Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[C:4]2[CH:10]=[C:9](I)[NH:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>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>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH:28]=[C:29]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[C:2]([Br:1])[C:3]([Cl:12])=[C:4]3[CH:10]=2)[CH2:30][CH2:31]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Clc1c(Br)cnc2[nH]c(I)cc12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)c(Br)cnc3[nH]2)CC1

Procedure:
To a mixture of 5-bromo-4-chloro-2-iodo-1H-pyrrolo[2,3-b]pyridine (46 mg, 0.12 mmol), potassium carbonate (36 mg, 0.25 mmol), dichlorobis-(triphenylphosphine)palladium (9 mg, 0.01 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (42 mg, 0.13 mmol) were added degassed dioxane (4 mL) and water (1 mL), and the mixture was heated to reflux for 5 h. The reaction was evaporated under reduced pressure and the residue was dissolved in DCM and filtered. The DCM filtrate was evaporated and the crude product obtained was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with DCM:methanol 100:0→99.5:0.5], yielding the title compound. MS (ES+): m/z 413.84 (100) [MH+]; HPLC: tR=6.95 min (ZQ2000, nonpolar—15 min).
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][CH3:28])[N:26]=1)[C:21](O)=[O:22]>>[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][CH3:28])[N:26]=1)[C:21]([NH:14][CH:12]([C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=1)[CH3:13])=[O:22]
Reactant: COc1cc(C(=O)O)cc(N)n1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: Cl
Product: COc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)cc(N)n1
Yield: 65 %

Procedure:
The title compound is prepared in 65% yield (187 mg, a white solid) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (200 mg, 0.78 mmol, Amine-1, single enantiomer) and 2-amino-6-methoxyisonicotinic acid (131 mg, 0.78 mmol) by the similar manner in Step-1 of Example-8.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH:12]=[C:11]([Cl:23])[C:10]=1[F:24])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH:12]=[C:11]([Cl:23])[C:10]=1[F:24]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)N2CCOCC2)cc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cc(C(=O)N2CCOCC2)cc(Cl)c1F

Procedure:
was prepared according to Scheme C3 (step B) from [3-chloro-2-fluoro-5-(morpholine-4-carbonyl)-benzyl]-carbamic acid tert-butyl ester (72 mg, 0.19 mmol) and TFA (1 mL) in CH2Cl2. MS (LC-MS): 273.0 [M]+; tR (HPLC conditions c): 2.64 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[F:34][C:35]1[CH:36]=[C:37]([N:50]2[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]2)[CH:38]=[CH:39][C:40]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:34][C:35]1[CH:36]=[C:37]([N:50]2[CH2:55][CH2:54][N:53]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][CH2:51]2)[CH:38]=[CH:39][C:40]=1[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:25])=[O:26])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4F)cnc32)cc1
Yield: 83.3 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (130 g, 0.248 mmol) was coupled with tert-butyl 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (intermediate 69B) (151 mg, 0.372 mmol) using sodium carbonate (79 mg, 0.714 mmol) and Pd(PPh3)2Cl2 (9 mg, 0.124 mmol) in DME/water (5/2 mL). This afforded 150 mg (83.3% yield) after purification by column (Silica gel 60/120) using 50% ethyl acetate in hexane as eluent. MS: m/z=725.3 (M+1).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:19]>B(Br)(Br)Br.C(Cl)Cl>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:19]
Reactant: COc1cccc2c1cc(C)n2Cc1ccccc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 54.8 %

Procedure:
By the method used in Example 1, Part D, 1.6 g (4.9 mmol) of 1-([1,1′-biphenyl]-2-ylmethyl)-4-methoxy-2-methyl-1H-indole was O-demethylated by treating it with 20 mL of 1M BBr3/CH2Cl2. The crude product was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 841 mg (55% yield) of 1-([1,1′-biphenyl]-2-ylmethyl)-4-hydroxy-2-methyl-1H-indole
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][N:8]([CH3:13])[CH:9]2[CH2:12][O:11][CH2:10]2)=[CH:5][C:4]([NH2:14])=[N:3]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1>>[Br:22][C:20]1[CH:21]=[C:16]([NH:14][C:4]2[CH:5]=[C:6]([CH2:7][N:8]([CH3:13])[CH:9]3[CH2:10][O:11][CH2:12]3)[N:2]([CH3:1])[N:3]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: CN(Cc1cc(N)nn1C)C1COC1
Reactant: Cn1cc(Br)cc(Br)c1=O
Product: CN(Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1C)C1COC1
Yield: 63 %

