Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)[CH2:6][C:7]([O:9]C(C)(C)C)=[O:8])[CH3:2]>C(Cl)Cl.FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)[CH2:6][C:7]([OH:9])=[O:8])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)Nc1ccc2[nH]ncc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(CC(=O)O)Nc1ccc2[nH]ncc2c1

Procedure:
A stirred solution of 2-(1H-indazol-5-ylamino)-succinic acid 4-tert-butyl ester 1-ethyl ester (123.6 mg, 0.37 mmol) in methylene chloride (2 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate and washed with saturated ammonium chloride solution, water and brine. The organic layer was dried and concentrated to give a dark green oil: LC/MS: tR=0.643 min, 278.19 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:21]([CH2:23][C:24](O)=[O:25])#[N:22].CN(C=O)C.CCN=C=NCCCN(C)C.Cl>O>[C:21]([CH2:23][C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)=[CH:6][CH:7]=1)=[O:25])#[N:22]
Reactant: N#CCC(=O)O
Reactant: COC(=O)c1ccc(CCCc2ccc(N)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCc2ccc(NC(=O)CC#N)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
To a mixture of 16.0 g of methyl 4-[3-(4-aminophenyl)propyl]benzoate, 7.70 g of cyanoacetic acid, and 50 mL of DMF was added 17.1 g of EDCI/hydrochloride under ice-cooling. After stirring at room temperature for 18 hours, to the reaction mixture was added 200 mL of water at room temperature. After vigorous stirring at room temperature for 30 minutes, the precipitate was collected by filtration to obtain 19.3 g of methyl 4-(3-{4-[(cyanoacetyl)amino]phenyl}propyl)benzoate as a beige solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[Cl:10][C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:2]2[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: Cn1cc(Br)ccc1=O
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: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(Cl)nc2)ccc1=O
Temperature: 110 °C
Yield: 72.7 %

Procedure:
A mixture of 5-bromo-1-methylpyridin-2(1 H)-one (2.2 g, 11.7 mmol), 6-chloropyridin-3-ylboronic acid (1.57 g, 9.98 mmol), Na2CO3 (2.2 g, 20.76 mmol), and tetrakis(triphenylphosphine)palladium (0) (500 mg, 0.05 mmol) in dioxane:water (15:1, 20 ml) was degassed and heated at 110° C. in a microwave for 1 hr. The reaction was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was purified by silica gel chromatography (AcOEt-Hexanes) to provide title compound, 5-(6-Chloropyridin-3-yl)-1-methylpyridin-2(1 H)-one (1.6 g, 73% yield).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[CH3:28][C:29]1([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>ClC(Cl)C.O1CCCC1>[CH3:20][O:19][C:16]1[C:17]2[N:18]=[C:10]([NH:9][C:8]([N:32]3[CH2:33][CH2:34][C:29]([OH:35])([CH3:28])[CH2:30][CH2:31]3)=[O:27])[S:11][C:12]=2[C:13]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[N:14][CH:15]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: CC1(O)CCNCC1
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N3CCC(C)(O)CC3)nc12

