Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:4]=1.[CH2:17]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23])[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([N:13]1[CH2:14][CH:15]2[CH:11]([CH2:10][N:9]([C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=3)[CH2:16]2)[CH2:12]1)=[O:23])[CH3:18]
Reactant: COc1ccnc(N2CC3CNCC3C2)n1
Reactant: CCOc1ccccc1C(=O)O
Product: CCOc1ccccc1C(=O)N1CC2CN(c3nccc(OC)n3)CC2C1

Procedure:
The title compound was prepared according to the procedure used for Example 15 utilizing 2-(4-methoxy-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole and 2-ethoxybenzoic acid. MS (ESI) mass calcd. for C20H24N4O3, 368.44; m/z found, 369.3 [M+H]+. 1H NMR (CDCl3): 8.07 (d, J=5.7 Hz, 1H), 7.37-7.28 (m, 2H), 6.99 (t, J=7.4 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 6.02 (d, J=5.7 Hz, 1H), 4.07 (q, J=7.0 Hz, 2H), 4.01-3.85 (m, 5H), 3.84-3.70 (m, 2H), 3.65-3.45 (m, 3H), 3.34-3.22 (m, 1H), 3.16-2.92 (m, 2H), 1.35 (t, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([CH2:14][C:15]2[CH:36]=[CH:35][C:18]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:23]([F:34])[CH:22]=3)=[CH:17][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O1CCCC1.Cl>CO>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([CH2:14][C:15]2[CH:36]=[CH:35][C:18]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:23]([F:34])[CH:22]=3)=[CH:17][CH:16]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(C(C)(C)C)cc3C(C)(C)C)cc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1cc(C(C)(C)C)n(Cc2ccc(COc3ccc(CCC(=O)O)c(F)c3)cc2)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
A mixture of ethyl 3-[4-({4-[(3,5-di-tert-butyl-1H-pyrazol-1-yl)methyl]benzyl}oxy)-2-fluorophenyl]propanoate (0.73 g, 1.6 mmol), 1 N aqueous sodium hydroxide solution (3.0 mL), tetrahydrofuran (6 mL) and methanol (6 mL) was stirred at 60° C. for 1 hr. 1 N Hydrochloric acid (3.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (0.61 g, yield 81%) as colorless crystals. melting point 152-153° C., 1H NMR (CDCl3) δ: 1.26 (9H, s), 1.31 (9H, s), 2.55-2.66 (2H, m), 2.83-2.95 (2H, m), 4.96 (2H, s), 5.48 (2H, s), 5.92 (1H, s), 6.56-6.67 (2H, m), 6.84-6.94 (2H, m), 7.00-7.14 (1H, m), 7.26-7.34 (2H, m).
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15](I)=[CH:16][CH:17]=2)[O:12][C:11]=1[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O1[CH2:38][CH2:37][CH2:36][CH2:35]1>[Cl-].[Zn+2].[Cl-]>[CH2:2]([O:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([CH2:35][CH2:36][CH:37]([CH3:38])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:13])[CH2:19][CH2:10][CH2:11][CH:22]([CH3:27])[CH3:23])=[CH:16][CH:17]=2)[O:12][C:11]=1[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc(-c2oc3cc(I)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OC
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Mg]
Agent: [Zn+2]
Product: COc1cc(-c2oc3cc(CCC(C)CCCC(C)CCCC(C)C)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OC
Temperature: 50 °C
Reaction time: 25 h
Yield: 15 %