Procedure:
Following Example 136d, 320c and 3,5-dibromo-1-methylpyridin-2(1H)-one were reacted to give 320d in 63% yield. LCMS: (M+H)+ 383. 1H NMR (500 MHz, DMSO) δ 8.35 (s, 1H), 7.99 (d, J=2.5, 1H), 7.36 (d, J=2.5, 1H), 5.99 (s, 1H), 4.50 (t, J=7, 2H), 4.40 (t, J=6.5, 2H), 3.77 (s, 3H), 3.57 (m, 1H), 3.49 (s, 3H), 3.35 (s, 2H), 2.01 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][C:4]#[CH:5].[Br:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1>C(NC(C)C)(C)C.[Cu]I>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:5]#[C:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:10][CH:9]=1
Reactant: C#CCN(C)C
Reactant: Brc1ccc(I)cc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: CN(C)CC#Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 105.1 %

Procedure:
Copper(I) iodide (17.4 mg, 0.0913 mmol), 0.113 ml (1.06 mmol) of N,N-dimethylprop-2-yn-1-amine, and 67.8 mg (0.0966 mmol) of bistriphenyl phosphine palladium dichloride were added in that order to a solution of 280.8 mg (0.993 mmol) of 1-bromo-4-iodobenzene in diisopropylamine (2 ml), and the mixture was stirred at room temperature for 50 min. The reaction solution was filtered through Celite. The solvent was removed by distillation, and the residue was then purified by column chromatography on silica gel (hexane:ethyl acetate=2:1 to 0:100) to give 248.4 mg (yield 99%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[OH-].[K+:38]>C(O)C.O>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O-:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[K+:38]
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Placed 245.12 mg of the product of Example 49-7 into a 10 mL receiver flask. Added 6 mL of 50/50 ethanol/water. Warmed to in an oil bath on a hot-plate set to 90° C. and added 29.02 mg of potassium hydroxide. Solution clarified. Cooled in 10° C. increments to 55° C. Solid precipitated. Cooled to 40° C. and held for ˜1 hour. Cooled to ambient temperature and stirred overnight. Collected solid via vacuum filtration the next morning and dried the solid at 50° C./vacuum for 3 days.
Reaction SMILES: B.[Na].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Cl.O>C(O)(C)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][OH:16])=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCOc1ccc(C=O)cc1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCOc1ccc(CO)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
A suspension of sodium boron hydride (6.9 g) in isopropyl alcohol (500 ml) was dropwise added to a solution of p-heptyloxybenzaldehyde (119 g) in isopropyl alcohol (300 ml), followed by heating the mixture to 70° C. to form a uniform solution, which was then agitated at 70° C. for 3 hours and allowed to stand overnight, followed by adding 6N-HCl (100 ml) and water (200 ml), heating the mixture to 60° C., distilling off most of the solvent, extracting with toluene, washing with water, washing with alkali, washing with water to make it neutral, drying, concentrating and recrystallizing the residue from a mixed solvent of ethanol (200 ml) and water (60 ml) to obtain p-heptyloxybenzyl alcohol (74.9 g). This product (40 g) together with 47% aqueous hydrogen bromic acid (200 g) were agitated at 80° C. for 7 hours and allowed to stand overnight, followed by extracting with n-heptane (200 ml), washing the n-heptane layer with water till the washing water became neutral, drying, concentrating and subjecting the residue to vacuum distillation to obtain p-heptyloxybenzyl bromide (IIa-2) (28 g) having a b.p. of 174°-175° C./6 Torr.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:33]([CH2:35][NH2:36])[OH:34]>CS(C)=O>[OH:34][CH2:33][CH2:35][NH:36][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4cccc(Cl)c4)c3)csc12
Solvent: CS(C)=O
Product: O=C(Nc1cccc(OCc2csc3c(C(=O)NCCO)cncc23)c1)c1cccc(Cl)c1
Temperature: 135 °C

Procedure:
A suspension of 3-[3-(3-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (34.0 mg, 0.073 mmol) (from Example 10 supra) in methyl sulfoxide (1 mL) and ethanolamine (3 mL) (Aldrich) was heated at 135° C. for 2 hours in a microwave reactor. The solvent was removed in vacuum and the residue was treated with MeOH (2 mL). The resulting white precipitate was filtered, washed with cold MeOH and dried to give 3-[3-(3-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white solid. (Yield 25.7 mg, 73%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]3[CH:19]=[C:20]([F:24])[CH:21]=[C:22]([F:23])[C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25].O1CCOCC1>C(Cl)Cl>[ClH:25].[F:24][C:20]1[CH:21]=[C:22]([F:23])[C:17]2[O:16][N:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:18]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc3c(F)cc(F)cc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Fc1cc(F)c2onc(N3CCNCC3)c2c1
Temperature: 25 °C