Procedure:
From (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester with 4-methyl-piperidin-4-ol in dichloroethane and tetrahydrofuran. ES-MS m/e (%): 408 (M+H+, 100).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:10]([Cl:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([F:22])[CH:13]=2)[O:8][N:7]=1)(=O)C.[Li+].[OH-]>O1CCCC1>[Cl:11][C:10]1[C:6]([CH2:5][OH:4])=[N:7][O:8][C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([F:22])[CH:13]=1
Reactant: CC(=O)OCc1noc(-c2ccc(C(F)(F)F)c(F)c2)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCc1noc(-c2ccc(C(F)(F)F)c(F)c2)c1Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
To a solution of (4-chloro-5-(3-fluoro-4-(trifluoromethyl)phenyl)isoxazol-3-yl)methyl acetate (1 g, 2.96 mmol) in tetrahydrofuran (20 mL) an aqueous solution of 1N LiOH (8.88 mL, 8.88 mmol) was added. The biphasic reaction mixture was stirred vigorously for 3 hours at 60° C., then allowed to cool and left to stand over the weekend. The reaction mixture was transferred to a separating funnel and the organic layer removed. The aqueous layer was extracted with diethyl ether (2×20 mL), the organics were combined, washed with water (20 mL) and brine (20 mL) before drying with Na2SO4. Filtration and evaporation to dryness in vacuo afforded (4-chloro-5-(3-fluoro-4-(trifluoromethyl)phenyl)isoxazol-3-yl)methanol (878 mg, 2.97 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[O:5][CH2:6][CH:7]([N:20]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN>C(O)C>[NH2:20][CH:7]([CH2:6][O:5][C:4]1[CH:31]=[CH:32][C:33]([F:34])=[C:2]([F:1])[CH:3]=1)[CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(NCC(COc1ccc(F)c(F)c1)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Agent: CN
Solvent: CCO
Product: NC(CNC(=O)OCc1ccccc1)COc1ccc(F)c(F)c1
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
1.8 g of rac-benzyl [3-(3,4-difluorophenoxy)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-carbamate (Example 139A) were dissolved in 25 ml of ethanol, 4.8 ml of 40% strength aqueous methylamine solution (56 mmol, 15 equivalents) were added and the mixture was stirred at 60° C. for 4.5 h. The reaction mixture was concentrated and the residue was then chromatographed on silica gel (Biotage Isolera; mobile phase: dichloromethane/methanol gradient). This gave 600 mg (45% of theory; purity 93%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][Mg]Br.[CH2:12]([N:19]1[CH2:24][CH2:23][O:22][CH:21]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)=[O:26])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>O1CCCC1>[CH2:12]([N:19]1[CH2:24][CH2:23][O:22][CH:21]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)([OH:26])[CH2:5][C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccccc1C[Mg]Br
Reactant: O=C(c1cccc(F)c1)C1CN(Cc2ccccc2)CCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1CC(O)(c1cccc(F)c1)C1CN(Cc2ccccc2)CCO1
Temperature: 25 °C

Procedure:
A magnetically stirred 0.25M tetrahydrofuran solution of commercially available 2-methoxybenzylmagnesium bromide (available from Rieke-Metals) (80 ml, 3 equiv.) under nitrogen atmosphere was cooled to −10° C. and to this was added neat (4-Benzyl-morpholin-2-yl)-1-(3-fluoro-phenyl)-methanone (2.1 g, 1 equiv.). The solution was allowed to warm to room temperature and reaction progress followed using mass spectrometry. After 1.5 hours 2-methoxybenzylmagnesium bromide solution (14 ml, 0.5 equiv.) was again added to the reaction and after a further 0.5 hours an aqueous saturated solution of NaHCO3 (50 mL) was added to halt the reaction. The aqueous solution was extracted with diethyl ether, the organic phase dried with MgSO4, evaporated in vacuo to give 2.8 g of a yellow amorphous solid. The compound was taken without further purification in the next step. LCMS (6 minutes method) [M+H]+=422 @ Rt 3.03 and 2.86 min. major peaks.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(CCCC#N)=NCCCC#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2ccc(Cl)cc21
Agent: N#CCCCN=NCCCC#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2ccc(Cl)cc21

Procedure:
6-Chlorophthalide (7.66 gms; 0.0452 mole), N-bromosuccinimide (8.1 gms; 0.0452 mole) and azobisbutyronitrile (0.1 gm) were gently refluxed in dry carbon tetrachloride (150 ml.) for 11/2 hours. On cooling, the succinimide was filtered off and the solvent removed in vacuo to leave a yellow solid, which was used immediately. Yield 9.57 gms. 86.2%
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:17]([CH2:18][CH2:19][C:20]#[N:21])[N:16]=[C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:28])=[N:4][CH:3]=1>N.CO.[Ni]>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:17]([CH2:18][CH2:19][CH2:20][NH2:21])[N:16]=[C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:28])=[N:4][CH:3]=1
Reactant: Cc1ncc(C)n2nc(CCc3nc(-c4ccccc4)nn3CCC#N)nc12
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1ncc(C)n2nc(CCc3nc(-c4ccccc4)nn3CCCN)nc12

