Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[O:11][C:9]2=[O:10])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.[CH2:25]([NH2:27])[CH3:26]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]([OH:11])=[O:10])[CH:20]([C:19]3[CH:22]=[CH:23][CH:24]=[C:17]([O:16][CH3:15])[CH:18]=3)[N:27]([CH2:25][CH3:26])[C:12](=[O:14])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)C(=O)O1
Reactant: COc1cccc(C=O)c1
Reactant: CCN
Solvent: Cc1ccccc1C
Product: CCN1C(=O)CC(C(=O)O)(c2ccc(Cl)cc2)C1c1cccc(OC)c1
Temperature: 0 °C

Procedure:
8.13 g of (4-chlorophenyl)-succinic anhydride (0.0386 mole) and 6.3 g (0.0386 mole) of Schiff based, prepared from 3-methoxybenzaldehyde and ethylamine, are refluxed in 100 ml of xylene at 140° C. for 12 hr. After cooling to 0° C. the solid is collected and washed with xylene and ether: 11.5 g (84%) of title compound mp 153°-6° C. (diastereoisomeric mixture).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[C:5]([O:8]C)=[N:6][CH:7]=1.[Br:13]Br>Br>[Br:13][CH2:11][C:10]([C:4]1[C:5]([OH:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:12]
Reactant: COc1ncc(Br)cc1C(C)=O
Reactant: BrBr
Agent: Br
Product: O=C(CBr)c1cc(Br)cnc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
To a solution of 1-(5-bromo-2-methoxypyridin-3-yl)ethanone (2.0 g, 8.69 mmol) in HBr (20 mL, HOAc solution), Br2 (1.4 g, 8.76 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 5 hours. Then the reaction mixture was filtered to collect the HBr salt. The solid was suspended with Na2CO3 solution, extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 2-bromo-1-(5-bromo-2-hydroxypyridin-3-yl)ethanone (2.0 g, yield: 74%). 1H-NMR (DMSO, 400 MHz) δ 12.83 (br s, 1H), 8.11˜8.13 (m, 2H), 4.85 (s, 2H). MS (M+H)+: 295.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N:9]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:18]([CH2:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>Cl.O.C(OCC)C.C(O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][N:9]=[C:26]([C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: O=C(C(=NNc1ccc(Cl)cc1)C(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.4 %

Procedure:
4-Chloroaniline (3.2 g) was dissolved in concentrated hydrochloric acid (5.8 mL) and water (11.6 mL), and the solution was stirred for 15 minutes. Then, ice (30 g) was added thereto, an aqueous solution (4 mL) of sodium nitrite (1.8 g) was added dropwise under ice cooling, and the resulting mixture was stirred for 30 minutes. The reaction solution was returned to room temperature, and an aqueous solution (60 mL) of sodium acetate (6.2 g), and a mixed solution of dibenzoylmethane (5.7 g) in diethyl ether (20 mL)-ethanol (25 mL) were added thereto. The mixture was stirred vigorously for 3 hours. Precipitated yellow crude crystals were collected by filtration, washed with water and then dried under reduced pressure, to obtain (4-chlorophenylhydrazono)dibenzoylmethane (9.5 g) as yellow crystals. To a mixed solution of these crude crystals (9.5 g) and sodium acetate (5.1 g) in acetic acid (60 mL)-acetic anhydride (15 mL), a solution of bromine (1.3 mL) in acetic acid (8.0 mL) was slowly added dropwise under ice cooling. The mixture was stirred for 30 minutes, and then for 16 hours at room temperature. The reaction solution was poured onto ice water (200 mL), and the mixture was stirred for 1 hour. Precipitated crude crystals were collected by filtration, washed with hydrous ethanol and diethyl ether, and dried under reduced pressure, to obtain the title compound (4.4 g) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Cl.C1C[O:19][CH2:18][CH2:17]1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:13][C:6]1([CH3:14])[C:5]2[C:10](=[CH:11][C:2]([C:18](=[O:19])[CH3:17])=[CH:3][CH:4]=2)[C:9](=[O:12])[CH2:8][CH2:7]1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: C1CCOC1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Reaction time: 0.17 h

