Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C([C:21]1[CH:22]=[CH:23][C:24]([OH:32])=[C:25]([CH:31]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])#C.[CH2:33](N(CC)CC)[CH3:34].Cl>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O1CCCC1>[OH:32][C:24]1[CH:23]=[C:22]([C:33]#[C:34][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=3)(=[O:10])=[O:9])[CH:3]=2)[CH:21]=[CH:31][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCN(CC)CC
Reactant: Cc1cccnc1NS(=O)(=O)c1cccc(I)c1
Reactant: C#Cc1ccc(O)c(C(=O)OCC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2cccc(S(=O)(=O)Nc3ncccc3C)c2)cc1O

Procedure:
3-Iodo-N-(3-methyl-2-pyridinyl)benzenesulfonamide (18.7 g, 50 mmol), ethyl 5-ethynyl-2-hydroxybenzoate (9.5 g, 50 mmol), triethylamine (65 ml) and tetrahydrofuran (65 ml) were stirred at 60 ° C. Dichlorobis(triphenylphosphine)palladium (250 mg, 0.36 mmol) and copper(I)iodide (140 mg, 0.7 mmol) were added with stirring. After 1 h the solution was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried, treated with activated carbon and the solvent evaporated. The residue was recrystallized from methanol, then from toluene and finally from acetic acid. Yield 12.7 g 58%.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>ClC1C=CC=CC=1.CS(C)=O>[CH:5]1([N:11]=[C:1]=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1
Solvent: CS(C)=O
Product: O=C=NC1CCCCC1
Yield: 178.3 %

Procedure:
500 g of chlorobenzene and 2 g of dimethyl sulfoxide (0.025 mol) were placed in the glass vessel and 35 g of gaseous phosgene was introduced at room temperature. The reaction mixture was subsequently heated to 78° C., with vigorous phosgene reflux being established. While stirring vigorously at 78–82° C., a total of 99.2 g of cyclohexylamine (1 mol) dissolved in 200 g of chlorobenzene and at the same time a further 113 g of phosgene were introduced over a period of 3 hours. After addition was complete, the system was maintained at 78–82° C. for a further one hour without introduction of phosgene to allow further reaction to occur and the residual unreacted phosgene was subsequently stripped out at 40° C. by means of nitrogen. The reaction mixture obtained was a fluid suspension from which the solid obtained was separated by filtration. 2.2 g of solid were able to be isolated in this way. The filtered crude product was worked up by distillation. Removal of the solvent and fractional distillation gave 79.7 g of cyclohexyl isocyanate (0.631 mol). This corresponds to 63.1% of the theoretical yield.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][N:9]([CH3:19])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][S:2]([O:6][CH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][N:9]([CH3:19])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CC(O)c1ccccc1)S(=O)(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(CC(OS(C)(=O)=O)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
Methanesulfonyl chloride (0.028 mL, 41 mg, 0.36 mmol) was added dropwise over 5 min to a 0° C. solution of N-(2-hydroxy-2-phenylethyl)-N-methylbenzenesulfonamide (100 mg, 0.357 mmol) and triethylamine (0.075 mL, 54 mg, 0.054 mmol) in 1.0 mL of ethyl acetate. After 15 min., the resulting suspension was poured into 40 mL of ice cold ethyl acetate and washed succesively with 20 mL of ice water, 20 mL of ice cold 2.0 N HCl, 20 mL of ice water and 20 mL of brine. The ethyl acetate layer was dried over sodium sulfate and evaporated to give 128 mg of crude N-(2-methanesulfonyloxy-2-phenylethyl)-N-methylbenzenesulfonamide.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:21]=[CH:20][C:15]([CH2:16][N:17]=[C:18]=[O:19])=[CH:14][CH:13]=1.C([O:24]CC)C>>[CH2:1]([N:8]1[C:9](=[O:24])[S:10][N:17]([CH2:16][C:15]2[CH:20]=[CH:21][C:12]([CH3:11])=[CH:13][CH:14]=2)[C:18]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CN=C=O)cc1
Reactant: S=C=NCc1ccccc1
Reactant: CCOCC
Product: Cc1ccc(Cn2sc(=O)n(Cc3ccccc3)c2=O)cc1

