Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:18]=[CH:17][C:10]2[N:11]([CH3:16])[C:12](=[O:15])[N:13]([CH3:14])[C:9]=2[CH:8]=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:29])[CH:27]=[O:28])=[C:22]([Cl:30])[CH:21]=1.O>C1COCC1>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:29])[CH:27]([C:7]2[CH:18]=[CH:17][C:10]3[N:11]([CH3:16])[C:12](=[O:15])[N:13]([CH3:14])[C:9]=3[CH:8]=2)[OH:28])=[C:22]([Cl:30])[CH:21]=1
Reactant: CC(C=O)c1ccc(Br)cc1Cl
Reactant: Cn1c(=O)n(C)c2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccc(Br)cc1Cl)C(O)c1ccc2c(c1)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
A 1.6M solution of n-BuLi in hexanes (0.62 ml) was added at −78° C. to a solution of 5-bromo-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (241 mg) in THF at (10 ml). The gray suspension was stirred for 10 min, then a solution of 2-(4-bromo-2-chloro-phenyl)-propionaldehyde (248 mg) in THF (2 ml) was added. The mixture was stirred for 10 min at −78° C. and then warmed to room temperature. Water (25 ml) was added and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 100% EtOAc/heptane) to give the title compound (194 mg) as a colorless oil. MS (m/e)=409.1 [M+H+].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:9][C:10](/[CH:12]=[CH:13]/[C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=O)=[O:11])[CH3:8].CCN(CC)CC.[F:34][C:35]([F:39])([F:38])[CH2:36][NH2:37]>C(Cl)Cl.CN(C=O)C>[F:34][C:35]([F:39])([F:38])[CH2:36][NH:37][C:16]([C:15]1[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:14]=1/[CH:13]=[CH:12]/[C:10]([O:9][CH2:7][CH3:8])=[O:11])=[O:18]
Reactant: NCC(F)(F)F
Reactant: CCOC(=O)/C=C/c1cc(C(F)(F)F)ccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1cc(C(F)(F)F)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
315 g of oxalyl chloride (2.48 mol) were added at a temperature between 15 and 18° C. over 24 min to a mixture of 650 g of 2-((E)-2-ethoxycarbonylvinyl)-4-trifluoromethylbenzoic acid (2.25 mol), 33 ml of DMF and 7.8 l of CH2Cl2. During the addition, gas evolution was observed. The mixture was stirred at RT for 1 h and then cooled to 5° C., and 285 g of Et3N (2.81 mol) was then added at a temperature between 5° C. and 10° C. over a period of 27 min. The mixture was stirred at 5° C. for a further 10 min, then 279 g of 2,2,2-trifluoroethylamine (2.81 mol) were added at a temperature between 9° C. and 20° C. over a period of 27 min. The mixture was stirred at RT for 10 min, in the course of which a thick precipitate precipitated out, and, to improve the stirrability of the mixture, an additional 1 l of CH2Cl2 was added. The reaction was monitored by HPLC (method C; 2-((E)-2-ethoxycarbonylvinyl)-4-trifluoromethylbenzoic acid rt=5.9 min; ethyl (E)-3-[2-(2,2,2-trifluoroethylcarbamoyl)-5-trifluoromethylphenyl]acrylate rt=13.2 min). After stirring at RT for a further 50 min, the reaction was complete. Volatile constituents of the reaction mixture were then removed under reduced pressure, and the residue was taken up with 12 l of EA and washed 3 times with 2.5 l each time of water, then twice with 2.5 l each time of a saturated aqueous NaHCO3 solution and finally with 1.5 l of a saturated aqueous NaCl solution. Drying was effected over MgSO4, and the solvent was removed under reduced pressure to obtain 802 g of ethyl (E)-3-[2-(2,2,2-trifluoroethylcarbamoyl)-5-trifluoromethylphenyl]acrylate as a brown solid. This crude substance was combined with the crude product of another batch (177 g) and dissolved at 60-70° C. in 3 l of EA, and 14 l of HEP were added at this temperature in 1 l portions. The mixture was then heated to 80° C. and stirred at this temperature for 1.5 h. This mixture was then added to 5.6 l of HEP at 70° C. and the mixture was then cooled to RT with stirring over a period of 5 h. The product was then filtered off, washed with 3 l of HEP and dried under air to obtain 689 g of ethyl (E)-3-[2-(2,2,2-trifluoroethylcarbamoyl)-5-trifluoromethylphenyl]acrylate (67%) as a light brown solid. Mp: 161.5-162° C.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[N:13][O:14][C:15]=3[CH3:16])[N:10]=2)[CH:7]=1.[NH:23]1[CH2:26][CH2:25][C:24]1=[O:27]>>[CH3:16][C:15]1[O:14][N:13]=[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]=1[C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([N:23]3[CH2:26][CH2:25][C:24]3=[O:27])=[CH:7][N:6]2[CH:8]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(I)ccc2n1