Procedure:
3-{5-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-3-phenyl-1,2,4-triazol-1-yl}-propionitrile (28 mg, 0.075 mmol) was dissolved in 2 M of Ammonia in Methanol (15 mL) and hydrogenated on an H-cube through a column of Raney-Nickel (50 bar hydrogen, rt). The solvent was evaporated off. The crude product was purified by silica gel chromatography (Eluent: 10% MeOH, 10% triethylamine, 80% EtOAc). Yield: 10 mg (35%) of the title compound as a clear oil. LC-MS: m/z=377.3 (MH+), tR=0.81 min, Method C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([OH:7])=O.[N:20]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][N:22]=[CH:21]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([NH:28][CH2:27][CH2:26][CH2:25][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:7]
Reactant: NCCCn1ccnc1
Reactant: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Product: O=C(NCCCn1ccnc1)c1cc(Br)ncc1Nc1ccc(I)cc1F

Procedure:
2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(3-imidazol-1-yl-propyl)-isonicotinamide was synthesized according to the General Method 3, starting with 145 mg (0.33 mmol) of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid and 103 mg (0.83 mmol) of 3-Imidazol-1-yl-propylamine. Yield: 55 mg, 30%, LC/MS: [7.31 min, 545 (M+1)]
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li]CCCC.[CH3:15][C:16]([CH:18]1[CH2:20][CH2:19]1)=[O:17].[F:21][CH:22]([F:27])[C:23](OC)=[O:24]>C(OCC)C>[CH:18]1([C:16](=[O:17])/[CH:15]=[C:23](\[OH:24])/[CH:22]([F:27])[F:21])[CH2:20][CH2:19]1
Reactant: COC(=O)C(F)F
Reactant: CC(=O)C1CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(/C=C(\O)C(F)F)C1CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 35.4 %

Procedure:
Hexamethyldisilazane (1 g, 6.2 mmol) and diethylether were taken in RBF and cooled to −78° C. under nitrogen atmosphere. n-BuLi (7.7 ml) was added and stirred for 15 mins Cyclopropyl methyl ketone (0.66 ml, 6.8 mmol) was added and stirred at −78° C. for 45 mins. At this stage methyl 2,2-difluoroacetate (1.62 ml, 18.58 mmol) was added and brought the reaction mixture to rt and allowed to stir for overnight. Reaction mixture quenched with water, ether layer separated and aqueous layer was acidified with 1N HCl. Aqueous layer extracted with diethyl ether and ether was dried over anhydrous Na2SO4. Diethyl ether was removed on rotavapour to obtain the title compound (390 mg) which was used in the next step without further purification. 1H-NMR (δ ppm, CDCl3, 400 MHz): 6.08 (s, 1H), 5.95 (t, J 54.2, 1H), 1.84-1.76 (m, 1H), 1.34-1.29 (m, 2H), 1.10-1.03 (m, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:12]=[CH:13][N:14](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:35][O:36][C:37](=[O:49])[CH:38](Br)[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([F:47])[CH:40]=1.CO.N(CC)CC>CC#N>[CH3:35][O:36][C:37](=[O:49])[CH:38]([N:12]1[C:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:15][N:14]=[CH:13]1)[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([F:47])[CH:40]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)C(Br)c1ccc(OC)c(F)c1
Solvent: CO
Solvent: CCNCC
Solvent: CC#N
Product: COC(=O)C(c1ccc(OC)c(F)c1)n1cncc1CCO[Si](C)(C)C(C)(C)C
Temperature: 75 °C

Procedure:
4-[2-(tert-Butyl-dimethylsilanyloxy)ethyl]-1-trityl-1H-imidazole (6.5 g, 14.0 mmol) and bromo-(3-fluoro-4-methoxyphenyl)acetic acid methyl ester (5.8 g, 21.0 mmol) are stirred in 60 mL MeCN at room temperature for 2 days. At that point MeOH (50 mL) and Et2NH (50 mL) are then added and the resulting solution heated at 75° C. for 0.5 h. The solution is evaporated and the residue purified via flash column chromatography (EtOAc/DCM 1:9→EtOAc/DCM 1:1) to give {5-[2-(tert-butyldimethylsilanyloxy)ethyl]-imidazol-1-yl}-(3-fluoro-4-methoxyphenyl)acetic acid methyl ester as an oil. MS (ESI) m/z 423.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: OC(c1ccncc1)c1c[nH]c2ccc(F)cc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc2[nH]cc(Cc3ccncc3)c2c1
Reaction time: 8 h
Yield: 75 %

