Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[CH3:5][S:6]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[CH:11]=1)(=[O:8])=[O:7]>C1(C)C=CC=CC=1>[CH3:5][S:6]([O:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][S:1](=[O:2])[O:19][CH2:18][C:17]([CH3:20])([CH3:21])[C:12]=2[CH:11]=1)(=[O:8])=[O:7]
Reactant: CC(C)(CO)c1cc(OS(C)(=O)=O)ccc1O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)COS(=O)Oc2ccc(OS(C)(=O)=O)cc21
Temperature: 50 °C
Yield: 90 %

Procedure:
Thionyl chloride (12 parts) was added dropwise at room temperature to a suspension of 4-hydroxy-3-(2-hydroxy-1,1-dimethylethyl)phenyl methanesulphonate (5 parts) (from Example 1) in toluene (50 parts). The mixture was gently warmed to 50° C. when reaction commenced, then maintained at this temperature for 15 minutes. The temperature was then raised to boiling point and the mixture boiled under reflux for 2 hours. The solvent was then evaporated off under reduced pressure to give crude 4,5-dihydro-5,5-dimethyl-2-oxido-1,3,2-benzodioxathiepin-7-yl methanesulphonate (5.2 parts, 90% yield). Recrystallisation from ethanol gave the pure product (2.4 parts), melting point 96°-98° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[N:10]=[C:11]([NH2:27])[C:12]2[N:13]=[CH:14][N:15]([C:25]=2[N:26]=1)[C@@H:16]1[O:24][C@H:21]([CH2:22][OH:23])[C@@H:19]([OH:20])[C@H:17]1[OH:18])#[N:2].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[P:35](O[CH2:44][CH3:45])([O:40]CC)([O:37][CH2:38]C)=[O:36]>>[P:35]([O:23][CH2:22][C@H:21]1[O:24][C@@H:16]([N:15]2[C:25]3[N:26]=[C:9]([C:8]#[C:7][CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[N:10]=[C:11]([NH2:27])[C:12]=3[N:13]=[CH:14]2)[C@H:17]([OH:18])[C@@H:19]1[OH:20])([O-:40])([O-:37])=[O:36].[CH2:9]([NH+:10]([CH2:44][CH3:45])[CH2:11][CH3:12])[CH3:8].[CH2:16]([NH+:15]([CH2:25][CH3:12])[CH2:14][CH3:38])[CH3:17]
Reactant: N#CCCCCC#Cc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CCOP(=O)(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC[NH+](CC)CC
Product: N#CCCCCC#Cc1nc(N)c2ncn([C@@H]3O[C@H](COP(=O)([O-])[O-])[C@@H](O)[C@H]3O)c2n1
Reaction time: 5 h

