Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[CH2:14][CH:15]([OH:18])[CH2:16][OH:17]>[OH-].[Na+].O>[OH:18][CH:15]([CH2:16][OH:17])[CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)c1c(C)cc(O)cc1C
Reactant: OCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1c(C)cc(OCC(O)CO)cc1C
Temperature: 140 °C
Yield: 57.4 %

Procedure:
A pressure glass vessel charged with 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (2.00 g, 12.2 mmol, 1.0 equiv) and 3-chloropropane-1,2-diol (1.02 mL, 12.2 mmol, 1.0 equiv) in 50% aqueous NaOH solution (20.0 mL) was heated at 140° C. for 16 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30% EtOAc in hexanes as eluant) to provide 1-(4-(2,3-dihydroxypropoxy)-2,6-dimethylphenyl)ethanone (1.66 g, 7.0 mmol) as yellow oil in 57% yield: 1H NMR (CDCl3, 500 MHz) δ o 6.57 (s, 2 H), 4.10-4.11 (m, 1 H), 4.08-4.09 (m, 2 H), 4.01-4.02 (m, 1 H), 3.74-3.75 (m, 1 H), 2.58-2.59 (s, 1 H), 2.45 (s, 3 H), 2.23 (s, 6 H), 2.05-2.10 (s, 1 H); ESI-MS: m/z 239.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:10]2([O:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([OH:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[C:15]1([O:25][CH2:11][C:10]2([OH:12])[CH2:13][CH2:14][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(CN2CCC3(CO3)C2)cc1
Reactant: Oc1cccc2ccccc12
Solvent: c1ccccc1
Product: OC1(COc2cccc3ccccc23)CCN(Cc2ccccc2)C1
Temperature: 115 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
A mixture of 18.9 g (0.1 mole) of 5-benzyl-1-oxa-5-azaspiro[2.4]heptane and 15.6 g (0.11 mole) of 1-naphthol was heated to 115° C. to form a homogenous melt, which was stirred with a magnetic stirrer for 2 hours. Upon cooling, a paste-like material formed. The reaction mixture was dissolved in benzene, filtered and ligroin added to the filtrate until cloudy. The suspension was warmed to solution and allowed to stand in the refrigerator overnight. The precipitate was collected by filtration to give 20.2 g (60%) of crude material. A portion of this solid was recrystallized from 190 ethanol to give a white crystalline solid, m.p. 129.5°-130° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]1C[O:14][CH2:13][CH2:12]1.C(O)CCO.CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]1[O:14][CH2:13][CH2:12][CH2:11][O:5]1
Reactant: C1CCOC1
Reactant: O=Cc1cc(O)ccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: OCCCO
Product: Oc1ccc(Br)c(C2OCCCO2)c1

Procedure:
To the solution of 2-bromo-5-methoxy-benzaldehyde (10 g, 46.5 mmol) at −78° C. is added BBr3 (25 g, 93.75 mmol) and allowed to warm to room temperature. After 2 h, the reaction is quenched with water and extracted with ethyl acetate. The combined organic layers are washed with water, brine, dried over MgSO4, concentrated and purified by column chromatography to afford 3.6 g of 2-bromo-5-hydroxy-benzaldehyde. To the solution of 2-bromo-5-hydroxy-benzaldehyde (1.45 g, 7.2 mmol in benzene (30 ml) and THF (6 ml) is added 1,3-propanediol (2.74 g, 36 mmol) and TsOH (37 mg, 0.22 mmol). The mixture is refluxed for 24. After cooling down, the solvent is evaporated. The residue is loaded on silica and purified by column chromatography to afford the titled compound (2.3 g) as brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:33])[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](O)=[O:24])[CH:20]=[CH:19][C:18]=1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[CH3:12][N:13]([CH3:33])[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[O:24])[CH:20]=[CH:19][C:18]=1[C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: CN(C)CCOc1cc(C(=O)O)ccc1-c1ccc(F)cc1
Product: CN(C)CCOc1cc(C(=O)Nc2ccc3cccnc3c2)ccc1-c1ccc(F)cc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (20 mg, 0.14 mmol) and 2-(2-dimethylaminoethoxy)-4′-fluoro-1,1′-biphenyl-4-carboxylic acid (D79) (50 mg, 0.17 mmol) as a yellow solid. MS(ES): MH+ 430, M-H+ 428
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:4]([CH:5]=[C:6]([C:13]([F:16])([F:15])[F:14])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]1[C:17](O)=[O:18].S(Cl)([Cl:23])=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:20])[CH:4]([CH:5]=[C:6]([C:13]([F:16])([F:15])[F:14])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]1[C:17]([Cl:23])=[O:18]
Reactant: CC1(C)C(C=C(c2ccccc2)C(F)(F)F)C1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(C=C(c2ccccc2)C(F)(F)F)C1C(=O)Cl
Yield: 92.5 %

