Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])[CH3:16])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[N:15]([CH3:16])[C:13](=[O:14])[CH2:12][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=1)=[O:34]
Reactant: CN(C(=O)CN(C(=O)CN)c1ccccc1)c1ccc(F)cc1F
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccc(F)cc2F)c2ccccc2)c1
Yield: 37.2 %

Procedure:
The procedure is analogous to that described in Example 1, but 1.2 g of 2-(2-amino-N-phenyl-acetamido)-N-(2,4-difluorophenyl)-N-methylacetamide and 0.46 g of 3-methylphenyl isocyanate are used as the starting material. The product obtained is purified by chromatography on 70 g of silica (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: dichloromethane/methanol (99-1 by volume)], collecting 15 cm3 fractions. Fractions 24 to 36 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from diisopropyl ether, 0.6 g of N-(2,4-difluorophenyl)-N-methyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 100° C. is obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH:28]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([CH3:39])[CH3:38])[C:32]=1[N:40]=[C:41]=[O:42])([CH3:30])[CH3:29]>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:16][CH:15]=2)[C:41]([NH:40][C:32]2[C:31]([CH:28]([CH3:29])[CH3:30])=[CH:36][CH:35]=[CH:34][C:33]=2[CH:37]([CH3:39])[CH3:38])=[O:42])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCc1ccc(NCc2ccc(OCCCC)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCCCCCCCc1ccc(N(Cc2ccc(OCCCC)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 35.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-butoxyphenylmethyl)(4-octylphenyl)amine (1.65 g) and 2,6-diisopropylphenyl isocyanate (1.05 g) as starting materials, N-(4-butoxyphenylmethyl)-N′-(2,6-diisopropylphenyl)-N-(4-octylphenyl)urea (0.92 g) was obtained.
Reaction SMILES: [Cl-].[Li+].[CH2:3]([O:10][C:11]1[C:16](=[O:17])[C:15](Br)=[CH:14][N:13]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:31][O:32][B:33](OC)[O:34][CH3:35]>C1COCC1>[CH3:31][O:32][B:33]([C:15]1[C:16](=[O:17])[C:11]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:12][N:13]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[CH:14]=1)[O:34][CH3:35]
Reactant: COB(OC)OC
Reactant: O=c1c(Br)cn(-c2cccc(-c3ccccc3)c2)cc1OCc1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COB(OC)c1cn(-c2cccc(-c3ccccc3)c2)cc(OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lithium chloride (515 mg, 12.1 mmol) in a 25 mL round bottom flask under high vacuum was heated with a heat gun until a free flowing granular solid was obtained (˜5 min). The flask was cooled to room temperature, purged with N2, and treated with isopropylmagnesium chloride (6.1 mL of a 2 M solution in THF). After stirring at room temperature for 1 h, the mixture was cooled to −10° C. and treated with 3-(benzyloxy)-1-(biphenyl-3-yl)-5-bromopyridin-4(1H)-one (1.05 g, 2.4 mmol) as a suspension in 3.5 mL of THF. After stirring for 0.5 h, trimethylborate (1.35 mL, 12.1 mmol) was added drop wise and the reaction mixture was stirred an additional 3.5 h, before being quenched with the addition of MeOH (12 mL) to provide a solution of crude dimethyl[5-(benzyloxy)-1-(biphenyl-3-yl)-4-oxo-1,4-dihydropyridin-3-yl]boronate which was used directly in the subsequent step. LC/S (M+H)+ 398.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>COCCOC>[NH:1]1[C:9]2=[N+:8]([O-:18])[CH:7]=[CH:6][CH:5]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Solvent: COCCOC
Product: [O-][n+]1cccc2cc[nH]c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-azaindole (2.0 g, 16.93 mmol) in dry DME (60 mL) was added m-CPBA (70%) (6.3 g, 25.55 mmol). The resulting yellow solution was stirred at RT for 2 h during which time the product was precipitated out. The mixture was cooled and the light yellow product was isolated by filtration and washed with ether. A suspension of this yellow solid in water (60 mL) was basified to pH 9 with sat. K2CO3 solution. The solution was then cooled in refrigerator for a weekend. A white precipitate was collected by filtration and the filtrate was half evaporated and cooled again to repeat the crystallization procedure. The precipitates were combined and dried on the pump for the next reaction (1.5 g, 11.2 mmol, 66%). MS (ES+): m/e=135.1 (M+H); LC: 1.37 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Cl[CH2:13][C:14](=O)[CH2:15][O:16][C:17](=[O:19])[CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:13]=[C:14]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[N:11]=2)=[N:6][CH:7]=1
Reactant: CC(=O)OCC(=O)CCl
Reactant: NC(=S)Nc1ccc(Br)cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1csc(Nc2ccc(Br)cn2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
(5-Bromo-pyridine-2-yl)-thiourea (1 mmol) is dissolved in DMF (2 ml) and acetic acid 3-chloro-2-oxo-propyl ester (1 eq.) is added and stirred 2 h at 70° C. After cooling to RT the reaction solution is poured into water and the resulting precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. “A5” is obtained as colourless powder in a yield of 82%; mp. 200.9-201.6° C.; HPLC (method C): 1.80 min; LC-MS (method A): 1.800 min, 327.95 (M+H+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 11.516 (s, 1H), 8.391 (d, 1H, J=2.4 Hz), 7.892 (dd, 1H, J=8.9 Hz, J=2.4 Hz), 7.020 (d, 1H, J=8.9 Hz), 6.998 (s, 1H), 5.015 (s, 2H), 2.062 (s, 3H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[CH2:27]([N:29]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[CH:31]=[N:30]1)[CH3:28]>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:38]([C:34]3[CH:33]=[C:32]4[C:37](=[CH:36][CH:35]=3)[N:29]([CH2:27][CH3:28])[N:30]=[CH:31]4)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCn1ncc2cc(N)ccc21
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CCn1ncc2cc(N3CCC4(CCN(S(=O)(=O)c5ccccc5Cl)CC4)C3=O)ccc21

