Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=O)[CH2:16][CH2:17][CH3:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].Cl.[NH2:24][OH:25].[OH-].[NH4+]>CO.O>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:15](=[N:24][OH:25])[CH2:16][CH2:17][CH3:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: NO
Reactant: CCCC(=O)c1cccc2c1CC(N(CCC)CCC)CC2
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(=NO)c1cccc2c1CC(N(CCC)CCC)CC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 105.3 %

Procedure:
2-Di-n-propylamino-8-butyryl-1,2,3,4-tetrahydronaphthalene (1 g; 3.3 mmol) (prepared as in Example 22) was dissolved in 40 ml of methanol, and 2.3 g (33 mmol) of hydroxylamine hydrochloride dissolved in water were added. The mixture was stirred at room temperature for 20 hours after which it was poured into water, and the pH was adjusted to 10 using ammonium hydroxide. The mixture then was extracted with methylene chloride, and the extract was dried over sodium sulfate and evaporated. The residue was placed on a silica gel column and was eluted with a gradient mixture of 3-5% methanol in methylene chloride containing a trace of ammonium hydroxide. The appropriate fractions were combined and evaporated to give 1.1 g of 2-di-n-propylamino-8-(1-oximino-butyl)-1,2,3,4-tetrahydronaphthalene. (Rf=0.30 in 4% methanol and methylene chloride containing a trace of ammonium hydroxide) MS(FD): 316(100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)[CH:5]=[N:6][C:7]=1[Cl:8].[CH2:23]([O:25][C:26]([Sn](CCCC)(CCCC)CCCC)=[CH2:27])[CH3:24].[Sn]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([O:25][C:23]([C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][NH:12]2)[CH:5]=[N:6][C:7]=1[Cl:8])=[CH2:24])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Sn]
Solvent: Cc1ccccc1
Product: C=C(OCC)c1cc(OC[C@@H]2CCCN2)cnc1Cl
Temperature: 25 °C

Procedure:
To a solution of 5-bromo-6-chloro-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine (500 mg, 1.28 mmol) in toluene (10.0 mL) was added (1-ethoxyvinyl)tributyltin (489 mL, 1.41 mmol) and tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.-45 mmol). After being refluxed overnight, the resulting mixture was cooled to room temperature. Solvent was removed and the residue was chromatographed on a silica gel column, eluting with hexane/EtOAc 2:1 and 1:1 to afford an oil (568 mg, >100%; some tin reagent contamination). MS (CI/NH3) m/z 383 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.25-1.45 (m, 3H), 1.47 (s, 9H), 1.55-1.71 (m, 1H), 1.98-2.07 (m, 3H), 3.32-3.45 (m, 1H), 3.87-3.96 (m, 2H), 4.05-4.21 (m, 3H), 4.43-4.47 (m, 2H), 7.26-7.34 (m, 1H), 8.03-8.06 (m, 1H).
Reaction SMILES: [OH:1][CH:2]([C:4]1[NH:5][C:6]([C:10]2[C:11]([CH3:21])=[CH:12][C:13](C)=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])=[C:7]([CH3:9])[N:8]=1)[CH3:3].CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1.CC1C=C(C)C(B2OC(C)(C)C(C)(C)O2)=CC=1C(OC)=O>>[OH:1][CH:2]([C:4]1[NH:5][C:6]([C:10]2[CH:19]=[C:14]([CH:13]=[CH:12][C:11]=2[CH3:21])[C:15]([O:17][CH3:18])=[O:16])=[C:7]([CH3:9])[N:8]=1)[CH3:3]
Reactant: COC(=O)c1cc(-c2[nH]c(C(C)O)nc2C)c(C)cc1C
Agent: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)c1ccc(C)c(-c2[nH]c(C(C)O)nc2C)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 198.3, except methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) was used in place of methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH2:32][CH2:33][CH2:34][OH:35]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:31][CH2:32][CH2:33][CH2:34][OH:35])=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: NCCCO
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCO)O2
Yield: 48.3 %