Procedure:
A solution of 4,4-dimethyl-7-bromo-3,4-dihydronaphthalen-1(2H)one (Compound G) (1.78 g, 7 mmol), 1-ethoxyyinyltributyltin (EVTB) (3.3 g, 9.12 mmol), bis(triphenylphosphine)palladium(II)chloride (260 mg, 0.23 nmol) in THF (25 mL) was refluxed for 24 h under argon atmosphere. To the reaction, additional EVTB (1.5 g, 4.1 mmol) and bis(triphenylphosphine)palladium(II)chloride (200 mg, 0.2 mmol) were added and the mixture was and refluxed for an additional 24 h. The reaction mixture was cooled to room temeperature and 10% hydrochloric acid (10 ml) was added. After 10 min, the mixture was extracted with ether (3×50 mL), the combined organic layer was washed with water (10 mL), 10% sodiumbicarbonate (10 mL), brine (10 mL), dried with magnesium sulfate. Solvent was removed under reduced pressure, and after purification by flash chromatography the title compound was obtained as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Br:23])=[C:20]([Br:22])[CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:33][C:34](=O)[NH:35][C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]3=[O:48])=[CH:38][C:37]=2[F:49])=CC=1)([O-])=O>>[F:49][C:37]1[CH:38]=[C:39]([N:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]2=[O:48])[CH:40]=[CH:41][C:36]=1[NH:35][C:34]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Br:23])=[C:20]([Br:22])[CH:21]=2)=[O:16])[CH2:9]1)=[O:33]
Reactant: O=C(NC[C@H]1CCNC1)c1cc(Br)c(Br)s1
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1cc(Br)c(Br)s1

Procedure:
58.3 Using general method H, 4,5-dibromo-thiophene-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (R)-3-{[(4,5-dibromo-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Pale yellow solid. MS 598.8 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[C:3]([C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=2)(=[O:25])=[O:26])=[CH:20][C:19]=1[C:28]([F:31])([F:29])[F:30]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)cnc1C(=O)c1cccnc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(c1cccnc1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A solution of (3-amino-5-chloro-pyridin-2-yl)-pyridin-3-yl-methanone (26 mg, 0.11 mmol), 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (28 mg, 0.10 mmol), DMAP (7.3 mg, 0.06 mmol) in anhydrous pyridine (0.5 mL) was heated at 60° C. for 2 days. The reaction mixture was separated by preparative HPLC and pure product fractions were lyophilized to provide pure product as a solid. 1H NMR (400 MHz, CDCl3) δ 11.03 (s, 1 H), 9.15 (s, 1 H), 8.81-8.80 (m, 1 H), 8.37 (d, J=2.0 Hz, 1 H), 8.29-8.26 (m, 1 H), 8.20-8.18 (m, 2 H), 7.98 (dd, J=8.4, 2.8 Hz, 1 H), 7.63 (d, J=8.4 Hz, 1 H), 7.51-7.48 (m, 1 H). Mass spectrum m/z: 476.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:16])[C:9]([CH:13]([CH3:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(C)C)c(O)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(C(C)C)c(OC)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
A mixture of methyl 2,4-dihydroxy-5-isopropylbenzoate (420 mg, 2.0 mmol) and anhydrous potassium carbonate (331 mg, 2.4 mmol) in acetonitrile (10 ml) was treated with dimethyl sulphate (0.2 ml, 2.1 mmol) and the mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The solid material was collected by suction filtration, rinsed with water (2×10 ml) and sucked dry under reduced pressure to afford methyl 2-hydroxy-5-isopropyl-4-methoxybenzoate (440 mg, 98%) as a colourless solid. 1H NMR (DMSO-d6) 10.70 (1H, br s), 7.54 (1H, s), 6.53 (1H, s), 3.87 (3H, s), 3.84 (3H, s), 3.12 (1H, m), 1.13 (6H, d). MS: [M+H]+ 225.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].Cl[C:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[O:15]=[C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:16])[N:6]1[O:5][CH2:4][CH2:3][NH:2][C:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19]
Reactant: NCCON1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)NC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=O)NCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a mixture of 2-(2-aminoethoxy)-1H-isoindole-1,3(2H)-dione hydrochloride 75 (0.40 g, 1.65 mmol, EP 1674452 A1, 2006), tert-butyl (chlorocarbonyl)carbamate 82 (1.70 g crude, US 2005/187277 A1) in DCM (10 mL) was added triethylamine (0.69 mL, 4.95 mmol) slowly at 0° C. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue which was subjected to chromatography to give 83 (0.56 g, 96%) as a white solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:3])[CH3:2].Cl.[F:26][C:27]1([F:35])[CH2:31][NH:30][C@H:29]([C:32]([NH2:34])=[O:33])[CH2:28]1.CO>C(Cl)Cl>[F:26][C:27]1([F:35])[CH2:31][N:30]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]([CH3:24])[N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@H:29]([C:32]([NH2:34])=[O:33])[CH2:28]1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(C(C)C)n1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4CC(F)(F)C[C@H]4C(N)=O)cc2OCC3)n(C(C)C)n1
Yield: 17 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol and 4,4-difluoro-L-prolinamide hydrochloride with added TEA (2.5 eq.) were reacted and the crude product subjected to flash chromatography (SiO2, gradient 0 to 5% methanol in DCM) to give 383 as a white solid (29 mg, 17%). LCMS: RT=3.14 min, [M+H]+=459. 1H NMR 400 MHz (DMSO-d6) δ: 9.09 (1H, s), 7.85 (1H, d, J=0.64 Hz), 7.55 (1H, br), 7.15 (1H, br), 6.05 (1H, s), 5.93-5.81 (1H, m), 4.61 (1H, dd, J=9.53, 4.24 Hz), 4.58-4.49 (4H, m), 4.00-3.98 (2H, m), 2.91-2.90 (1H, m), 2.45 (1H, dd, J=13.51, 4.18 Hz), 2.25 (3H, s), 1.49 (6H, dd, J=6.59, 3.35 Hz)
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH2:16].CO>CC1C=CC(C)=CC=1>[C:7]([OH:14])(=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O
Solvent: Cc1ccc(C)cc1
Solvent: c1ccncc1
Solvent: CO
Product: O=C(O)c1ccccc1
Reaction time: 1 h