Reactant: O=C1CCN1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(N3CCC3=O)ccc2n1
Yield: 6 %

Procedure:
As described for Example 60, 6-iodo-2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine (100 mg, 0.25 mmol) was converted, using 2-azetidinone instead of benzamide, to the title compound (4.8 mg, 6%) which was obtained as a light yellow oil. MS: m/e=345.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([F:40])[CH:39]=1)[O:5][CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:26][CH:25]=2)=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([F:40])[CH:39]=1)[O:5][CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:26][CH:25]=2)=[CH:15][CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Oc1cc(F)cc(F)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2cc(F)cc(F)c2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Yield: 90 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(3,5-difluorophenoxy)-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (410 mg), which is the product of Example 138, was reacted with aqueous sodium hydroxide solution (1N, 2.00 ml) and the reaction mixture was treated to give the title compound (350 mg) as a white powder.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].Cl[C:12]1[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.[Cu].[Cu](I)I>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH2:1][OH:10])[CH:13]=[C:14]([O:20][CH3:21])[CH:15]=1
Reactant: COc1cc(Cl)cc(OC)c1
Reactant: O=C(O)c1ccccc1S
Agent: I[Cu]I
Agent: [Cu]
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: COc1cc(OC)cc(Sc2ccccc2CO)c1
Temperature: 190 °C
Yield: 10 %

Procedure:
Thiosalicylic acid (44 g), 5-chloro-1,3-dimethoxybenzene (49.2 g), potassium carbonate (78 g), copper (4.3 g) and copper iodide (4.3 g) were dissolved in N-methyl-2-pyrrolidone (390 ml) and the solution was stirred at 190° C. for ten hours. The reaction solution was partitioned between ethyl acetate and diluted hydrochloride and filtered, the organic layer was washed with diluted hydrochloride, water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo. To the residue was added anhydrous tetrahydrofuran (200 ml) and the mixture was dropped into a suspension of lithium aluminum hydride (16.24 g) in anhydrous tetrahydrofuran (100 ml) at 0° C. The reaction solution was stirred overnight at room temperature, saturated sodium chloride solution was added to the reaction solution until no more hydrogen was generated, after decantation the organic layer was evaporated in vacuo. The residue was purified by a silica gel column chromatography (developing solvent; hexane:ethyl acetate=3:1) to give 2-(3,5-dimethoxyphenylthio)benzyl alcohol (7.9 g; yield of 10%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12](=[O:15])[CH2:11][CH:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:9][C:8]=3[C:6]=2[CH:7]=1>O1CCOCC1>[OH:15][C:12]1[CH:11]=[C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:9]=[C:8]2[C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[O:14][C:13]=12
Reactant: O=C1CC(c2ccccc2)Nc2c1oc1ccc(Br)cc21
Solvent: C1COCCO1
Product: Oc1cc(-c2ccccc2)nc2c1oc1ccc(Br)cc12
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A mixture of 8-bromo-2-phenyl-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (23.8 g, 69.55 mmol) and FeCl3.6H2O (112.78 g, 417.3 mmol) was added to 1,4-dioxane (300 mL) The mixture was refluxed for 16 hours. TLC showed the reaction completed. The mixture was cooled to room temperature and poured into ice-water (500 mL) The yellow solids precipitated out were collected by filtration to give 4-hydroxyl-8-bromo-2-phenyl-benzofuro[3,2-b]pyridine (6D) (15.7 g, 66.36% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:16]=[CH:15][C:8]2[NH:9][C:10](=[O:14])[CH:11]([CH3:13])[O:12][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].[CH:19]1(Br)[CH2:23][CH2:22][CH2:21][CH2:20]1.O>CN(C)C=O.C(OCC)(=O)C>[CH:19]1([N:9]2[C:8]3[CH:15]=[CH:16][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=3[O:12][CH:11]([CH3:13])[C:10]2=[O:14])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc2c(c1)OC(C)C(=O)N2
