Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.CC1(C)[O:37][CH:36]([CH2:38]O)[CH2:35][O:34]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[OH:37][CH:36]([CH2:35][OH:34])[CH2:38][O:28][C:27](=[O:29])[C:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:14]2[CH:13]=[C:12]([NH:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:17]=[C:16]([O:18][CH3:19])[N:15]=2)[CH:21]=1)([CH3:31])[CH3:30]
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Reactant: CC1(C)OCC(CO)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)OCC(O)CO)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
To a solution of 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [145 mg, 0.315 mmol, Example 49(b)] in N,N′-dimethylformamide (4 mL) is added (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol [62 mg, 0.472 mmol] and TBTU (151 mg, 0.472 mmol) followed by triethylamine (1 mL). The reaction mixture is stirred for 16 hours at ambient temperature, quenched with the addition of water (200 mL) and brine (25 mL) and extracted twice with EtOAc (200 mL). The extracts are concentrated in vacuo and the residue is stirred in MeOH (4 mL). 1 N hydrochloric acid is added (4 mL). After one hour the reaction is poured into water (150 mL) and extracted twice with EtOAc (150 mL). The extracts are concentrated and the residue is subjected to flash column chromatography on silica (4 g) eluting with 60 to 80% EtOAc in heptane to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid 2,3-dihydroxy-propyl ester (135 mg, Example 89) as an oil. MS: 534 (M+H), 1H NMR [300 MHz, (CD3)2SO]: δ 7.9 (1H, s); 7.8 (1H, s); 7.6 (2H, s); 7.45 (2H, m); 7.35 (2H, s); 6.6 (1H, s); 4.8 (1H, d); 4.55 (1H, t); 4.05 (1H, m); 3.9 (1H, m); 3.85 (3H, s); 3.6 (3H, m); 3.25 (2H, t); 2.95 (2H, t), 1.5 (6H, s). IC50=18 nM
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:48]1N=N[C:50]2[CH:51]=CC=C[C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)CC>CN(C=O)C>[CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([NH:48][CH2:49][CH2:50][CH3:51])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCCN
Product: CCCNC(=O)c1cc(F)c(C)c(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and propylamine (6.78 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (18.7 mg, 58%). LC-MS m/z 581 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][C:14](=[O:17])[CH:15]=[CH2:16])=O)(C)(C)C.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:10]1[CH:9]2[N:8]([CH2:16][CH2:15][C:14](=[O:17])[CH2:13]2)[CH2:12][CH2:11]1
Reactant: C=CC(=O)CC1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCN2CCCC2C1
Temperature: 70 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
(±)-1-(t-Butoxycarbonyl)-2-(2-oxo-3-butenyl)pyrrolidine (140 mg (0.59 mmol), prepared as described in 2)) was dissolved in tetrahydrofuran (2 ml). To the solution was added an aqueous solution of 1N hydrochloric acid (1.76 ml, 1.76 mmol), and the resulting mixture was stirred at 70° C. for 4 hours. At the end of this time, to the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate and the resulting mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure, to give the title compound (76 mg) as a light brown oil (yield 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([Cl:17])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 104.5 %

Procedure:
To a suspension of 5-chloro-2-nitrobenzoic acid (21 g, 100 mmol) in dry methylene chloride (200 mL) at 0° C. were added several drops of DMF, followed by oxalyl chloride (13 mL, 150 mmol). The reaction was warmed to ambient temperature. After 16 hours the solvents were removed and the viscous oil dried in vacuo to afford 23 g (quantitative yield) of 5-chloro-2-nitrobenzoyl chloride; NMR (CDCl3) 8.1 (d, 1), 7.7 (m, 2) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cc(Br)c2cc[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(Br)c2ccn(S(=O)(=O)c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
4-Bromo-6-methoxy indole (0.07 g, 0.3 mmol) was dissolved in dry dichloromethane (4 mL) and benzenesulphonyl chloride (0.06 g, 0.3 mmol), tetrabutylammonium hydrogen sulphate (0.01 g, 0.01 mmol) and 4N NaOH (0.5 mL) were added and the mixture was stirred at rt for 50 min. The mixture was extracted with water (2×4 mL), dried (Na2SO4) and evaporated. The crude product was combined with an earlier batch of this intermediate (followed this experimental and starting with 4-bromo-6-methoxy indole (0.35 g, 1.5 mmol). MS (ESI+) for C15H12BrNO3S m/z 366 (M+H)+.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]([CH3:24])([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10])[CH3:7].[CH3:25][CH2:26][CH:27]=O.Cl.[OH-].[NH4+]>ClCCl.CO>[CH3:7][C:6]([CH3:24])([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[C:22]([NH:23][CH2:25][CH2:26][CH3:27])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:16]1)=[O:10])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Reactant: CCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: CCCNc1cccnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
Sodium cyanoborohydride (0.31 g) is added to a cold solution of 1-[1,1dimethylethoxycarbonyl]-4-[3-amino-2-pyridinyl]piperazine (International Publication No. WO 88/08424, 2.8 g), propional (0.87 g), and methanol (15 ml). After the exotherm has subsided, the reaction is stirred at 20°-25° overnight. The reaction is acidified (pH 2) with aqueous hydrochloride and then diluted with dichloromethane. The pH is adjusted with aqueous ammonium hydroxide (pH 8), and the phases are separated. The organic phase is dried over sodium sulfate, and concentrated under reduced pressure to a crude product which is dissolved in diethyl ether and allowed to crystallize at -5°. The solid is identified as starting material. The mother liquor is concentrated in vacuo to give the title compound.
Reaction SMILES: [O:1]=[C:2]([CH2:9][C:10](=[O:13])[C:11]#[CH:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].B.C1COCC1>C1COCC1.CO>[OH:1][CH:2]([CH2:9][CH:10]([OH:13])[C:11]#[CH:12])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C#CC(=O)CC(=O)CC(=O)OCC
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: C#CC(O)CC(O)CC(=O)OCC
Reaction time: 20 h