Procedure:
4-(5,7-Difluoro-benzo[d]isoxazol-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.69 g, 5.0 mmol) was dissolved in CH2Cl2 (30 ml) and 4 N HCl in dioxane (24.9 ml, 100 mmol) was slowly added. The resulting mixture was stirred over night at r.t. After dilution with iPr2O the product was collected by filtration and washed with one portion of iPr2O before drying it under high vacuum at 50° C. to obtain 1.35 g (98%) as a white solid. m/z=240.1 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CN(C=O)C.O>[Cl:12][C:4]1[N:3]=[C:2]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2nc(Cl)cc(N)c2[N+](=O)[O-])CC1
Reaction time: 0.08 h

Procedure:
A solution of 2,6-dichloro-3-nitro-pyridin-4-ylamine (0.500 g, 2.40 mmol) in DMF (5 mL) was treated with K2CO3 (1.66 g, 12.0 mmol) and 1-methylpiperazine (0.267 mL, 2.40 mmol) at room temperature for 18 h. The resulting mixture was diluted with water (75 mL) and extracted three times with EtOAc (50 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g SEPRA Si 50 SPE column (Isco system: Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 3:1 v/v for 5 min, then 3:1 to 1:0 v/v over 40 min) to yield 6-chloro-2-(4-methyl-piperazin-1-yl)-3-nitro-pyridin-4-ylamine as a bright yellow solid. 1H-NMR (400 MHz, CD3OD) δ: 6.22 (s, 1H), 3.39-3.45 (m, 4H), 2.49-2.55 (m, 4H), 2.34 (s, 3H). Mass Spectrum (LCMS, APCI pos.): Calculated for C10H14ClN5O2: 272.1 (M+H); Measured: 272.1.
Reaction SMILES: [BrH:1].[NH+]1C=CC=CC=1.[CH3:8][O:9][N:10]=[C:11]([C:17]([O:21][CH3:22])([O:19][CH3:20])[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13].O>O1CCCC1>[CH2:15]([O:14][C:12](=[O:13])[C:11](=[N:10][O:9][CH3:8])[C:17]([O:21][CH3:22])([O:19][CH3:20])[CH2:18][Br:1])[CH3:16]
Reactant: Br
Reactant: CCOC(=O)C(=NOC)C(C)(OC)OC
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=NOC)C(CBr)(OC)OC

Procedure:
Pyridinium hydrobromide perbromide (1.82 g) was added to a solution of ethyl 2-methoxyimino-3,3-dimethoxybutyrate (syn isomer, 1.0 g) in dry tetrahydrofuran (10 ml) and heated under reflux for an hour. The resultant solution was poured into water (30 ml) and extracted with diethyl ether (10 ml×2). The extract was washed with 5% aqueous sodium thiosulfate solution (5 ml×5) and a saturated aqueous solution of sodium chloride (10 ml×1) successively. The solution was dried over magnesium sulfate and evaporated under reduced pressure to give ethyl-2-methoxyimino-3,3-dimethoxy-4-bromobutyrate (syn isomer, 2.02 g).
Reaction SMILES: [C:1]1([C@@H:7]([OH:14])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([Cl:26])[C:23](Cl)=[O:24]>O1CCCC1.CN(C1C=CN=CC=1)C>[N:9]1([CH2:8][C@H:7]([O:14][C:23](=[O:24])[CH:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[Cl:15])[Cl:26])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O[C@@H](CN1CCCC1)c1ccccc1
Reactant: O=C(Cl)C(Cl)c1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C(O[C@@H](CN1CCCC1)c1ccccc1)C(Cl)c1ccccc1Cl

Procedure:
A solution of 5.7 g of (R)-1-phenyl-2-(1-pyrrolidinyl)-ethanol in 25 ml of tetrahydrofurane was added to a solution of 6.5 g of 2,α-dichlorophenyl acetyl chloride in 25 ml of tetrahydrofurane containing 0.9 g of 4-dimethylamine pyridine. According to a similar procedure as in example 3, a mixture of diastereomeric esters containing 72% (R,R) and 28% (R,S) of the product in a yield of 8.4 g (74%) was obtained.
Reaction SMILES: N#N.C([Si](C)(C)[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[N:26]=[CH:27][O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:24])=[N:18]2)=[CH:14][N:15]=1)[CH3:10])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[OH:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]3[N:26]=[CH:27][O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:24])=[N:18]2)=[CH:14][N:15]=1)[CH3:10]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)c1ncc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-phenyl-oxazole-4-carboxylic acid (1-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-1H-pyrazol-3-yl)-amide (271 mg, 0.55 mmol) in dry THF (5.5 mL) was treated at 0° C. with TBAF (1.1 mL of a 1M solution in THF, 1.1 mmol). The reaction mixture was stirred at 0° C. for 30 min. The mixture was then diluted with EA (10 mL), washed with NaHCO3 (10 mL) followed by brine (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (EA) gave the title compound as a white foam. TLC: rf (EA)=0.18. LC-MS-conditions 02: tR=0.87 min; [M+H]+=380.34.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][C:12]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:8][N:7]=1)=O)C.CO.[CH2:39]([NH2:41])[CH3:40]>>[CH2:39]([NH:41][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:14]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:13][C:12]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:8][N:7]=1)=[O:3])[CH3:40]
Reactant: CCN
Reactant: CCOC(=O)c1cc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Solvent: CO
Product: CCNC(=O)c1cc(-c2cc(CC(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 120 °C