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)OC(C)C(=O)N2C1CCCC1
Temperature: 70 °C
Yield: 51.5 %

Procedure:
To a solution of 7-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (prepared in Preparation 1) (4.0 g) in dimethylformamide (80 ml) were added 60% sodium hydride (in oil) (0.73 g) and cyclopentyl bromide (2.5 g) and the mixture was stirred at 70° C. for a day. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using chloroform to give 4-cyclopentyl-7-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.5 g) as an oil.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[N:8]([CH3:11])[C:7](=[O:12])[N:6]([CH3:13])[C:5]1=[O:14])(=O)[CH3:2].[CH2:15]([O:17][NH2:18])[CH3:16]>C(O)C>[CH2:15]([O:17][NH:18][C:1](=[C:4]1[C:9](=[O:10])[N:8]([CH3:11])[C:7](=[O:12])[N:6]([CH3:13])[C:5]1=[O:14])[CH3:2])[CH3:16]
Reactant: CCON
Reactant: CC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Solvent: CCO
Product: CCONC(C)=C1C(=O)N(C)C(=O)N(C)C1=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1.5 g of 5-acetyl-1,3-dimethylbarbituric acid was dissolved in 50 ml of ethanol and 1.5 ml of ethoxyamine was added to it. After the resulting solution was stirred at 40° C during 2 hours, it was allowed to stand at a room temperature. The separated white plates were filtered and recrystallized from ethanol, and thereby 1.4 g of the desired compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:14]2[N:19]=[CH:18][C:17]([NH:20][C:21]([C@H:23]([NH:26]C(=O)OC(C)(C)C)[CH2:24][CH3:25])=[O:22])=[CH:16][N:15]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:26][C@H:23]([CH2:24][CH3:25])[C:21]([NH:20][C:17]1[CH:16]=[N:15][C:14]([O:13][C:5]2[C:6]3[C:10]4([CH2:9][O:8][C:7]=3[C:2]([CH3:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]4)=[N:19][CH:18]=1)=[O:22]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](N)C(=O)Nc1cnc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a solution of tert-butyl N-[(1R)-1-[[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]carbamoyl]propyl]carbamate (Intermediate 20, 42 mg) in dry DCM (3 ml) at 0° C. TFA (1 ml) was slowly added and the reaction mixture was stirred for 3 hours at the same temperature. The solvent and the excess of TFA were removed under reduced pressure and the residue was diluted with DCM (10 ml) and an aqueous saturated solution NaHCO3 was added while the pH was allowed to reach ˜8. Two phases were separated and the organic layer was dried (Na2SO4), filtered and evaporated affording the title compound (25 mg) as light yellow gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.CC(C)[O-].[Na+].C([O:17][C:18](=O)[C:19]([CH2:21][N:22]([CH3:24])[CH3:23])=[CH2:20])C.S(=O)(=O)(O)O>C(O)(C)C>[CH3:23][N:22]([CH2:21][CH:19]1[CH2:20][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:9][C:18]1=[O:17])[CH3:24]
Reactant: NNc1ccc(Cl)cc1
Reactant: C=C(CN(C)C)C(=O)OCC
Agent: CC(C)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Product: CN(C)CC1CN(c2ccc(Cl)cc2)NC1=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
p-Chlorphenylhydrazine (14.5g) was added to a solution of sodium isopropoxide (2.3g of sodium) in dry isopropanol (200 ml). The solution was boiled under reflux and ethyl-2-dimethylaminomethylacrylate (15.7g) was added in one portion. After boiling for 20 minutes, the solution was cooled to 0° C in a stoppered flask. Sulphuric acid (125 ml, 2N) was added and the mixture was extracted with ether (3 × 250 ml). The ether extract was discarded and the aqueous solution was adjusted to a pH of 8 with sodium hydroxide solution (approx 125 ml, 2N). Extraction of the aqueous mixture with chloroform gave a pale yellow extract, which, after evaporation of the chloroform, gave a buff solid. The solid was recrystallised from carbon tetrachloride as colourless needles of 4-dimethylaminomethyl-p-chlorphenylpyrazolidin-3-one (9g, 35%, melting point 107° C).