Procedure:
7.1 g (0.025 mol) of 2,2-dimethyl-3-(2-trifluoromethyl-2-phenyl-vinyl)-cyclopropanecarboxylic acid were dissolved in 100 ml of carbon tetrachloride, and 9 g of thionyl chloride were slowly added dropwise at 25° C., while stirring. The mixture was then heated to the reflux temperature for 4 hours. After this reaction time, excess thionyl chloride and carbon tetrachloride were distilled off under a waterpump vacuum. The oil which remained was freed from last residues of solvent by brief incipient distillation at a bath temperature of 40° C./2 mm Hg. 7 g (92.7% of theory) of 2,2-dimethyl-3-(2-trifluoromethyl-2-phenyl-vinyl)-cyclopropanecarboxylic acid chloride were obtained. The structure was confirmed by the 1H-NMR spectrum.
Reaction SMILES: C([O-])(=O)C.[K+].FC(F)(F)S(O[C:12]1[CH:13]=[C:14]2[C@@:25]3([CH2:29][O:28][C:27]([NH2:30])=[N:26]3)[C:24]3[C:19](=[N:20][CH:21]=[C:22](C#CC4(C)COC4)[CH:23]=3)[O:18][C:15]2=[CH:16][CH:17]=1)(=O)=O.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.BrC1C=NC=CC=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.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.O>[O:28]1[CH2:29][C:25]2([C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[O:18][C:15]3[C:14]2=[CH:13][CH:12]=[CH:17][CH:16]=3)[N:26]=[C:27]1[NH2:30]
Reactant: CC1(C#Cc2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2O3)COC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: NC1=NC2(CO1)c1ccccc1Oc1ncccc12
Temperature: 100 °C

Procedure:
A solution of potassium acetate (0.210 g, 2.140 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.022 g, 0.027 mmol), (S)-2′-amino-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (0.265 g, 0.535 mmol), and bis(pinacolato)diboron (0.143 g, 0.562 mmol) in 5 mL DMF was heated to 100° C. for 3 hours. Pd(PPh3)4 (0.031 g, 0.027 mmol) was added, followed by 3-bromo-4-fluoropyridine (0.141 g, 0.802 mmol), potassium carbonate (0.296 g, 2.140 mmol), and 2 mL water. The reaction mixture was capped with argon and was heated to 100° C. for 2 hours. After cooling to RT, the reaction mixture was diluted with EtOAc and was washed sequentially with water and brine. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography [0-100% (9:1 CH2Cl2:MeOH)/CH2Cl2] then HPLC (10-90% MeCN/H2O) provided (S)-7-(4-fluoropyridin-3-yl)-3-(3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine. MS m/z=443.0 [M+H].
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3=[N:17][C:18]([CH3:22])=[CH:19][C:20]([CH3:21])=[C:15]3[N:14]=[C:13]2[CH2:23][CH3:24])=[CH:8][C:7]=1[Cl:25])=[N+]=[N-].[NH4+].[Cl-]>C(O)C.O.[Fe]>[Cl:25][C:7]1[CH:8]=[C:9]([N:12]2[C:16]3=[N:17][C:18]([CH3:22])=[CH:19][C:20]([CH3:21])=[C:15]3[N:14]=[C:13]2[CH2:23][CH3:24])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][NH2:1]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN=[N+]=[N-])c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN)c(Cl)c1
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of methyl 3-[4-(2-azidoethyl)-3-chlorophenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 10, 430 mg, 1.2 mmol) in ethanol/water (4/1) were added Fe (335 mg, 6.0 mmol) and NH4Cl (409 mg, 7.8 mmol). The mixture was stirred for 1 h under reflux temperature. The solvent was removed and the residue was diluted with CH2Cl2. The mixture was washed with brine, dried (MgSO4) and concentrated to give 390 mg of title compound as orange oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][O:5]1.[C-]#N.[Na+].[I-].[Na+].[CH3:19][N:20](C=O)C>O>[C:19]([CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][O:5]1)#[N:20]
Reactant: ClCCC1OCCc2ccccc21
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: N#CCCC1OCCc2ccccc21

