Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[C@@:14]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13]3)=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[CH2:2].Br[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=1.CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:31][C:27]1[CH:26]=[C:25](/[CH:2]=[CH:1]/[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C@H:12]4[C@@:14]5([C:22]6[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=6)[NH:16][C:15]5=[O:23])[CH2:13]4)=[CH:9][CH:10]=3)[NH:5][N:4]=2)[CH:30]=[CH:29][N:28]=1
Reactant: Cc1cc(Br)ccn1
Reactant: C=Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(/C=C/c2n[nH]c3cc([C@@H]4C[C@@]45C(=O)Nc4ccccc45)ccc23)ccn1
Yield: 29.3 %

Procedure:
To a mixture of (1R*,2S*)-2-(3-vinyl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (60.2 mg, 0.2 mmol) and 4-bromo-2-methylpyridine (34.4 mg, 0.2 mmol) in DMF (2 mL) was added iPr2NEt (0.07 mL), followed by Pd(OAc)2 (2.2 mg, 0.01 mmol) and P(o-tol)3 (6.7 mg, 0.022 mmol). The resulting mixture was purged with argon, and then microwaved 2 h at 125° C. Purification by prep-HPLC gave the title compound as a yellow solid (23 mg, 23%). NMR indicated 7% of the branched isomer. 1H NMR (400 MHz, CD3OD) δ 8.53 (d, J=6.4 Hz, 1H), 8.13-8.03 (m, 4H), 7.59 (d, J=16.4 Hz, 1H), 7.53 (s, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.05 (t, J=7.6 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.56 (t, J=7.6 Hz, 1H), 5.97 (d, J=7.6 Hz, 1H), 3.56 (t, J=8.0 Hz, 1H), 2.77 (s, 3H), 2.25 (dd, J=7.6 Hz, J=4.8 Hz, 1H), 2.18 (dd, J=9.2 Hz, 4.8 Hz, 1H); MS ESI 393.2 [M+H]+, calcd for [C25H20N4O+H]+ 393.2.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCOc1ccc(-c2ccccc2)cc1
Yield: 71.1 %

Procedure:
A mixture of 34 g (0.2 mole) of 4-phenylphenol, 63 g (0.4 mole) of 1-bromo-3-chloropropane and 82.9 g (0.6 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 17 hr. The mixture was cooled, filtered, and the filtrate concentrated under reduced pressure. The residue was triturated with petroleum ether (30°-60° C.) and a solid crystallized. The solid was collected by filtration and was subjected to flash chromatography on 400 g of silica gel on a 10-cm diameter column to remove starting phenol. The column was eluted with a 1:2 mixture of benzene and cyclohexane, and fractions containing title compound were combined and concentrated to give a solid residue. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration, and dried to yield 35.1 g (71%) of title compound as a white solid. An analytical sample was recrystallized from petroleum ether (60°-110° C.), mp 65°-66° C.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][C:6](=[O:8])[CH:7]=1.[Cl:10][C:11]1([Cl:20])[C:15]([Cl:16])=[C:14]([Cl:17])[C:13]([Cl:18])=[C:12]1[Cl:19]>C1(C)C=CC=CC=1>[Cl:16][C:15]12[C:11]([Cl:10])([Cl:20])[C:12]([Cl:19])([CH:4]3[CH:5]1[C:6](=[O:8])[CH:7]=[C:2]([CH3:1])[C:3]3=[O:9])[C:13]([Cl:18])=[C:14]2[Cl:17]
Reactant: CC1=CC(=O)C=CC1=O
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Product: CC1=CC(=O)C2C(C1=O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 135 °C

Procedure:
To a mixture of methyl-p-benzoquinone (60 g.), and hexachlorocyclopentadiene (140 g.), was added 20 ml. of toluene. This reaction mixture was then heated at 130-140° C. for 3 hours. Upon cooling to room temperature the mixture solidified. This solid was washed with Skelly "B" solvent several times on a Buchner funnel and recrystallized from a Skelly "B"-benzene mixed solvent (20/80). Pale yellow crystals were obtained, m.p. 163°-165° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH2:20][CH3:21])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[C:4]([F:22])[CH:3]=1.IC.[C:25](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH2:20][CH3:21])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:25])[CH:17]=2)=[O:11])=[C:4]([F:22])[CH:3]=1
Reactant: CCCC(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCCC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1F