Reaction SMILES: [ClH:1].C([O:9][C:10]1[C:15](=[O:16])[CH:14]=[CH:13][N:12]([CH2:17][CH2:18][OH:19])[C:11]=1[CH:20]([OH:30])[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[ClH:1].[OH:9][C:10]1[C:15](=[O:16])[CH:14]=[CH:13][N:12]([CH2:17][CH2:18][OH:19])[C:11]=1[CH:20]([OH:30])[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=c1ccn(CCO)c(C(O)c2ccc([N+](=O)[O-])cc2)c1OCc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=c1ccn(CCO)c(C(O)c2ccc([N+](=O)[O-])cc2)c1O
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
1.9 ml of 37% conc. HCl are poured over 0.19 g of 3-benzyloxy-1-(2-hydroxy-ethyl)-2-[hydroxy-(4-nitro-phenyl)-methyl]-1H-pyridin-4-one. The mixture is heated with stirring at 100° C. for 45 minutes. 20 ml of toluene are added and distillation is carried out at a bath temperature of 50° C. and under a pressure of 60 mbar using a rotary evaporator. The addition of toluene and the distillation are repeated four times. The crystalline residue is recrystallised from ethanol, yielding 3-hydroxy-1-(2-hydroxy-ethyl)-2-[hydroxy-(4-nitro-phenyl)-methyl]-1H-pyridin-4-one hydrochloride. Brown crystals, m.p.: from 204° C. with decomposition.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]1[N:12]([CH3:28])[C:13](=[O:27])[C:14]2[N:15]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:16]=[N:17][C:18]=2[N:19]=1)[CH:4]1[CH2:9]CCC[CH2:5]1.[CH3:29]O>>[OH:1][CH2:2][CH:3]([NH:10][C:11]1[N:12]([CH3:28])[C:13](=[O:27])[C:14]2[N:15]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:16]([CH3:29])=[N:17][C:18]=2[N:19]=1)[CH:4]([CH3:9])[CH3:5]
Reactant: Cn1c(N[C@H](CO)C2CCCCC2)nc2ncn(Cc3ccccc3)c2c1=O
Reactant: CO
Product: Cc1nc2nc(NC(CO)C(C)C)n(C)c(=O)c2n1Cc1ccccc1

Procedure:
5A28 2-[2-hydroxy-1 (S)-(cyclohexyl)ethylamino]-1-methyl-7-(phenylmethyl)purin-6-one, solid, [α]D23.5 =+12.1° (CH3OH)
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[CH2:10][C:11]([OH:13])=O.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:14][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[CH2:10][C:11]([N:28]1[CH2:27][CH:26]2[CH:30]([C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24][C:25]2=[O:31])[CH2:29]1)=[O:13]
Reactant: CN(C)c1cccc(F)c1CC(=O)O
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cccc(F)c1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
N,N'-Carbonyldiimidazole (1.62 g) is added to a solution of (2-dimethylamino-6-fluorophenyl)acetic acid (1.97 g) in dry dichloromethane (50 cc), cooled to +5° C. The mixture is stirred for 90 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (3.27 g) and triethylamine (2.8 cc) in dichloromethane (50 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 25 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 50 cc fractions. Fractions 6 to 19 are combined and concentrated to dryness under reduced pressure. The residue is triturated in ethyl ether. The crystals are drained and dried. (3aRS,7aRS)-2-[(2-dimethylamino-6-fluorophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (3.6 g) is obtained in the form of white crystals melting at 210° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[OH:13].[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:10])[F:11])=[CH:4][C:3]=1[OH:13])=[O:18]
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1O
Reactant: O=C(O)c1ccncc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(Cl)c(C(F)(F)F)cc1O)c1ccncc1Cl
Temperature: 80 °C
Yield: 69.9 %

Procedure:
A mixture of 0.60 g of 2-amino-4-chloro-5-trifluoromethylphenol, 0.43 g of 3-chloroisonicotinic acid, 0.67 g of WSC and 5 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.67 g of 3-chloro-N-[5-chloro-2-hydroxy-4-trifluoromethylphenyl]isonicotinamide.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[C:7]([C:10]1[CH:11]=[CH:12][C:13]2[O:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH2:15][C:14]=2[CH:23]=1)(=[O:9])[CH3:8]>CC(C)=O>[C:7]([C:10]1[CH:11]=[CH:12][C:13]2[O:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[C:15](=[O:2])[C:14]=2[CH:23]=1)(=[O:9])[CH3:8]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(=O)c1ccc2c(c1)Cc1cccnc1O2