Procedure:
Under argon, A 2-(6-cyano-1-hexyn-1-yl)adenosine (2.41 g) was dissolved in triethyl phosphate (15 mL), and, under ice-cooling conditions, phosphorous oxychloride (25.2 mL, 3.9 eq.) was added thereto, followed by stirring at the same temperature for 5 hours. The reaction mixture was added dropwise to a 10% sodium hydroxide solution (300 mL), and the resultant mixture was washed with ether. The aqueous layer was separated and water was removed under reduced pressure, and the residue was purified by C18 silica gel column chromatography (0.1M triethylammonium acetate buffer:acetonitrile=100:0 to 60:40). The thus-obtained fraction was concentrated, and the concentrate was subjected to C18 silica gel column chromatography (water:acetonitrile=100:0 to 60:40), to thereby remove the triethylammonium acetate buffer. The residue was freeze-dried, to thereby yield 1.14 g of the above-titled compound as a colorless amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C@@H:4]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C@@H:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=4)=[CH:17][CH:16]=3)[C:12](=[O:31])[NH:11][C:10]=2[CH:32]=1.CO.[C:44]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:41])[C@@H:4]([NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C@@H:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=4)=[CH:19][CH:20]=3)[C:12](=[O:31])[N:11]([CH3:44])[C:10]=2[CH:32]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)NC(=O)[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc2c(c1)N(C)C(=O)[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}-propionic acid methyl ester (9.5 mmol) was dissolved in 60 mL THF-DCM (1:1) and methanol (14.2 mmol) and resin-bound triphenylphosphine (14.2 mmol) was added. The mixture was cooled to 0° C. and DIAD (14.2 mmol) added. The mixture was agitated for 10 min at 0° C. and the mixture was slowly allowed to warm up to r.t. and agitated for 16 h. The reaction mixture was filtered, concentrated and the residue purified over silica-gel hexanes ethyl acetate (8-2) to afford (S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}-propionic acid methyl ester. (4.9 g). 1H NMR (400 MHz, CDCl3): 7.51 (d, 1H), 7.44 (d, 1H), 7.31 (m, 2H), 7.25 (m, 1H), 6.96-6.88 (m, 3H), 6.74 (m, 2H), 5.63 (s, 1H), 5.03 (m, 1H), 4.98 (s, 2 h), 4.58 (m, 1 h), 3.70 (s, 3H), 3.41 (s, 3H), 3.05 (m, 2H), 1.28 (s, 9H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[N:27]1([CH2:33][C:34]2[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=2)[NH2:37])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[N:27]1([CH2:33][C:34]2[CH:35]=[C:36]([NH:37]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:38]=[CH:39][CH:40]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1cccc(CN2CCCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1cccc(CN2CCCCC2)c1)c1ccccc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-piperidinomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([OH:28])[CH2:18][C@@H:19]2[OH:27])=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7].CC1(C)COC(C([C@@H]2[C@]3(C)[C@H](C4[C@H](CC3)[C@]3(C)C(C[C@@H](O)C[C@@H]3O)=CC=4)CC2)C)OC1>>[OH:27][C@@H:19]1[C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[CH:6]([CH:2]=[O:1])[CH3:7])[CH2:16][C@@H:17]([OH:28])[CH2:18]1
Reactant: CC(C1OCCO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 78.4 %

Procedure:
The procedure of Example 25 was repeated except that 3.9 mg (0.010 mmole) of 20-(1,3-dioxolan-2-yl)-pregna-5,7-diene-1α,3β-diol was used in lieu of 4.3 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-5,7-diene-1α,3β-diol to give 2.7 mg of 1α,3β-dihydroxypregna-5,7-diene-20-carbaldehyde (yield: 78%).
Reaction SMILES: [CH3:1][C:2]1([N:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3]1.CCN(CC)CC.[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:1][C:2]1([N:5]2[CH2:10][CH2:9][N:8]([S:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19]([F:18])([F:30])[F:31])(=[O:28])=[O:27])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: CC1(N2CCNCC2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(N2CCN(S(=O)(=O)c3ccccc3C(F)(F)F)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
1-(1-Methylcyclopropyl)piperazine (TFA salt) (50.9 mg, 0.200 mmol) was dissolved in dichloromethane (1.0 mL) and NEt3 (0.3 mL) was added. To this mixture, 2-trifluoromethylbenzenesulfonyl chloride (73.4 mg, 0.300 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated in vacuo and the resulting crude mixture was purified by HPLC (25-40% acetonitrile in water (0.05 TFA buffer). The product containing fractions were concentrated in vacuo until only water was left, basified with NaHCO3 (sat. aq., 20 mL) and extracted with dichloromethane (3×7 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a white solid (56.6 mg, 81%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.28-0.32 (m, 2 H), 0.39-0.44 (m, 2 H), 0.98 (s, 3 H), 2.59 (t, J=4.80 Hz, 4 H), 3.08 (m, 4 H), 7.84-7.93 (m, 2 H), 7.99-8.04 (m, 2 H); ESI-MS: m/z 349.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:9]#[N:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)[OH:21].[OH-].[Na+]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH3:11])[C:9]([NH2:10])=[O:21])=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: CC(C#N)(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C(N)=O)(c1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
) A mixture of 0.020 mol of p-nitro-α-phenylhydratroponitrile and 28 ml of concentrated sulfuric acid solution (90%) is heated in a water-bath for 3.5 hours. The reaction mixture is poured onto crushed ice, neutralized with a sodium hydroxide solution and the product is extracted with chloroform. The organic layer is washed with water, dried and evaporated in vacuo and the residue is crystallized from either, yielding 2.4 grams of p-nitro-α-phenylhydratropamide. (interm. 7)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.CN(C)[CH:26]=[O:27].O1CCCC1.C(OCC)(=O)C>C[O-].[Na+].O>[CH3:26][O:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: CN(C)C=O
Reactant: BrCCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COCCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of 4-[4-(8-Bromooctyloxy)phenyl]bromobenzene (3.7 g) in a mixture of sodium methoxide (4.9M in methanol, 17 ml), N,N-dimethylformamide (20 ml) and tetrahydrofuran (8 ml) was heated to 80° C. for 3 hours. The reaction mixture was taken up into a mixture of ethyl acetate (200 ml) and water (100 ml). The separated organic layer was washed in turn with water, brine, dried over magnesium sulfate. Evaporation gave a residue which was subjected to column chromatography (silica gel, 100 ml) eluting with n-hexane to give 4-[4-(8-Methoxyoctyloxy)phenyl]bromobenzene (2.73 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:34])[C:17]([CH3:33])([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30]#[CH:31])=[CH:22][C:21]=1[CH3:32])[CH3:18])[CH3:14]>N1CCCCC1.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.[Cu]I>[CH2:13]([O:15][C:16](=[O:34])[C:17]([CH3:33])([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30]#[C:31][C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)=[CH:22][C:21]=1[CH3:32])[CH3:18])[CH3:14]
Reactant: C#CCCCOc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCCC#Cc2ccc(OC(F)(F)F)cc2)cc1C
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 81.8 %

