Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.C([O:21][CH2:22][CH3:23])(=O)C>C([O-])([O-])=O.[Na+].[Na+].C(#N)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>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:5]3[CH:4]=[C:23]([CH:9]=[CH:8][CH:6]=3)[CH:22]=[O:21])=[CH:8][C:6]=2[N:7]=1
Reactant: CCOC(C)=O
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=Cc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (300 mg), 130 mg of 3-formylbenzenelboronic acid and 55 mg of Bis(triphenylphosphine)palladium(II) dichloride in 0.6 mL of 1M Na2CO3 and 0.6 mL of acetonitrile was heated to 100° C. in the microwave reactor for 15 min. The reaction mixture was diluted with ethyl acetate (60 mL), and then washed with H2O (40 mL). The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by ISCO CombiFlash (0-40% ethyl acetate/hexane) to yield 99 mg of 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzaldehyde.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=O)[NH:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:20])=CC=1>C(#N)C>[S:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[S:20])[NH:3][CH2:2]1
Reactant: O=C1NCSc2ccsc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CC#N
Product: S=C1NCSc2ccsc21

Procedure:
(aae) 19.6 g of 2.3-dihydro-4H-thieno[2,3-e][1,3]-thiazin-4-one were heated under reflux together with 23.1 g of Lawesson reagent in 200 ml of acetonitrile until all of the starting material reacted. The reaction mixture was cooled and the crystallized-out product was removed by filtration. By recystallization from ethyl acetate there was obtained pure 2,3-dihydro-4H-thieno[2,3-e][1,3]thiazine-4-thione of m.p. 136°-138°. Additional material can be obtained by evaporation of the mother liquor and recrystallization.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[N:12]=1)([CH3:10])([CH3:9])[CH3:8]>CCO>[C:7]([C:11]1[N:12]=[C:13]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[CH:14]=[C:15]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:16]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1nc(Cl)cc(C2CCC2)n1
Reactant: C1CNCCN1
Solvent: CCO
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Yield: 87.4 %

Procedure:
piperazine (7.54 g, 87.57 mmol) was dissolved in EtOH, 2-tert-butyl-4-chloro-6-cyclobutyl-pyrimidine (3.28 g, 14.60 mmol) was added dropwise at 80° C. over 10 min. The solution was refluxed overnight and then concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (3.5 g, 87%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([NH2:10])=[O:9].[C:11](O)(=O)[CH3:12].[C:15]([BH3-])#N.[Na+]>CO>[CH:12]1([N:2]2[CH2:7][CH2:6][O:5][CH2:4][CH:3]2[C:8]([NH2:10])=[O:9])[CH2:11][CH2:15]1
Reactant: NC(=O)C1COCCN1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(=O)C1COCCN1C1CC1
Temperature: 70 °C
Yield: 47.3 %

Procedure:
To 1.2 g (7.2 mmol) of morpholine-3-carboxamide hydrochloride (a synthesis of which is described in WO-2005/026 156, Hennequin L. F. A. et al.) dissolved in methanol (36 ml) are successively added 2.9 g of 3 Å molecular sieves, 4.3 g (72 mmol) of acetic acid, 7. g (43.2 mmol) of 2-[(1-ethoxycyclopropyl)oxy]trimethylsilane and 4.4 g (31.7 mmol) of sodium cyanoborohydride. The reaction mixture is heated at 70° C. for 3 hours 30 minutes, and then cooled to room temperature and filtered. The filtrate is concentrated under reduced pressure and the residue is then taken up in dichloromethane (200 ml) and washed three times with aqueous NaOH solution (1N) (100 ml). The organic phase is dried over Na2SO4, filtered and then concentrated under reduced pressure. 0.58 g of product is obtained, in the form of a white powder. Yield 47%. Melting point 116° C. MH+: 171.2 (tr: 1.03 min., condition 1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[NH:27][C:26](=[O:28])[CH2:25][CH2:24][NH:23][C:22]=4[N:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:39]I.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:20][C:21]4[N:27]([CH3:39])[C:26](=[O:28])[CH2:25][CH2:24][NH:23][C:22]=4[N:29]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CCN4)cc2)CCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCNc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-7-yl)phenyl)cyclobutyl)carbamate (53 mg, 0.11 mmol) in dry DMF (1 ml) was added sodium hydride (4.4 mg, 0.11 mmol) and methyliodide (6.9 μl, 0.11 mmol) under nitrogen. The resulting mixture was stirred for 1 hour at room temperature. Water was added and the mixture was extracted with EtOAc (3×15 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 57% EtOAc in cyclohexane) to give the title compound (21 mg, 38%). 1H NMR (500 MHz, CDCl3): 7.39 (1H, s), 7.27-7.23 (7H, m), 7.16-7.14 (2H, m), 5.04 (1H, s), 4.91 (1H, br s), 3.88 (2H, br s), 3.39 (3H, s), 2.74 (2H, t), 2.55-2.25 (4H, m), 2.10-2.03 (1H, m), 1.86-1.78 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH:11]([C:13](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:14])=[O:12]>C1(C)C=CC=CC=1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:13]([CH3:14])[CH:11]=[O:12])=[CH:5][CH:4]=1
Reactant: CC(C=O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(C=C(C)C=O)cc1