Procedure:
In a reaction vessel having a capacity of 20 l, 1100 g of the so-obtained block copolymer-containing composition was dissolved in 11 l of p-xylene in a nitrogen atmosphere at 100° C. After the composition had been completely dissolved in p-xylene, 400 ml of pyridine was added into the reaction vessel, and 800 g of benzoyl chloride was continuously supplied in the reaction system over a period of 1 hour. Then, reaction was conducted at 100° C. for 1.5 hours after completion of the addition of benzoyl chloride, and the reaction was stopped by adding 2 l of distilled water into the reaction mixture. After termination of the reaction, the temperature was lowered close to room temperature and the liquid reaction mixture was thrown into a great excess of methanol (in a mixer) to precipitate a benzoic acid-esterified polymer composition. The precipitate was recovered by filtration. After filtration, the benzoic acid-esterified polymer composition was washed with methanol repeatedly and dried under reduced pressure at 50° C. for 24 hours to obtain an intended benzoic acid-esterified polymer composition.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1(O)[C:17]2[CH:16]=[C:15]([F:18])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:4].S(Cl)([Cl:22])=O>>[CH3:1][O:2][C:3]([C:5]1([Cl:22])[C:17]2[CH:16]=[C:15]([F:18])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C1(O)c2ccccc2-c2ccc(F)cc21
Product: COC(=O)C1(Cl)c2ccccc2-c2ccc(F)cc21

Procedure:
A mixture of 2-fluoro-9-hydroxy-9H-fluorene-9-carboxylic acid methyl ester (5) (4.00 g, 15.5 mmol) and 50 mL thionyl chloride was refluxed 3 h. After the thionyl chloride was removed on the rotavapor, the material was redissolved in 50 mL benzene and the benzene then evaporated to remove trace thionyl chloride. The crude product, 4.3 g (100%), was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.N(C([C:19]1[C:20]([Cl:25])=[N:21][CH:22]=[CH:23][CH:24]=1)=O)=[N+]=[N-].C[N:27](C)[CH:28]=[O:29]>>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:28]([NH:27][C:19]2[C:20]([Cl:25])=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:29])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: CN(C)C=O
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: [N-]=[N+]=NC(=O)c1cccnc1Cl
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccnc2Cl)c1O
Yield: 18 %