Procedure:
A mixture of 1-(2-chloroethyl)isochroman (LXIV, PREPARATION 2, 0.9874 g, 5.02 mmol), sodium cyanide (0.3793 g, 7.74 mmol), sodium iodide (a few mg) and DMF (5 ml) is heated overnight at 856. Additional sodium cyanide (0.5826 g, 11.9 mmol) is then added in two portions, along with DMF (14 ml) and a few mgs of sodium iodide. The mixture is heated at 97° for another two days and then cooled and poured into water. The mixture is extracted several times with ethyl acetate and the combined organic phase is backwashed twice with water, followed by two saline washes, then dried over magnesium sulfate and concentrated to dryness. The crude product is chromatographed on silica gel eluting with ethyl acetate/hexane (10/90). The appropriate fractions are pooled and concentrated to give 1-(2-cyanoethyl)isochroman (LXVI), NMR (CDCl3) 2.11, 2.27-2.72, 2.98, 3.77, 4.13, 4.86 and 7.17 δ.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([CH3:11])=[CH2:10])[CH:8]=1.[BH4-].[Na+].Cl>CCO.C1COCC1>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1
Reactant: C=C(C)c1cc(CN)cc(N(C)S(C)(=O)=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1cc(CN)cc(N(C)S(C)(=O)=O)c1
Reaction time: 3.5 h

Procedure:
To a stirring solution of crude N-(3-(aminomethyl)-5-(prop-1-en-2-yl)phenyl)-N-methylmethanesulfonamide and 68.3 mg (0.2871 mmol) of CoCl2.6H2O in 3 mL of EtOH and 1 mL of THF at 50° C. was added 0.169 g of NaBH4 in 2 portions. After the mixture was stirred for about 3.5 h, 5 N HCl was added to a pH=1. The mixture was concentrated and (28-30) % NH4OH solution was added to pH=8. The aqueous layer was extracted with the extract of (40 mL of CHCl3: 5 mL of H2O: 5 mL of MeOH) (3×). The combined extracts were dried over Na2SO4, filtered, and concentrated. N-(3-(aminomethyl)-5-isopropylphenyl)-N-methylmethanesulfonamide was used in the next reaction without further purification.
Reaction SMILES: [ClH:1].C(C1C=CC=CC=1C=CC1C=CC=CC=1)#[N:3].Cl.C(O[C:22](=[NH:37])[C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)C.C(=N)([O-])C1C=CC=CC=1.N>CO.C(O)C.C1C=CC=CC=1>[ClH:1].[CH:29]([C:26]1[CH:25]=[CH:24][C:23]([C:22]([NH2:37])=[NH:3])=[CH:28][CH:27]=1)=[CH:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=N)c1ccc(C=Cc2ccccc2)cc1
Reactant: N#Cc1ccccc1C=Cc1ccccc1
Agent: Cl
Agent: N
Agent: N=C([O-])c1ccccc1
Solvent: CCO
Solvent: CO
Solvent: c1ccccc1
Product: N=C(N)c1ccc(C=Cc2ccccc2)cc1
Temperature: 100 °C

