Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=C[C:3]([CH2:6][NH:7][C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=2[C:10]#[N:11])=[CH:2]1.[CH3:20]C(C)([O-])C.[K+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[C:31]([O:30][C:28]([C:27]1[N:7]([C:6]2[CH:3]=[CH:2][S:1][CH:5]=2)[C:8]2[C:9]([C:10]=1[NH2:11])=[C:12]([CH3:20])[C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1cc(C(F)(F)F)ccc1NCc1ccsc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(C(F)(F)F)ccc2c1c(N)c(C(=O)OC(C)(C)C)n2-c1ccsc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.1 %

Procedure:
To a solution of 2-[(thiophen-3-yl-methyl)amino]-5-trifluoromethylbenzonitrile 1C (1.42 g, 5.04 mmol) in anhydrous tetrahydrofuran (THF) (10 mL) and anhydrous N,N-dimethylformamide (DMF) (10 mL) at 0° C. was added potassium tert-butoxide (1.13 g, 10.1 mmol). The reaction mixture was stirred at 0° C. for 5 minutes and tert-butyl bromoacetate 1D (1.47 g, 7.54 mmol) was added. The reaction mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added and the organic layer was washed with 1 N hydrochloric acid and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to provide 3-amino-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1E (1.74 g, 4.39 mmol).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:21][OH:22])=[NH:20])=[C:14]([Cl:23])[CH:13]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:40]1([O:46]C(Cl)=O)C=CC=CC=1.C(OCC)(=O)C>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[NH:20][C:40](=[O:46])[O:22][N:21]=2)=[C:14]([Cl:23])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(CC(=N)NO)c(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(Cc2noc(=O)[nH]2)c(Cl)c1
Temperature: 25 °C

Procedure:
2.3 g crude 2-{4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-phenyl}-N-hydroxy-acetamidine were dissolved in 30 ml dichloromethane. 0.46 ml pyridine and 0.71 ml phenylchloroformate were added and the mixture stirred at room temperature for ten minutes. The mixture was diluted by the addition of 150 ml ethyl acetate, washed with brine and dried over MgSO4. The solvent was evaporated in vacuo. The resulting residue was dissolved in 20 ml acetonitrile and 0.70 ml 1,8-Diazabicyclo[5.4.0]undec-7-ene were added. The mixture was stirred at room temperature for 10 minutes. The mixture was evaporated in vacuo and the resulting crude material was purified by reversed phase HPLC to obtain 820 mg 3-{4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-benzyl}-4H-[1,2,4]oxadiazol-5-one as an amorphous lyophilisate.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH2:15])[N:9]=2)=[CH:5][C:4]([C:16]([F:19])([F:18])[F:17])=[N:3]1.C(N(C(C)C)CC)(C)C.[C:29](Cl)(=[O:33])[CH:30]=[CH:31][CH3:32]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:29](=[O:33])[CH:30]=[CH:31][CH3:32])[NH2:15])[N:9]=2)=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[N:3]1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cccc(CN)n1
Reactant: CC=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC=CC(=O)C(N)c1cccc(Oc2cc(C(F)(F)F)nn2C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.100 g (0.368 mmol) of 2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-6-(aminomethyl)-pyridine was introduced in 5 ml of methylene chloride together with 71.1 mg (0.55 mmol) of diisopropylethylamine, at room temperature 46.1 mg (0.44 mmol) of but-2-enoyl chloride were added and the mixture was stirred at room temperature for 3 h. The crude product was concentrated, subjected to extraction with 1 N HCl and ethyl acetate and then filtered over a silica gel bed. The filtrate was concentrated. The residue was crystalline.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])[CH3:2].[CH:12]([NH2:15])([CH3:14])[CH3:13].C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[NH:15][CH:12]([CH3:14])[CH3:13])=[O:5])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)C1CCCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1=C(NC(C)C)CCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (3.00 g, 19.2 mmol) in ethanol (20 mL) was treated with isopropylamine (1.135 g, 19.2 mmol), sodium cyanoborohydride (2.42 g, 38.4 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the crude product, 2-isopropylamino-cyclopent-1-enecarboxylic acid ethyl ester (2.44 g, 12.38 mmol, 64.5%), as a light yellow oil. LC-MS (ESI) calcd for C11H19NO2 197.14, found 198.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]([C:4]1[N:5]([CH3:15])[C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][C:9]([CH3:14])=[CH:8][CH:7]=2)=[O:3].[Na].[C:17](OCC)(=O)[C:18]([O:20]CC)=[O:19].[Na][Na]>C(O)C>[CH3:15][N:5]1[C:6]2[CH:7]=[CH:8][C:9]([CH3:14])=[CH:10][C:11]=2[C:12]2[O:13][C:17]([C:18]([OH:20])=[O:19])=[CH:1][C:2](=[O:3])[C:4]1=2
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1c(O)c2cc(C)ccc2n1C
Agent: [Na]
Agent: [Na][Na]
Solvent: CCO
Product: Cc1ccc2c(c1)c1oc(C(=O)O)cc(=O)c1n2C