Procedure:
50 mg (0.27 mmol) of ethyl 3,5-dioxo-6-heptynoate was dissolved in 5 ml of THF and 52 ml of methanol. Then, with or without addition of aluminum tri-i-propoxide as a metal reagent, a reaction was conducted at 20° C. for 20 hours using 5.4 ml of a 1.0M BH3.THF solution and 6.2 mg (0.027 mmol) of the (S)-N-(P-naphthyl)methyl-2-pyrrolidine methanol (compound (S)-II-1) obtained in Example 1, to obtain ethyl 3,5-dihydroxy-6-heptynoate (VI-2) as oily desired product.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]2[C:11]([O:13][C:14](=[O:15])[C:2]=12)=[O:12].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:11]([C:3]2[C:2]([C:14]([OH:13])=[O:15])=[CH:1][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)=[O:12])=[CH:19][CH:18]=1
Reactant: O=C1OC(=O)c2cc3ccccc3cc21
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)c1cc2ccccc2cc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 113.8 %

Procedure:
45.0 g (227 mmol) of 2,3-naphthalenedicarboxylic acid anhydride are suspended in 200 ml (2.1 moles) of fluorobenzene. 75.5 g (565 mmol) of powdered aluminium chloride are added in the course of 5 minutes, with vigorous stirring (exothermic reaction up to about 32° C.). The dark red suspension is refluxed and stirred for 6 hours. The solution is then allowed to cool to room temperature and is poured onto about 500 g of ice, and is stirred to bring the hydrolysis to completion. Excess fluorobenzene is evaporated off and the resulting product is suspended in water. The suspension is filtered, the filtrate is rinsed with water and the product is dried. 76 g of crude 2-(4-fluorobenzoyl)-naphthalene-3-carboxylic acid are obtained. The crude product is stirred with 2 liters of 10% sodium carbonate solution, the resulting solution is acidified with hydrochloric acid and the white precipitate is filtered off and dried. 54.2 g (81% of theory) of 2-(4-fluorobenzoyl)-naphthalene-3-carboxylic acid are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21]S(C)(=O)=O)[CH:18]=[CH:17][C:16]=2[Cl:26])[C:10](=[O:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C(O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:16]=2[Cl:26])[C:10](=[O:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(OS(C)(=O)=O)ccc2Cl)C(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(O)ccc2Cl)C(=O)C1

Procedure:
A solution of product from step C (3.88 g, 9.65 mmol) and potassium t-butoxide (2.16 g, 19.3 mmol) in ethanol (100 mL) and H2O (5 ml) was heated at reflux for 3 hours. The reaction was concentrated in vacuo and the residue was partitioned between EtOAc and sat. NH4Cl. The organic layer was washed with H2O and brine, dried over magnesium sulfate, and concentrated in vacuo to give title product which was sufficiently pure for use in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Si:20]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]O)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(C=P(CCCC)(CCCC)CCCC)#N.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Si:20]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:11]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([C:33]([CH3:34])([CH3:35])[CH3:36])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](OCCCCCCO)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCCCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Yield: 79.4 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (470 mg, 1.55 mmol) obtained in Example 5 and 6-(t-butyldiphenylsilyloxy)-1-hexanol (740 mg, 2.08 mmol) were dissolved in toluene (20 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (500 mg, 2.07 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 7 hours. After the reaction mixture was allowed to cool down, the residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=10:1 eluate was concentrated under reduced pressure, whereby the title compound (786 mg, 1.23 mmol, 79%) was obtained as a pale yellowish brown oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.C[Si]([CH:31]=[N+:32]=[N-:33])(C)C>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[CH:14][CH:13]=[C:9]([C:10](=[O:12])[CH:31]=[N+:32]=[N-:33])[CH:8]=1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=CC(=O)c1cccc(-c2ccccc2)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 21 %