Procedure:
Reagents: Benzylisothiocyanate (6.5 mmol, 0.85 mL), 4-methylbenzyl-isocyanate (6.5 mmol, 0.90 mL) and SO2Cl2 (6.5 mmol, 0.52 mL) in diethyl ether (25 mL). Isolation: filtration of reaction mixture. Purification: recrystallization from MeOH.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.[I-].[K+].[CH2:32](Br)[CH3:33]>CN(C=O)C.C(OCC)(=O)C>[CH2:32]([O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:12])=[CH:3][C:2]=1[O:1][CH2:20][CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)[CH3:33]
Reactant: CCBr
Reactant: ClCCCOC1CCCCO1
Reactant: O=C1CCc2cc(O)c(O)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OCCCOC1CCCCO1)CCC2=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 5,6-dihydroxy-indan-1-one (Intermediate O) (1.80 g, 0.01098 mole), potassium carbonate (3.80 g, 0.02744 mol), 2-(3-chloro-propoxy)-tetrahydro-pyran (Compound 18a) (1.37 g, 0.00769 mol) and potassium iodide (1.28 g, 0.00769 mol) in DMF (20 mL) was stirred at 60° C. for 4 hours. To this mixture was then added ethyl bromide (1.64 mL, 0.02196 mol) and continued to heat for further 4 h. The reaction mixture was then diluted with ethyl acetate, washed with water and dried over MgSO4. The solvent was removed in vacuo and the title compound was purified by silica gel column chromatography using 3:1 Hexanes:ethyl acetate as the eluent. MS m/z 334.2 (M+H)+;
Reaction SMILES: [OH-].[K+].[CH2:3]1OCCOCCOCCOCCOCCOC1.[C:21]([C:25]1[CH2:29][CH:28]=[C:27](C)[CH:26]=1)([CH3:24])([CH3:23])[CH3:22].[C:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=O)[CH3:32].Cl>C1COCC1>[C:21]([C:25]1[CH:26]=[C:27]([CH3:28])[C:32](=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:3])[CH:29]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CC1=CCC(C(C)(C)C)=C1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1=CC(C(C)(C)C)=CC1=C(C)c1ccccc1
Reaction time: 3 h
Yield: 241.5 %

Procedure:
To a 100 ml three-neck flask equipped with a magnetic stirrer chip and a three-way cock, 1.50 g (25.8 mmol) of potassium hydroxide pulverized in mortar, 0.91 g (3.44 mmol) of 18-crown-6 and 45 ml of THF were charged under a nitrogen atmosphere. Thereto in a water bath, 2.70 g (16.0 mmol) of 1-tert-butyl-3-methylcyclopentadiene was added dropwise over 10 minutes and stirred for 3 hours. The solution was added with 11.33 g (94.3 mmol) of acetophenone dropwise over 10 minutes, and stirred for 22 hours. The reaction solution was poured into 100 ml of 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with 200 ml of hexane. The separated organic layers were combined, washed with a saturated aqueous solution of sodium hydrogencarbonate, water, and saturated aqueous solution of sodium chloride. After the solution was dried over magnesium sulfate, the obtained product was purified by column chromatography to obtain 1.98 g of a red orange liquid. The yield was 52%. Identification was done by 1H-NMR spectrum and FD-mass analysis spectrum. The result of the 1H-NMR spectrum proved that the obtained compounds are mixture of isomers. The measurement results are shown as follows.
Reaction SMILES: [C:1](O)(=O)C(O)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][C@:18]2([CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[CH2:21][CH2:20][NH:19]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[OH-].[NH4+].C1(C)C=CC=CC=1.[I:50]C>O>[I-:50].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:17][C@:18]2([CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[CH2:21][CH2:20][NH+:19]2[CH3:1])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(C[C@@]2(CCC(=O)OC(C)(C)C)NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: O=C(O)C(=O)O
Reactant: CI
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C[C@]2(CCC(=O)OC(C)(C)C)c3cc(OC)c(OC)cc3CC[NH+]2C)cc1OC
Product: [I-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
(1R)-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-tert-butoxycarbonylethylisoquinoline oxalate (7.0 g, 0.0125 moles), prepared as described in example 1, was dissolved in water (50 ml) and 25% aqueous ammonium hydroxide solution was added to produce a pH in the range of 9-10. Toluene (100 ml) was added and the mixture was stirred for 15 minutes at ambient temperature. The upper organic layer was separated and washed with 10% sodium chloride solution. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure to afford a solid residue. Iodomethane (30 ml, 0.482 moles) was added to the residue and the mixture was stirred to obtain a solution and kept at ambient temperature overnight. The resulting precipitate was collected by filtration, washed with diethyl ether and dried at room temperature to afford a mixture of 81.5% of the cis and 18.5% of the trans isomers of (1R)-1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-2-tert-butoxycarbonylethyl-isoquinolinium iodide (5.5 g; 72% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[OH:7].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.N1C=CC=CC=1>O>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:7][CH:3]2[CH2:4][CH2:5][CH2:6][CH:2]2[CH3:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1CCCC1O
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC2CCCC2C)cc1
Reaction time: 10 h