Procedure:
In a manner analogous to that of Example 14, 8.2 g (0.040 mole) of 1,5-dimethyl-3-hydroxy-1H-indol-2-yl methyl ketone (Example 12) was reacted with sodium metal (3.7 g, 0.16 mole) and diethyl oxalate (21.5 g, 0.20 mole) in 200 ml absolute ethanol. The red disodium salt intermediate was then converted to the title compound as described in Example 17. Two recrystallizations of the final product from DMF-water yielded yellow needles of mpt. 290°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH:10]2[NH:11][CH2:12][CH2:13][N:14]([S:28]([C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)(=[O:30])=[O:29])[CH2:15]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COc1ncccc1CC1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncccc1CC1CN(S(=O)(=O)c2cccs2)CCN1
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a 100-mL round-bottomed flask was added 2-((2-methoxy-3-pyridinyl)methyl)piperazine (350 mg, 1.69 mmol), triethylamine (0.353 mL, 2.54 mmol), and 2-thiophenesulfonyl chloride (0.34 mL, 1.86 mmol, Aldrich, St. Louis, Mo.) in DCM (5 mL). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with saturated NaHCO3 (5 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow glass. The crude product was purified by silica gel chromatography, eluting with 10% MeOH/EtOAc to give 3-((2-methoxy-3-pyridinyl)methyl)-1-(2-thiophenylsulfonyl)piperazine (202 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:6][CH:5]([OH:7])[CH2:4]1)[CH3:2].[C:8]1([OH:18])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.[OH-].[K+]>>[C:8]1([O:18][CH2:4][CH:5]([OH:7])[CH2:6][NH:3][CH2:1][CH3:2])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CCN1CC(O)C1
Reactant: Oc1cccc2ccccc12
Agent: [K+]
Agent: [OH-]
Product: CCNCC(O)COc1cccc2ccccc12
Temperature: 160 °C
Yield: 70 %

Procedure:
To a mixture of 10.2 parts of 1-ethyl-3-azetidinol and 14.4 parts of α-naphthol 0.2 part of potassium hydroxide was added, and the mixture was heated under nitrogen gas at 160° C. for 18 hours. The reaction mixture was cooled and extracted with ether. The ether extract was washed with 2N-NaOH aqueous solution and then with water. The liquor was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was recrystallized from cyclohexane to yield 17.2 parts of 1-(α-naphthoxy)-3-ethylamino-2-propanol. The melting of the product was 106°-107° C. The yield was 70%.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.Cl[CH2:14][CH:15]1[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]1.O>CN(C=O)C.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[N:10][N:11]([CH2:14][CH:15]2[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16]2)[CH:12]=1
Reactant: CC1(C)OCC(CCl)O1
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)OCC(Cn2cc(Br)cn2)O1
Temperature: 65 °C
Reaction time: 14 h

