Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([OH:20])[CH2:11][C@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1.[CH3:21]I>C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]([O:20][CH3:21])[CH2:11][C@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=[O:14])=[CH:8][CH:9]=1
Reactant: CI
Reactant: CCCC[C@@H](C[C@@H](O)c1ccc(F)cc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[C@@H](C[C@@H](OC)c1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of NaH (129 mg, 60% oil dispersion) in 20 mL THF was slowly added at room temperature the crude (S)-2-((R)-2-(4-fluorophenyl)-2-hydroxyethyl)hexanoic acid isolated above as a solution in 10 mL THF. To this mixture was added dropwise methyl iodide (164 mL, 373.9 mg, 2.6 mmol) and the resulting stirred for 3 h at room temperature. The reaction was quenched by the slow addition of 15 mL 1M aqueous HCl and the mixture extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (2×20 mL) and dried over sodium sulfate. Evaporation of solvent afforded the product as an oil which was used directly in the next reaction without further purification.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>ClCCl>[Br:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:23]([CH:20]2[CH2:22][CH2:21]2)=[O:24])=[CH:5][CH:4]=1
Reactant: NCc1ccc(Br)cc1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(Br)cc1)C1CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
4-Bromo-benzylamine hydrochloride (367.8 mg, 1.7 mmol) was dissolved in dichloromethane (15 mL), and the solution was cooled to 0° C. DIEA (380 μL, 2.2 mmol) was then added, and the reaction was stirred at 0° C. for 5 minutes. Then cyclopropanecarbonyl chloride (180 μL, 2.3 mmol) was added, and the reaction was stirred at 0° C. for 20 minutes. The reaction was quenched with distilled water, and the solvents were removed. The resulting mixture was redissolved in DMF (10 mL) and purified by reverse phase HPLC to give the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[N:2].[CH:10](O)=[O:11]>>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:10]=[O:11])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=CO
Reactant: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(NC=O)cc1

Procedure:
Was prepared according to Example 2 from 4-cyanoaniline and formic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=O)[O:5][C:6]=1[CH3:7].[NH3:16]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:16][C:6]=1[CH3:7]
Reactant: Cc1cc(C(=O)c2cccnc2)oc1C
Reactant: N
Solvent: CO
Product: Cc1cc(O)c(-c2cccnc2)nc1C
Temperature: 160 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(3-pyridyl)-methanone (1.8 g), methanol (30 ml), and a 28% aqueous ammonia solution (30 ml) were placed in a sealed tube and were stirred at 160° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography using hexane-ethyl acetate to give 5,6-dimethyl-[2,3′]-bipyridin-3-ol (1.1 g, yield 63%).
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[CH:15]([NH:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][OH:22])([CH3:17])[CH3:16]>O1CCOCC1>[CH:15]([NH:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22])([CH3:17])[CH3:16]
Reactant: CC(C)Nc1ccccc1CO
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(C)Nc1ccccc1C=O
Yield: 80.1 %

Procedure:
After 13.2 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was added by several portions to a solution of 9.6 g of 2-isopropylaminobenzyl alcohol in 200 ml of dioxane, the mixture was stirred for further an hour. The solvent was removed by distillation to concentrate the reaction mixture, and methylene chloride was then added thereto followed by filtration. The filtrate was concentrated and the resulting oily substance was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain 7.6 g of 2-isopropylaminobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cccc(N3CCOCC3)c21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2c(cccc2N2CCOCC2)CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-8-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C[O-].[Na+].[C:4]([O:12]CC)(=O)[CH2:5][C:6]([O:8]CC)=O.[F:15][C:16]([F:25])([F:24])[CH:17]1[CH2:22][CH2:21][NH:20][C:19]([NH2:23])=[N:18]1.Cl>CO.O>[OH:8][C:6]1[N:23]=[C:19]2[NH:18][CH:17]([C:16]([F:25])([F:15])[F:24])[CH2:22][CH2:21][N:20]2[C:4](=[O:12])[CH:5]=1
Reactant: NC1=NC(C(F)(F)F)CCN1
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1cc(O)nc2n1CCC(C(F)(F)F)N2
Temperature: 40 °C
Yield: 80.4 %