Procedure:
2-Methylcyclopentanol (21.06 g, 0.210 mol) and p-toluenesulfonyl chloride (48.3 g, 0.252 mol) were charged into a 500 cc three-necked flask equipped with a stirrer, and then pyridine (170 ml) was added dropwise thereto under ice-cooling. The mixture was stirred for 10 hours while gradually elevating the temperature to room temperature. After completion of the reaction, cold water (500 ml) was added to the reaction mixture, and the mixture was extracted with ether (200 ml×3). The organic layers were combined, washed successively with 2N hydrochloric acid, water and a saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. The drying agent was separated by filtration, and the solvent was distilled off under reduced pressure to obtain substantially pure 2-methylcyclopentyl p-toluenesulfonate as a colorless transparent oily substance (49.7 g, 0.195 mol, 934 yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C-]#N.[K+].C1OCCOCCOCCOCCOCCOC1.[C:36](#[N:38])C>O>[C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:36]#[N:38]
Reactant: CC#N
Reactant: BrCc1ccccc1-c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CCc1ccccc1-c1ccccc1

Procedure:
2-(Bromomethyl)biphenyl (1.35 g, 5.48 mmol), potassium cyanide (368 mg, 5.65 mmol), and a catalytic amount of 18-crown-6 ether were added to acetonitrile (10 ml), and the mixture was heated under reflux for 5 days. The reaction mixture was added with water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over magnesium sulfate. Insoluble solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound as colorless solid (1.07 g, yield: quantitative).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:16](Br)[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CBr
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(CC(C)C)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=254.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and isobutylbromide.
Reaction SMILES: [CH:1]([C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:15]([C:20]1[N:21]=[CH:22][N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:24]=1)([OH:19])[CH:16]([CH3:18])[CH3:17])=[CH:8]2)=[CH2:2].Cl.N1C=CC=CC=1>CO.C1COCC1>[CH:1]([C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:15]([C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)([OH:19])[CH:16]([CH3:18])[CH3:17])=[CH:8]2)=[CH2:2]
Reactant: C=Cc1c(OC)ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CO
Product: C=Cc1c(OC)ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
1-(5-Ethenyl-6-methoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (230 mg) was dissolved in a mixed solution of methanol and THF (3:1, 20 ml). To the solution was added pyridine hydrochloride (0.12 g), and the mixture was stirred at 60° C. for 3 h. The reaction mixture was concentrated to dryness, and to the residue were added ethyl acetate and 1N-hydrochloric acid (10 ml). The organic layer was extracted four times with 1N-hydrochloric acid. The aqueous layer was neutralized with an aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried and concentrated. The residue was purified by silica gel chromatography (eluent, dichloromethane-methanol=10:1) to give the titled compound (91 mg).
Reaction SMILES: CN(C)C=O.Br.[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][CH:13]=1.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>C(N(CC)CC)C>[N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=3)=[CH:16][CH:17]=2)=[O:32])[CH:27]=1
Reactant: O=C(O)c1cccnc1
Reactant: NCCCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCCCc1ccc(-c2ccc(=O)[nH]n2)cc1)c1cccnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
Under ice cooling, a dimethylformamide solution (10 ml) containing 1.06 g of diethylphosphoric cyanide was added dropwise to a dimethylformamide suspension (30 ml) containing 1.65 g of 6-[4-(4-aminobutyl)phenyl]pyridazin-3(2H)-one hydrobromide, 0.78 g of nicotinic acid and 1.55 g of triethylamine, and the mixture was stirred for 1 hour. The reaction mixture was poured into ice water, and precipitated crystal was collected by filtration. The obtained crystal was washed with water, dried and then recrystallized from methanol to obtain 1.11 g of 6-[4-(4-(pyridin-3-ylcarbonylamino)butyl)phenyl]pyridazin-3(2H)-one.
Reaction SMILES: O.[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5][C:4]1=[CH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>CCO.C(OCC)(=O)C>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][C:14]([CH2:13][C:4]2[C:3](=[O:2])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][CH:5]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(C=C2COc3ccccc3C2=O)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Cc2coc3ccccc3c2=O)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
Water (0.2 ml) and RhCl3.H2O (7 mg, 0.034 mmol) was added to a suspension of compound 260 (200 mg, 0.680 mmol) in EtOH (2 ml) and CHCL3 (2 ml). The reaction mixture was stirred 16 h at 70° C. The reaction mixture was cooled down and diluted in ethyl acetate, washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (0.5-1% MeOH/CH2Cl2) to afford the title compound 261 (118 mg, 59%) as a white solid. 1H NMR: (DMSO) δ (ppm): 8.45 (s, 1H), 8.03 (dd, J=7.9, 1.8 Hz, 1H) 7.87 (d, J=8.4 Hz, 2H), 7.83-7.77(m, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.50-7.43 (m3, 1H), 3.82 (s, 3H), 3.80 (s, 2H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:24][CH2:23][C:22]2[C:21]([O:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([C:35](=[O:48])[NH:36][C:37]3[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=3[F:47])[CH:30]=[CH:29]4)=[N:20][CH:19]=[N:18][C:17]=2[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[F:47][C:38]1[CH:39]=[CH:40][C:41]([C:43]([F:44])([F:45])[F:46])=[CH:42][C:37]=1[NH:36][C:35]([N:31]1[C:32]2[C:28](=[CH:27][C:26]([O:25][C:21]3[C:22]4[CH2:23][CH2:24][NH:15][CH2:16][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:34][CH:33]=2)[CH:29]=[CH:30]1)=[O:48]
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C(F)(F)F)ccc3F)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(C(F)(F)F)ccc1F)n1ccc2cc(Oc3ncnc4c3CCNC4)ccc21