Procedure:
Cs2CO3 (5.3 g, 16.3 mmol) was added to a solution of 4-bromo-1H-pyrazole (2 g, 13.6 mmol) in DMF (10 mL), followed by 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (2.46 g, 16.3 mmol) and the resulting mixture heated to an internal temperature of 65° C. After stirring for 14 h, water and EtOAc was added and the layers separated. The organic layer was washed a second time with water, dried with over anhydorus magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude residue was absorbed on silica gel and purified by column chromatography on silica (0 to 100% EtOAc/Hex) to afford 4-bromo-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazole as a light yellow oil, MS ESI calcd. for C9H14BrN2O2 [M+H]+ 261. found 261.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[O:6][C:7]=1COC1C=CC(C#N)=C(C)C=1.C(N([CH2:32][CH3:33])CC)C.CS(Cl)(=O)=O.Cl[CH2:40][Cl:41]>>[Cl:41][CH2:40][C:7]1[O:6][C:5]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[N:4][C:3]=1[CH2:2][O:1][CH:33]1[CH2:32][CH2:7][CH2:3][CH2:2][O:1]1
Reactant: ClCCl
Reactant: COc1ccc(-c2nc(CO)c(COc3ccc(C#N)c(C)c3)o2)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Product: COc1ccc(-c2nc(COC3CCCCO3)c(CCl)o2)cc1
Temperature: 25 °C

Procedure:
4.1 g 4-[4-Hydroxymethyl-2-(4-methoxy-phenyl)-oxazol-5-ylmethoxy]-2-methyl-benzonitrile were dissolved in 90 ml dichloromethane and cooled in an ice bath. 2.44 ml triethylamine were added, followed by the addition of 1.08 ml methanesulfonylchloride. The ice bath was removed and the resulting mixture stirred at room temperature over night. The reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 2.5 g of 5-chloromethyl-2-(4-methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazole as an oil which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[CH:20](Br)([CH3:22])[CH3:21].O>CN(C=O)C>[CH:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1)([CH3:22])[CH3:21]
Reactant: CC(C)Br
Reactant: O=C1CCCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc2c(c1)C(=O)CCCC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a suspension of 2-hydroxy-6,7,8,9-Tetrahydro-5H-benzocyclohepten-9-one (9.69 g, 56.3 mmol) and potassium carbonate (23.3 g, 0.17 mol) in DMF (60 ml) was added dropwise, under ice-cooling, isopropyl bromide (34.6 g, 0.28 mol). The reaction mixture was stirred for one hour at 100° C., which was poured into water, followed by extraction of the organic substance with ethyl acetate. The extract solution was washed with brine and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=9:1) to give the above-titled compound (11.4 g, yield 93%, oil).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.Cl.CCOC(C)=O>O.C1COCC1>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:24])=[O:4]
Reactant: COC(=O)CCCCC=C(c1ccccn1)c1ccccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCC=C(c1ccccn1)c1ccccn1
Reaction time: 19 h
Yield: 47.1 %