Procedure:
Hydrogen chloride is bubbled through a mixture of 4L -cyanostilbene (13.5 g., 0.065 mole), obtained according to the method of Belgian Patent 641,415 (Chem. Abs. 63: 3092g (1965)), in 35 ml. of dry benzene and 17.5 ml. of absolute ethanol at 0° to 5° C. for a period of 3 hr. The reaction is maintained at 0° to 5° C. for 48 hr. and the solvent and excess hydrogen chloride removed under reduced pressure. The residue stirred with 50 ml. of dry benzene and collected provides 13.0 g. of ethyl-4-styrylbenzimidate hydrochloride. A methanol solution of the benzimidate salt is cooled to 5° to 10° C., saturated with ammonia and heated at a temperature of 100° C. for a period of 3 hr. in an enclosed container. Concentration of the reaction mixture provides 4-styrylbenzamidine hydrochloride.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](NCCNC(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)CC)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)=O)=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:62][C:63]([F:68])([F:67])[C:64]([OH:66])=[O:65].[C:69]1([CH:75]([C:113]2[CH:118]=[CH:117][CH:116]=[CH:115][CH:114]=2)[CH2:76][NH:77][C:78]2[N:86]=[C:85]([N:87]3[CH2:91][CH2:90][C@@H:89]([NH:92][C:93]([NH:95][C@@H:96]4[CH2:100][CH2:99][NH:98][CH2:97]4)=[O:94])[CH2:88]3)[N:84]=[C:83]3[C:79]=2[N:80]=[CH:81][N:82]3[C@@H:101]2[CH2:105][C@H:104]([NH:106][C:107](=[O:110])[CH2:108][CH3:109])[C@@H:103]([OH:111])[C@H:102]2[OH:112])[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>>[F:62][C:63]([F:68])([F:67])[C:64]([OH:66])=[O:65].[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([N:98]2[CH2:99][CH2:100][C@@H:96]([NH:95][C:93]([NH:92][C@@H:89]3[CH2:90][CH2:91][N:87]([C:85]4[N:84]=[C:83]5[C:79]([N:80]=[CH:81][N:82]5[C@@H:101]5[CH2:105][C@H:104]([NH:106][C:107](=[O:110])[CH2:108][CH3:109])[C@@H:103]([OH:111])[C@H:102]5[OH:112])=[C:78]([NH:77][CH2:76][CH:75]([C:113]5[CH:114]=[CH:115][CH:116]=[CH:117][CH:118]=5)[C:69]5[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=5)[N:86]=4)[CH2:88]3)=[O:94])[CH2:97]2)=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)N[C@@H]5CCNC5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(C(=O)OCc5ccccc5)CC4)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)N[C@@H]5CCN(C(=O)NC6CCN(C(=O)OCc7ccccc7)CC6)C5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to 4-[3-(2-{[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carbonyl]-amino}-ethyl)-ureido]-piperidine-1-carboxylic acid benzyl ester (Example 108) by replacing 9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-ethyl)-amide with N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-((R)-3-pyrrolidin-3-ylureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate (Example 17 step 1). (MH+ 943.4)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=1)[O:8][C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C(C)C)[CH:18]=1)=[CH:6][C:5]2=[O:27].S(=O)(=O)(O)O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=1)[O:8][C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)=[CH:6][C:5]2=[O:27]
Reactant: CCOC(=O)c1cc(Br)cc2c(=O)cc(-c3cccc(OC(C)C)c3)oc12
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Br)cc2c(=O)cc(-c3cccc(O)c3)oc12
Temperature: 0 °C
Yield: 80 %

Procedure:
6-Bromo-8-ethoxycarbonyl-3'-isopropoxyflavone were refluxed under heat for 0.5 to 1 hour in acetic acid which contained 3% of sulfuric acid. The mixture was charged into ice water, followed by extraction with ethyl acetate. The organic layer was washed with water and 4% aqueous solution of sodium hydrogencarbonate, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The thus-obtained crude crystals were recrystallized from ethanol, whereby the title compound was obtained (yield: 80%).
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:4]1.CI.[CH3:19]COCC>O1CCCC1>[CH3:19][CH:12]([C:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:3][N:4]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)Cc1nsc2ccccc12
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1nsc2ccccc12
Reaction time: 0.5 h

Procedure:
A mixture of sodium hydride (1.25 g, 60% in oil, 31.3 mmol) in tetrahydrofuran is added to a solution of methyl 1,2-benzisothiazole-3-acetate (6.0 g, 29.0 mmol) in tetrahydrofuran. After stirring for 30 minutes, the reaction mixture is treated with methyl iodide (2.0 mL, 32.0 mmol), stirred for one hour and quenched with ice. The aqueous mixture is neutralized with hydrochloric acid (pH5-pH6) and extracted with methylene chloride. The organic extracts are combined, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a brown oil. Chromatography of the oil using silica gel and 10% to 25% ether in hexanes solutions gives the title product as an amber oil which is identified by NMR spectral analyses.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][C:17]=1[C:24]([F:27])([F:26])[F:25]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][C:17]=1[C:24]([F:25])([F:26])[F:27]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Cl)c(C(F)(F)F)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)c(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-3-(trifluoromethyl)phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.25 (2H, s), 5.76 (1H, d, J=1.6 Hz), 7.42 (1H, dd, J=1.6, 5.2 Hz), 7.54 (2H, s), 7.58 (1H, d, J=2.0 Hz), 7.89 (1H, s), 8.00 (1H, s), 8.06 (1H, s), 8.69 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H10ClF3N4O, 379; Found, 379.
Reaction SMILES: [OH-].[Na+:2].[C:3]([OH:20])(=[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:3]([O-:20])(=[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].[Na+:2]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
then adding a quantity of sodium hydroxide as a 2M aqueous solution (for quantity see table 7) at the same temperature as the palmitic acid dispersion with stirring over a particular time (see table 7 for the time of addition) thereby producing a clear solution with a pH of about 9.2 substantially containing sodium palmitate;
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[C:5]([CH2:7][CH2:8][CH3:9])[N:6]=1>CO.[Ni]>[CH3:1][C:2]1[S:3][C:4]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[C:5]([CH2:7][CH2:8][CH3:9])[N:6]=1
Reactant: CCCc1nc(C)sc1Cc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Product: CCCc1nc(C)sc1Cc1ccc(N)cc1
Yield: 69.3 %

