Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18]/[CH:19]=[CH:20]/[C:21]2[CH:22]=[C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:26]=2)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18]/[CH:19]=[CH:20]/[C:21]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:24]=[C:23]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:22]=2)=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2cc(-c3ccccc3)cc(-c3ccccc3)c2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C/c2cc(-c3ccccc3)cc(-c3ccccc3)c2)cc1)C(=O)O
Yield: 91.9 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 2-ethoxy-3-[4-(3-[1,1′;3′,1″]terphenyl-5′-yl -allyloxy)-phenyl]-propionate (Example 109) (405 mg, 0.8 mmol) and sodium hydroxide (1M, 1.6 ml, 1.6 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-2-ethoxy-3-[4-(3-[1,1′;3′,1″]terphenyl-5′-yl-allyloxy)-phenyl]-propionic acid (352 mg, 92%) as a colourless glass.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH3:23])[N:15]=3)[C@H:11]([C:24]([F:27])([F:26])[F:25])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:29]12[CH2:35][C@H:32]([NH:33][CH2:34]1)[CH2:31][O:30]2>>[CH3:23][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([CH2:13][N:12]2[C:4]3=[N:3][C:2]([N:33]4[CH2:34][C@@H:29]5[CH2:35][C@H:32]4[CH2:31][O:30]5)=[CH:7][C:6](=[O:8])[N:5]3[CH2:9][CH2:10][C@H:11]2[C:24]([F:25])([F:27])[F:26])=[N:15]1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: Cn1nc(CN2c3nc(Cl)cc(=O)n3CC[C@H]2C(F)(F)F)c2ccccc21
Agent: Cl
Product: Cn1nc(CN2c3nc(N4C[C@@H]5C[C@H]4CO5)cc(=O)n3CC[C@H]2C(F)(F)F)c2ccccc21

Procedure:
250 mg (0.63 mmol) of (8S)-2-chloro-9-(1-methyl-1H-indazol-3-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 102.26 mg (0.75 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride were used in the reaction. After purification by chromatography on silica gel (eluent: 60/40 DCM/MeOH), 230 mg of (8S)-9-(1-methyl-1H-indazol-3-ylmethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([CH2:18][CH2:19][C:20]3[NH:24][N:23]=[N:22][N:21]=3)=[CH:16][CH:15]=[C:14]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:9][CH:8]=1)(C)(C)C>C(O)=O>[C:25]1([C:14]2[N:13]([C:10]3[CH:9]=[CH:8][C:7]([C:6]([OH:31])=[O:5])=[CH:12][CH:11]=3)[C:17]([CH2:18][CH2:19][C:20]3[NH:24][N:23]=[N:22][N:21]=3)=[CH:16][CH:15]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c(CCc3nnn[nH]3)ccc2-c2ccccc2)cc1
Solvent: O=CO
Product: O=C(O)c1ccc(-n2c(CCc3nnn[nH]3)ccc2-c2ccccc2)cc1
Yield: 32.4 %

Procedure:
A solution of 4-{2-phenyl-5-[2-(1h-tetrazol-5-yl)ethyl]-pyrrol-1-yl}-benzoic acid tert-butyl ester (1.34 mmol, 1.0 eq) in formic acid (4.2 ml) was stirred at room temperature for 42 hours. The solvent was evaporated in vacuo and the residue purified by prep HPLC. Removal of the solvent in vacuo yielded 156 mg desired product 4-{2-phenyl-5-[2-(1H-tetrazol-5-yl)ethyl]-pyrrol-1-yl}-benzoic acid (32%) and 180 mg byproduct in which the t-butyl group had migrated to the tetrazole ring (37%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][CH2:19][CH2:20][CH2:21][OH:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>ClCCl.C(N(CC)CC)C>[CH2:11]([O:18][CH2:19][CH2:20][CH:21]=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCOCc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCCOCc1ccccc1
Temperature: -50 °C
Reaction time: 0.08 h

Procedure:
Under nitrogen, a solution of DMSO (8.4 mL, 118 mmoles) in dry dichloromethane (125 mL) is cooled to -60° C., and oxalyl chloride (5 mL, 59 mmoles) in CH2Cl2 (40 mL) is added slowly. After stirring for 5 min at -50° C., 3-benzyloxy-1-propanol (14), 8.9 g, 53.7 mmoles) in CH2Cl2 (27 mL) is added at -60° C. Stirring is continued for 15 min, then triethylamine (47 mL) is added slowly at -60° C. After 5 min at this temperature, the mixture is allowed to warm up to room temperature. After addition of 0.5N HCl and phase separation, the organic phase is washed with water until neutral. Drying (Na2SO4) and evaporation gives the crude aldehyde as an oil: 10.6 g. Distillation under vacuum gives pure 15: 6.54 g (74%), bp 170° C. (15 mm Hg).
