
A solution of 18.9 g of 3,3,6-trimethyl-1-indanone, 22.4 ml of 3-buten-2-ol and 300 mg of p-toluenesulfonic acid in 200 ml of 2,2-dimethoxy-propane was boiled under reflux for 64 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 6:1). In addition to 4.5 g of educt, there were obtained 12.7 g (51%) of (RS)-2-(2-buten-1-yl)-3,3,6-trimethyl-1-indanone as a yellow oil
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])=[CH:10][C:9]=2[F:19])[O:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[Cl:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:6][CH:7]=[C:3]([CH2:2][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:4]=2)=[C:9]([F:19])[CH:10]=1
Reactant: C1CCNCC1
Reactant: Fc1cc(OCCCCl)ccc1-c1nc(CCl)co1
Solvent: CC#N
Product: Fc1cc(OCCCCl)ccc1-c1nc(CN2CCCCC2)co1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A solution of 4-(chloromethyl)-2-[4-(3-chloropropoxy)-2-fluorophenyl]-1,3-oxazole i84 (0.23 g, 0.75 mmol, 1 eq) in acetonitrile (10 ml) is treated with piperidine (0.14 ml, 1.5 mmol, 2 eq). The mixture is stirred at room temperature for 24 h and concentrated under vacuum. The residue is taken up in dichloromethane and washed with water. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure to give 0.20 g of 1-({2-[4-(3-chloropropoxy)-2-fluorophenyl]-1,3-oxazol-4-yl}methyl)piperidine i86.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]3[C:13](=[O:14])[N:12]=[CH:11][C:10]([C:15]([OH:17])=O)=[C:8]3[S:9][C:5]=2[CH:4]=1.O.[NH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1>CN(C)C=O>[NH:23]1[C:22]([NH:21][C:15]([C:10]2[CH:11]=[N:12][C:13](=[O:14])[N:7]3[C:6]4[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[S:9][C:8]=23)=[O:17])=[N:26][N:25]=[N:24]1
Reactant: Nc1nnn[nH]1
Reactant: COc1ccc2c(c1)sc1c(C(=O)O)cnc(=O)n12
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)sc1c(C(=O)Nc3nnn[nH]3)cnc(=O)n12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5.52 g. 7-Methoxy-1-oxo-1H-pyrimido[6,1-b]benzthiazole-4-carboxylic acid (prepared according to Example 1) in 150 ml. dimethylformamide are mixed with 7.14 g. N,N'-carbonyldiimidazole. The reaction mixture is subsequently stirred for 90 minutes at 100° C. and for 1 hour at ambient temperature, then mixed with 2.26 g. 5-aminotetrazole monohydrate and again heated for 3 hours at 100° C. The solvent is substantially removed in vacuo and the residue stirred with water. The precipitate consists of 5.2 g. N-(5-tetrazolyl)-7-methoxy-1-oxo-1H-pyrimido[6,1-b]benzthiazole-4-carboxamide (75.7% of theory); m.p. 234°-235° C. (recrystallized from nitromethane).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:1][C:2]2[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(O)cn1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(OCc2ccc(Cl)cc2)cn1
Reaction time: 0.17 h

Procedure:
A mixture of 5-hydroxy-2-nitropyridine (7 g), K2CO3 (6.9 g) and DMF (100 ml) is stirred for about 10 minutes. To the mixture is added 4-chlorobenzyl chloride (8.1 g) in portions over about 15 minutes. The reaction mixture is stirred about 16 hours and then heated to 45° for about 30 minutes. After cooling, the reaction is diluted with CHCl3, washed with water and saturated NaCl, dried (Na2SO4) and stripped. The crystalline solid is washed with 20% ethyl acetate/hexane, giving 5-(4-chlorobenzyloxy)-2-nitropyridine.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=O)[C:15]([OH:17])=[O:16].C(O)C>O>[OH:3][N:2]=[C:14]([C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)[C:15]([OH:17])=[O:16]
Reactant: NO
Reactant: O=C(O)C(=O)c1cccs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=NO)c1cccs1

Procedure:
A cooled solution of hydroxylamine hydrochloride (0.884 g) and sodium bicarbonate (1.08 g) in water (20 ml.) was added to a cooled (0° ) solution of thien-2-yl-glyoxylic acid (2.0 g) and sodium bicarbonate (1.08 g) in water (20 ml.). After two days at 20° the solution was extracted with ether, cooled and acidified with concentrated hydrochloric acid. The resulting white solid was filtered off (0.564 g) and the filtrate was then thoroughly extracted with ether. The combined extracts were washed with brine, dried and concentrated. The solid residue was triturated with benzene to give the exime (synisomer) (1.05 g; 51%), m.p. 132°, λmax. (ethanol) 284 nm (Ε9,500),νmax. (Nujol) 2590 and 1706 (SO2H) and 1655 cm-1 (C=N), τ (DMSO-d6), -2.5 to -0.5 (broad multiplet; N-OH and COOH), 2.36 (multiplet; thienyl C-5 H) and 2.82 (multiplet; thienyl C-3 H and C-4 H).