Procedure:
A suspension of 4-methoxybenzaldehyde (10 g, 0.073 mol) and α-formylethylidenetriphenylphosphorane (25.7 g, 0.081 mol) in dried toluene (200 ml)was heated with stirring at reflux under an atmosphere of nitrogen for 24 h. The cooled reaction mixture was decanted to removed insoluble material and evaporated to give a brown oil. The oil was taken up in diethylether and the resulting suspension purified on flash silica eluting with hexane-diethyl ether (3:2). The resulting oil was a mixture of required product and 4-methoxybenzaldehyde and therefore dissolved in dried toluene (150 ml) and reaction continued as described above with α-formylethylidenetriphenylphosphorane (5.76 g, 0.018 ml) for 7 h. Following the work up and chromatography as above 3-(4-methoxyphenyl)-2-methylpropenaldehyde was obtained as a yellow oil.
Reaction SMILES: C1(C([NH:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[O:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=3)=[CH:30][CH:29]=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[ClH:43]>C(O)C.C(Cl)Cl>[ClH:43].[NH2:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[O:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[O:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:32][CH:33]=1
Reactant: c1ccc(C(N[C@@H]2CCC[C@H]2OCc2ccc(-c3nc4ccccc4o3)cc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: N[C@@H]1CCC[C@H]1OCc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 8 h

Procedure:
To a mixture of trans-2-triphenylmethylamino-[4-(benzoxazol-2-yl)benzyloxy]-cyclopentane (3.67 g; 6.67 mmol)in ethanol (100 ml) and CH2Cl2 (20 ml) is added ethanolic HCl until pH≈2. This is stirred overnight, concentrated in vacuo, washed with CH2Cl2, dried under vacuum and flash chromatographed using 3:1; CH2Cl2:EtOH. The product is rechromatographed using 3:1; CH2Cl2 :EtOH to obtain trans-2-amino-[4-(benzoxazol-2-yl)benzyloxy]cyclopentane hydrochloride (m.p. >200° C.).
Reaction SMILES: [O:1]([C:8]1[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:18][C:19](=[O:29])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)C.CCN(C(C)C)C(C)C>CN(C=O)C>[O:1]([C:8]1[O:12][C:11]([C:13]([NH:28][C:24]2[CH:23]=[C:22]([CH:21]=[CH:20][C:19]([OH:29])=[O:18])[CH:27]=[CH:26][CH:25]=2)=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)o1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)C=Cc1cccc(NC(=O)c2ccc(Oc3ccccc3)o2)c1