Procedure:
To a stirring suspension of zinc chloride (0.367 g, 2.7 mmol, 3 eq) and magnesium (0.100 g, 4.1 mmol, 4.7 eq) in tetrahydrofuran (2.5 ml) under argon was added 7 (1.268 g, 3.8 mmol, 4.2 eq) in tetrahydrofuran (2.5 ml). The reaction was heated to 50° C. for 19 hours then cooled. 34 (0.481 g, 0.8 mmol) in tetrahydrofuran (7 ml) and dichlorobis-[tri-(o-tolyl)-phosphinyl]palladium (0.063 g, 0.08 mmol, 0.09 eq) added and the reaction stirred for 25 hours. The reaction was then quenched with 3 N HCl (10 ml), diluted with water and extracted into ethyl acetate (3×). The combined aqueous layers were dried (MgSO4) and concentrated in vacuo to give a purple oil. Column chromatography (silica gel, petrol:EtOAc 9:1>2:1) yielded 48 (0.082 g, 15%) as a pale yellow oil.
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9](=[N:12][CH3:13])SC)=[CH:5][CH:4]=1.[N:16]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]([NH:12][CH3:13])=[N:24][CH2:23][CH2:22][CH2:21][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: CN=C(NCc1ccc(Cl)cc1)SC
Reactant: NCCCN1CCCC1
Agent: [I-]
Solvent: CCO
Product: CNC(=NCCCN1CCCC1)NCc1ccc(Cl)cc1
Yield: 73 %

Procedure:
A solution of the product from step b (358 mg, 1.00 mmol) and 3-pyrrolidin-1-yl-propylamine (0.19 ml) in ethanol (4 ml) was stirred at ambient temperature for 16 h followed by heating at reflux for 1 h. The solvent was removed at reduced pressure and the residue was partitioned between DCM (20 ml) and aqueous ammonia (880, 20 ml). The aqueous phase was extracted with further DCM (10 ml) and then discarded. The combined organic phases were washed twice with water (20 ml) and once with brine (20 ml). The organic phase was dried over anhydrous sodium sulfate and the filtrate evaporated to afford the title compound (225 mg, 73%). 1H NMR 7.40-7.29 (4H, m), 4.60 (2H, s), 3.42-3.47 (2H, m), 2.97 (3H, s), 2.50-2.44 (6H, m), 1.83-1.63 (6H, m).
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Cl:9][C:10]1=[C:11]([Cl:17])[C:12]([O:14][C:15]1=O)=[O:13].C(O)(=O)C>CCOCC>[CH:1]1([N:8]2[C:15](=[O:14])[C:10]([Cl:9])=[C:11]([Cl:17])[C:12]2=[O:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: NC1C=CCCCC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C1C(Cl)=C(Cl)C(=O)N1C1C=CCCCC1
Yield: 70.7 %