Procedure:
5.5 g of 2-methyl-4-propyl-5-(4-nitrobenzyl)thiazole in 60 ml of methanol are hydrogenated at normal pressure and room temperature in the presence of Raney nickel. After filtration of the catalyst and concentration of the filtrate, the residue is taken up with isopropyl ether, filtered off and then taken up in ethanol, passed over animal charcoal and concentrated to give 3.4 g of 2-methyl-4-propyl-5-(4-aminobenzyl)thiazole in the form of a greenish solid, which is used as such for the next step.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[Cl:34][C:35]1[S:39][C:38]([C:40]2[N:44]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[F:52])[C:43](=[O:53])[N:42]([CH2:54][C:55]([OH:57])=O)[N:41]=2)=[CH:37][CH:36]=1.C(N(CC)C(C)C)(C)C.O[N:68]=[C:69]([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=1[C:77]([F:80])([F:79])[F:78])[NH2:70]>CN(C=O)C.O>[Cl:34][C:35]1[S:39][C:38]([C:40]2[N:44]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[F:52])[C:43](=[O:53])[N:42]([CH2:54][C:55]3[O:57][N:70]=[C:69]([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=4[C:77]([F:78])([F:79])[F:80])[N:68]=3)[N:41]=2)=[CH:37][CH:36]=1
Reactant: NC(=NO)c1ccccc1C(F)(F)F
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(Cc2nc(-c3ccccc3C(F)(F)F)no2)nc(-c2ccc(Cl)s2)n1Cc1ccccc1F
Reaction time: 0.33 h

Procedure:
Under argon, 95 mg (0.18 mmol) of benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate were added to a solution of 56 mg (0.15 mmol) of [3-(5-chloro-2-thienyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid [preparation according to WO 2007/134862 Example 154A] and 32 μl (0.18 mmol) of N,N-diisopropylethylamine in 1.5 ml of dry DMF. After 20 min of stirring, 34 mg (0.17 mmol) of N′-hydroxy-2-(trifluoromethyl)benzene-carboximidamide were added. The mixture was then stirred at RT for 16 h. For work-up, 10 ml of water were added and the mixture was extracted three times with in each case 10 ml of ethyl acetate. The combined organic phases were washed with in each case 10 ml of water and saturated sodium chloride solution, filtered through Extrelut and concentrated under reduced pressure. The residue was dissolved in 2 ml of DMF and stirred in a microwave oven at 250° C. for 15 min. After cooling, the solvent was removed under reduced pressure on a rotary evaporator and the crude product was chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). This gave 60 mg (72% of theory) of the target compound as a yellow resin.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11](=[O:17])[NH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:18][N:12]1[C:13]2[C:8](=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][C:11]1=[O:17]
Reactant: O=c1ccc2c(-c3ccccc3)nccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)ccc2c(-c3ccccc3)nccc21
Reaction time: 1 h
Yield: 72.8 %

Procedure:
A mixture containing 22.2 g of 5-phenyl-1,6-naphthyridin-2(1H)-one, 13.18 g of anhydrous potassium carbonate and 300 ml of dimethylformamide was heated with stirring on a steam bath for 1 hour and to this mixture was added 6.9 g of methyl iodide. The resultig mixture was heated with stirring for an additional 6 hours, allowed to cool and the solvent removed by distillation under reduced pressure. To the residue was added 100 ml of 20% acetic acid and the resulting pale yellow solid was collected, washed with water, dried, recrystallized from methanol and dried at 90° C. to yield 16.4 g of 1-methyl-5-phenyl-1,6-naphthyridin-2(1H)-one, m.p. 190°-192° C.