Procedure:
5-phenoxy-2-furoic acid (3) (213 mg, 1.05 mmol) was coupled to aniline (2) (200 mg, 1.05 mmol) using Method B, except that DIPEA (270 mg, 2.09 mmol) and DMF (2 mL) were used to give the title compound. Yield: 178 mg, 96%; LC/MS tr 1.65 min; HPLC Purity: 95%; MS (ES+) m/z 378 (M+H)
Reaction SMILES: CO[CH:3]([O:21][CH3:22])[CH2:4][N:5]1[C:10]([C:11]([O:13]C)=O)=[C:9]([O:15][CH3:16])[C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]1.CC(O)=O.CS(O)(=O)=O.[NH2:32][C@H:33](CO)[CH3:34]>CC#N>[CH3:34][C@@H:33]1[N:32]2[C:11](=[O:13])[C:10]3[N:5]([CH:6]=[C:7]([C:18]([OH:20])=[O:19])[C:8](=[O:17])[C:9]=3[O:15][CH3:16])[CH2:4][C@H:3]2[O:21][CH2:22]1
Reactant: C[C@H](N)CO
Reactant: COC(=O)c1c(OC)c(=O)c(C(=O)O)cn1CC(OC)OC
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1c2n(cc(C(=O)O)c1=O)C[C@H]1OC[C@H](C)N1C2=O
Temperature: 61.5 °C
Reaction time: 15 h

Procedure:
1-[2,2-bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-1,4-dihydro-3-pyridinecarboxylic acid (22.54 g) was dissolved in 220 mL of CH3CN. HOAc (20 mL) and CH3SO3H (1.4 mL) were added at room temperature and the mixture was heated to 58-65° C. for 19.5 h. Alaninol (7.511 g) in CH3CN (15 mL) was added slowly and the resultant mixture was stirred at 64° C. for 18.5 h. The mixture was concentrated, and the residue was redissolved in CH2Cl2 (170 mL). HCl (1 N, 170 mL) was added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (170 mL×2) and the organic layers were combined and concentrated. MeOH (50 mL) was added and the resultant mixture was again concentrated. MeOH (80 mL) was added and the resultant mixture was heated at reflux for 4 h, gradually cooled to 20° C. and held at 20° C. for 15 h. The product was collected by filtration and dried under vacuum.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[CH:14][C:13]=1[OH:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:27])[CH3:28])[CH:21]=2)=[CH:14][C:13]=1[O:32][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(Oc3ccc([N+](=O)[O-])cn3)c2)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (1.00 g, 6.35 mmol) and N-(4-chloro-3-hydroxyphenyl)-3-(1-cyano-1-methylethyl)benzamide (2.00 g, 6.35 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (1.31 g, 9.52 mmol), and the mixture was stirred at 70° C. for 16 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Water (100 mL) was added to the obtained residue, and the mixture was twice extracted with ethyl acetate (50 mL)/hexane (50 mL). The combined organic layer was washed with water (150 mL) and saturated brine (150 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (2.57 g, 93%) as a yellow oil.
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])C(=O)C=1)C1C=CC=CC=1.[Br:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[N:41][NH:40][C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1>>[Br:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[N:41][N:40]([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=3[CH3:26])=[O:17])[C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1
Reactant: O=c1cc(OCc2ccc(Br)cn2)cn[nH]1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CO)ccc1C(=O)Cn1ncc(OCc2ccc(Br)cn2)cc1=O
Yield: 90 %

Procedure:
5-(5-Bromo-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 1c employing 5-(5-bromo-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (described in WO 09/103,478) instead of 4-benzyloxy-1H-pyridin-2-one.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:15][C:16]1[CH:17]=[C:18]([OH:25])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C.CCOC(C)=O>[CH2:7]([O:25][C:18]1[CH:19]=[CH:20][C:21]([N+:22]([O-:24])=[O:23])=[C:16]([F:15])[CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Reaction time: 8 h

Procedure:
K2CO3 (8.97 g) and benzylbromide (4.25 mL) were added to a solution of 3-fluoro-4-nitrophenol (5.10 g) in anhydrous DMF (30 mL) at room temperature, and the mixture was stirred overnight. The mixture was diluted with EtOAc and washed with H2O and brine. The organic layer was dried over magnesium sulfate and concentrated. The residual solid was crystallized from EtOAc/hexane to yield 7.31 g of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:23]#[N:24])[N:6]=1)[CH:2]=[CH2:3].[CH3:25][C:26]1([CH3:33])[O:30][C@@H](CO)C[O:27]1>>[CH3:25][C:26]1([CH3:33])[O:30][C@@H:2]([CH2:1][O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:7]([C:23]#[N:24])[N:6]=2)[CH2:3][O:27]1
Reactant: C=CCOc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12
Reactant: CC1(C)OC[C@H](CO)O1
Product: COc1ccc2c(OC[C@H]3COC(C)(C)O3)nc(C#N)c(-c3ccccc3)c2c1