Procedure:
Light brown crystalline solid. MS (ESI): 473.2 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chlorobenzenesulfonyl chloride and 1-ethyl-1H-indazol-5-ylamine (for synthesis: Chakrabarty et al. Tetrahedron; 64; 2008; 6711).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[CH2:5]([N:12]1[CH2:16][CH2:15][C@@H:14](N)[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OCC)(=O)C>[CH2:5]([N:12]1[CH2:16][CH2:2][CH:1]([OH:4])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:5]([N:12]1[CH2:16][CH:15]=[CH:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)O
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Solvent: CCOC(C)=O
Product: C1=CCN(Cc2ccccc2)C1
Product: OC1CCN(Cc2ccccc2)C1

Procedure:
When 960 mg of acetic acid (16 mmol) was added to a solution in ethyl acetate (30 mL) of 3.6146 g of crude (R)-1-benzyl-3-aminopyrrolidine produced in the step 1-1 (14.6 mmol, optical purity: 92.4% e.e., including 29.5% by weight 1-benzyl-3-pyrrolidinol, and 0.8% by weight 1-benzyl-2,5-dihydro-1H-pyrrole as impurities), a crystal was precipitated. After stirring at 5° C. for 30 min, the crystal was filtrated under reduced pressure, which was washed with 20 mL of ethyl acetate, and thereafter vacuum drying was carried out to give a white crystal of 2.5804 g (yield: 75%, optical purity: 94.3% e.e., with no 1-benzyl-3-pyrrolidinol and 1-benzyl-2,5-dihydro-1H-pyrrole detected).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl.[O:5]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C-:20]#[N:21].[Na+].CCCCCCCCCC1C=CC(O)=CC=1.C1OC1>O.ClCCl>[CH3:1][N:2]([CH3:3])[CH:15]([C:14]1[CH:17]=[CH:18][CH:19]=[C:12]([O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:13]=1)[C:20]#[N:21]
Reactant: [C-]#N
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CNC
Agent: CCCCCCCCCc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1CO1
Solvent: ClCCl
Solvent: O
Product: CN(C)C(C#N)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h