Procedure:
5-(2,4-Bis-benzyloxy-5-isobutyl-phenyl)-isoxazole-3-carboxylic acid ethyl ester was dissolved in 2M ethylamine in methanol (10 eq) and heated in the Smith Synthesiser microwave at 120° C. for 600 seconds. The solution was concentrated in vacuo to give 5-(2,4-bis-benzyloxy-5-isobutyl-phenyl)-isoxazole-3-carboxylic acid ethylamide as a white solid which was used without additional purification.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[OH-].[Na+].Cl[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>O.CO>[CH3:2][N:1]1[C:12](=[O:13])[C:11]2[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: OCCCCCCCCl
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(=O)c2c(ncn2CCCCCCCO)n(C)c1=O
Temperature: 70 °C
Yield: 21.4 %

Procedure:
18 g of theophylline are added under stirring at room temperature to a solution of 4.1 g of sodium hydroxide in 50 ml of water and 50 ml of methanol. After stirring the mixture at 70° C. 15.8 g of 7-chloro-1-heptanol are added. The mixture is then maintained at 70° C. for 22 hours and then it is subjected to evaporation under reduced pressure until it is dry. The residue is dissolved in 150 ml of 1-N-sodium hydroxide and the mixture is extracted with methylene chloride. After washing out with water and drying over sodium sulfate the methylene chloride solution is concentrated under reduced pressure and the oily residue is several times recrystallized from diisopropyl ether. 6.3 g of 1,3-dimethyl-7-(7'-hydroxyheptyl)-xanthine are obtained (yield, referred to reacted theophylline, =79.3%).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.[OH-:21].[Ca+2].[OH-:23]>ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[S:6](=[O:23])(=[O:21])[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1
Reactant: [OH-]
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1NC2=O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Dissolve 570 mg (2 mmoles) of the ester of Example 2 in a mixture of 2.3 gm of m-chloroperbenzoic acid and 75 cc of chloroform and stir for 12 hours at room temperature. Basify with calcium hydroxide. Filter and evaporate to dryness. Chromatograph the residue over silica gel eluding with 30% ethyl acetate in benzene. Collect the sulfone fractions and evaporate to dryness. Stir the residue in ether for 30 minutes, filter and dry to obtain the title product (m.p. 300°-302° C.), sintered around 295° C.).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[CH3:13][C:14](=[CH:16][CH2:17][CH2:18][CH:19]([CH2:21][CH2:22]O)[CH3:20])[CH3:15].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:22][CH2:21][CH:19]([CH3:20])[CH2:18][CH2:17][CH:16]=[C:14]([CH3:15])[CH3:13])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccccc1C(=O)O
Reactant: CC(C)=CCCC(C)CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccccc1C(=O)OCCC(C)CCC=C(C)C
Reaction time: 75 h
Yield: 81.9 %

Procedure:
A solution of 6.49 g (30.0 mmol) 2-acetylbenzoic acid, 3.81 g (31.2 mmol) DMAP and 12.48 g (80.0 mmol) citronellol in 60 ml dichloromethane was cooled in an ice bath before adding a solution of 8.84 g (42.9 mmol) DCC in 40 ml dichloromethane over 5 min. The reaction mixture was maintained with stirring at 40° for 75 h. The precipitate formed during the reaction was filtered and the filtrate washed with HCl (10%, 2×) and with a saturated Na2CO3 solution (2×). The organic phase was dried (Na2SO4), and the solvent evaporated. The excess citronellol was distilled (1 Torr, 60-80°), and the residue chromatographed (SiO2, 9:1 toluene/ethyl acetate) and distilled (0.6 Torr, 150-155°), to give 7.43 g (63%) of 3,7-dimethyl-6-octenyl 2-acetylbenzoate in the form of a colourless oil.
Reaction SMILES: Cl[C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][S:5][N:6]=1.[CH2:13]([NH2:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CS(C)=O>[CH2:13]([NH:19][C:2]1[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][S:5][N:6]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCCCCCN
Solvent: CS(C)=O
Product: CCCCCCNc1nsnc1-c1cccnc1

Procedure:
A solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (0.59 g, 3 mmol) and hexylamine (1.52 g, 15 mmol) in DMSO (5 ml) was heated at 100° C. for 48 h. After evaporation, water was added to the residue and extracted with ether. The combined organic extracts were dried and evaporated to give the title compound.