Procedure:
Following the procedure for 1-(allyloxy)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using (S)-(+)-2,2,-dimethyl-1,3-dioxolane-4-methanol in place of allyl alcohol, the title compound was synthesized.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]([CH3:19])=[CH2:18]>CC(C)=O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:17]([CH3:19])=[CH2:16])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: C=C(C)COc1ccc(Br)cc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a solution of 4-bromo phenol (7.0 g, 40.40 mmol) in acetone (165 mL) was added K2CO3 (27.8 g, 202 mmol) followed by 3-bromo-2-methylprop-1-ene (4.9 mL, 44.5 mmol). The mixture was stirred at reflux temperature for 16 h. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2 (200 mL), washed with H2O (2×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound (6) (8.0 g, 93%) as a colorless liquid. 1H NMR (CDCl3, 400 MHz) δ 7.37 (d, J=9.2 Hz, 2H), 6.81 (d, J=9.2 Hz, 2H), 5.08 (s, 1H), 5.00 (s, 1H), 4.41 (s, 2H), 1.83 (s, 3H); MS (ESI, M+H+) C10H12BrO, calcd. 227.1. found 227.0, 229.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N-:10]=[N+:11]=[N-:12].[Na+].O>CO>[N:10]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:11]=[N-:12]
Reactant: CCOC(=O)CCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CCCN=[N+]=[N-]
Yield: 98.5 %

Procedure:
A solution of ethyl 4-bromobutyrate (10.0 g, 51.3 mmol), NaN3 (6.66 g, 102 mmol) and 25 ml of water in 75 ml of MeOH was refluxed for 3.5 hrs. The MeOH was removed in vacuo and residue was partitioned between CHCl3 (200 ml) and water (50 ml). The organic. layer was separated and washed with water. After drying and evaporation of solvent, ethyl 4-azidobutyrate (7.94 g, 98.6%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[CH3:8][C:2]([CH3:1])([CH3:9])[CH2:3][CH2:4][C:5]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7]
Reactant: CC(C)(C)CCC(=O)O
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CCC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4,4-Dimethylvaleric acid (348 g), piperidine (291 mL) and DMF (1.7 L) were mixed. To the mixture were added HOBt.H2O (450 g) and WSC.HCl (563 g) at ice temperature. After the mixture was stirred at RT overnight, water (1.7 L) was added to the reaction mixture at ice temperature and the mixture was extracted with toluene (500 mL, and 400 mL×2). The organic layer was washed with aqueous 10 w/v % sodium carbonate (1 L) and water (1 L), then concentrated in vacuo to give the title compound (508 g) as a crude product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([C:10]1[C:15]([C:16](OCC)=[O:17])=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([C:27](OCC)=[O:28])=[C:12]([CH:32]([CH3:34])[CH3:33])[N:11]=1)([CH3:9])[CH3:8].O>CCOCC.O1CCCC1>[OH:17][CH2:16][C:15]1[C:10]([CH:7]([CH3:9])[CH3:8])=[N:11][C:12]([CH:32]([CH3:33])[CH3:34])=[C:13]([CH2:27][OH:28])[C:14]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(C(=O)OCC)c1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)c1nc(C(C)C)c(CO)c(-c2ccccc2)c1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40.5 ml (40.5 mmol) of a 1 molar solution of lithium aluminum hydride in ether are added dropwise under nitrogen to a solution of 6.4 g (16.2 mmol) of the compound from Example 11 in 100 ml of dry tetrahydrofuran at 0° C. The mixture is stirred overnight at room temperature, warmed to 50° C. for 3 h and cooled again to 0° C. 200 ml of water are cautiously added dropwise to the mixture, and it is filtered over kieselguhr with suction and washed with 250 ml of ether. The organic phase is separated, washed once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is stirred with petroleum ether, and the precipitate is filtered off with suction and dried in a desiccator.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.Cl.O1CCOCC1.[CH3:26][CH:27](O)[CH3:28]>>[F:1][C:2]1[CH:3]=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH:27]([CH3:28])[CH3:26])=[O:17])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)O
Reactant: O=C(O)CCCCNc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)OC(=O)CCCCNc1cc(F)ccc1[N+](=O)[O-]

