Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[N:6]2[C:7]3[C:12]([NH:13][C:14](=[O:15])[CH:5]2[CH2:4][NH:3][CH2:2]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.Cl.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:3]2[CH2:2][CH2:1][N:6]3[C:7]4[C:12]([NH:13][C:14](=[O:15])[CH:5]3[CH2:4]2)=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:19][CH:18]=1
Reactant: ClCc1ccncc1
Reactant: O=C1Nc2ccccc2N2CCNCC12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1Nc2ccccc2N2CCN(Cc3ccncc3)CC12

Procedure:
A solution of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one 6.1 g. (0.03 mole) and 4.92 g. (0.03 mole) of 4-picolyl chloride hydrochloride, 10 g. of potassium carbonate, 0.5 ml. of tirethylamine in 200 ml. of acetone was refluxed for 40 hours with stirring. The reaction mixture was allowed to cool and the precipitate was filtered and washed with acetone. The acetone was removed under reduced pressure and the oily residue was dissolved in methylene chloride. This solution was washed with water, dried over magnesium sulfate, filtered and the solvent removed. The residue was dissolved in ethanol and treated with dry hydrogen chloride. The product hydrogen chloride was filtered and recrystallized from methanol to give 2 g. of the title compound as the dihydrochloride salt, m.p. 253°-255° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1(N=C=NC2CCCCC2)CCCCC1.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30]>N1C=CC=CC=1>[C:29]([NH:33][C:11]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=1[OH:1])=[O:13])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1cccc(C(=O)O)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CC(C)(C)NC(=O)c1cccc(C(=O)O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Hydroxyisophthalic acid (1.82 g) and N,N'-dicyclohexylcarbodiimide (2.17 g) were dissolved together in dry pyridine (30 ml) and the mixture was stirred for 2 hours at room temperature. The mixture was then treated with dry tert-butylamine (5 ml), and the mixture was stirred at 60° C. for 20 hours. The solvents were removed in vacuo, and the residue was treated with saturated aqueous sodium bicarbonate solution (50 ml). The mixture was stirred for 15 minutes. The insoluble N,N'-dicyclohexylurea was then removed by filtration and the resulting filtrate was treated with charcoal and filtered again. The filtrate was then acidified by treatment with concentrated hydrochloric acid to give a white solid which was filtered off and recrystallized from a mixture of petroleum ether (b.p. 60°-80° C.) and benzene to give 3-tert-butylcarbamoylsalicylic acid (1.2 g), m.p. 191°-195° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][Si:14]([CH3:18])([CH3:17])[CH2:13][CH2:12]1.C([O-])(O)=O.[Na+].[C:24](Cl)([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].O>C1COCC1.[Pd]>[CH3:17][Si:14]1([CH3:18])[CH2:15][CH2:16][N:11]([C:3]2[CH:4]=[CH:5][C:6]([NH:8][C:24](=[O:25])[O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:7][C:2]=2[F:1])[CH2:12][CH2:13]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[Si]1(C)CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si]1(C)CCN(c2ccc(NC(=O)OCc3ccccc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of compound 9 (610 mg, 2.28 mmol) in THF (25 mL), Pd/C (30 mg) is added and hydrogenated under a pressure of 35 psi in a par hydrogenator for 8 h. The reaction mixture is filtered through celite. Celite pad is washed with THF (2×20 mL). To the filtrate, saturated NaHCO3 (420 mg, 5.01 mmol) and CBzCl (427 mg, 2.5 mmol) are added at 0° C. and stirred at 25° C. for 5 h. 10 mL water is added to reaction mixture and the aqueous layer is extracted with EtOAc (2×20 mL). The crude mixture is then subjected to column chromatography on silica gel using hexane-EtOAc mixtures to afford the product as a viscous liquid 10 (690 mg) in 82% yield.
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:21][CH3:22])[O:13][CH2:12]2)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.I[CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:30]([N:10]([CH:11]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[O:21][CH3:22])[O:13][CH2:12]1)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]2[C:1]1=[O:28])[CH2:31][CH3:32]
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)c3ccccc3C1=O)CO2
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(CCCCN1C(=O)c2ccccc2C1=O)C1COc2cccc(OC)c2C1
Temperature: 60 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
1.5 mmol of the compound prepared in Example 1 is dissolved in 10 ml of dimethylformamide in the presence of 4.4 mmol of 1-iodopropane and 4.4 mmol of potassium carbonate. After 24 hours' stirring at 60° C., the solvent is evaporated off and the crude reaction mixture is taken up with 10 ml of water and extracted with dichloromethane. The organic phase is dried and evaporated and the expected product is obtained after purification by chromatography on a silica column (elution solvent: ether/petroleum ether, 1:99).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH:11]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:17][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1cccc(Br)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCCC1)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
After 6-bromopicolinic acid (500 mg, 2.48 mmol) was suspended in acetonitrile (25 ml), cyclohexylamine (0.34 ml, 2.97 mmol), N,N-diisopropylethylamine (0.65 ml, 3.72 mmol), and HBTU (1.13 g, 2.97 mmol) were sequentially added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 3 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (30% EtOAc/Hexanes), to obtain 624 mg of colorless oil (94%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:19]=1>>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([N:26]2[CH2:27][CH2:28][N:29]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=3)[CH2:30][CH2:31]2)[N:19]=1
Reactant: COc1cc(OC)nc(N2CCNCC2)n1
Reactant: CC(=O)NC(C)(C)c1ccc(CCl)cc1
Product: COc1cc(OC)nc(N2CCN(Cc3ccc(C(C)(C)NC(C)=O)cc3)CC2)n1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide obtained in Example 95(4) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(4,6-dimethoxypyrimidin-2-yl)piperazine obtained in Example 90(2) instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=199-202° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:17][C:18]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:19]=1[NH2:20]>C(O)(C)C>[ClH:2].[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH3:16])[N:6]=[CH:5][N:4]=[C:3]2[NH:20][C:19]1[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:18]=1[F:17]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1cc(O)ccc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3cc(O)ccc3F)c2cc1OC
Yield: 14.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline hydrochloride (342 mg, 1.3 mmol), and 2-fluoro-5-hydroxyaniline (183 mg, 1.4 mmol) in isopropanol (10 ml) were heated at reflux for 2 hours. The reaction mixture was allowed to cool, the precipitated product collected by filtration, washed with isopropanol and dried to give 6,7-dimethoxy4-(2-fluoro-5-hydroxyanilino)quinazoline hydrochloride (66 mg, 15%) as a solid.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.C[N:14]1CCOCC1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[C:2]([Cl:1])(=[O:4])[NH2:14].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CN1CCOCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: NC(=O)Cl
Temperature: 25 °C