Procedure:
A mixture of 3-phenylbenzoic acid (595 mg, 3 mmol) and thionyl chloride (1 mL) was heated at 60° C. for 2.5 hours. After this time, the thionyl chloride was removed under vaccum. Toluene was then added and the resulting solution was concentrated. This procedure was repeated two more times. The oily residue was then dissolved in dry THF. At 0° C., triethylamine (304 μL, 3 mmol) and trimethylsilyldiazomethane were added successively. The reaction was then stirred for 20 hours at room temperature. The reaction was concentrated. Purification of the residue by flash chromatography using CH2Cl2/AcOEt 95:5 to 85:15 gave the compound as a yellow thick oil (141 mg, 21%). NMR 1H (ppm, CDCl3): 7.98 (t., J3=1.37 Hz, 1H), 7.74-7.67 (m, 2H), 7.60-7.57 (m, 2H), 7.50-7.24 (m, 4H), 5.95 (s, 1H). MS (+ESI): M+H+: 222.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[N:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]1=[O:18].[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Br.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN(C=O)C.C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[N:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:20]=2[F:19])=[CH:12][C:11]1=[O:18]
Reactant: Cc1cc(O)cc(=O)n1-c1cc(CO)ccc1Cl
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1cc(CO)ccc1Cl
Temperature: 0 °C
Reaction time: 6 h

Procedure:
1-[2-chloro-5-(hydroxymethyl)phenyl]-4-hydroxy-6-methylpyridin-2(1H)-one (from step 2) (3.5 g, 13.2 mmol) was taken up in DMF (10 ml) and cooled to 0° C. 2,4-Difluorobenzyl bromide (1.7 ml, 13.2 mmol) and K2CO3 (1.8 g, 13.2 mmol) were added and the reaction stirred for 6 hours. The reaction was worked up by adding saturated NaHCO3 (aq.) and extracting with ethyl acetate. The ethyl acetate extraction was washed with water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over Na2SO4, filtered, and the solvent removed in vacuo. The product was obtained in 83% crude yield and carried through to the next step as a brown oil. LC/MS, tr=2.48 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 392 (M+H). ES-HRMS m/z 392.0853 (M+H calcd for C20H17ClF2NO3 requires 392.0860).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[OH-].[Na+].[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1/[CH:17]=[CH:18]/[C:19](=[O:21])[CH3:20]>CS(C)=O>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[C@@H:17]1[CH2:2][C@H:18]1[C:19](=[O:21])[CH3:20]
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)/C=C/c1ccc(Cl)cc1Cl
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(=O)[C@@H]1C[C@H]1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask equipped with magnetic stirrer, nitrogen inlet and additional funnel was charged with trimethylsulfoxonium iodide (0.61 g, 2.78 mmol), DMSO (10 ml) and powdered sodium hydroxide (97 mg, 2.44 mmol). The suspension was stirred for 1.0 hour at ambient temperature to yield a solution. So prepared solution was added drop wise at ambient temperature to a solution of (E)-4-(2,4-dichloro-phenyl)-but-3-en-2-one (0.50 g, 2.32 mmol) prepared as described in example P30 in DMSO (10 ml). The reaction mixture was stirred for 0.5 hours, poured onto ice water (100 ml) and extracted with ether (3×25 ml). Combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (25 g) (eluent: n-hexane/ethyl acetate 10:1) to afford 0.33 g (62% of theory) of trans 1-[2-(2,4-dichloro-phenyl)-cyclopropyl]-ethyanone in form of an oil.
Reaction SMILES: [CH2:1]([N:3]([CH:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][NH:26][C:27](=[O:40])[C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:30][CH:29]=2)=[CH:19][CH:18]=1)[C:11]([O:13]CC)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([N:3]([CH:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][NH:26][C:27](=[O:40])[C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:32][CH:33]=2)=[CH:19][CH:18]=1)[C:11]([OH:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)N(CC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(c1ccccc1)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)O

Procedure:
Ethyl 2-(N-ethyl-N-phenylamino)-3-[4-[2-(4-pyridine-2-ylbenzoylamino)-ethoxy]phenyl]propionate, which is the product in Example 179, is hydrolyzed by sodium hydroxide in methanol to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>CCCCCC>[CH:5]1[C:4]2[C:9](=[CH:10][C:11]3[C:16]([C:3]=2[CH2:2][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1
Reactant: CCOP(OCC)OCC
Reactant: ClCc1c2ccccc2cc2ccccc12
Solvent: CCCCCC
Product: CCOP(=O)(Cc1c2ccccc2cc2ccccc12)OCC
Temperature: 140 °C