Procedure:
62.10 g (1150 mmol) of sodium methoxide are added to a mixture of 340 mL (2230 mmol) of diethyl malonate heated to 40° C. The mixture is heated at 100° C. until a clear solution is obtained. 59.50 g (360 mmol) of 4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine dissolved in 100 mL of methanol are then added to the reaction medium. The mixture obtained is maintained at 100° C. for 1 hour and then cooled to room temperature overnight. The reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up in 250 mL of water. 12 N hydrochloric acid is added to the thick suspension obtained, to pH=5-6. The suspension obtained is filtered through a sinter funnel and the insoluble matter is rinsed with acetonitrile to give 68.10 g of 2-hydroxy-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in the form of a yellow solid, the characteristics of which are as follows:
Reaction SMILES: Cl.[NH2:2][OH:3].O=[C:5]([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=2)[N:33]=[CH:32][C:31]=1[F:42])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:10][CH:9]1[CH2:25][C:26]([O:28][CH3:29])=[O:27]>N1C=CC=CC=1>[OH:3][N:2]=[C:5]([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=2)[N:33]=[CH:32][C:31]=1[F:42])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:10][CH:9]1[CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: NO
Reactant: COC(=O)CC1CN(CCSc2cc(F)ccc2F)CCC1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)CC1CN(CCSc2cc(F)ccc2F)CCC1CCC(=NO)c1c(F)cnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 20 h
Yield: 79.2 %

Procedure:
0.347 g of hydroxylamine hydrochloride were added, in several portions, to a mixture of 1 g of methyl (3RS,4RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl)-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate in 10-cm3 of pyridine, with stirring and under an inert atmosphere, and the resulting mixture was stirred in the region of 20° C. for 24 hours and then for 20 hours in the region of 50° C. and for 1.25 hours in the region of 62° C. After cooling in the region of 20° C., the reaction mixture was concentrated to dryness under reduced pressure (1.5 kPa) at a temperature in the region of 50° C. The evaporation residue was taken up in 70-cm3 of ethyl acetate and 40-cm3 of distilled water. The organic phase was separated after settling out, washed 3 times with 40-cm3 of distilled water and 40-cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The evaporation residue was purified by chromatrography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a successive mixture of cyclohexane-ethyl acetate (60/40 by volume) and then dichloromethane-methanol (90/10 by volume) and collecting 10-cm3 fractions. Fractions 1 to 21 were combined and then concentrated to dryness according to the conditions described above. 0.813 g of methyl (3RS,4RS)-4-[3-hydroxyimino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate were obtained in the form of a whitish viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:18][C:17]3([Br:20])[Br:19])=[CH:12][CH:11]=2)=O)[CH:7]=1.C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:18][C:17]3([Br:20])[Br:19])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: O=C(c1ccc(C2CC2(Br)Br)cc1)c1cc(Br)ccc1Cl
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(Br)cc1Cc1ccc(C2CC2(Br)Br)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
Trifluoromethanesulfonic acid (0.5 g, 0.0033 mol) was added slowly to a stirred solution of Example 4B (104 g, 0.211 mol) and triethylsilane (66.8 g, 0.574 mol) in trifluoroacetic acid (300 mL) cooled to 30° C. in a water-bath. The reaction became refluxed. After 0.5 h, the water bath was replaced by an oil bath. The reaction mixture was heated to reflux for 3 h. After cooling to room temperature, the reaction mixture was allowed to stir for another 1 h. The solid was filtered, washed with hexane (100 mL) and dried under vacuum at 30° C. to get the desired product as a pale gray solid (86.4 g, yield 85%) 1H NMR (CDCl3, 400 MHz): δ 7.2˜87.34 (m, 3H), 7.18˜7.25 (m, 4H), 4.08 (s, 1H), 2.93˜2.98 (m, 1H), 2.13-˜2.17 (m, 1H), 2.00˜2.03 (m, 1H).
Reaction SMILES: C(Br)C1C=CC=CC=1.I[CH2:10][CH2:11][CH2:12][CH3:13].[CH3:14][C:15]1[N:16]=[C:17]([N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])[S:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:10]([N:27]1[CH2:28][CH2:29][N:25]([C:17]2[S:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]([CH3:14])[N:16]=2)[C:26]1=[O:30])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCI
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCc1ccccc1
Product: CCCCN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Yield: 73 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 1-iodobutane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 73% yield: 1H NMR (300 MHz, CDCl3) δ 4.08 (q, J=7.2 Hz, 2H), 3.99-3.85 (m, 2H), 3.47-3.33 (m, 2H), 3.11 (t, J=7.5 Hz, 2H), 2.38 (s, 3H), 1.41-1.22 (m, 7H), 0.74 (t, J=7.2 Hz, 3H); MS (ES+) m/z 312.3 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:24]1([CH2:30][CH2:31][C:32](O)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:32](=[O:33])[CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: O=C(O)CCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CCc1ccccc1
Reaction time: 2 h
Yield: 93.5 %