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-2-fluoro-phenyl)-hexanoyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless oil, MS (ESI+): m/z=380.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][C:6]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:7]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][C:6]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:7]1=[S:31]
Reactant: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCNC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCNC1=S
Temperature: 100 °C
Reaction time: 8 h
Yield: 127.6 %

Procedure:
To a mixture of ethyl 3-(3,4-difluorobenzyl)-2-oxopiperidine-3-carboxylate (2.8 g) in toluene (50 mL) was added Lawesson's reagent (2.67 g) at room temperature, and the mixture was stirred at 100° C. overnight. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.64 g).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[S:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][O:20][CH2:21][C:22]([OH:24])=[O:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:19]([CH3:18])[O:20][CH2:21][C:22]([OH:24])=[O:23])=[S:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: CNOCC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(OCC(=O)O)C(=S)Nc1ccc(Oc2ccccc2)cc1
Yield: 101.2 %

Procedure:
A mixture of 4-phenoxyphenyl-isothiocyanate (11.35 g), N-methyl aminooxy acetic acid hydrochloride (7.1 g), triethylamine (10.5 g) and chloroform (300 mL) was heated at reflux for three hours, then evaporated to dryness. The residue was dissolved in ethyl acetate (600 mL) and washed with 2N HCl (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness to give (16.8 g) of [[[[(4-phenoxyphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid as an oil. 1H-NMR (DMSO-d6; 300 Mhz) δ13.10 (br s, 1H), 10.50 (s, 1H), 7.50 (m, 2H), 7.38 (m, 2H), 7.12 (t, 1H), 6.98 (m, 4H), 4.63 (s, 2H), and 3.52 ppm (s, 3H). The acid (16.8 g) was dissolved in benzene (300 mL). Phosphorus pentachloride (10.4 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (600 mL) and washed with sodium bicarbonate saturated solution (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (40% methylene chloride in hexane). The title compound (8.6 g) was obtained as a solid, m.p. 159-160° C. Mass spectrum (El, M.+) m/z 314. 1H-NMR (DMSO-d6; 400 MHz) δ7.43 (m, 2H), 7.19 (m, 3H), 7.09 (m, 2H), 7.00 (m, 2H), 5.07 (s, 2H), and 3.68 ppm (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].C(=O)([O-])[O-].[Na+:12].[Na+].O.[Br:15][CH2:16][C:17](Br)=[O:18]>C(Cl)Cl>[Na+:12].[Br:15][CH2:16][C:17]([NH:1][CH2:2][CH2:3][S:4]([O-:7])(=[O:6])=[O:5])=[O:18]
Reactant: NCCS(=O)(=O)O
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)NCCS(=O)(=O)[O-]
Temperature: 10 °C
Yield: 43.8 %

Procedure:
Taurine (50 g, 0.40 mol) and sodium carbonate (48 g, 0.45 mol) were combined with 250 mL of water in a 1-L flask and chilled in an ice bath (10° C.). Bromoacetyl bromide (100 g, 0.50 mol) in 250 mL of methylene chloride was added dropwise over a 1 hr period with rapid stirring while maintaining the temperature at 10°-15° C. After addition, the ice bath was removed and the mixture was stirred for 3 hr. The aqueous layer was separated and washed with two portions of methylene chloride, and most of the water was evaporated affording a moist white solid. The solid was washed thoroughly with acetone and dried (90 g, 85% yield). The product was purified by dissolving it in 1200 mL of hot methanol, filtering, and evaporating the methanol until the product crystallized out (volume ca 650 mL). This afforded 47 g (44% yield) of product; mp>250° C. Anal. Calcd. for C4H7BrNO4SNa: C, 17.9; H, 2.6; N, 5.4. Found: C, 17.6; H, 2.4; N, 4.5.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH2:13](O)[CH2:14][CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: OCCCO
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)C1(OCCCO1)C(=O)N2
Yield: 73.6 %