Procedure:
A solution of dimethylamine in water (5 ml of a 26% w/v solution; 30 mmole) and water (5 ml) was neutralised with concentrated hydrochloric acid. 3-Phenoxybenzaldehyde (3.96 g, 20 mmole) was added to the stirred solution followed by sodium cyanide (1.5 g, 30 mmole) and "Teric" N8 (5 drops of a 10% aqueous solution; "Teric" is an ICI Australia Limited Trade Mark and "Teric" N8 is the product of condensation of nonylphenol and ethylene oxide in the mole ratio of 1:8). The mixture was stirred vigorously for a period of 1 hour and then dichloromethane (50 ml) was added. The organic phase was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to give the title compound as a pale yellow oil (5.2 g). Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 2.3 (6H, s, N(CH3)2); 4.8 (1H, s, CH); 6.9-7.6 (9H, m, aromatic protons).
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=O)=[O:13])=[CH:8][CH:7]=1)#[N:2].[OH2:23].[NH2:24][NH2:25]>C1COCC1>[NH2:2][C:1]1[NH:25][N:24]=[C:4]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([S:12]([NH2:15])(=[O:13])=[O:23])=[CH:10][CH:11]=2)[N:3]=1
Reactant: NN
Reactant: N#CN=C(Nc1ccc(S(N)(=O)=O)cc1)Oc1ccccc1
Reactant: O
Solvent: C1CCOC1
Product: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)n[nH]1
Temperature: 70 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
To a solution of 4-(3-cyano-2-phenyl-isoureido)-benzenesulfonamide (1.35 mmol) in THF (5 ml), was added a solution of hydrazine monohydrate (2 mmol; 1.5 equivalents). The solution was stirred at 70° C. for 16 hours. The reaction mixture was allowed to cool to room temperature. A white solid precipitated out. It was removed by filtration and was washed with ethanol to afford the title compound (300 mg; 87% yield). 1H NMR (400 MHz, DMSO-d6) 5.95-6.00 (2H, s), 7.00-7.05 (2H, s), 7.55-7.65 (4H, m), 9.15-9.20 (1H, s); MS (ES+) m/e=255
Reaction SMILES: Br.[NH2:2][C@H:3]1[CH2:8][CH2:7][O:6][C:4]1=[O:5].C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:22](=[O:28])OC(Cl)(Cl)Cl)Cl.[C:30]1([NH:36][C:37]2[C:38]([NH2:43])=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[NH:36]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH:43][C:22]([NH:2][C@H:3]1[CH2:8][CH2:7][O:6][C:4]1=[O:5])=[O:28])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@H]1CCOC1=O
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccccc1Nc1ccccc1)N[C@H]1CCOC1=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.48 g (8.15 mmoles) of (S)-2-amino-4-butyrolactone hydrobromide and 3.12 ml (17.9 mmoles) of diisopropylethylamine in 80 ml of anhydrous CH2Cl2 is added slowly (4 hours) into a three-necked flask containing a solution of 0.89 g (3 mmoles) of triphosgene in 45 ml of anhydrous CH2Cl2, under an inert atmosphere. After stirring for a further 15 minutes, a solution of 1.5 g (8.15 mmoles) of N1-phenyl-1,2-benzenediamine and 3.12 ml (17.9 mmoles) of diisopropylethylamine in 45 ml of anhydrous CH2Cl2 is added in one go. The reaction mixture is then heated for 5 hours at 60° C. After concentration to dryness under vacuum, the residue is divided between 50 ml of AcOEt and 50 ml of water. After stirring and decanting, the organic phase is washed successively with 50 ml of water and 50 ml of salt water. The organic solution is then dried over Na2SO4, filtered and concentrated under vacuum. The evaporation residue is then purified on a silica column (eluent: Heptane/AcOEt: 1/2). Pink solid.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([F:12])[C:4]=1[F:13].[O:14]1[C:18]2([CH2:23][CH2:22][CH:21]([CH:24]3[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1>[O:14]1[C:18]2([CH2:19][CH2:20][CH:21]([CH:24]3[CH2:29][CH2:28][C:27]([C:3]4[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([F:12])[C:4]=4[F:13])([OH:30])[CH2:26][CH2:25]3)[CH2:22][CH2:23]2)[O:17][CH2:16][CH2:15]1
Reactant: CCOc1ccc(Br)c(F)c1F
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1ccc(C2(O)CCC(C3CCC4(CC3)OCCO4)CC2)c(F)c1F
Temperature: 40 °C
Reaction time: 1 h
Yield: 120.3 %