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 357 mg CDI (2.20 mmol) and 165 mg 3-aminopropanol (2.2 mmol) produced 297 mg of 6-hydroxy-N-(3-hydroxypropyl)-2,5,7,8-tetramethylchroman-2-carboxamide as an amorphous white solid.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][C:15](O)=[O:16].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH:43]1([NH2:50])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>CN(C)C=O>[CH:43]1([NH:50][C:15](=[O:16])[CH2:14][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:12][C:13]=3[CH:1]=2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: NC1CCCCCC1
Reactant: O=C(O)Cc1ccc2c(c1)Cc1ccccc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cc1ccc2c(c1)Cc1ccccc1-2)NC1CCCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
In dimethylformamide (50 ml) was dissolved 2-fluoreneacetic acid (2.24 g) followed by addition of 1-hydroxybenztriazole (2.0 g) and, then, dicyclohexylcarbodiimide (3.1 g) with constant stirring and ice-cooling. The mixture was further ,stirred at room temperature for 15 minutes. Cycloheptylamine (1.7 g) was then added under ice-cooling and the mixture was stirred at room temperature for 8 hrs. The resulting solid was filtered off and the filtrate was distilled under reduced pressure. The residue was extracted with 50 ml of chloroform and the extract was washed with 1N aqueous sodium hydroxide solution, 1N hydrochloric acid and water in the order mentioned and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give 2.1 g of N-cycloheptyl-2-fluoreneacetamide as a solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[C:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[CH2:20][C@@H:19]1[C:32]([O:34]C)=[O:33]>O1CCOCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[C:26][C:27]2[CH:31]=[CH:30][S:29][CH:28]=2)[CH2:20][C@@H:19]1[C:32]([OH:34])=[O:33]
Reactant: COC(=O)[C@H]1CN(CC#Cc2ccsc2)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CC#Cc4ccsc4)C[C@@H]3C(=O)O)c2c1
Temperature: 65 °C
Yield: 55 %

Procedure:
3.9 cm3 of 1N aqueous sodium hydroxide were added to a solution of 0.6 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-3-yl)prop-2ynyl]piperidine-3-carboxylate in 10 cm3 of dioxane and then the mixture was heated at a temperature in the region of 65° C. for 16 hours. The mixture was cooled and then the organic phase was extracted with 3 times 50 cm3 of ethyl acetate. The aqueous phase was acidified with 3.9 cm3 of 1N hydrochloric acid. The solution was taken up in 10 cm3 of a saturated aqueous sodium bicarbonate solution and then the organic phase was extracted with 2 times 20 cm3 of ethyl acetate and 2 times 20 cm3 of dichloromethane, dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 45° C. 0.32 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-3-yl)prop-2-ynyl]piperidine-3-carboxylic acid was obtained in the form of a foam with a white color.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:15](=[O:29])[N:16]([CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[C:30]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:32])[CH3:31].C(Cl)Cl.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:30]([C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:3]3[N:4]([C:15](=[O:29])[N:16]([CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=4)[N:17]=3)[CH:5]=[CH:6][C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:35][CH:34]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(Br)c(-c3ccc(Cl)cc3)ccn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2c(-c3ccc(Cl)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc23)cc1
Temperature: 90 °C

Procedure:
To a stirring solution of 8-bromo-7-(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (170 mg, 0.35 mmol) in THF (5 mL) at room temperature under argon was added 4-acetylphenylboronic acid (173 mg, 1.05 mmol), Pd(dppf)Cl2.CH2Cl2 (32.2 mg, 0.035 mmol), and K3PO4 (224 mg, 1.05 mmol). The resulting suspension was purged of oxygen by bubbling with argon for 15 min, sealed in a vial under argon, heated at 90° C. for 12 h, and then cooled to room temperature. The reaction mixture was diluted with EtOAc and washed once with brine. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with EtOAc/hexanes). Pooling of the desired fractions, washing with saturated aq. NaHCO3 solution to eliminate any possible boronic acid contaminant, drying the organic phase (MgSO4), filtering and evaporation provided the title compound as a yellow solid, after recrystallization from EtOAc/hexanes, to obtain 110 mg, 60%. HPLC/MS: retention time=3.20 min, [M+H]+=523. 1H NMR (CDCl3): δ 8.77 (s, 1H), 7.88 (m, 4H), 7.66 (d, J=8.2 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H), 7.23 (d, J=8.3 Hz, 2H), 7.04 (d, J=8.2 Hz, 2H), 6.66 (d, J=7.2 Hz, 2H), 5.25 (s, 2H), 2.60 (s, 3H).
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:10]=[C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:9]=1
Reactant: N=C(N)c1ccccc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Clc1nc(-c2ccccc2)ns1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
To a solution of benzamidine hydrochloride (5.00 g, 31.9 mmol) and perchloromethyl mercaptan (3.43 ml, 39.2 mmol) in dichloromethane (32 ml) was added dropwise a solution of sodium hydroxide (6.38 g, 160 mmol) in water (13 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.90 g (46.2%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:18]([OH:20])=[O:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:21].[CH3:22]O>>[ClH:21].[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:18]([O:20][CH3:22])=[O:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2c(n1)CCN(Cc1ccccc1)C2
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2c(n1)CCN(Cc1ccccc1)C2
Temperature: 80 °C
Yield: 100 %