Procedure:
A stirring solution of triphosgene (27.78 g, 0.103 mol) in 40 mL toluene was cooled to -20 ° C. in an ice/salt bath under a blanket of nitrogen and treated with a solution of N-methylmorpholine (27.3 g, 0.27 mol) in 20 mL of toluene dropwise over 1 h. This solution was then treated with a solution of pyrrolidine (19.8 g, 0.27 mol) in 30 mL of toluene over a period of 30 m. The solution was allowed to warm to room temperature, filtered and the filtrate concentrated in vacuo to give an oil that was purified by vacuum distillation through a 12" Vigeraux column to give 20.7 g, 56%, bp 58° C. @0.6 mm, of pure product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([OH:8])[CH3:7].Br[CH2:10][C:11]([OH:13])=[O:12]>O>[C:11]([CH2:10][N:3]1[CH:4]=[CH:5][S:1][CH:2]1[CH:6]([OH:8])[CH3:7])([OH:13])=[O:12]
Reactant: O=C(O)CBr
Reactant: CC(O)c1nccs1
Solvent: O
Product: CC(O)C1SC=CN1CC(=O)O
Temperature: 25 °C
Reaction time: 96 h
Yield: 107.9 %

Procedure:
1-(2-Thiazolyl)ethanol (0.5 g, 3.87 mmole) and bromoacetic acid (0.538 g, 3.87 mmole) were warmed to melt the bromoacetic acid, then were allowed to cool and were stirred 4 days at room temp. The mixture was dissolved in 15–20 mL water and extracted with 4×10 mL ether. The water layer was evaporated in vacuo to give 0.79 g of residue, which was stored under 30 mL acetonitrile at room temp. overnight to effect crystalization. Filtration and washing with 30% ether/acetonitrile gave 0.335 g of the title compound, mp 160–161 C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:14][CH3:15])[C:10]=1[CH:11]([CH3:13])[CH3:12])[CH2:6]Br.[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[OH:23])[CH:8]=[C:9]([O:14][CH3:15])[C:10]=1[CH:11]([CH3:13])[CH3:12]
Reactant: COc1cc(CBr)cc(OC)c1C(C)C
Reactant: O=C(c1ccccc1)c1ccccc1
Product: COc1cc(CC(O)(c2ccccc2)c2ccccc2)cc(OC)c1C(C)C