Procedure:
First Step: 6.1 g of well dried magnesium and 20 mL of THF were placed in a reactor under nitrogen atmosphere, and heated to 40° C. 59.7 g of 1-bromo-4-ethoxy-2,3-difluorobenzene (1) dissolved in 300 mL of THF was slowly added dropwise thereto at a temperature range of from 40 to 60° C., followed by stirring for 60 minutes. Thereafter, 50.0 g of 4-(1,4-dioxaspiro[4,5]dec-8-yl)cyclohexanone (2) dissolved in 150 mL of THF was slowly added dropwise thereto at a temperature range of from 50 to 60° C., followed by stirring for 60 minutes. After cooling the resulting reaction mixture to 30° C., the reaction mixture was mixed with 900 mL of a 3% ammonium chloride aqueous solution and 500 mL of toluene cooled to 0° C. in a vessel and separated into an organic layer and an aqueous layer by standing still, so as to attain extraction. The resulting organic layer was fractionated and washed with water, a saturated sodium bicarbonate aqueous solution, and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off under reduced pressure to obtain 100.1 g of 4-(1,4-dioxaspiro[4,5]dec-8-yl)-1-(4-ethoxy-2,3-difluorophenyl)cyclohexanol (3). The resulting compound (3) was a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH:6]=[C:7]([CH:13]=O)[C:8]=1[O:9][CH2:10][C:11]#[N:12].[OH-].[Na+].Cl.[CH3:25][O:26][NH2:27]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH:6]=[C:7]([CH:13]=[N:27][O:26][CH3:25])[C:8]=1[O:9][CH2:10][C:11]#[N:12]
Reactant: CON
Reactant: COc1cc(NC(=O)OC(C)C)cc(C=O)c1OCC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=Cc1cc(NC(=O)OC(C)C)cc(OC)c1OCC#N
Reaction time: 12 h
Yield: 94.5 %

Procedure:
Isopropyl N-(3-methoxy-4-cyanomethoxy-5-formylphenyl)carbamate (0.59 g) was dissolved in ethanol (20 ml). To the solution was added an aqueous solution (10 ml) containing sodium hydroxide (0.32 g) and methoxyamine hydrochloride (0.66 g). After being allowed to stand for 12 hours, the reaction mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate. The resultant solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give isopropyl N-(3-methoxy-4-cyanomethoxy-5-methoxyiminomethylphenyl)carbamate (Compound No. 78) (0.62 g) in a yield of 94.5%.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4](C(O)=O)[C:3]=1C(O)=O.S([O-])([O-])(=O)=[O:18].[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:8]([F:13])=[C:9]([F:12])[C:10]=1[F:11].[F:1][C:2]1[CH:3]=[CH:4][C:8]([OH:18])=[C:9]([F:12])[C:10]=1[F:11]
Reactant: O=S(=O)([O-])[O-]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1ccc(F)c(F)c1F
Product: Oc1ccc(F)c(F)c1F
Temperature: 200 °C

Procedure:
In an autoclave having an inner volume of 100 ml, 3.0 g (0.0126 mole) of 3,4,5,6-tetrafluorophthalic acid containing no sulfate ion, 0.5 g (0.0125 mole) of sodium hydroxide, and 50 g of water were placed and heated for reaction at 200° C. for 25 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with 150 ml of diisopropyl ether. By analyzing this extract by gas chromatography using a 2 m column packed with SE52 and kept at 50° C., the reaction was found to have produced 2.9 mole % of 1,2,3,4-tetrafluorobenzene, 89.1 mole % of trifluorophenol, and substantially no 2,3,4,5-tetrafluorobenzoic acid based on the 3,4,5,6-tetrafluorophthalic acid used as the starting material [pH 2.75 at 25° C. at the time of charging].
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21].Cl.[OH-].[Na+]>CC(O)C.O.CCN(CC)CC>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([NH:1][CH:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1)=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cccc(C(=O)Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cccc(C(=O)NC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Step R1-4: To a solution of tert-butyl 4-aminopiperidine-1-carboxylate (150 g) and Et3N (209 mL) in IPA (1.0 L) was added 3-methoxybenzoyl chloride (102 mL) over 40 minutes under ice cooling. The mixture was stirred at room temperature for 2 hours. After cooling to 0° C., 12 M aqueous HCl (0.5 L) was added to the mixture over 30 minutes and the mixture was stirred at 50° C. for 1 hour. After cooling to 0° C., 12 M aqueous NaOH (0.5 L) and water (0.4 L) were added over 40 minutes to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to obtain 3-methoxy-N-(piperidin-4-yl)benzamide as a light brown solid (160 g).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]2[CH2:15][O:14]2)=[CH:9][CH:8]=1)[CH:2]=[CH2:3].[CH:18]([NH2:21])([CH3:20])[CH3:19]>CO>[CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]([OH:14])[CH2:15][NH:21][CH:18]([CH3:20])[CH3:19])=[CH:9][CH:8]=1)[CH:2]=[CH2:3]
Reactant: C=CCOCCc1ccc(OCC2CO2)cc1
Reactant: CC(C)N
Solvent: CO
Product: C=CCOCCc1ccc(OCC(O)CNC(C)C)cc1
Yield: 73.9 %