Procedure:
LiOH (10 mg, 0.42 mmol) in water (0.2 mL) was added to III (25 mg, 0.085 mmol) in THF (0.8 mL) at rt. After 19 h, the reaction mixture was neutralized with 2N HCl, poured onto brine (2 mL), and EtOAc (3 mL) was added. The phases were separated and the aqueous phase was extracted with EtOAc (2×3 mL). The organic phases were combined, dried over MgSO4, filtered, and then evaporated under reduced pressure. The resulting residue was then purified by silica gel column chromatography using CH2Cl2/MeOH (100:2 to 100:4) as eluant to furnish IV as a colourless oil (11.3 mg, 46%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:23](=[O:25])[NH2:24])=O)(C)(C)C.O1CCOCC1.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:23]([C@@H:9]1[CH2:10][C@H:11]([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:12][NH:8]1)(=[O:25])[NH2:24]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
1.92 g of (2S, 4S)-1-(t-butoxycarbonyl)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine [prepared as described in step (4) above] was dissolved in 25 ml of ethyl acetate, and 26.2 ml of a 4N dioxane solution of hydrogen chloride were added to the solution, whilst ice-cooling. The mixture was then stirred at 0° to 5° C. for 2 hours and at room temperature for 30 minutes. At the end of this time, it was poured into a saturated aqueous solution of sodium bicarbonate, to make it weakly basic, and was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 1.36 g of the title compound as a powder, melting at 120°-121° C.
Reaction SMILES: C([N:3]([CH2:6]C)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[C:14](=[O:20])[C:13](C(O)=O)=[C:12]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:38])C=CC=CC=1>C1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[C:14](=[O:20])[C:13]([N:3]=[C:6]=[O:38])=[C:12]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cn1c(=O)c(C(=O)O)c(-c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Product: Cn1c(=O)c(N=C=O)c(-c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (0.7 ml, 5 mmol) was added dropwise with stirring at room temperature to a solution of 6-chloro-4-(2-chlorophenyl)-1,2-dihydro-1-methyl-2-oxoquinoline-3-carboxylic acid (1.75 g, 5 mmol) and diphenylphosphoryl azide (1.19 ml, 5.5 mmol) in 35 ml benzene. The mixture was stirred at room temperature for 15 minutes and then refluxed for 30 minutes to yield a solution of 6-chloro-4-(2-chlorophenyl)-1,2-dihydro-3-isocyanato-1-methyl-2-oxoquinoline. 4-Nitrobenzyl alcohol (2.31 g, 15.1mmol) and dibutyltin oxide (35 mg) were added to the cooled reaction mixture which was then refluxed for 4 h. The reaction solution was cooled to room temperature, washed with water, dried (sodium sulfate) and concentrated in vacuo. The solid residue was purified by column chromatography on silica gel (650 g), eluting with 3:2 hexane/ethyl acetate to yield the title compound as an off-white solid (1.9 g, 76% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=2)[C:9](O)=[O:10])=[CH:4][CH:3]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH:25]1([NH:28][C:9](=[O:10])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:12][C:13]2[CH:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:18]=2)[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: COC(=O)/C=C/c1ccc(C=C(C(=O)O)c2ccc(F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(C=C(C(=O)NC2CC2)c2ccc(F)cc2)cc1
Yield: 114 %

Procedure:
A mixture of 2-(4-fluorophenyl)-3-(4-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenyl)acrylic acid (0.23 g, 0.71 mmol) and cyclopropylamine (0.03 g, 0.60 mmol), EDCI (0.27 g, 1.4 mmol), HOBt (0.10 g, 0.71 mmol) was dissolved in N,N-dimethylformamide (DMF) (6 mL) under stirring. Triethylamine (TEA) (0.75 mL, 36 mmol) was added dropwise with constant stirring to the above reaction mixture and it was stirred at 30° C. for 2 hours. Subsequently the reaction mixture was diluted with ethyl acetate and washed successively with water (3×50 mL) and brine (3×50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to afford the pure compound (0.25 g, 96% yield).
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(CN3CCC([CH2:18][O:19]C)CC3)=CC=2N=1.COCC1CCNCC1.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46](CO)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].[H-].[Na+].CI>C1COCC1>[C:36]([O:40][C:41]([N:43]1[CH2:44][CH2:45][CH:46]([O:19][CH3:18])[CH2:47][CH2:48]1)=[O:42])([CH3:37])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: COCC1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: COCC1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C