Procedure:
A mixture of 5-methylisatin (8.00 g, 49.6 mmol), 1,3 propanediol (10.89 mL, 149 mmol, 3 eq) and p-toluenesulfonic acid monohydrate (1.89 g, 9.92 mmol, 0.2 eq) in benzene (940 mL) was heated to reflux under a Dean Stark Trap for 17.5 hr. The reaction mixture was concentrated. The residue was taken up in EtOAc (300 mL) and washed with sat. aq. NaHCO3 (2×) and concentrated. The crude product was purified on Biotage KP silica gel eluting with 60/40 Pet ether/EtOAc to give the title compound as a yellow solid (8.0 g., 74% yield). NMR (300 Mz, DMSO-d6): consistent.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8](F)=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:4]2[CH:3]=[CH:2][C:11]3[C:6](=[CH:7][C:8]([NH:22][CH2:21][CH2:20][C:17]4[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=4)=[CH:9][CH:10]=3)[N:5]=2)=[CH:16][CH:15]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: Fc1ccc2c(Cl)ccnc2c1
Product: Clc1ccc(CCNc2ccc3ccc(NCCc4ccc(Cl)cc4)nc3c2)cc1

Procedure:
A mixture of 2.0 g of 4-chloro-7-fluoroquinoline and 3.5 g of 2-(4-chlorophenyl)ethyl amine was heated neat until fuming began. The mixture was then cooled. The product was extracted into a CHCl3 /ammonium hydroxide solution, which was then washed with water. Solvent was removed by reducing pressure. The residue was placed on a silica gel column with acetone, then flushed with ethanol. Solvent was removed by reducing pressure, giving the title product as a yellow-brown foam. Yield 1.1 g. M.P. 55°-60° C.
Reaction SMILES: [C:1](=[O:17])([O:15][CH3:16])[O:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.OS(O)(=O)=O.[N+:23]([O-])([O-:25])=[O:24].[K+]>>[C:1](=[O:17])([O:15][CH3:16])[O:2][C:3]1[CH:8]=[C:7]([N+:23]([O-:25])=[O:24])[C:6]([Cl:9])=[CH:5][C:4]=1[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)Oc1ccc(Cl)cc1C1CCCC1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(Cl)cc1C1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
4-Chloro-2-cyclopentylphenyl methyl carbonate (1.0 g, 3.93 mmol) was added portion wise to H2SO4 (2.9 mL, 54.1 mmol) to generate a colorless homogeneous solution. The solution was then cooled to 0° C. and KNO3 (476 mg, 4.71 mmol) was added portion-wise maintaining the internal temperature below 5° C. The reaction was stirred for 2 h and then poured on ice water. The aqueous layer was extracted with dichloromethane (3×10 mL), dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (10% EtOAc/hexane) provided 4-chloro-2-cyclopentyl-5-nitrophenyl methyl carbonate (1021 mg, 87% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.39 (s, 1H), 5.23 (s, 1H), 3.92-3.88 (m, 3H), 3.13-3.06 (m, 2H), 2.04-1.96 (m, 2H), 1.81-1.62 (m, 2H), 1.53-1.44 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([C:8](OCC)=[O:9])=O)[CH3:2].C(=O)(O)O.[NH2:18][C:19]([NH2:21])=[NH:20]>C(O)C.O>[CH2:1]([O:3][C:4]([C:5]1[N:18]=[C:19]([NH2:21])[NH:20][C:8](=[O:9])[CH:6]=1)=[O:13])[CH3:2]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(=O)[nH]c(N)n1

Procedure:
A solution of oxalacetic acid diethyl ester (8.5 g, 45.2 mmol) in ethanol (100 mL) was treated with guanidine carbonate (8.1 g, 45.2 mmol) and this was stirred under reflux for 2 hours. The mixture was diluted with water, concentrated to removed ethanol, and the solid was collected by filtration. The solid was then suspended in ethanol (40 mL) and concentrated hydrochloric acid (1 mL) and refluxed for 15 minutes. The mixture was then cooled, basified with potassium carbonate, diluted with water and concentrated to removed ethanol. The white solid was collected by filtration and vacuum dried to give J1.1 (1.67 g, 20%). 1H-NMR (DMSO-d6) δ: 10.34 (1H, br s), 8.92 (1H, br s), 7.46 (1H, br, s), 5.42 (1H, s), 4.18 (2H, q, J=7 Hz), 1.24 (3H, t, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[C:12]([O-])(=O)CC([O-])=O.C(C(CC)(O[Mg+2])C)C>O1CCCC1>[OH:11][C:3]1[C:2]([Cl:1])=[CH:10][C:6]([C:7](=[O:8])[CH3:12])=[CH:5][N:4]=1
Reactant: O=C([O-])CC(=O)[O-]
Reactant: O=C(Cl)c1cnc(O)c(Cl)c1
Agent: CCC(C)(CC)O[Mg+2]
Solvent: C1CCOC1
Product: CC(=O)c1cnc(O)c(Cl)c1
Yield: 93.3 %