Procedure:
A solution of the compound of formula (5) (3.70 g, 0.016 mol), isopropyl amine (7.46 ml, 0.127 mol) in methanol (20 ml) was stirred under reflux for 2 hours and then concentrated. The residue was partitioned between chloroform and water. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated. The residue was crystallized from pet ether to afford compound of formula (1) as a white solid 3.47 g (75%) mp 52–53° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]([Cl:22])([Cl:21])[CH2:5][O:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:8].S(OC)(O[CH3:27])(=O)=O.O>O1CCCC1>[CH3:27][N:9]([C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([O:6][CH2:5][C:4]([Cl:21])([Cl:22])[Cl:3])=[O:8]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cccc(NC(=O)OCC(Cl)(Cl)Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(N(C)C(=O)OCC(Cl)(Cl)Cl)c1
Yield: 80.7 %

Procedure:
To a suspension of 0.14 g of 60% sodium hydride in 5 ml of tetrahydrofuran was dropwise added a solution of 1.0 g of ethyl 3-(2,2,2-trichloroethoxycarbonylamino)benzoate in 5 ml of tetrahydrofuran, and the resultant mixture was stirred at room temperature. Then, a solution of 0.45 g of dimethyl sulfate in 5 ml of tetrahydrofuran was dropwise added, and the resultant mixture was stirred at room temperature for 3 hours. After water was added to the mixture, the mixture was subjected to extraction with ethyl acetate, and an organic layer was washed twice with water and dried with anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane ethyl acetate=4:1) to obtain 0.84 g (yield 79%) of the title compound as an oily material.
Reaction SMILES: [CH2:1]([N:8]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:10]([CH2:11][C@@H:12]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[NH:13]C(OC(C)(C)C)=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:37].O1CCOCC1>C(Cl)Cl>[ClH:37].[CH2:1]([N:8]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:10]([CH2:11][C@@H:12]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[NH2:13])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@@H](Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Yield: 81 %

Procedure:
The same procedures as in Example 143 were carried out from the compound obtained in Example 152 (12.2 g), 4 mol/L of hydrogen chloride-dioxane solution (31 mL), and methylene chloride (300 mL), to give the captioned compound (8.6 g, 81%) as crystals.
Reaction SMILES: C([NH:4]C(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([O:23]CC)(=O)[CH2:20][CH3:21].[CH:26](=O)/[CH:27]=[CH:28]/[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[CH3:21][C@H:20]1[C@@H:26]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:4][C:19]1=[O:23]
Reactant: CCOC(=O)CC
Reactant: CC(C)NC(C)C
Reactant: O=C/C=C/c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@@H]1C(=O)N[C@@H]1C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisopropylamine (1.19 g, 11.9 mmol) in dry tetrahydrofuran (20 ml), at -40° C. under dry nitrogen was added a solution of n-butyllithium in hexane (2.5M; 4.76 ml, 11.9 mmol). The resulting solution was stirred for 0.5 hours, whilst being allowed to warm to room temperature, then cooled to -70° C. before dropwise addition of a solution of ethyl propanoate (1.19 ml, 10 mmol) in dry tetrahydrofuran (20 ml), at such a rate that the temperature did not exceed -65° C. After a further 10 minutes, a solution of N-(trimethylsilyl)cinnamaldimine [prepared by the addition of trans cinnamaldehyde (1.32 g, 10 mmol) to a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1M; 10 ml, 10 mmol) under dry nitrogen at room temperature] was added, again maintaining the internal temperature at <65° C., and stirring was continued for 15 minutes at -70° C. before removal of the cooling bath.