Procedure:
This compound was prepared from 3,5-dimethoxy-4-i-propylbenzyl bromide obtained in example 6(b), Mg and benzophenone by the same procedure as described in example 1 (b). 1HNMR (CDCl3, ppm): δ 1.24 (d, J=7.1 Hz, 6H), 3.3-3.5 (m, 1H), 3.56 (s, 6H), 3.72 (d, J=15.4 Hz, 2H), 6.04 (s, 2H), 7.2-7.7 (m, 10H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH:11]=[O:12])#[N:2].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][SH:18])[CH3:14].C(N(CC)CC)C>C(OCC)C>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([S:18][CH2:17][CH:16]([O:19][CH2:20][CH3:21])[O:15][CH2:13][CH3:14])=[CH:10][CH:11]=[O:12])#[N:2]
Reactant: N#CCCCCCCC=CC=O
Reactant: CCOC(CS)OCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(CSC(=CC=O)CCCCCCC#N)OCC
Reaction time: 48 h

Procedure:
The starting material is prepared as follows: The mixture of 1.8 g of 9-cyano-2-nonenal, 1.4 g of 2,2-diethoxy-ethane-thiol and 50 μl of triethylamine is allowed to stand at room temperature for 48 hours. It is taken up in 100 ml of diethyl ether, the solution washed with water, dried and evaporated, to yield the 9-cyano-3-(2,2-diethoxy-ethylmercapto)-nonenal, showing in NMR spectrum peaks at 9.78, 4.55, 3.57 and 2.61 ppm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)=[C:7]([CH:23]=1)[C:8]([NH:10][C@H:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=1)[CH3:12])=[O:9])#[N:2].B(Br)(Br)Br.O>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)=[C:7]([CH:23]=1)[C:8]([NH:10][C@H:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)[CH3:12])=[O:9])#[N:2]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(C#N)ccc2Oc2cccc(F)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=O)c1cc(C#N)ccc1Oc1cccc(F)c1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.6 %

Procedure:
To a stirred solution of methyl 4-((1S)-1-{[5-cyano-2-(3-fluorophenoxy)benzoyl]amino}ethyl)benzoate (step 2, 200 mg, 0.47 mmol) in dichloromethane (10 mL) was added a solution of boron tribromide (1 M in dichloromethane, 0.95 mL, 0.95 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 6 h. The reaction mixture was poured into water (10 mL) and the whole was extracted with ethyl acetate (50 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (1/1) to afford 62 mg (33%) of the title compound as white solids: 1H-NMR (DMSO-d6) δ 12.86 (1H, br.s), 8.95 (1H, d, J=7.9 Hz), 8.04 (1H, d, J=2.2 Hz), 7.90 (1H, dd, J=8.6, 2.2 Hz), 7.81 (2H, d, J=8.3 Hz), 7.51–7.40 (3H, m), 7.12–6.90 (4H, m), 5.07 (1H, m), 1.37 (3H, d, J=6.9 Hz); MS (ESI) m/z 405 (M+H)+, 403 (M−H)−.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Mg]Br)[CH3:20].C(=O)([O-])O.[Na+]>O1CCCC1>[CH:1]([N:14]1[CH2:17][C:16]([CH2:19][CH3:20])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 59.9 %