Procedure:
The synthesis was performed following a procedure of Stara, Irena G.; Stary, Ivo; Kollarovic, Adrian; Teply, Filip; Saman, David; Fiedler, Pavel, Coupling reactions of halobenzenes with alkynes. The synthesis of phenylacetylenes and symmetrical or unsymmetrical 1,2-diphenylacetylenes, Collect. Czech. Chem. Commun. (1999), 64(4), 649-672. To a degassed (argon) solution of 178 mg (0.60 mmol) 1-iodo-4-trifluoromethoxy-benzene in 2 ml piperidine was added 29 mg (0.03 mmol) Pd(PPh3)4 and 5 mg (0.03 mmol) CuI. The reaction mixture was stirred at 50° C. for 10 min, then a solution of 152 mg (0.50 mmol) 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid ethyl ester (example 13A]) in 2 ml piperidine was added dropwise within 1 h. During the addition the oil bath was slowly heated to 80° C. starting after 30 min. The reaction mixture was stirred at this temperature for 3 h and then extracted with chilled aqueous 10% KHSO4/Et2O (three times). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification by flash-chromatography on silica gel (n-heptane/EtOAc 95:5 to 9:1) yielded 190 mg of the title compound as a light yellow viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH:16]=2)[CH:10]=[C:9]([CH3:33])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].I[CH3:37]>CN(C=O)C>[CH3:37][O:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH:16]=2)[CH:10]=[C:9]([CH3:33])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1c(C)cc(OCc2cccc(OCc3ccc4ccccc4n3)c2)cc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cc(OCc2cccc(OCc3ccc4ccccc4n3)c2)cc1OC
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 2-hydroxy-6-methyl-4-[3-(quinolin-2-ylmethoxy)-benzyloxy]-benzoate (150 mg, 0.34 mmol, example 65) in DMF (5 mL) is added sodium hydride (60%, 14 mg, 0.34 mmol) and the reaction is stirred 20 min. Iodomethane (0.03 mL, 0.5 mmol) is added and the reaction is heated at 50° C. for 7 h. The reaction is concentrated in vacuo and the residue is partioned between dichloromethane and aqueous ammonium chloride. The water layer is back-extracted with dichloromethane, the organic phases are combined, dried over magnesium sulfate, filtered and concentrated to yield crude product. The residue is purified by column chromatography (silica, 10 to 20% ethyl acetate in hexanes to provide the title compound; MS (ESI) 458 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:12]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[C:8]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: C=CC(C)O
Reactant: O=C1CCc2ccc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2ccc(Br)cc2C1=O
Yield: 78 %