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc2oc3ncccc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.5 g of potassium permanganate is added in small portions to a solution of 9 g of 7-acetyl-5H-[1]benzopyrano[2,3-b]pyridine in 180 ml of acetone at 10°-15°C. The mixture is stirred at room temperature for 1 hour. The reaction mixture is filtered, and the crystalline residue is washed thoroughly with chloroform. The filtrate and washings are concentrated, and the residue is recrystallized from toluene to give 7-acetyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine melting at 195°-197°C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:34][O:33][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:39]1[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCN1CCN(C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (60 mg), 4-methylpiperazine (39 mg), and potassium carbonate (90 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (41 mg, yield 60%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]([C:18]2[NH:19][N:20]=[CH:21][CH:22]=2)=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:39])(=[N:32][C:33](=[O:38])[NH:34][CH:35]([CH3:37])[CH3:36])=[O:31])=[CH:26][CH:25]=1>>[CH:35]([NH:34][C:33]([N:32]=[S:30]([C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:5]([C:18]3[NH:19][N:20]=[CH:21][CH:22]=3)=[CH:4][N:3]=2)=[CH:29][CH:28]=1)([CH3:39])=[O:31])=[O:38])([CH3:37])[CH3:36]
Reactant: CC(C)NC(=O)N=S(C)(=O)c1ccc(N)cc1
Reactant: Clc1ncc(-c2ccn[nH]2)c(NCCCN2CCOCC2)n1
Product: CC(C)NC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3ccn[nH]3)c(NCCCN3CCOCC3)n2)cc1
Yield: 34 %

Procedure:
In the reaction of [2-chloro-5-(2H-pyrazol-3-yl)-pyrimidin-4-yl]-(3-morpholin-4-yl-propyl)-amine (212.8 mg, 0.66 mmol) with (RS)—S-(4-aminophenyl)-N-(isopropylcarbamoyl)-S-methylsulphoximide (153 mg, 0.6 mmol) according to procedure 5c, the desired product is obtained in 34% yield (109 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [CH2:1]([O:3]C(=O)OCC)C.[H-].[Na+].[Br:11][C:12]1[C:13]([OH:22])=[C:14]([C:19](=[O:21])[CH3:20])[CH:15]=[C:16]([Br:18])[CH:17]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:18][C:16]1[CH:17]=[C:12]([Br:11])[C:13]2[O:22][C:1](=[O:3])[CH:20]=[C:19]([OH:21])[C:14]=2[CH:15]=1
Reactant: CC(=O)c1cc(Br)cc(Br)c1O
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=c1cc(O)c2cc(Br)cc(Br)c2o1
Temperature: 105 °C
Reaction time: 5 h
Yield: 18.4 %

Procedure:
A solution is prepared of diethylcarbonate (62.5 mmol, 7.6 mL) in 150 mL of toluene to which is added NaH (37.5 mmol, 1.5 g of 60% dispersion in mineral oil) in portions. To this solution is added, dropwise, 3′,5′-dibromo-2′-hydroxyacetophenone (12.5 mmol, 3.67 g) in 50 mL of toluene. The reaction is heated to 105° C. overnight, cooled to ambient temperature, 100 mL of 1N NaOH, is added and the reaction is stirred vigorously for 5 hrs at ambient temperature. The layers are separated and the aqueous layer is washed with EtOAc 2×. The combined organic layers are washed with H2O 1×. The combined aqueous layers are acidified to pH 2 with conc HCl to form a precipitate that is filtered and is washed with H2O. The solid material is dissolved in ACN/H2O and speed vacced to dryness to afford the title compound as a light tan solid (0.737 g, 18%). 1H NMR (DMSO-d6, 300 MHz) δ 12.98 (1H, br s), 8.18 (1H, d, J=2.25 Hz), 7.90 (1H, d, J=2.25 Hz), 5.64 (1H, s); MS (ESI, Pos.) calcd for C9H4Br2O3 m/z [M+H]=318.9, found 318.9.