Procedure:
7.2 g (37.5 mmol) of 5-chloro-6-hydroxynicotinoyl chloride in 10 ml of absolute tetrahydrofuran are added to a boiling solution of 8.55 g (37.5 mmol) of diethyl ethoxymagnesium-malonate (prepared in accordance with Org. Synth. Coll. Vol. IV (1963), 285) in 120 ml of absolute tetrahydrofuran and the mixture is heated under reflux for 2 hours. After neutralization with 2N sulphuric acid, the organic phase is separated off and evaporated. The residue is heated under reflux in a mixture of 30 ml of glacial acetic acid, 20 ml of water and 5 ml of concentrated sulphuric acid for 4 hours. The mixture is stirred into ice-water, brought to pH 4 and extracted with ethyl acetate. Drying and evaporation gives 6 g (93%) of the title compound, melting point: 188° to 189° C.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([NH:9][C:10]([C:12]1[CH:17]=[N:16][C:15]([CH:18]2[CH2:20][CH2:19]2)=[C:14]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[N:13]=1)=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6].[OH-].[Li+].Cl>C1COCC1.O>[CH:18]1([C:15]2[N:16]=[CH:17][C:12]([C:10]([NH:9][C@@H:4]([C:5]([CH3:8])([CH3:7])[CH3:6])[C:3]([OH:26])=[O:2])=[O:11])=[N:13][C:14]=2[O:21][CH2:22][CH:23]2[CH2:24][CH2:25]2)[CH2:20][CH2:19]1
Reactant: COC(=O)[C@@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[C@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(=O)O
Yield: 109.7 %

Procedure:
To a solution of (S)-2-[(5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carbonyl)-amino]-3,3-dimethyl-butyric acid methyl ester (58 mg, 160 μmol) in THF (3 mL) was added lithium hydroxide (30 mg, 715 μmol) in water (1 mL) and the mixture was stirred at reflux temperature for 3 hours. After cooling the mixture was poured into water (10 mL), acidified with 1 N HCl (1 mL) and extracted with TBME. Organic phases were combined, dried with Na2SO4, filtered and concentrated in vacuo to give the title compound (61 mg, quant.) as white solid; LC-MS (UV peak area/ESI) 100%, 348.1920 (M+H).
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1.[Cl:24][C:25]1[C:31]([OH:32])=[CH:30][C:28]([NH2:29])=[C:27]([F:33])[CH:26]=1>CC(O)CCC>[Cl:24][C:25]1[C:31]([OH:32])=[CH:30][C:28]([NH:29][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[N:5][CH:4]=2)=[C:27]([F:33])[CH:26]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: COc1cc2c(Cl)cnnc2cc1OCCCN1CCCC1
Agent: Cl
Solvent: CCCC(C)O
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)cnnc2cc1OCCCN1CCCC1

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-pyrrolidinopropoxy)cinnoline hydrochloride (0.1 g, 0.25 mmol) and 4-chloro-2-fluoro-5-hydroxyaniline (57 mg, 0.35 mmol), (prepared as described in EP 061741 A2), in 2-pentanol (5ml) was heated at 120° C. for 2.5 hours. The solid was filtered off, washed with isopropanol and then ether and dried under vacuum to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(3-pyrrolidinopropoxy)cinnoline as the hydrochloride salt (yellow solid, 94 mg, 72%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][NH:6][N:5]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1>>[CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[N:5]=1
Reactant: COCc1n[nH]cc1C(=O)OC
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: COCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(=O)OC
Yield: 51.6 %

Procedure:
Using methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (7.4 g) synthesized above and 2-chloro-5-trifluoromethylpyridine (5.8 g) and in the same manner as in Example 1(4), the title object compound (5.2 g, 38%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[Cl-].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:23]=[N+:24]([CH3:26])[CH3:25].COC1C=C(C=CC=1OC)C=O.CNC>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:23]([N:24]([CH3:26])[CH3:25])[C:22]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:20]([O:19][CH3:18])[CH:21]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:7]=1
Reactant: COc1ccc(C=[N+](C)C)cc1OC
Reactant: Clc1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: CNC
Agent: COc1ccc(C=O)cc1OC
Agent: [Cl-]
Product: COc1ccc(C(c2c(-c3ccc(Cl)cc3)[nH]c3ccccc23)N(C)C)cc1OC