Procedure:
A solution of 10.0 g of 6-bromo-1-indanone, 9.79 ml of 3-buten-2-ol and 100 mg of p-toluenesulfonic acid in 100 ml of 2,2-dimethoxypropane was boiled under reflux for 71 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/diethyl ether 1:1). In addition to 3.07 g of educt, there were obtained 9.86 g (78%) of (RS)-2-(2-buten-1-yl)-6-bromo-1-indanone as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[N:13]([CH2:22][CH3:23])[CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:24](Br)CC>>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[N:13]([CH2:22][CH2:23][CH3:24])[CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CCCBr
Reactant: CCn1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Product: CCCn1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Yield: 75 %

Procedure:
This compound was prepared in the manner described above for intermediate 5b by replacing ethylbromide with n-propylbromide (13.1 g, 11 mmol) to afford 4.33 g (75%) of the title compound as a oil: MS EI m/e 324 (M+).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[CH2:13]([O:15][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[CH3:14].NC1C=CC=CC=1>>[CH2:13]([O:15][C:16](=[O:27])[CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])=[CH:24][CH:25]=1)[CH3:14]
Reactant: CCOC(=O)CCCc1ccc(N)cc1
Reactant: COC(=O)c1ccccc1CBr
Solvent: Nc1ccccc1
Product: CCOC(=O)CCCc1ccc(N2Cc3ccccc3C2=O)cc1

Procedure:
By using 2-bromomethyl-benzoic acid methyl ester and 4-(4-amino-phenyl)butyric acid ethyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 4-[4-(1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-butyric acid ethyl ester (Compound 19) as a white powdery substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C:5]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:6]([C:8]2[C:9]([CH3:14])=[N:10][NH:11][C:12]=2[NH2:13])[CH:7]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[OH:34])[CH:29]=O.FC(F)(F)C(O)=O>CO>[ClH:25].[Cl:25][C:26]1[CH:27]=[C:28]([C:29]2[C:7]3[C:2]([F:1])=[CH:3][C:4]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:5]([O:15][CH2:16][CH2:17][O:18][CH3:19])[C:6]=3[C:8]3[C:9]([CH3:14])=[N:10][NH:11][C:12]=3[N:13]=2)[CH:31]=[CH:32][C:33]=1[OH:34]
Reactant: COCCOc1cc(F)cc(-c2c(C)n[nH]c2N)c1OCCOC
Reactant: O=Cc1ccc(O)c(Cl)c1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1cc(F)c2c(-c3ccc(O)c(Cl)c3)nc3[nH]nc(C)c3c2c1OCCOC
Product: Cl
Temperature: 70 °C
Yield: 33.3 %

Procedure:
A mixture of 4-(5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)-3-methyl-1H-pyrazol-5-amine 0.153 mg, 0.45 mmol), 3-chloro-4-hydroxybenzaldehyde (141 mg, 0.9 mmol) and trifluoroacetic acid (3 mL) was heated at 70° C. for 18 hours. Then the reaction mixture was concentrated, dissolved in 10 mL of N,N-dimethylformamide, and purified by preparatory HPLC (Shimadzu LC-8A HPLC, Waters Xterra C18 30 mm×100 mm column, acetonitrile-water-trifluoroacetic eluent). After concentration then lyophillization of the pure fractions a yellow powder was obtained. It was dissolved in 4 mL of 1:1 methanol: 4M hydrogen chloride in dioxane, and evaporated to dryness (repeated three times) to give 2-chloro-4-(6-fluoro-1-methyl-8,9-bis{[2-(methyloxy)ethyl]oxy}-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol hydrochloric acid salt (77 mg, 0.15 mmol, 33% yield), 1H NMR (400 MHz, d6-DMSO): 10.48 (b, 1H), 7.48 (s, 1H), 7.32-7.28 (m, 2H), 7.05-7.03 (d, 1H), 4.35-4.33 (m, 2H), 4.25-4.21 (m, 2H), 3.77-3.75 (m, 2H), 3.69-3.66 (m, 2H), 3.35 (s, 3H), 3.22 (s, 3H), 2.80 (s, 3H); MS (EI) for C23H23ClFN3O5: 476 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH2:20][CH2:21][OH:22])[C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][N:2]([CH2:20][CH2:21][O:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCC(=O)N(C)CCO
Reactant: O=C(Cl)c1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)N(C)CCOC(=O)c1ccccc1