Procedure:
Under Ar, a solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (50 mg, 0.22 mmol) and 3-(azidocarbonyl)-2-chloropyridine (123 mg, 0.67 mmol) in 1 mL of N,N-dimethyl-formamide was stirred at room temperature for 3 days. Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90, v/v to 90/10, v/v, over 10 min), gave the desired product (15 mg, 18%). LC-MS (m/z) 377.0 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[S:36]>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:35]([NH:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH3:26])=[S:36])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: COc1ccccc1N=C=S
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CC#N
Product: COc1ccccc1NC(=S)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 55 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 8 ml of acetonitrile. 83 μl (2 molar equivalents) of 2-methoxyphenyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 45 hours at 55° C. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 142 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=95%) which was characterized as follows:
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH3:11])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)(=O)/C=C/C(O)=O>>[CH2:10]([O:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=[C:2]1[N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:11]
Reactant: C1CNCCN1
Reactant: CCOCCn1c(Cl)nc2ccccc21
Agent: O=C(O)/C=C/C(=O)O
Product: CCOCCn1c(N2CCNCC2)nc2ccccc21

Procedure:
In the same manner as described in Example 1 using 2-chloro-1-[2-(ethoxy)ethyl]benzimidazole (5.00 g), piperazine (19.00 g) and fumaric acid (3.19 g), there are obtained crude crystals, which are recrystallized from ethyl acetate-ethanol to give 1-[2-(ethoxy)ethyl]-2-(1-piperazinyl)benzimidazole.3/2 fumarate (2.29 g), as colorless needles, m.p. 167°-169° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.[Cl:19][C:20]1[C:21](F)=[N:22][CH:23]=[C:24]([O:26]CCC2OCCO2)[CH:25]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[N:22][C:21]=1[O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:7][C:4]1[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=1
Reactant: Fc1ncc(OCCC2OCCO2)cc1Cl
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ncc(O)cc4Cl)cc23)n1

Procedure:
Using 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol and 3-chloro-5-[2-(1,3-dioxolan-2-yl)ethoxy]-2-fluoropyridine, and in the same manner as in Example 6-2) and 6-3) or according to a method similar to it or according to a combination thereof with an ordinary method, 5-chloro-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (738 mg) was obtained as a pale yellow amorphous solid.
Reaction SMILES: C(C[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C@@H:13]2[CH2:17][C@H:16]([O:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[CH2:15][N:14]2C(OC(C)(C)C)=O)=[N:9][CH:10]=1)(O)=O.[C:36]([OH:42])(C(F)(F)F)=[O:37].[CH2:43](Cl)Cl>>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[O:18][C@@H:16]1[CH2:15][NH:14][C@H:13]([CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([C:36]([O:42][CH3:43])=[O:37])=[CH:10][N:9]=2)[CH2:17]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc3ccccc3c2)C[C@H]1COc1ccc(CC(=O)O)cn1
Reactant: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2)nc1
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirred solution of 5-carboxymethyl-2-[(2S,4S)-1-tert-butoxycarbonyl-4-(2-napthyloxy)-2-pyrrolidinyl]methoxypyridine (170 mg, 0.36 mmol) in CH2Cl2 (5 ml) was added TFA (2 ml) at room temperature. After 2 h stirring, the mixture was concentrated in vacuo, which was diluted with CH2Cl2 and basified by the addition of 1 N NaOH. The combined reaction mixture was extracted with CH2Cl2. The organic layer was washed with brine, which were dried over NaSO4 and concentrated. The residue was purified on TLC [CHCl3/MeOH (10/1)], to give methyl 2-[(2S,4S)-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxypyridine-5-carboxylate (107 mg, 80%) as a colorless oil 1H-NMR (CDCl3) δ1.95 (m, 1H), 2.27 (br, 1H), 2.46 (m, 1H), 3.19 (dd, J=12.2, 4.9 Hz, 1H), 3.41 (d, J=12.2 Hz, 1H), 3.65 (m, 1H), 3.89 (s, 3H), 4.58 (m, 2H), 5.00 (br, 1H), 6.77 (d, J=8.8 Hz, 1H), 7.06 (br, 1H), 7.11 (dd, J=8.8, 2.7 Hz, 1H), 7.31-7.45 (m, 2H), 7.69-7.76 (m, 3H), 8.13 (dd, J=8.8, 2.4 Hz, 1H), 8.78 (d, J=2.2 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([O:13][CH3:14])[CH:5]=1)(=[O:3])[CH3:2].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20]>>[C:1]([C:4]1[CH:5]=[C:6]([O:13][CH3:14])[C:7]([O:12][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:8]([O:10][CH3:11])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(C(C)=O)cc(OC)c1O
Reactant: CCOC(=O)CCCBr
Product: COc1cc(C(C)=O)cc(OC)c1OCCCC(=O)O