Procedure:
To a suspension of (5-fluoro-1H-indol-3-yl)-pyridin-4-yl-methanol (0.799 g, 3.3 mmol) in methylene chloride (13 mL) was added triethylsilane (0.60 mL, 3.7 mmol) followed by trifluoroacetic acid (2.85 mL, 37 mmol) at room temperature. After addition of trifluoroacetic acid, a clear black solution was obtained. The reaction mixture was stirred overnight and the solvent and excess trifluoroacetic acid was removed on a rotary evaporator. To the residue was added saturated Na2CO3 to adjust the pH>9. The aqueous layer was extracted with methylene chloride and the combined organic extracts was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (methylene chloride to methylene chloride/ethyl acetate to ethyl acetate, 100% to 50% to 100%) to give 0.56 g (75%) of a solid: mp 141-142° C. [(mp 149° C.; previously reported in J. Med. Chem. 36, 1194 (1993)].
Reaction SMILES: [N+]([C:4]1[C:9]([CH3:10])=[CH:8][N+:7]([O-])=[CH:6][C:5]=1[CH3:12])([O-])=O.P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1>[Br:14][C:4]1[C:9]([CH3:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH3:12]
Reactant: Cc1c[n+]([O-])cc(C)c1[N+](=O)[O-]
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: Cc1cncc(C)c1Br
Yield: 31.4 %

Procedure:
By proceeding in a similar manner to the procedure contained in J. Chem. Soc., 1956, page 771 but using 4-nitro-3,5-dimethylpyridine-N-oxide (23.06 g), phosphorous tribromide (111.47 g) in toluene (50 ml) there was prepared the title compound (8 g) as a yellow oil.
Reaction SMILES: [SH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(=O)CC>[C:16]1([CH2:15][S:1][C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1cccnc1S
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Oc1cccnc1SCc1ccccc1
Yield: 65.7 %

Procedure:
To a mixture of 10.0 g of 2-mercapto-3-pyridinol, 11.0 g of potassium carbonate and 100 mL of 2-butanone was added dropwise with stirring, 13.3 g of benzyl bromide. After stirring at 22° C. for two hours, the mixture was heated to reflux for thirty minutes. The reaction mixture was concentrated under reduced pressure, the residue treated with water, and the mixture brought to pH 6 by the addition of acetic acid. The crude product was filtered and recrystallized from toluene to give 11.1 g of the title compound as a grey crystalline solid, mp 103–104° C. The structure of the product was confirmed by its 1H nmr and mass spectra.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].B(F)(F)F.CCOCC.[C:21]1(C)[CH:26]=CC=C[CH:22]=1>CC(C)=O>[C:5]([C:4]1[CH:8]=[CH:9][C:10]2[O:11][C:21]([CH3:26])([CH3:22])[S:1][C:2]=2[CH:3]=1)([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(O)c(S)c1
Reactant: Cc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC1(C)Oc2ccc(C(=O)O)cc2S1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
16 g of 3-mercapto-4-hydroxybenzoic acid (III) was dissolved in a mixture of 300 ml of toluene and 50 ml of acetone. 50 ml of boron trifluoride etherate was added and the mixture was stirred at room temperature for 4 hours. Ice (50 g) was added and the mixture was stirred for a further 1 hour. The organic layer was separated, washed with brine, dried with magnesium sulfate and evaporated to leave a solid residue. The residue was recrystallized from aqueous methanol to yield 15 g of 5-carboxy-2,2-dimethyl-1,3-benzoxathiole (IV), m.p. 124°-125° C.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[O:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]>BrCCBr.C1COCC1>[OH:13][CH:14]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: CCCCCCCCCCBr
Reactant: COC(=O)CCCCCCC=O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CCCCCCCCCCC(O)CCCCCCC(=O)OC
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
Magnesium metal (0.209 g, 8.71 mmol) was added into dry THF (10 ml) in a 50 ml two-necked round bottom flask fitted with a condenser and nitrogen gas inlet. The flask was heated to 70° C., then a few drops of 1,2 dibromoethane were added to the mixture, followed by the slow addition of 1-bromodecane (1.3 g, 5.81 mmol) while at reflux temperature. Stirring was continued for 30 min. After cooling, the Grignard reagent was added dropwise to a stirred solution of methyl 8-oxooctanoate (1.0 g, 5.8 mmol) in THF (10 ml) at −20° C., and the reaction mixture was slowly warmed to room temperature, where stirring was continued for 2 h. The mixture was quenched with saturated ammonium chloride solution, extracted with (3×25 ml) of ethyl acetate, and the combined organic layers were washed with brine solution, dried on anhydrous MgSO4, concentrated and purified on silica gel (2:8 ethyl acetate and hexanes) to obtain an off-white solid (450 mg, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].Br[CH2:21][CH:22]([CH3:24])[CH3:23]>>[CH2:21]([N:7]1[C:6](=[O:19])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[N:8]1)[CH:22]([CH3:24])[CH3:23]
Reactant: COC(=O)c1cc(-c2ccc(SC)cc2)n[nH]c1=O
Reactant: CC(C)CBr
Product: COC(=O)c1cc(-c2ccc(SC)cc2)nn(CC(C)C)c1=O
Yield: 77.3 %