Procedure:
N-methyl-N-(2-benzoyloxyethyl)palmitamide was prepared by the procedure of example 1 from 31 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)palmitamide and 14 gms. (0.1 mole) of benzoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:34][CH2:35][CH2:36][CH3:37])[C:14]([N:16]1[C@H:20]([C:21](O)=[O:22])[CH2:19][CH2:18][N:17]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[NH2:44].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1>C(#N)C.C(OCC)(=O)C>[CH:1]([N:3]([CH2:12][C@@H:13]([CH2:34][CH2:35][CH2:36][CH3:37])[C:14]([N:16]1[C@H:20]([C:21]([NH:44][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=2)=[O:22])[CH2:19][CH2:18][N:17]1[C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2]
Reactant: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1
Reactant: Nc1ccccn1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2ccccn2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a solution of (3S)-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)hexanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (Intermediate 4) (150 mg, 0.3 mmol), 2-pyridinamine (32 mg, 0.33 mmol) and 2-chloro-4,6-bis(methyloxy)-1,3,5-triazine (58 mg, 0.33 mmol) in acetonitrile (4 mL) under N2 was added 4-methylmorpholine (65 mg, 0.66 mmol) dropwise. The mixture was stirred at rt overnight. TLC showed that the reaction was complete. The mixture was diluted with ethyl acetate and washed with 5% citric acid, followed by brine. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography to provide the titled compound (110 mg, 70%).
Reaction SMILES: O[N:2]=[C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=O.[NH:19]([C:21](=[S:23])N)[NH2:20].Cl.[C:25](=O)([O-])[O-].[K+].[K+].IC>O.CO.O>[CH3:25][S:23][C:21]1[N:19]=[N:20][C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)=[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:2]=1
Reactant: O=C([O-])[O-]
Reactant: NNC(N)=S
Reactant: Cc1ccc(C(=O)C(=NO)c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CI
Product: CSc1nnc(-c2ccc(C)cc2)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
To a suspension of 2-(hydroxyimino)-2-phenyl-1-p-tolylethanone (1.99 g, 8.32 mmol) in a 1:1 mixture of MeOH/H2O (40.0 mL) was added hydrazinecarbothioamide (1.134 g, 12.44 mmol) followed by concentrated HCl (0.75 mL, 24.68 mmol). The reaction was stirred at room temperature for 1 h then at 60° C. overnight. Additional hydrazinecarbothioamide (˜3×100 mg) was added portionwise and the reaction was stirred at 60° C. until the starting material was consumed. The reaction was neutralized with saturated NaHCO3. The solid was removed by filtration and rinsed with H2O. To the solid was added a solution of potassium carbonate (5.78 g, 41.8 mmol) in H2O (85 mL) and the mixture was heated at 90° C. overnight. The reaction mixture was cooled to room temperature then placed in an ice bath. Iodomethane (0.52 mL, 8.35 mmol) was added and the reaction was stirred at 0° C. and then slowly warmed to room temperature. After stirring overnight, the solution was decanted. The solid was dissolved in CH2Cl2, and the solution was washed with H2O and brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a yellow solid (1.302 g). LCMS m/z=294.2 [M+H]+.