Procedure:
In a sealed container, 6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid (1.00 g, 3.73 mmol) was dissolved in MeOH (40.0 mL) and HCl (3.29 mL, 14.9 mmol, 4.0 M in 1,4-dioxane). The resulting solution was heated at 80° C. for 13 h. The solvent and acid were completely evaporated to yield methyl 6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate hydrochloride (1.25 g, 100%). LC-MS: (FA) ES+ 283; 1H NMR (Methanol-d4, 400 MHz) δ8.08 (d, J=8.0 Hz, 1 H), 7.92 (d, J=8.3 Hz, 1 H), 7.63 (m, 2 H), 7.54 (m, 3 H), 4.88 (s, 2 H), 4.58 (s, 4 H), 3.99 (s, 3 H), 3.40 (s, 2 H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[OH:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26].[OH-].[Na+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[O:14][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: CCCC(=O)c1ccc(O)c(Cl)c1Cl
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(=O)c1ccc(OCCCC(=O)O)c(Cl)c1Cl
Temperature: 100 °C
Yield: 82.1 %

Procedure:
A mixture of 2,3-dichloro-4-butyrylphenol (69.9 g, 0.30 mole), potassium carbonate (75 g, 0.54 mole) and ethyl 4-bromobutyrate (87.8 g, 0.45 mole) in N,N-dimethylformamide (900 ml of sieve-dried material) were stirred and heated at 55°-60° C. for 16.5 hours. The mixture was then treated with 10 normal sodium hydroxide solution (120 ml) and water (600 ml) and stirring and heating at 100° C. maintained for 2 hours. The solution was cooled and poured into ice water (4 liters) containing concentrated hydrochloric acid (250 ml). The solid that separated was removed by filtration, washed with water and dried. The product (88 g) was recrystallized from butyl chloride (500 ml) to give 78.6 g of 4-(2,3-dichloro-4-butyrylphenoxy)butyric acid, m.p. 111°-113° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: ClCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: ClCCCCCn1nnc2ccccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
Benzotriazole (11.9 g, 0.10 mol) is dissolved into 100 ml of 30% wt. sodium hydroxide, 5-chlorobromopentane (36.8 g, 0.20 mol), tetrabutyl ammonium bromide (0.8 g) are added, and mixed for 5 min. The reaction solution is gradually heated to 60° C., stirred for reaction for 2 hours. Then the reaction solution was cooled down to ambient temperature, 100 ml of dichloromethane was added for extraction and liquid separation. To the aqueous phase, 100 of dichloromethane was added for extraction. Organic phases were mixed, washed with 100 ml of saturated saline. Liquid was separated, and organic phase was evaporated to dryness to produce oily product. Oily products were separated and purified by chromatography with neutral Al2O3, and eluted with dichlormethane to produce 15.8 g of 1-(5-chloropentyl)-1H-benzotriazole, with a yield of 71.0%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].Br[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(OCCOC2CCCCO2)ccc1Br
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A solution of 4-bromo-3-methyl-phenol (10.6 g, 56.9 mmol) and 2-(2-bromo-ethoxy)-tetrahydro-pyran (11.9, 56.9 mmol) were dissolved in dry DMF (25 mL). K2CO3 (19.7 g, 142 mmol) was added and the resulting reaction mixture was stirred at 80° C. for 48 h. The reaction mixture was cooled to RT and poured into a mixture of EtOAc and aqueous NaOH (2 N). The organic phase was separated, dried (MgSO4), filtered, and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography using EtOAc/pentane 1:20 as the eluent to afford the title compound as colourless oil.
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[O:28]=[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[CH:31][NH:30]1.O>C1COCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]=[CH:39][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29](=[O:28])[NH:30][CH:31]=2)[CH:11]=1
Reactant: O=Cc1c[nH]c(=O)c2ccccc12
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]cc(C=Cc2cccnc2)c2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Under an N2 atmosphere,147 g (377 mmol) of triphenyl-(pyridin-3-yl-methyl)-phosphonium chloride in 2.2 l of THF are mixed with 44.1 g (393 mmol) of potassium-tert-butylate and stirred for 30 min. The suspension is heated to 50° C. and a mixture of 50.0 g (289 mmol) of 1-oxo-1,2-dihydro-isoquinoline-4-carbaldehyde and 2.2 l of THF is added dropwise and finally stirred for 10 h at 60° C. To the cooled reaction mixture is added 700 ml of water and then the THF is evaporated off on a RE. The residue is taken up in 5 l of water and 8 l of EtOAc, the water phase is separated and extracted 3 more times with EtOAc. The organic phases are washed with water and with brine, combined, dried (Na2SO4) and left to stand over night. A solid separates from the mixture and is filtered off and washed with EtOAc [→(E) 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one]. The filtrate is extracted twice with 1 N HCl and then discarded. The acidic aqueous phases are immediately rendered basic with sat. Na2CO3 solution and extracted 3 times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2, EtOAc/ethanol 19:1→9:1) yields first of all (Z) 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one, followed by an (E/Z) mixture of 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one. (E) 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one: m.p. 222-224° C.; 1H NMR (DMSO-d6) δ11.57 (sb, HN), 8.80 (s, 1H), 8.44 (d, 1H), 8.26 (d, 1H), 8.12 (m, 2H, m), 7.79 (t, 1H), 7.68 (d, J=16.3 Hz, 1H), 7.56 (m, 2H), 7.39 (dd, 1H), 7.07 (d, J=16.3 Hz 1H). (Z) 4-[2-(pyridin-3-yl)-vinyl]-2H-isoquinolin-1-one: 1H NMR (DMSO-d6) δ11.24 (sb, HN), 8.39 (s, 1H), 8.32 (d, 1H), 8.25 (d, 1H), 7.71 (t, 1H), 7.65 (d, 1H), 7.54 (m, 2H), 7.21 (dd, 1H), 6.90 (s, 1H), 6.81 (s, 2HOlef.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11](#[N:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[CH:5]=[C:6]([CH:7]([OH:8])[CH2:12][C:11]#[N:13])[CH:9]=1
Reactant: O=Cc1cc(Cl)cc(Br)c1
Reactant: CC#N
Product: N#CCC(O)c1cc(Cl)cc(Br)c1