Procedure:
To a tetrahydrofuran solution (10 mL) of 1-benzhydrylazetidin-3-one (3.23 g, 13.61 mmol), a 1M-tetrahydrofuran solution of ethylmagnesium bromide (13.61 mL, 27.22 mmol) was added at −78° C. under a nitrogen stream, and the mixture was allowed to warm to −10° C. over 5 hours. A saturated aqueous solution of sodium hydrogen carbonate (20 mL) was added to the reaction liquor, and the mixture was stirred for 15 minutes. Then, the reaction liquor was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, and then dried over anhydrous sodium sulfate. Sodium sulfate was separated by filtration, and the solvent was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 40M, ethyl acetate/n-hexane=1/9 to 6/4), to obtain the title compound (2.18 g, 60%) as an oily matter.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.CS(C)=O.Br[CH2:14][C:15]1[O:19][N:18]=[C:17]([CH:20]([C:22]#[CH:23])[OH:21])[CH:16]=1.OP([O-])(O)=O.[K+]>C(Cl)Cl>[OH:21][CH:20]([C:17]1[CH:16]=[C:15]([CH:14]=[O:5])[O:19][N:18]=1)[C:22]#[CH:23]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C#CC(O)c1cc(CBr)on1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: C#CC(O)c1cc(C=O)on1
Reaction time: 5 h
Yield: 292.3 %

Procedure:
9.8 g of 4-methyl morpholine oxide, 68 cm3 of dimethylsulphoxide and 34 cm3 of methylene chloride are added at 0° C. to a solution containing 4 g of the product prepared in Stage C and 30 cm3 of methylene chloride. The mixture is allowed to return to 20° C. and agitated for 5 hours. It is poured into an aqueous solution of potassium acid phosphate. Extraction is carried out with ethyl acetate, the extracts are dried, filtered and brought to dryness. 8.18 g of product is obtained which is chromatographed on silica, eluting with a hexane-ethyl acetate mixture (1-1). In this way 1.96 g of desired product is obtained.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH:30]([CH2:34][CH2:35][OH:36])[CH2:31][CH2:32][OH:33]>>[OH:33][CH2:32][CH2:31][N:30]([CH2:34][CH2:35][OH:36])[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: OCCNCCO
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N(CCO)CCO)nc1

Procedure:
6-[Bis-(2-hydroxy-ethyl)-amino]-N-(7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-yl-methyl)-nicotinamide was prepared starting from intermediate E and diethanolamine. MS calcd. for C26H25ClN4O4 [(M+H)+] 493, obsd. 493.
Reaction SMILES: [ClH:1].O1CCOCC1.[F:8][C:9]1([F:32])[C:13]2[N:14]=[CH:15][N:16]=[C:17]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:12]=2[C@H:11]([CH3:31])[CH2:10]1>O1CCOCC1>[ClH:1].[ClH:1].[F:32][C:9]1([F:8])[C:13]2[N:14]=[CH:15][N:16]=[C:17]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:12]=2[C@H:11]([CH3:31])[CH2:10]1
Reactant: C[C@@H]1CC(F)(F)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CC(F)(F)c2ncnc(N3CCNCC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
4M HCl/dioxane (2.27 mL, 9.09 mmol) was added to a solution of (R)-tert-butyl 4-(7,7-difluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.092 g, 0.260 mmol) in dioxane (2 mL.) The reaction mixture was stirred at room temperature overnight, after which it was concentrated to dryness and dried on under high vacuum to give (R)-7,7-difluoro-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (0.079 g, 93.0% yield) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10](=[O:25])[C:11]2[CH:16]=[C:15]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:14]=[C:13]([F:24])[CH:12]=2)=[CH:6][C:3]=1[C:4]#[N:5].[O:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O.[BH4-].[Na+]>CO.[Ni](Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([C:11]2[CH:16]=[C:15]([O:17][C:18]([F:23])([F:22])[CH:19]([F:20])[F:21])[CH:14]=[C:13]([F:24])[CH:12]=2)[OH:25])=[CH:6][C:3]=1[CH2:4][NH:5][C:27](=[O:26])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: N#Cc1cc(C(=O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cc(C(O)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-fluoro-5-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzoyl)benzonitrile (1.30 g, 3.62 mmol), BOC2O (1.68 mL, 7.24 mmol) and Nickel (II) chloride (0.47 g, 3.62 mmol) in MeOH at 0° C. was added sodium borohydride (0.96 g, 25.3 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for 6 h. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was diluted with EtOAc and the solution was washed with sat. NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to yield tert-butyl 2-fluoro-5-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(hydroxy)methyl)benzylcarbamate as a clear, colorless oil (1.43 g, 85% yield). This product was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (m, 1H), 7.22 (m, 1H), 7.03 (m, 3H),), 6.87 (d, J=8.84 Hz, 1H), 5.90 (m, 2H), 4.98 (br. s., 1H), 4.31 (d, J=5.05 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)[CH3:2].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:13](=[O:15])[CH2:12][CH2:11]1)[CH3:2]
Reactant: CCOc1ccccc1C1CCC(=O)N1
Reactant: Fc1ccc(CBr)cc1
Product: CCOc1ccccc1C1CCC(=O)N1Cc1ccc(F)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 5-(2-ethoxyphenyl)pyrrolidin-2-one with commercially available 1-(bromomethyl)-4-fluorobenzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=1.01 min.; [M+H]+: 313.99 g/mol.
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][CH2:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:32](Cl)(=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]([CH2:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=2)[C:32](=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(CNCc2ccc(OCC(=O)OC)cc2)cc1
Reactant: CCCCCC(=O)Cl
Product: CCCCCCCCC#Cc1ccc(CN(Cc2ccc(OCC(=O)OC)cc2)C(=O)CCCCC)cc1