Procedure:
A mixture of 2.19 g (8.55 mmol) of 5-(3-fluoro-6-nitrophenyl)aminovaleric acid, 100 ml of 2-propanol and 5 ml of 4N hydrochloric acid-dioxane was subjected to heating under reflux for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (developing solvent: hexane:ethyl acetate=9:1 to 6:1) to give 2.55 g (stoichiometric) of isopropyl 5-(3-fluoro-6-nitrophenyl)aminovalerate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[F:27][C:28]1[N:29]=[CH:30][C:31]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=2)=[CH:32][CH:33]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccc(F)nc3)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 56.4 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.12 g) and 2-fluoropyridine-5-boronic acid (0.072 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.015 g) to obtain the title compound (0.070 g) as a colorless solid. MS (ISP): 485.3 (M+H)+
Reaction SMILES: [CH3:1][CH:2]([CH2:4][N:5]1[C:9]2C3C=CC=CC=3N=C(N)C=2N=[CH:6]1)C.C[C@@H](O)CCCC[N:25]1C(=O)N(C)C2N=CN(C)[C:28]=2[C:26]1=[O:27].C[C:40]1[C:45](OC)=[C:44](C/C=C(/CCC(OCCN2CCOCC2)=O)\C)[C:43](O)=[C:42]2[C:66]([O:68]C[C:41]=12)=[O:67]>CC(O)=O.C1N=CNC=1C[C@H](NC(CN)=O)C(N[C@H](C(O)=O)CCCCN)=O.[Cu+2]>[CH3:1][CH:2]([OH:27])[CH2:4][N:5]([CH3:9])[CH3:6].[CH3:28][C:26]([NH:25][C:45]1[CH:40]=[CH:41][C:42]([C:66]([OH:68])=[O:67])=[CH:43][CH:44]=1)=[O:27]
Reactant: C[C@@H](O)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Agent: [Cu+2]
Agent: NCCCC[C@H](NC(=O)[C@H](Cc1cnc[nH]1)NC(=O)CN)C(=O)O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(=O)O)cc1
Product: CC(O)CN(C)C

Procedure:
imiquimod; interferon beta-lb; lisofylline; mycophenolate mofetil; prezatide copper acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13](=O)[CH3:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].BrBr.C(O)C.[NH:21]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[S:28])=[N:22]1>O1CCOCC1.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:28][C:27]([NH:26][C:23]3[CH:24]=[CH:25][NH:21][N:22]=3)=[N:29][C:13]=2[CH3:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: NC(=S)Nc1cc[nH]n1
Reactant: CC(=O)Cc1ccc(S(C)(=O)=O)c(F)c1
Agent: BrBr
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1nc(Nc2cc[nH]n2)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
1-(3-Fluoro-4-methanesulfonyl-phenyl)-propan-2-one (68c) (6.0 g, 26 mmol) is dissolved in dioxan (50 ml) and the solution is cooled to 10° C. at which point the mixture is semi frozen. A solution of bromine (0.9 ml, 17 mmol) in chloroform (2 ml) is added slowly over 30 minutes and the mixture is stirred for an additional 15 minutes in a semi frozen state. The mixture is then allowed to warm to room temperature and the solvent is removed to give a red oil. Ethanol (70 ml) and (1H-pyrazol-3-yl)-thiourea (35a) (3.2 g, 22 mmol) are added and the reaction is stirred at 60° C. for 30 minutes. The solution is allowed to cool to room temperature whereupon the product crystallises. Filtration affords the titled compound.