Procedure:
Alkylation of 5-bromo-3-chlorobenzaldehyde with acetonitrile following the method used in Example 115 gave 3-(5-bromo-3-chlorophenyl)-3-hydroxypropanenitrile as a clear oil. Yield (3.21 g, 54%): 1H NMR (400 MHz, DMSO-d6) δ 7.62 (t, J=2.0 Hz, 1H), 7.58-7.57 (m, 1H), 7.49-4.48 (m, 1H), 6.18 (d, J=4.8 Hz, 1H), 4.93-4.90 (m, 1H), 2.93 (ABd, J=16.8, 5.2 Hz, 1H), 2.86 (ABd, J=17.2, 6.8 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22]([CH3:51])=[C:23]([C:42]([O:49][CH3:50])=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:29]([CH:33]=1)[C:30](O)=[O:31]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22]([CH3:51])=[C:23]([C:42]([O:49][CH3:50])=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:29]([CH:33]=1)[C:30]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:31]
Reactant: C1COCCN1
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
Morpholine (0.451 g, 5.17 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.49 g, 7.76 mmol) were added to a methylene chloride solution (80 ml) of 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (1.17 g, 2.59 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to obtain the titled compound (1.27 g, 2.59 mmol, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:3]=1[O:4][C:5]1[C:6]([O:11]C)=[N:7][CH:8]=[CH:9][CH:10]=1.B(Br)(Br)Br>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:3]=1[O:4][C:5]1[C:6](=[O:11])[NH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc[nH]c3=O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a mixture of 0.5 g of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-2-methoxypyridine and 10 ml of chloroform, 0.5 g of boron tribromide was added and stirred at room temperature for 3 hours. Then the reaction mixture was concentrated. The residue was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and conventrated. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate) to give 0.31 g of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-1H-pyridin-2-one.
Reaction SMILES: C([O:5][C:6](=[O:59])[C@@H:7]([NH:11][C:12]([C@@H:14]1[CH2:18][C@@H:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:21]=2)[CH2:16][C@H:15]1[C:38](=[O:58])[NH:39][C@H:40]([C:44](=[O:57])[NH:45][C@@H:46]([CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1)[C:47]([O:49][CH3:50])=[O:48])[CH:41]([CH3:43])[CH3:42])=[O:13])[CH2:8][CH2:9][CH3:10])(C)(C)C.C([SiH](CC)CC)C>C(Cl)Cl.FC(F)(F)C(O)=O>[CH:51]1([C@H:46]([NH:45][C:44]([C@@H:40]([NH:39][C:38]([C@@H:15]2[CH2:16][C@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:18][C@H:14]2[C:12]([NH:11][C@@H:7]([CH2:8][CH2:9][CH3:10])[C:6]([OH:59])=[O:5])=[O:13])=[O:58])[CH:41]([CH3:42])[CH3:43])=[O:57])[C:47]([O:49][CH3:50])=[O:48])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)OC)C1CCCCC1)C(C)C)C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)OC)C1CCCCC1)C(C)C)C(=O)O
Reaction time: 2 h
Yield: 100.8 %

Procedure:
Tert.butyl ester 56 (28 mg, 0.034 mmol) and triethylsilane (14 μL, 0.088 mmol) was dissolved in DCM (2 mL) after which trifluoroacetic acid (2 mL) was added and the mixture was stirred for 2 h. Co-evaporation with toluene gave 57 (26 mg, 100%) as a colorless solid.