Procedure:
The title compound was prepared following the procedure G using methyl (4-{[(4-dec-1-ynylbenzyl)amino]methyl}phenoxy)acetate and hexanoyl chloride (purification by flash chromatography on SiO2, c-Hex/EtOAc 9:1) as a colorless oil (63%). M+ (ESI): 520.6. HPLC, Rt: 6.2 min (purity: 99.30%). 1H NMR (CDCl3) δ: 7.39 (d, J=8.3 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.16-7.05 (m, 4H), 6.91 (d, J=8.7 Hz. 1H), 6.85 (d, J=8.7 Hz, 1H), 4.65 (s, 1H), 4.63 (s, 1H), 4.54 (s, 1H), 4.52 (s, 1H), 4.40 (s, 1H), 4.36 (s, 1H), 3.83 (s, 1.5H), 3.82 (s, 1.5H), 2.41 (m, 4H), 1.70 (m, 2H), 1.61 (m, 2H), 1.45 (m, 2H), 1.31 (brs, 12H), 0.90 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[N:4][O:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C1C(=O)N([Br:24])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:1][C:2]1[C:3]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[N:4][O:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1onc(-c2cccs2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(-c2cccs2)c1CBr

Procedure:
Ethyl 4-methyl-3-(thiophen-2-yl)isoxazole-5-carboxylate (3.9 g, 16.5 mmol), NBS (3.5 g, 19.7 mmol), and benzoyl peroxide (0.4 g, 1.65 mmol) were added to 100 mL of carbon tetrachloride and the mixture was refluxed for 16 h. The reaction mixture was filtered and the filtrate was removed in vacuo. The residue, containing both unreacted starting material and the title compound, was used in the next reaction without purification. MS: (+) m/z 316, 318 (M+1, 79Br/81Br).
Reaction SMILES: ClCCCCC[C:7]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[CH:9][C:8]=1[CH:17]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:18]#[N:19].[CH3:28][C:29]([Si:32]([CH3:47])([CH3:46])[O:33][C:34]1[CH:43]=[C:42]2[C:37]([CH2:38][CH2:39][NH:40][CH2:41]2)=[CH:36][C:35]=1[O:44][CH3:45])([CH3:31])[CH3:30]>>[CH3:14][O:13][C:12]1[CH:7]=[C:8]([C:17]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)([CH2:9][CH2:8][CH2:7][CH2:12][CH2:11][N:40]2[CH2:39][CH2:38][C:37]3[C:42](=[CH:43][C:34]([O:33][Si:32]([C:29]([CH3:28])([CH3:30])[CH3:31])([CH3:46])[CH3:47])=[C:35]([O:44][CH3:45])[CH:36]=3)[CH2:41]2)[C:18]#[N:19])[CH:9]=[CH:10][C:11]=1[O:15][CH3:16]
Reactant: COc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CNCC2
Reactant: COc1ccc(C(C#N)Sc2ccc(C)cc2)c(CCCCCCl)c1OC
Product: COc1ccc(C(C#N)(CCCCCN2CCc3cc(OC)c(O[Si](C)(C)C(C)(C)C)cc3C2)Sc2ccc(C)cc2)cc1OC

Procedure:
The procedure of Example 3 is repeated using 2.5 g of α-(5-chloropentyl-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile and 2.54 g 7-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1,2,3,4-tetrahydro-6-methoxyisoquinoline. This affords 1.2 g of the desired product as a light yellow oil.