Procedure:
After a mixture of 28.5g of 9-chloromethylanthracene and 62.3g of triethyl phosphite was heated at a temperature of 140° C for 2 hours with stirring, the mixture was cooled to a room temperature to obtain light yellowish needle-like crystalline product. The crystalline product was filtered off and washed with petroleum ether, and then dried. A crude product was obtained in a yield of 34.4g (83.8%). A pure crystalline product of diethyl 9-anthrylmethylphosphonate (m.p. 103.5° C - 104° C) was obtained by the recrystallization of the crude product from n-hexane in a yield of 31.2g.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11]([OH:13])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:14]([N:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15]>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][C:11]([C:25]2[CH:24]=[CH:23][C:20]3[CH2:21][CH2:22][N:16]([CH:14]=[O:15])[CH2:17][CH2:18][C:19]=3[CH:26]=2)=[O:13])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: O=CN1CCc2ccccc2CC1
Reactant: CC(=O)N1CCC(CC(=O)O)CC1
Product: CC(=O)N1CCC(CC(=O)c2ccc3c(c2)CCN(C=O)CC3)CC1

Procedure:
Using (1-acetyl-4-piperidinyl)acetic acid and 3-formyl-2,3,4,5-tetrahydro-1H-3-benzazepine as obtained in Reference Example 2, the procedure of Example 23-1) was similarly repeated to provide 2-(1-acetyl-4-piperidinyl)-1-(3-formyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-ethanone as light-yellow oil.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17]3[C:22](C)=[CH:21][CH:20]=[CH:19][C:18]=3C)[CH:12]=2)[C:7]1=[O:25].[CH2:27](O)[CH2:28][CH2:29]C>>[CH2:2]([O:3][C:4]([C:5]1[N:6]=[C:14]([OH:15])[C:13]2[C:8]([C:7]=1[OH:25])=[CH:9][CH:10]=[C:11]([O:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[CH:12]=2)=[O:26])[CH2:27][CH2:28][CH3:29]
Reactant: COC(=O)CN1C(=O)c2ccc(Oc3c(C)cccc3C)cc2C1=O
Reactant: CCCCO
Agent: [Na]
Product: CCCCOC(=O)c1nc(O)c2cc(OC3CCCCC3)ccc2c1O
Reaction time: 3 h

Procedure:
0.79 g of sodium (34 mmol) were dissolved in 100 ml of n-butanol with stirring. Then the temperature was raised to 95° C. to 100° C., 5.70 g of [5-(2,6-dimethyl-phenoxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetic acid methyl ester (16.8 mmol) were added in one portion and stirring was continued at 95° C. to 100° C. for 3 h. Subsequently, the solvent was evaporated in vacuo, 25 ml of aqueous 2N HCl and 100 ml of ethyl acetate were added and the mixture was stirred vigorously for 30 min before it was filtered by suction. The organic phase was separated from the filtrate, dried over MgSO4 and was evaporated in vacuo to give a brown gum that was triturated with methanol. The resulting precipitate was filtered by suction and dried in vacuo to give 870 mg of a yellowish solid (A). The filtrate was evaporated in vacuo, dissolved in a small amount of methanol and stored overnight in a refrigerator. The resulting precipitate was filtered by suction and dried in vacuo to give 246 mg of a yellowish solid (B). A and B were pooled and purified by flash column chromatography on silica gel eluting with dichloromethane:ethyl acetate (98:2). Evaporation of the first fraction yielded 762 mg of the title compound; 1H NMR (CDCl3): δ=8.31 (bs, 1H), 8.12 (d, 1H), 7.60 (d, 1H), 7.35 (m, 1H), 7.09 (bs, 3H), 4.39 (t, 2H), 2.11 (s, 6H), 1.77 (m, 2H), 1.44 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][C:13]2([O:15][CH:14]2[CH3:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[OH-].[NH4+:26]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][C:13]([CH:14]([NH2:26])[CH3:16])([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1OC12CCN(C(=O)OCc1ccccc1)C2
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(N)C1(O)CCN(C(=O)OCc2ccccc2)C1

Procedure:
A solution of 2-methyl-1-oxa-5-azaspiro[2,4]heptane-5-carboxylic acid benzyl ester (Example A9, 0.31 g, 1.25 mmol) in methanol (10 mL) and ammonium hydroxide (7 mL) is heated in a sealed tube at 100° C. for 16 hours. After cooling, the reaction mixture is dissolved ethyl acetate, washed with water, dried over Na2SO4 and evaporated to afford the title compound (0.340 g). 1H NMR (200 MHz, CDCl3): δ 7.33–7.26 (m, 5H), 5.28 (bs, 2H), 5.07 (s, 2H), 3.56–3.16 (m, 5H), 2.03–1.76 (m, 2H), 1.15 (d, 3H).