Procedure:
To a solution of L-proline benzyl ester hydrochloride (20.0 g) in methylene chloride (250 ml) were added triethylamine (11.5 ml), 3-phenylpropionic acid (13.7 g) and DCC (18.8 g) under ice-cooling, and the mixture was stirred for 2 hours. After stirring at room temperature for 14 hours, the insoluble material was filtered off, and the filtrate was concentrated. The residue was dissolved in ethyl acetate, and the solution was washed with 1N hydrochloric acid, saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluate: hexane-ethyl acetate). To thus-obtained N-(3-phenylpropionyl)-L-proline benzyl ester (26.1 g) in 1% water-containing methanol (200 ml) was added 10% Pd--C (3.0 g), and the mixture was stirred at room temperature under hydrogen atmosphere for 2.5 hours. The catalyst was filtered off, and the filtrate was concentrated to give 17.4 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[N:5][C:6]([N:12]2[CH2:15][CH:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=3)[CH2:13]2)=[C:7]([CH:11]=1)[C:8](O)=[O:9].Cl.[NH2:30][C:31]1([C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)[CH2:33][CH2:32]1>>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[N:5][C:6]([N:12]2[CH2:15][CH:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[N:18]=3)[CH2:13]2)=[C:7]([CH:11]=1)[C:8]([NH:30][C:31]1([C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:9]
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cccc(C(F)(F)F)n2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4cccc(C(F)(F)F)n4)C3)CC2)cc1
Yield: 68.4 %

Procedure:
The title compound (D181) (75 mg) was prepared according to the experimental procedure described in Description 144 starting from 5-(trifluoromethyl)-2-(3-((6-(trifluoromethyl)pyridin-2-yl)oxy)azetidin-1-yl)nicotinic acid (D130) (77 mg, 0.189 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (43.04 mg, 0.189 mmol).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[NH:9])[CH:5]=[CH:4][CH:3]=1.[C:11](OC)(=[O:17])[CH2:12][C:13](OC)=[O:14].C[O-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:10]=[C:13]([OH:14])[CH:12]=[C:11]([OH:17])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C(=N)N)n1
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(-c2nc(O)cc(O)n2)n1
Temperature: 25 °C

Procedure:
A solution of 6-methyl-pyridine-2-carboxamidine (Intermediate B) (1.2 eq, 8.23 mmol, 1.41 g) in MeOH (5 ml) under an inert atmosphere of argon, at room temperature is treated with dimethyl malonate (1 eq, 6.86 mmol, 1.04 ml) and 0.5 M sodium methoxide in MeOH (3 eq, 20.6 mmol, 41.2 ml). The resulting mixture is heated at reflux overnight and then allowed to cool to room temperature. Silica is added and the solvent is removed in vacuo. Purification by flash chromatography eluting with 0-5% MeOH in DCM affords the title compound as a pale yellow solid; [M+H]+=204/205.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl.C(N(CC)CC)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:18](=[O:19])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[C:15]([F:14])([F:25])[F:26])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-Boc-piperazine (1.96 g, 10.5 mmol) in dichloromethane (50 mL) was added 2-trifluoromethylbenzoyl chloride (2.08 g, 10.0 mmol) dissolved in dichloromethane in the presence of triethylamine (3 mL) at 0° C. The resulting mixture was stirred at room temperature for 18 hours and then quenched with water (25 mL). The organic phase was washed with water, brine, then dried over MgSO4 and concentrated in vacuo to afford 4-(2-trifluoromethylbenzoyl)piperazine-1-carboxylic acid tert-butyl ester as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-cyclohexylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.37 g). To the solution was added 1N sodium hydroxide solution (7.5 ml), and the mixture was stirred at room temperature overnight and concentrated, which was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-cyclohexylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.32 g) as yellow crystals.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:19])=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:19])[N:3]=[C:2]([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:10]2
Reactant: NCCCN1CCOCC1
Reactant: Clc1cc2nc(Cl)c(-c3ccccn3)nc2cc1Cl
Solvent: Cc1ccccc1
Product: Clc1cc2nc(NCCCN3CCOCC3)c(-c3ccccn3)nc2cc1Cl
Yield: 83.2 %