Procedure:
A mixture of 2-cycloheptenylamine (1.01 g), dichloromaleic anhydride (1.67 g) and acetic acid (10 ml) was heated under reflux for 3 hours. After cooling, ether (20 ml) was added to the reaction mixture which was then washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The deposited crystal was purified by recrystallization from hexane to obtain 1.67 g of N-(2-cycloheptenyl)dichloromaleinimide [Compound (217)].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:11])[C:3]=1[F:12].[C:13]([NH:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]2[CH2:28][CH2:27][N:26]([CH2:25][C:21]3[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=3)[C:18]([NH:17][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:32])[CH2:31][CH2:30]2)=[O:8])=[C:4]([Cl:11])[C:3]=1[F:12]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Reactant: Nc1ccc(C(=O)O)c(Cl)c1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3Cl)CC2)c1
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To 4-amino-2-chloro-3-fluorobenzoic acid (2.64 mmol, 500 mg) and N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (2.54 mmol, 700 mg) and triethylamine (10.76 mmol, 1.5 mL, 1089 mg) in dichloromethane (30 mL) was added 1-propanephosphonic acid cyclic anhydride (6.75 mmol, 4 mL, 4296 mg, 50% solution in ethyl acetate). After 2 hours stirring, ethyl acetate was added. The organic mixture was washed with saturated sodium hydrogen carbonate, water, and saturated sodium chloride. The organic mixture was dried sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica chromatography (eluting with 5% methanol in dichloromethane) to yield the title compound (325 mg). MS (ESI) m/z 447.1 [M+H]+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:20]([O:22][CH3:23])=[O:21])[C:7]([NH:9][CH:10]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11]([OH:13])=O)=[O:8].C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:37]([NH:40][CH2:41][CH2:42][CH3:43])[CH2:38][CH3:39]>ClCCl>[CH2:37]([N:40]([CH2:41][CH2:42][CH3:43])[C:11](=[O:13])[CH:10]([NH:9][C:7](=[O:8])[C:6](=[C:2]1[S:1][CH:5]=[CH:4][S:3]1)[C:20]([O:22][CH3:23])=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:38][CH3:39]
Reactant: COC(=O)CCC(NC(=O)C(C(=O)OC)=C1SC=CS1)C(=O)O
Reactant: CCCNCCC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC)C(=O)C(CCC(=O)OC)NC(=O)C(C(=O)OC)=C1SC=CS1
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
2-((2-(1,3-Dithiol-2-ylidene)-3-methoxy-3-oxopropanoyl)amino)-5-methoxy-5-oxopentanoic acid (4) (239 g) was dissolved in dichloromethane (1.5 l), followed by the addition of 70.7 g of triethylamine. To the resulting solution, 71.8 g of ethyl chlorocarbonate were added dropwise at 5-10° C. under stirring over 30 minutes. Subsequent to further stirring at 15-20° C. for 3 hours, di-n-propylamine (70.7 g) was added dropwise at 5-10° C., followed by stirring at room temperature for 12 hours. The solvent was removed under reduced pressure, and ethyl acetate (2 l) was then added to the residue. The resulting precipitate was filtered off. After the ethyl acetate layer was washed with 0.5 N hydrochloric acid and then with water, the solvent was removed under reduced pressure. Diethyl ether (800 ml) was added to the residue and the resulting precipitate was collected by filtration, whereby methyl 5-(dipropylamino)-4-((2-(1,3-dithiol-2-ylidene)-3-methoxy-3-oxopropanoyl)amino)-5-oxopentanoate (5) (113 g, yield: 57%) was obtained as pale yellow crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[S:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])=[CH:13][C:8]2[N:7]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[S:37][CH:38]=[C:39]([CH2:41][OH:42])[N:40]=4)[CH:31]=3)[CH2:28][C:27](=[O:50])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isopropyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.17 g) (Example J26) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (Example K27) (0.23 g) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light-brown solid (0.05 g).
Reaction SMILES: I[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Br:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1>[C:16]1([C:9]2[C:10]3[C:15]([C:2]([C:26]4[CH:27]=[CH:28][C:23]([Br:22])=[CH:24][CH:25]=4)=[C:3]4[C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Ic1c2ccccc2c(-c2ccccc2)c2ccccc12
Reactant: OB(O)c1ccc(Br)cc1
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: [K+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Temperature: 80 °C
Reaction time: 9 h
Yield: 52.2 %

Procedure:
1.0 g (2.63 mmol) of 9-iodo-10-phenylanthracene, 542 mg (2.70 mmol) of p-bromophenylboronic acid, 46 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), 3 mL (6 mmol) of an aqueous potassium carbonate (K2CO3) solution (2 mol/L), and 10 mL of toluene were collected, mixed, and stirred for 9 hours at 80° C. After the reaction, toluene was added and the mixture was filtered through florisil, Celite®, and alumina. The filtrate was washed with water and a saturated aqueous sodium chloride solution and then dried with magnesium sulfate. After natural filtration, the filtrate was concentrated and the obtained solid was recrystallized with chloroform and hexane, thereby obtaining 562 mg of objective 9-phenyl-10-(4-bromophenyl)anthracene as a light-brown solid with a yield of 45%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([CH3:18])[NH:13][C:14](=O)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:14]1[C:15]2[N:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[S:9][C:10]=2[N:11]=[C:12]([CH3:18])[N:13]=1
Reactant: Cc1nc2sc(-c3ccc(F)cc3)nc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 40 %