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-(4-chloro-phenyl)-1H-indole and (3,4-dimethoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3,4-dimethoxy-benzaldehyde and dimethylamine.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.Cl.C(N=C=NCCCN(C)C)C.[CH2:28]([O:35][C:36]([N:38]1[CH2:42][C@@H:41]([OH:43])[C@H:40]([C:44](O)=[O:45])[CH2:39]1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[CH:12]1([NH:15][C:44]([C@H:40]2[C@H:41]([OH:43])[CH2:42][N:38]([C:36]([O:35][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[CH2:39]2)=[O:45])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=C(O)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1CC1)[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Temperature: 25 °C
Yield: 48.9 %

Procedure:
17.9 g of 1-hydroxybenzotriazole hydrate (117 mmol), 16.9 mL of cyclopropylamine (244 mmol) and 22.4 g of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (117 mmol) were successively added to a solution of (3R,4S)-1-benzyloxycarbonyl-4-hydroxypyrrolidine-3-carboxylic acid (25.9 g, 97.5 mmol) in 259 mL of dehydrated tetrahydrofuran under stirring at room temperature. The mixture was further stirred at room temperature for 5 hours. Subsequently, the reaction mixture was concentrated under reduced pressure, followed by addition of 130 mL of ethyl acetate and 260 mL of 1 mol/L hydrochloric acid and subsequent stirring for 30 minutes. The resulting crystals were collected by filtration and washed with 26 mL of ethyl acetate. The organic layer was collected and washed with 130 mL of a 10% aqueous sodium bicarbonate solution and 130 mL of 28% brine. To this layer, 39.0 g of anhydrous sodium sulfate was added and the mixture was stirred for 1 hour. The insoluble material was separated by filtration and washed with 52 mL of ethyl acetate. The filtrate was concentrated under reduced pressure. To the resulting residue, 156 mL of diisopropyl ether was added and the product was tritulated. The precipitated powder was collected by filtration and washed with 39 mL of diisopropyl ether. The washed product was dried by air-blowing at room temperature for 30 minutes. 25.6 g of the resulting crystals were added to 308 mL of ethylacetate. The mixture was heated at an external temperature of 80° C. for 25 minutes under stirring, then allowed to cool in the air for 40 minutes under stirring, then cooled in a water bath for 5 minutes under stirring at an internal temperature of 40° C., and then stirred at room temperature for 5 minutes at an internal temperature of 25° C. The precipitated powder was collected by filtration and washed with 52 mL of diisopropyl ether. The washed product was dried for 1 hour by air-blowing. Further drying the product by air-blowing at 60° C. for 16 hours gave 14.5 g of the title compound as fluffy colorless crystals (43% yield in the 3 steps).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:18]([NH:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])c[nH]c1=O
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc([N+](=O)[O-])c[nH]c1=O)c1ccccc1

Procedure:
A solution of 100 mg. of 3-amino-5-nitro-2-pyridone in 1.5 ml. of pyridine was cooled and treated with 200 mg. of benzoyl chloride. After 2 hours water was added. The oil that separated was washed with water and triturated with ether. The resultant solid was recrystallized from ethyl acetate to give 3-benzoylamino-5-nitro-2-pyridone, m.p. 267°-268° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([OH:14])[CH2:8][CH2:7]2)[CH3:2].[H-].[Na+].Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][N:19]=1>C1COCC1.CCOCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([O:14][C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=1)[CH2:8][CH2:7]2)[CH3:2]
Reactant: CCOc1ccc2c(c1)CCC(O)C2
Reactant: Clc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1)CCC(Oc1ncnc3ccccc13)C2
Temperature: 25 °C

Procedure:
2.57 g (13.3 mmol) of 6-ethoxytetralin-2-ol in 5 ml of THF were added, with ice-cooling, to a suspension of 400 mg of NaH (80% pure, 13.3 mmol in 40 ml of THF). The mixture was subsequently refluxed for 1 hour and cooled to room temperature, and 2.0 g (12.2 mmol) of 4-chloroquinazoline were added. The mixture was refluxed for 24 hours and cooled and then diluted with ether and washed with saturated sodium hydrogen carbonate and saturated sodium chloride solution. After the organic phase had been dried and concentrated, the residue was chromatographed on silica gel using petroleum ether/ethyl acetate (9:1, 8:2). This gave 2.39 g (61% of theory) of colorless crystals (m.p.115-117° C.).