Procedure:
TFA (1 mL, 13.0 mmol) is added to a solution of 4-[1-(2-fluoro-5-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (0.125 g, 0.219 mmol) and DCM (2.5 mL). After 1 h the solution is concentrated in vacuo. The residue is taken up in MeOH and neutralized to pH 7 by the addition of NH4OH and the solution is separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give 5-(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (2-fluoro-5-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 472.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (s, 1H), 8.25 (d, J=8.8 Hz, 1H), 8.07 (d, J=3.8 Hz, 1H), 8.03-8.07 (m, 1H), 7.67-7.75 (m, 1H), 7.56-7.64 (m, 1H), 7.45 (d, J=2.5 Hz, 1H), 7.11 (dd, J=9.0, 2.4 Hz, 1H), 6.79 (d, J=3.5 Hz, 1H), 3.83 (s, 2H), 3.04 (t, J=5.8 Hz, 2H), 2.73 (t, J=5.6 Hz, 2H).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:23][NH2:24].O>CCO>[NH:23]([C:16]([C:15]1[CH:20]=[CH:21][C:12]([NH:11][C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:14]=1)=[O:17])[NH2:24]
Reactant: COC(=O)c1ccc(NC(=O)COc2ccccc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(NC(=O)COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46 %

Procedure:
To a suspension of methyl 4-[(phenoxyacetyl)amino]benzoate (843 mg, 2.95 mmol) in EtOH (10 mL) was added hydrazine hydrate (2.15 mL). After stirring for 15 hrs at reflux, the reaction mixture was cooled to rt. Water (10 mL) was added to the reaction mixture and a white solid precipitated out. Filtration, washing with EtOH/water (2×2 mL) and water (3×1 mL), and drying under vacuo at 70° C. for 6 hrs gave 389 mg of the title compound (46%) as a white solid in 95.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=2[CH2:12][OH:13])[CH2:4][CH2:3]1.[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17]>CO>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:2]2([NH:1][C:16](=[O:17])[C:15]([F:22])([F:21])[F:14])[CH2:4][CH2:3]2)=[C:6]([CH2:12][OH:13])[CH:7]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NC1(c2ccc(Br)cc2CO)CC1
Solvent: CO
Product: O=C(NC1(c2ccc(Br)cc2CO)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 850 mg of 1-(1-aminocyclopropyl)-4-bromo-2-hydroxymethylbenzene and 8.5 ml of methanol was added 1.24 g of ethyl trifluoroacetate, and the resulting mixture was stirred at room temperature for 24 hours. The solvent was removed by distillation under reduced pressure, and the residue obtained was purified by a column chromatography (eluent: chloroform:ethanol=30:1), to obtain 1.02 g of colorless, crystalline 4-bromo-2-hydroxymethyl-1-(1-trifluoroacetylaminocyclopropyl)benzene.