Procedure:
To a solution of 2-(4-fluorophenyl)-5-methyl-thiazolo[5,4-d]pyrimidin-7(6H)-one (0.40 g, 1.23 mmol) in POCl3 was added diisopropylethylamine (0.13 ml, 0.77 mmol). The reaction mixture was stirred under N2 at 90° C. for 3.5 hours. After cooling down to room temperature, the reaction mixture was poured into ice-water and the aqueous phase was extracted with diethyl ether. The combined organic layers were washed with a saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (hexane/EtOAc 10:1) to yield the title compound as a white solid (42.8 mg, 40%).
Reaction SMILES: C[O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[CH:6]=[C:7](\[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)/[CH:8]([CH3:10])[CH3:9].[OH-].[Na+]>CO>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11](/[C:7](/[CH:8]([CH3:10])[CH3:9])=[CH:6]\[CH:5]=[CH:4]\[C:3]([OH:19])=[O:2])=[CH:16][CH:15]=1
Reactant: COC(=O)/C=C/C=C(\c1ccc(OC)cc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(=C\C=C\C(=O)O)C(C)C)cc1
Yield: 95.6 %

Procedure:
As described in Example 99, (2E,4Z)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid methyl ester (4.2 g) was saponified in a refluxing mixture of methanol (15 mL) and 2N NaOH (15 mL). After 2 hours reaction was worked up in the usual way to afford 3.8 g of (2E,4Z)-5-(4-methoxyphenyl)-6-methyl-2,4-heptadienoic acid. A sample was crystallized from cyclohexane-hexane to give the analytical specimen, mp 131.5°-133° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@:8]2([CH3:15])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]2)[CH:7]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](Cl)([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1>>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([C:25]([NH:14][C:10]2[CH2:11][O:12][CH2:13][C@:8]([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[F:16])([CH3:15])[N:9]=2)([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:37][CH:36]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)COCC(N)=N1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 72 %

Procedure:
In analogy to step c) in the synthesis of Building block I, the reaction of (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine with 4,4′-dimethoxytriphenylmethyl chloride yielded the title compound as a white solid (72% of theory). Mass (calculated) C32H30BrFN2O3 [589.51]; (found) [M+H]+=589, [M+2-H]+=591.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:19]([OH:21])=O)[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:24])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:19]([Cl:24])=[O:21])[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C(=O)O)CCC3(CC2)OCCO3)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(C2(C(=O)Cl)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 245 parts of 8-(4-methoxyphenyl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid, 150 parts of thionyl chloride and 1350 parts of benzene is stirred first for 30 minutes at room temperature and further for 4 hours at reflux. The reaction mixture is evaporated, yielding 275 parts of 8-(4-methoxyphenyl)-1,4-dioxaspiro[4,5]decane-8-carbonyl chloride as a residue.
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([OH:20])[C:17]3[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:29]([O:31][C:32]([C:34]12[CH2:51][CH:50]1[CH:49]=[CH:48][CH2:47][CH2:46][CH2:45][CH2:44][N:43]([CH3:52])[C:42](=[O:53])[CH:41]1[CH:37]([CH2:38][CH:39](OS(C3C=CC(Br)=CC=3)(=O)=O)[CH2:40]1)[C:36](=[O:65])[NH:35]2)=[O:33])[CH3:30]>CN1C(=O)CCC1.C(Cl)(Cl)Cl>[CH2:29]([O:31][C:32]([C:34]12[CH2:51][CH:50]1[CH:49]=[CH:48][CH2:47][CH2:46][CH2:45][CH2:44][N:43]([CH3:52])[C:42](=[O:53])[CH:41]1[CH:37]([CH2:38][CH:39]([O:20][C:18]3[C:17]4[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=4)[N:11]=[C:10]([C:8]4[N:9]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[S:6][CH:7]=4)[CH:19]=3)[CH2:40]1)[C:36](=[O:65])[NH:35]2)=[O:33])[CH3:30]
Reactant: COc1ccc2c(O)cc(-c3csc(NC(C)C)n3)nc2c1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(OS(=O)(=O)c3ccc(Br)cc3)CC1C(=O)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4csc(NC(C)C)n4)nc4cc(OC)ccc34)CC1C(=O)N2
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 12.9 %