Procedure:
Via 2-Chloro-6-(4-methoxymethyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared from 4-methoxymethyl-piperidine. Amine preparation: To a solution of 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (212 mg) stirring in dry THF (10 mL) under a nitrogen atmosphere was added sodium hydride (60% in paraffin oil; 45 mg) followed after 20 min by methyl iodide and the reaction mixture was warmed to 70° C. After 4 h the mixture was cooled and quenched with water (10 mL) extracted into ethyl acetate, and dried (MgSO4). The residue was purified using flash chromatography to yield 4-methoxy-piperidine-1-carboxylic acid tert-butyl ester (158 mg) as a colourless oil. Treatment with TFA yielded the desired amine which was isolated as the TFA salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[H-].[Na+].[CH3:30][C:31]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([CH3:34])[CH2:32][CH3:33].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:41]([C:38]1[CH:39]=[CH:40][C:35]([C:31]([CH3:30])([CH3:34])[CH2:32][CH3:33])=[CH:36][CH:37]=1)(=[O:43])=[O:42])[C:6](=[O:11])[C:5]2([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[NH:12][CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: O=C1Nc2ccc(Cl)cc2C1(NCCN1CCOCC1)c1ccccc1Cl
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)(C)c1ccc(S(=O)(=O)N2C(=O)C(NCCN3CCOCC3)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
A solution of 1 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-[[2-(morpholin-4-yl)ethyl]amino]indol-2-one in 10 ml of DMF is cooled to 0° C. under an argon atmosphere and 0.108 g of sodium hydride as a 60% dispersion in oil is added. After stirring for 30 minutes, 0.607 g of 4-(1,1-dimethylpropyl)benzenesulfonyl chloride is added and the reaction mixture is stirred for 2 hours, the temperature being allowed to rise to RT. It is poured into water and extracted with AcOEt, the organic phase is washed with water and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (80/20; v/v) as the eluent to give 0.45 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=147° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5](C=C[C:8](/[CH:12]=C/C3C=C(C=CC=3)CO)=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:23][C:24]#[N:25].C(=O)([O-])[O-:27].[K+].[K+]>CO.C1(C)C=CC=CC=1.[OH-].[OH-].[Pd+2]>[C:24]([CH2:23][O:27][C:5]1[CH:4]=[CH:3][CH:2]=[C:11]2[C:10]=1[NH:9][CH:8]=[CH:12]2)#[N:25]
Reactant: O=C([O-])[O-]
Reactant: OCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reactant: N#CCBr
Agent: [Pd+2]
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#CCOc1cccc2cc[nH]c12

Procedure:
The protected 7-substituted indole (Example 34a part ii) (0.53 g, 1.75 mmol) in methanol (10 ml) and toluene (10 ml) was hydrogenated in a Parr apparatus at 50 p.s.i. for 1 hour in the presence of Pearlman's catalyst (0.33 g). The reaction mixture was filtered through Celite and the filtrate evaporated in vacuo. The crude 7-hydroxy indole was taken up in methyl ethyl ketone (20 ml), and bromoacetonitrile (0.65 g, 5.25 mmol) and anhydrous potassium carbonate (0.6 g, 4.35 mmol) added. The mixture was refluxed under nitrogen for 1 hour, cooled, poured into 2.5M hydrochloric acid/ice and extracted into dichloromethane. The organic phase was washed with water, dried, filtered and evaporated in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])/[CH:5]=[C:6](\[CH3:30])/[CH:7]=[CH:8]/[CH:9]=[C:10](/[C:15]1[C:24]([OH:25])=[CH:23][C:22]2[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=2[CH:16]=1)\[C:11]([F:14])([F:13])[F:12])[CH3:2].[C:32]([O-])([O-])=O.[K+].[K+].CI.CC(C)=O>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:31])/[CH:5]=[C:6](\[CH3:30])/[CH:7]=[CH:8]/[CH:9]=[C:10](/[C:15]1[C:24]([O:25][CH3:32])=[CH:23][C:22]2[C:21]([CH3:27])([CH3:26])[CH2:20][CH2:19][C:18]([CH3:29])([CH3:28])[C:17]=2[CH:16]=1)\[C:11]([F:13])([F:12])[F:14])[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(/c1cc2c(cc1O)C(C)(C)CCC2(C)C)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)/C=C(C)/C=C/C=C(/c1cc2c(cc1OC)C(C)(C)CCC2(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2E,4E,6Z)-8,8,8-trifluoro-7-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-methyl-octa-2,4,6-trienoic acid ethyl ester (Intermediate 5, 160 mg, 0.37 mmol), K2CO3 (253 mg, 1.83 mmol), MeI (0.12 mL, 1.83 mmol), and acetone (2 mL), was stirred at ambient temperature for overnight. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (3% EtOAc-hexane) to produce the title compound and its 2-Z isomer as a 2:1 mixture (167 mg). Further purification by HPLC (2.5% EtOAc-hexane) afforded the title compound as a clear oil (87 mg, 53%).