Reaction SMILES: C(P(C(C)(C)C)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C)(C)C.[OH-].[OH-].[C:24]1([B+2])C=CC=CC=1.ClC1C=CC(C)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:24][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[CH:6]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Reactant: [B+2]c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: Cc1ccc(Cl)cc1
Product: Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (4.5 mg, 0.015 mmol, 1.5 mol %), phenylboron dihydroxide (183 mg, 1.5 mmol), additive (3.0 mmol), and 4-chlorotoluene (0.12 mL, 1.0 mmol). The tube was evacuated and backfilled with argon, and THF (2 mL) was added through a rubber septum. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was then diluted with ethyl acetate (30 mL) and poured into a separatory funnel. The mixture was washed with 2.0M NaOH (20 mL), followed by brine (20 mL). The organic layer was submitted for GC analysis giving the results tabulated below.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][CH2:19]3)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CS(C)=O.[Br:28]N1C(=O)CCC1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:28][C:18]1[CH2:19][C:20]2[C:16]([CH:17]=1)=[C:15]([C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=1)[CH:23]=[CH:22][CH:21]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1cc(-c2cccc3c2C=CC3)cc(C(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2cccc3c2C=C(Br)C3)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
A cold solution (5° C.) of compound 5 (49 g, 161 mmol, 1 equiv), dimethyl sulfoxide (500 mL) and water (5 mL) was treated in one portion with N-bromosuccinimide (43 g, 241 mmol, 1.5 equiv). The bath was removed and the reaction allowed to stir at room temperature overnight. The reaction was poured into water (1 L) and the mixture extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with saturated brine (1 L), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in toluene (500 mL) and p-toluenesulfonic acid (6.2 g, 32.6 mmol, 0.2 equiv) was added. The mixture was refluxed for 20 hours while removing water with a Dean-Stark trap. The reaction was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified over silica gel (1 Kg) eluting with heptanes to give compound 6 (41 g, 66% yield) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:13][C:14](OCC)=[O:15])[CH2:11][CH2:10][CH2:9][NH:8][C:7]1=[O:12])=O)C.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+]>CO>[OH:15][CH2:14][CH2:13][C:6]1([CH2:4][OH:3])[CH2:11][CH2:10][CH2:9][NH:8][C:7]1=[O:12]
Reactant: CCOC(=O)CC1(C(=O)OCC)CCCNC1=O
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CO
Product: O=C1NCCCC1(CO)CCO
Temperature: 25 °C

Procedure:
A solution of 1 mmol of 3-ethoxycarbonylmethyl-2-oxo-piperidine-3-carboxylic acid ethyl ester, 1 mmol of calcium chloride, and 5 ml of methanol is cooled to 0° C. and treated with one portion of 1 mmol of sodium borohydride, keeping the temperature at 0-5° C. with cooling for 2 hours. The mixture is allowed to warm to room temperature overnight. The solids are filtered and washed with methanol. The methanol filtrate is concentrated. The residue is triturated with diethyl ether and decanted. The residue is treated with water and the separated solid is filtered and washed with water. The aqueous filtrates are saturated with potassium carbonate and extracted with dichloromethane (3×) methylene chloride. The combined organic extracts and are dried over potassium carbonate, filtered, and concentrated. From the residue the crude title compound is identified on the basis of the Rf value. The title compound is used without further purification in the next stage.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][N:7]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]1>>[CH3:6][N:7]1[C:11]([CH3:12])=[C:10]([S:2]([Cl:1])(=[O:5])=[O:3])[C:9]([C:13]([F:14])([F:16])[F:15])=[N:8]1
Reactant: Cc1cc(C(F)(F)F)nn1C
Reactant: O=S(=O)(O)Cl
Product: Cc1c(S(=O)(=O)Cl)c(C(F)(F)F)nn1C