Procedure:
2-(Isopropylamino-thiazol-4-yl)-7-methoxy-quinolin-4-ol (220 mg, 0.7 mmol) (prepared as described in WO 00/59929) was dissolved in 7 ml of NMP (N-methyl pyrrolidinone), one spoon of Cs2CO3 was added, stirred at 60° C. for 1.5 h. Then compound 108 (150 mg, 0.24 mmol) was added. The reaction mixture was stirred at 80° C. overnight. Was diluted with chloroform and washed with sodium bicarbonate, brine. Water phases were back-extracted with chloroform. The combined organic layers were dried over sodium sulphate and evaporated. The crude product was purified by preparative HPLC (Gilson) (MeOH—H2O, 65%) to give 21 mg of product (yield 13%) as well as 12 mg of isomer.
Reaction SMILES: [CH3:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH3:15])[N:11]=[N:10]1.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.[Br:34]N1C(=O)CCC1=O.ClC1C=CC=CC=1>O>[Br:34][CH2:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH3:15])[N:11]=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Br)cccc1-n1nnn(C)c1=O
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: O
Solvent: Clc1ccccc1
Product: Cn1nnn(-c2cccc(Br)c2CBr)c1=O
Yield: 68.7 %

Procedure:
A mixture of 1-(2-methyl-3-bromophenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 10) 8.47 g, 1,1′-azobis(cyclohexane-1-carbonitrile) 1.54 g, N-bromosuccinimide 6.44 g and chlorobenzene 125 ml was stirred with heating under reflux for five hours. After cooling the mixture, to the reaction solutions was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(2-bromomethyl-3-bromophenyl)-4-methyl-1,4-dihydrotetrazole-5-one 7.52 g.
Reaction SMILES: [CH2:1]([C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CN1C=CN=C1.[N+:29]([C:32]1[CH:37]=[C:36]([N+:38]([O-])=O)[CH:35]=[CH:34][C:33]=1Cl)([O-])=O>C(C(C)=O)C>[CH2:1]([C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][C:35]1[CH:34]=[CH:33][C:32]([NH2:29])=[CH:37][C:36]=1[NH2:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cn1ccnc1
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCc1cccc(Oc2ccc(N)cc2N)c1
Reaction time: 1.5 h

Procedure:
4-(-3-Pentadecylphenoxy)benzene-1,3-diamine is prepared as described in chapter 2 of Jinu Suju Mathew, “Novel Thermally Stable Polymers from a Renewable Resource (Cashew Nut Shell Liquid): Thesis, Characterization, and Applications,” Ph.D. Thesis, U. of Pune, July 2001, the disclosure of which is totally incorporated herein by reference. More specifically, to a 100 mL three necked round bottom flask equipped with a reflux condenser, thermowell, and magnetic stirrer is added 5 g (0.016 mol) of 3-pentadecylphenol, 1.35 g (1.3 mL, 0.016 mol) of N-methyl imidazole, and 50 mL methyl ethyl ketone, and the solution is stirred for 1.5 hours. Thereafter 3.33 g (0.016 mol) of 2,4-dinitrochlorobenzene is added to this mixture and the reaction mixture is refluxed for 3 hours. The solvent is then distilled off and the residue dissolved in ether. The ether solution is then washed with water, 5% NaOH solution, and again with water. The ether solution is then dried with sodium sulfate and the ether distilled off to obtain the crude product. The crude product is then recrystallized from petroleum ether at 40 to 60° C. to obtain pure 1-(3-pentadecylphenoxy)-2,4-dinitrobenzene, of the formula
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl.O>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 80 °C

Procedure:
A mixture of 1-bromo-4-nitrobenzene (5 g, 24.8 mmol) and 1-benzylpiperazine (8.6 ml, 49.5 mmol, 2 equiv) is heated to 80° C. for 17 h. The reaction mixture is allowed to cool to RT, and is diluted with DCM/H2O. The layers are separated and the aqueous phase is extracted with DCM. The combined organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by silica gel column chromatography (Hex/EtOAc, 1:1) affords the title compound as a yellow solid: ESI-MS: 298.3 [MH]+; tR=3.25 min (purity: 100%, system 1).