Procedure:
A solution of 2,6,7-trichloro-3-pyridin-2-yl-quinoxaline (0.50 g) and N-(3-aminopropyl)-morpholine (0.46 g) in toluene (25 mL) was refluxed under nitrogen for 16 hours. After refluxing, the reaction mixture was cooled, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 1:9 methanol/dichloromethane) to give a yellow solid. Recrystallization from methanol and water gave the product as yellow crystals (0.56 g); mp 119-121° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=O)=[O:4].[CH3:23][O:24][C:25](=[O:36])[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=1>CO>[CH3:1][O:2][C:3]([C:5]1[N:35]([CH2:34][C:31]2[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][C:25]([O:24][CH3:23])=[O:36])=[CH:29][CH:30]=2)[C:7](=[O:6])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:4]
Reactant: COC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: COC(=O)CCc1ccc(CN)cc1
Solvent: CO
Product: COC(=O)CCc1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
To a solution of 6-bromo-4-phenyl-3-isocoumarincarboxylic acid methyl ester (359 mg) in methanol (20 ml) was added 3-(4-aminomethylphenyl)propionic acid methyl ester (387 mg) and the mixture was stirred at room temperature for 18 hr. The solvent was evaporated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in methanol (30 ml) and conc. sulfuric acid (3 ml) was added. The mixture was heated under reflux for 3 hrs. The solvent was evaporated under reduced pressure, water was added under ice-cooling and the mixture was neutralized with potassium carbonate. The solution was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=19/1→3/1) to give the title compound (425 mg, 80%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[O:14]1[CH2:19][CH2:18][O:17][C:16]2[C:20]([CH:24]=O)=[CH:21][CH:22]=[CH:23][C:15]1=2>>[O:14]1[CH2:19][CH2:18][O:17][C:16]2[C:20]([CH:24]3[N:11]([CH2:10][C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=4)[C:15](=[O:14])[CH:16]([OH:17])[CH2:20]3)=[CH:21][CH:22]=[CH:23][C:15]1=2
Reactant: O=Cc1cccc2c1OCCO2
Reactant: NCc1ccc(OC(F)(F)F)cc1
Product: O=C1C(O)CC(c2cccc3c2OCCO3)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedures 10A2 (GP10A2), 10B (GP10B) and 10F (GP10F) using commercially available (4-(trifluoromethoxy)phenyl)methanamine and commercially available 2,3-dihydrobenzo[b][1,4]dioxine-5-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 409.94 g/mol.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([NH:11][C:12]1[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)=[C:14]([C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)[CH:13]=1)=[O:10].CN(C)C=O.[Cl:40][C:41]1[CH:49]=[CH:48][CH:47]=[C:46]2[C:42]=1[CH2:43][CH2:44][NH:45]2.Cl.CCOCC>Cl>[NH2:19][CH2:18][CH2:17][O:16][C:15]1[CH:27]=[CH:28][C:12]([NH:11][C:9]([N:45]2[C:46]3[C:42](=[C:41]([Cl:40])[CH:49]=[CH:48][CH:47]=3)[CH2:43][CH2:44]2)=[O:10])=[CH:13][C:14]=1[C:29]1[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=1
Reactant: Cn1nccc1-c1cc(NC(=O)ON2C(=O)CCC2=O)ccc1OCCNC(=O)OC(C)(C)C
Reactant: Clc1cccc2c1CCN2
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(NC(=O)N2CCc3c(Cl)cccc32)ccc1OCCN
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.5 %

Procedure:
A 1 mL aliquot of tert-butyl {2-[4-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}amino)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]ethyl}carbamate in dimethylformamide (78.8 μmol) was added to 4-chloroindoline (14.52 mg, 1.2 eq) and stirred at room temperature for 18 hr. To this was added 2.0M hydrochloric acid in ether (197 μL, 5 eq) and the reaction was stirred at room temperature for 24 hr (2-3 drops of concentrated hydrochloric acid was added if the deprotection was incomplete and the resulting mixture was stirred for another 24 hr). The ether and hydrochloric acid were evaporated under a stream of nitrogen and the resulting material was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 43.5% yield. LCMS m/z (%)=412 (M+H 35Cl, 100), 414 (M+H 37Cl, 36). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.10-3.24 (m, 4 H), 3.71 (s, 3 H), 4.13-4.21 (m, 4 H), 6.34 (d, J=2.02 Hz, 1 H), 6.96 (d, J=8.08 Hz, 1 H), 7.13-7.21 (m, 2 H), 7.48-7.50 (m, 2 H), 7.64 (dd, J=8.84, 2.78 Hz, 1 H), 7.81 (d, J=7.58 Hz, 1 H), 7.92 (s, 2 H), 8.63 (s, 1 H).