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:34])[C:19]2[CH:24]=[C:23]([CH2:25][NH:26][C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])[CH:22]=[CH:21][C:20]=2[Cl:33])=[CH:13][C:12]=1[C:35]([OH:37])=O.[NH2:38][C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][N:40]=1>C1COCC1>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:34])[C:19]2[CH:24]=[C:23]([CH2:25][NH:26][C:27]([C:29]([CH3:31])([CH3:32])[CH3:30])=[O:28])[CH:22]=[CH:21][C:20]=2[Cl:33])=[CH:13][C:12]=1[C:35]([NH:38][C:39]1[CH:44]=[C:43]([C:45]([F:47])([F:46])[F:48])[CH:42]=[CH:41][N:40]=1)=[O:37]
Reactant: COc1ccc(NC(=O)c2cc(CNC(=O)C(C)(C)C)ccc2Cl)cc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)ccn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2cc(CNC(=O)C(C)(C)C)ccc2Cl)cc1C(=O)Nc1cc(C(F)(F)F)ccn1
Reaction time: 2 h

Procedure:
1-Chloro-N,N,2-trimethylpropenylamine (23 was added to a mixture of N-[4-methoxy-3-hydroxycarbonyl-phenyl]-2-chloro-5-(tert-butylcarbonylamino)methyl-benzamide (60.0 mg, 0.143 mmol, prepared from ethyl 5-amino-2-methoxy benzoate in analogy to step 5c and 5d) in 2.0 mL THF and it was stirred for 2 h. additional 80 μL of 1-chloro-N,N,2-trimethylpropenylamine were added and it was stirred for another 2 h. Then TEA (0.100 mL) and 2-amino-4-trifluormethyl-pyridine (23.2 mg, 0.143 mmol) were added and it was stirred overnight. The reaction mixture was concentrated and purified via prep. HPLC (method A) to furnish the title compound.
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[O:13])[C:10]3[CH2:14][CH2:15][CH2:16][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:19](Br)[C:20]#[CH:21]>O1CCCC1.C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]1([C:7]2[N:12]([CH2:21][C:20]#[CH:19])[C:11](=[O:13])[C:10]3[CH2:14][CH2:15][CH2:16][C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CCBr
Reactant: O=c1[nH]c(-c2ccccc2)nc2c1CCC2
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C#CCn1c(-c2ccccc2)nc2c(c1=O)CCC2
Yield: 5.1 %

Procedure:
A slurry of 8.3 g (39.1 mmol) of 2-phenyl-3,5,6,7-tetrahydro-4H-cyclopentapyrimidin-4-one in 60 mL of tetrahydrofuran was added to 1.9 g (48 mmol) of 60% sodium hydride, with external cooling. A 6.4 g (43.0 mmol) portion of 80% by weight of propargyl bromide in toluene was added to the cooled solution. The ice bath was removed and the reaction was refluxed for 6 hours. The solvent was removed in vacuo, ether was added to the residue and the reaction was washed 3 times with water and once with brine. The organic layer was dried over MgSO4 and concentrated to yield 5.0 g of crude semisolid product. The crude product was dissolved in a small amount of methylene chloride and passed through a 6 inch plug of silica gel, washing with 1 of methylene chloride. The silica gel was washed further with 1 L of ether. The ether was removed in vacuo to yield 0.5 g (5.1%) of 2-phenyl-3-propargyl-3,5,6,7-tetrahydro-4H-cyclopentapyrimidin-4-one (Compound 1) as a white solid. 1H-NMR (CDCl3) δ 2.15 (2H,m), 2.35 (1H,t), 2.95 (4H,t), 4.65 (2H,t), 7.55 (3H,m), 7.7 (2H,m).