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To 53 mls of chlorosulfonic acid at 10° C. was added dropwise over fifteen minutes 1,5-dimethyl-3-(trifluoromethyl)pyrazole (24.0 grams). No significant exotherm resulted and after 15 minutes the cooling bath was removed and the reaction was heated to 110° C. for three hours. After standing overnight, the reaction was heated to 110° C. for an additional four hours and allowed to cool to 50° C. Then 19.0 g of thionyl chloride was dropwise over fifteen minutes. The reaction was then heated to 80° C. for twenty minutes and 110° C. for one hour. After cooling, the reaction was cautiously added to 600 g of ice. The aqueous phase was extracted with two 250 ml portions of ether. The combined organic extracts were dried with MgSO4 and concentrated under reduced pressure to yield 7.8 g of the desired product as a tan oil.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:18][CH3:19])[C:8](=[O:17])[CH2:9][CH:10]([S:15][CH3:16])[C:11]([F:14])([F:13])[F:12])=[CH:5][N:4]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1.FC(F)(F)C([OH:33])C(F)(F)F.OO>>[Cl:1][C:2]1[C:6]([N:7]([CH2:18][CH3:19])[C:8](=[O:17])[CH2:9][CH:10]([S:15]([CH3:16])=[O:33])[C:11]([F:14])([F:13])[F:12])=[CH:5][N:4]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1
Reactant: CCN(C(=O)CC(SC)C(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: OO
Product: CCN(C(=O)CC(S(C)=O)C(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Yield: 89 %

Procedure:
To a 20 mL vial was added N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-4,4,4-trifluoro-3-(methylthio)butanamide (82 mg, 0.209 mmol) and hexafluoroisopropanol (1.5 mL). Hydrogen peroxide (0.054 mL, 0.626 mmol, 35% solution in water) was added in one portion and the solution was stirred at room temperature. After 3 hours the reaction was quenched with saturated sodium sulfite solution and extracted with EtOAc (3×20 mL). The combined organic layers were dried over sodium sulfate, concentrated and purified by chromatography (0-10% MeOH/DCM) to give N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-4,4,4-trifluoro-3-(methylsulfinyl) butanamide (76 mg, 0.186 mmol, 89% yield) as white semi-solid: 1H NMR (400 MHz, CDCl3) δ 8.98 (d, J=2.3 Hz, 1H), 8.63 (td, J=4.8, 2.4 Hz, 1H), 8.14-8.01 (m, 2H), 7.46 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 4.26 (dd, J=17.2, 8.4 Hz, 1H), 3.89-3.61 (m, 2H), 3.01 (dd, J=17.6, 8.2 Hz, 1H), 2.77 (s, 2H), 2.48 (dd, J=17.7, 3.3 Hz, 1H), 1.19 (t, J=7.2 Hz, 3H) (only one isomer shown); ESIMS m/z 409 ([M+H]+); IR (Thin film) 1652 cm−1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[C:5]1([C:3](=[O:4])[CH2:2][S:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Sc1ccccc1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(CSc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
To a suspension of 2-bromoacetophenone (10 g) and potassium carbonate (7.1 g) in ethanol (150 mL) was added thiophenol (5.2 mL) under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=15:1) to give the title compound as yellow crystals (yield 11 g, 98%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:30][CH3:31])[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2[NH:17][CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22]CC)=O)=[O:5])[CH3:2]>C1(OC2C=CC=CC=2)C=CC=CC=1>[O:22]=[C:20]1[N:11]2[CH:12]=[N:13][C:14]3[CH:15]=[CH:16][C:7]([NH:6][C:4](=[O:5])[CH:3]([CH2:1][CH3:2])[CH2:30][CH3:31])=[CH:8][C:9]=3[C:10]2=[N:17][CH:18]=[C:19]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)C(=CNc1ncnc2ccc(NC(=O)C(CC)CC)cc12)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c3cc(NC(=O)C(CC)CC)ccc3ncn2c1=O
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
A mixture of diethyl [[6-(2-ethylbutyramido)-4-quinazolinylamino]methylene]propanedioate (0.6 g) in diphenyl ether (3 ml) was stirred at 250° C. for 15 minutes and cooled to ambient temperature. The resulting crystals were filtered, washed with ethyl acetate and dried. There was obtained ethyl 4-oxo-10-(2-ethylbutyramido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (0.5 g).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[F:11][C:12]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>>[F:11][C:12]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][N:10]([CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[C:19]([CH3:20])[C:12]=1[F:11])[C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: Cc1cccc(CBr)c1F