Procedure:
Using 4-methoxycarbonyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and 1-bromo-2-methylpropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 77.3%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:24]2[C:19]([CH:20]=[N:21][C:22]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH:34](C(N5CCN(C)CC5)=O)[CH2:33]4)=[CH:28][CH:27]=3)=[N:23]2)=[CH:18][CH:17]=1.NC1C=CC(N2CCC([C:60]([N:62]3[CH2:67][CH2:66][N:65]([CH3:68])[CH2:64][CH2:63]3)=[O:61])CC2)=CC=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:24]2[C:19]([CH:20]=[N:21][C:22]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([N:32]4[CH2:37][CH2:36][CH:35]([C:60]([N:62]5[CH2:67][CH2:66][N:65]([CH3:68])[CH2:64][CH2:63]5)=[O:61])[CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCCC(C(=O)N5CCN(C)CC5)C4)cc3)nn12
Reactant: CN1CCN(C(=O)C2CCN(c3ccc(N)cc3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCC(C(=O)N5CCN(C)CC5)CC4)cc3)nn12

Procedure:
The titled compound (1-{4-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-4-yl)-(4-methyl-piperazin-1-yl)-methanone; compound with trifluoro-acetic acid was prepared in an analogous fashion to (1-{4-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-3-yl)-(4-methyl-piperazin-1-yl)-methanone; compound with trifluoro-acetic acid of Example 443c after replacing [1-(4-Amino-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with [1-(4-Amino-phenyl)-piperidin-4-yl]-(4-methyl-piperazin-1-yl)-methanone, to give after purification via reverse phase HPLC (1-{4-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-4-yl)-(4-methyl-piperazin-1-yl)-methanone; compound with trifluoro-acetic acid as a brown lyophylate (38 mg, 42%). LC/MS (E/I+) 526.21 (M+H). NMR 1H (DMSO-d6)-10.0 (bs, 1H), 9.5 (bs, 1H), 8.97 (s, 1H), 7.81-7.74 (m, 3H), 7.50-7.11 (m, 5H), 6.97-6.93 (m, 2H), 4.2-3.85 (bm, TFA salt and water provided poor resolution), 3.81 (s, 3H), 3.62-2.85 (bm; smeared as TFA salt), 2.83 (s, 3H), 1.88 (bs, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1)([O-])=O.O.O.[Sn](Cl)Cl.C(Cl)Cl.CCOC(C)=O>CCO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]=[CH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:21]=3[N:22]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc2nc(-c3ccc(C=Cc4ccccc4[N+](=O)[O-])cc3)sc2c1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1ccc2nc(-c3ccc(C=Cc4ccccc4N)cc3)sc2c1
Yield: 39.2 %

Procedure:
Prepared as described in the Nitro Reduction section using 2-{4-[2-(2-nitrophenyl)-vinyl]-phenyl}-6-methylbenzothiazole (0.10 g, 0.268 mmol) and tin (II) chloride dihydrate (0.48 g, 2.15 mmol) in EtOH (3 ml) to give the title compound (0.036 g, 39%) as a yellow solid after work-up and flash chromatography (20:1 DCM/EtOAc).