Procedure:
Utilizing the procedure of Preparation 3, 2.61 g (13.32 mmol) of 4-acetyl-2,6-dimethoxyphenol is treated with ethyl 4-bromobutyrate. This gives the desired product after drying at -70° C., under high vacuum, as a brown oil. This is chromatographed on a column of silica gel, and eluted with a 1:1 mixture of ether/hexane leaving 0.40 g (10%) of 4-(4-acetyl-2,6-dimethoxyphenoxy)butanoic acid, ethyl ester as a colorless oil: IR (neat) 1735, 1675 cm-1 ; 1H-NMR (CDCl3) is consistent with the desired product; MS (FAB) m/e 311.1489 Δ=+0.6 mmμ (M+ +H). Analysis calculated for C16H22O6 : C, 61.92; H, 7.14; O, 30.94. Found: C, 61.48; H, 7.04; O, 31.48.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[C:7]=1[C:15]1[C:16]2[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=2[N:18]=[CH:19][N:20]=1.[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:39][CH2:38][C@@H:37]([NH2:40])[CH2:36][CH2:35]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:35][CH2:36][C@@H:37]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH2:3][O:2][CH3:1])[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:38][CH2:39]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)O)c[nH]c13)OCO2
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A72) and commercially available cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[C:11]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(=[O:13])[CH3:12].[H][H]>C1C=CC=CC=1>[O:13]=[C:11]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH2:12][C:3]([O:7][CH2:8][CH3:9])=[O:10]
Reactant: CC(=O)c1cccs1
Reactant: CCOC(=O)OCC
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)CC(=O)c1cccs1
Yield: 69.2 %

Procedure:
To a suspension of sodium hydride (7.13 g, 178 mmol, 60% in mineral oil) in benzene (100 mL) was added diethyl carbonate (14.0 g, 118 mmol). The mixture was heated to reflux and a solution of 2-acetylthiophene (7.48 g, 59.4 mmol) in benzene (20 mL) was added dropwise over 1 hour. When addition was complete, the mixture was refluxed for a further 3 hours, after which hydrogen evolution had ceased. The reaction was quenched with acetic acid (15 mL) and then with ice-cold water (45 mL). The organic phase was separated, the aqueous layer was extracted with benzene and the combined extracts were washed with cold water, dried (Na2SO4) and concentrated under reduced pressure. The residue was distilled under high vacuum to give 36 (8.15 g, 69%) as a colorless oil: by 130° C. (0.3 torr): IR (neat) 2925, 2848, 1742, 1669, 1459, 1373, 1030, 851, 723 cm−1; 1H NMR (400 MHz, CHCl3) δ 1.28 (t, 3H, J=7 Hz), 3.93 (s, 2H), 4.25 (q, J=Hz, 2H), 7.16 (m, 1H), 7.71-7.76 (m, 2H); 13C NMR (300 MHz, CDCl3) δ 14.1, 46.5, 61.6, 128.3, 133.2, 134.9, 142.4, 167.0, 185.2: HRMS (EI) m/z 198.0349 (calcd for C9H10O3S 198.0351).