Reactant: Nc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cccc(CN(Cc2cccc(C)c2F)c2ccc3[nH]cnc3c2)c1F

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 2-fluoro-3-methylbenzylbromide (447 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.072 g (19.1%); MS m/z: 378.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 2.24 (d, 6H, 4JH,F=1.5 Hz); 4.71 (s, 4H); 6.67-6.69 (m, 2H); 6.98 (t, 2H, 3J=7.5 Hz); 7.03-7.06 (m, 2H); 7.13-7.15 (m, 2H), 7.33-7.35 (m, 1H); 7.92 (s, 1H); 11.95 (br s, 1H); HPLC (METHOD [A]): rt 17.77 min (83.5%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])=[CH:7]2)([O-:3])=[O:2].[OH-].[Na+].Br[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[H-].[Na+].[Br-].Cl>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:8]([C:13]([NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:14])=[CH:7]2)([O-:3])=[O:2]
Reactant: BrCCc1ccccc1
Reactant: O=C(Nc1ccccc1)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: Cl
Agent: [Br-]
Agent: [H-]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cc2cc([N+](=O)[O-])ccc2n1CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 200 mg (0.71 mmol) of 5-nitro-N-phenyl-1H-indole-2-carboxamide from Example XLVIII are initially charged in 5 ml of dimethylformamide. 85.3 mg (2.13 mmol) of sodium hydroxide (60% dispersion in paraffin) are added a little at a time, and the mixture is stirred at RT for 30 min. 657 mg (3.56 mmol) of (2-bromoethyl)benzene are then added, and the mixture is stirred at 100° C. for another 5 h. To terminate the reaction, a further 3 eq. of sodium hydride and 5 eq. of bromide are added, and the mixture is stirred at 100° C. for 7 hours. The reaction mixture is poured into aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is removed using a rotary evaporator. The resulting crude product is purified by column chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate 6:1).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([NH:11][C:12]([N:14]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=2)=[N:15]1)=[O:13])[CH3:10].O>ClCCl>[CH2:9]([NH:11][C:12]([N:14]1[C:18]([CH3:19])=[C:17]([Br:1])[C:16]([O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:29])([F:30])[F:31])=[CH:23][N:22]=2)=[N:15]1)=[O:13])[CH3:10]
Reactant: CCNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: CCNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)c(Br)c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
N-Bromosuccinimide (0.64 g, 3.6 mmol) was added to a solution of N-ethyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (1.05 g, 3.0 mmol) in dichloromethane (20 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7), to give a white solid of N-ethyl-4-bromo-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.86 g, yield: 67.0%). mp: 123-125° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.23 (t, J=7.3 Hz, 3H), 2.67 (s, 3H), 3.40 (dq, J=5.9 and 7.3 Hz, 2H), 6.90-7.10 (m, 1H), 8.04 (d, J=2.0 Hz, 1H), 8.32 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1[CH3:7].[CH3:12][N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[N:14]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].P(OC)(OC)OC>[CH3:7][C:6]1[O:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:17]1[N:13]([CH3:12])[N:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1cc(Br)c(C)o1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: COP(OC)OC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C)o1
Temperature: 95 °C
Yield: 85.1 %

Procedure:
To a 5 mL sealed flask reactor was added methyl 4-bromo-5-methyl-2-furancarboxylate (1.13 g, 5.16 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.31 g, 6.30 mmol) [prepared according to the procedure of Preparation 7], K3PO4 (3.87 g, 18.23 mmol) and Pd2(dba)3 (153 mg, 0.17 mmol) and P(OMe)3 (32 μL, 0.27 mmol) in 1,4-Dioxane (23 mL). The reaction was heated at 95° C. for 4 hours, cooled to room temperature and partitioned between CHCl3/H2O. The organic layer was separated, dried with Na2SO4, adsorbed onto silica and purified via column chromatography (0-15% EtOAc/Hexanes) affording the title compound (967 mg, 4.39 mmol, 85%): LC-MS (ES) m/z=271 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][CH:9]1[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:12][C:13]1[N:14]([C:24]2[N:25]=[CH:26][N:27]=[C:28]([NH2:31])[C:29]=2[N:30]=1)[C@@H:15]1[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]1[OH:17].C(O)C>N1C(C)=CC=CC=1C.C(OC(=O)C)C.C(O)C>[OH:11][CH:9]([CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][S:12][C:13]1[N:14]([C:24]2[N:25]=[CH:26][N:27]=[C:28]([NH2:31])[C:29]=2[N:30]=1)[C@@H:15]1[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]1[OH:17]
Reactant: Nc1ncnc2c1nc(S)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: c1ccc(OCC2CO2)cc1
Solvent: Cc1cccc(C)n1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ncnc2c1nc(SCC(O)COc1ccccc1)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
A mixture of 1-phenoxy-2,3-epoxypropane (7.3 g, 48.6 mmoles), 8-mercaptoadenosine (11.5 g, 38.4 mmoles), 2,6 lutidine (about 20 drops) and ethanol (300 ml) is heated at reflux temperature for 1 hour, then it is concentrated to a small volume and ethyl ether is added to precipitate the compound of the title as a raw product. The precipitate is recovered by filtration, washed with ether and dried, dissolved in boiling ethanol, added to an equal amount (by weight) of silica gel and concentrated to dryness. The obtained residue is charged on a silica gel (120 g) column prepared in ethyl acetate and developed with an ethylacetate/ethanol 9/1 mixture. Fractions, containing only the end product, are combined and crystallized from dichloroethane/ethanol 9/1 yielding 6.5 g of the compound of the title. M.p. 100°-110° C. Fusion endotherm at 105° C. in DSC and [α]D30 -48.23° (c=1, CH3OH).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:19])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:20]([O:22][C:23](=[O:35])[CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=2)[CH:27]=[CH:26]1)[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:20]([O:22][C:23](=[O:35])[CH2:24][N:25]1[C:33]2[C:28](=[CH:29][C:30]([O:34][CH2:2][C:3]3[C:4]([CH3:19])=[N:5][C:6]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=4)=[N:7][CH:8]=3)=[CH:31][CH:32]=2)[CH:27]=[CH:26]1)[CH3:21]
Reactant: CCOC(=O)Cn1ccc2cc(O)ccc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2cc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
To a solution of 300 mg (0.94 mmol) 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine and 206 mg (0.94 mmol) (5-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 1 c]) in 3 ml DMF was added 375 mg (1.15 mmol) cesium carbonate. The reaction mixture was stirred for 3 h at RT and then partitioned between ether and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1.2 to give 194 mg of pure {5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([CH2:8][O:9][CH2:10][CH2:11][I:12])=[O:7])[CH3:2].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.N1CCCCC1>C(O)(C)C.C(O)(=O)C.N1CCCCC1>[CH2:1]([O:3][C:4](=[O:13])[C:5](=[CH:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[Cl:14])[C:6]([CH2:8][O:9][CH2:10][CH2:11][I:12])=[O:7])[CH3:2]
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)COCCI
Solvent: C1CCNCC1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccccc1Cl)C(=O)COCCI
Yield: 82.8 %

Procedure:
10 g (33 millimoles) of ethyl-4-(2-iodoethoxy)-acetoacetate (XIII) and 4.64 g (33 millimoles) of 2-chloro-benzaldehyde (V) are reacted in 100 ml of isopropanol in the presence of a piperidine acetate catalyst [0.28 g (3.3 millimoles) of piperidine+0.198 g (3.3 millimoles) of acetic acid] at room temperature for 10 hours. The reaction mixture is evaporated, the residual oil dissolved in dichloro methane, washed with water and dried. The organic phase is evaporated in vacuo. Thus 11.55 g of the desired product are obtained in the form of a reddish brown oil, yield 83%.