Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[N:2]=[CH:3][C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:13]3[CH:14]=[C:15]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:16]=[CH:17][CH:18]=3)=[CH:11][N:12]=[C:6]2[CH:5]=1.C(N(CC)CC)C.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[NH3:2].[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:10]2[N:7]3[CH:8]=[CH:9][C:4]([C:3]#[N:2])=[CH:5][C:6]3=[N:12][CH:11]=2)[CH:14]=1)#[N:26]
Reactant: N#Cc1ccccc1-c1cccc(-c2cnc3cc(C=NO)ccn23)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N
Product: N#Cc1ccn2c(-c3cccc(-c4ccccc4C#N)c3)cnc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 171.2 %

Procedure:
3′-(7-Hydroxyiminomethylimidazo[1,2-α]pyridin-3-yl)biphenyl-2-carbonitrile (105 mg, 0.31 mmol), triethylamine (157 mg, 1.55 mmol) and 1,1′-carbonyldiimidazole (252 mg, 1.55 mmol) were dissolved in dichloromethane (5 ml) and stirred at room temperature for 15 min then heated under reflux for 2.5 h. The mixture was cooled to ambient temperature, diluted with dichloromethane (40 ml) and washed with water (40 ml) and brine (40 ml). The organics were dried over anhydrous sodium sulfate and evaporated to dryness. Purification of this material by preparative thin-layer chromatography eluting with dichloromethane/methanol/conc. ammonia (98:2:0.2) gave the title compound (85 mg, 86%) as a white solid. 1H NMR (400 MHz, CDCl3) δH 7.03 (1H, dd, J 1 and 7), 7.52 (1H, dt, J 8 and 1), 7.58 (1H, d, J 7), 7.62-7.66 (2H, m), 7.69-7.74 (2H, m), 7.79-7.84 (2H, m), 7.97 (1H, s), 8.12 (1H, s), 8.69 (1H, d, J 7); m/z (ES+) 321 (M++H).
Reaction SMILES: N1(C2N=[C:9]([CH2:14][C:15]([O-])=O)NC(=O)C=2)CCOCC1.[Na+].[N:19]1([C:25]2[N:30]=[C:29]([CH2:31][C:32](=[O:48])[N:33]3[C:41]4[C:36](=[C:37](C5C=CC=CN=5)[CH:38]=[CH:39][CH:40]=4)[CH2:35][CH2:34]3)[NH:28][C:27](=[O:49])[CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH:14]1([CH:34]2[CH2:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:33]2[C:32](=[O:48])[CH2:31][C:29]2[NH:28][C:27](=[O:49])[CH:26]=[C:25]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[N:30]=2)[CH2:15][CH2:9]1
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(-c3ccccn3)cccc21
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1c2ccccc2CC1C1CC1
Yield: 160.9 %

Procedure:
(±)-2-[2-(2-Cyclopropyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one is prepared by following the procedure described in example 1 using 0.90 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 0.60 g of (±)-2-cyclopropylindoline (reference example 12d) and 0.86 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.56 ml of pyridine and 10 ml of N,N-dimethylformamide. After purification by chromatography on a 100 g column of 20-45 μm silica, elution being carried out with a 90/10 v/v dichloromethane/methanol mixture, 0.88 g of (±)-2-[2-(2-cyclopropyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one is obtained in the form of a cream foam, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)c1ccc(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
A solution of 4.05 g. (0.0126 mole) of ethyl 5-(ρ-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetate, 15 ml. of 1N sodium hydroxide solution and 2 ml. of ethanol is refluxed for 30 minutes. The solution is cooled, diluted with water and filtered. The filtrate is acidified with dilute hydrochloric acid. The precipitates solid is collected and recrystallized from methanol-water to give a white crystalline solid, 5-(ρ-chlorobenzoyl)-α-methyl-1-methylpyrrole-2-acetic acid, M.P. 135°-136° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-].[Na+].[CH2:14](Br)[CH2:15][CH2:16][CH3:17].O>C(O)C>[CH2:14]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCBr
Reactant: Oc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCOc1ccc2ccccc2c1
Yield: 84.9 %

Procedure:
In 100 g of ethanol were dissolved 50 g (0.347 mol) of 2-naphthol and 14.6 g (0.364 mol) of sodium hydroxide. Under reflux, 50 g (0.364 mol) of n-butyl bromide was added to the solution, which was refluxed for a further 4 hours. To the reaction solution were added 200 g of water and 4 g of sodium hydroxide. The organic layer thus separated, 75 g, was distilled in vacuo, obtaining 59 g of 2-n-butoxynaphthalene. The distillate (liquid) solidified when allowed to stand at room temperature.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23]>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:7]([C:6]2[S:5][N:4]=[N:3][C:2]=2[CH3:1])=[O:9])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1nnsc1C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnsc1C(=O)Nc1ccc(F)c(Cl)c1
Reaction time: 3 h
Yield: 60 %

Procedure:
4-Methyl-1,2,3-thiadiazole-5-carboxylic acid (39.6 mg, 0.275 mmol) was suspended in DCM (2.0 mL). Bromotris(pyrrolydino)phophonium hexafluorophosphate (128 mg, 0.27 mmol) and DIPEA (96 μL, 0.55 mmol) were added and premixed for 5 minutes. 3-Chloro-4-fluoroaniline (40 mg, 0.27 mmol) was added. The solution was stirred for 3 hrs, then purified by silica gel chromatography, (Hex/EA)—eluting at ˜60% EA in hexane to afford the desired product (44 mg). MF═C10H7ClFN3OS; LCMS calculated for C10H8ClFN3OS(M+H)+: m/z=272.0.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][C:9]([N:14]([CH3:16])[CH3:15])=[N:10][N+:11]([O-:13])=[O:12])=[CH:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].CC#N.[CH:26]1[CH:31]=[CH:30][C:29]([O:32][C:33](Cl)=[S:34])=[CH:28][CH:27]=1>O>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([C:33]([O:32][C:29]2[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=2)=[S:34])[C:9]([N:14]([CH3:16])[CH3:15])=[N:10][N+:11]([O-:13])=[O:12])=[CH:5][N:6]=1
Reactant: CN(C)C(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reactant: S=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(C)C(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)C(=S)Oc1ccccc1
Yield: 75.8 %

Procedure:
To a mixture of 1-(2-chloro-5-thiazolylmethyl)-3,3-dimethyl-2-nitroguanidine (200 mg), K2CO3 (420 mg) and CH3CN (13 ml) was added phenyl chlorothionoformate (260 mg) dropwise in 3 minutes at 3° C. under stirring. After stirring at room temperature for 4 hours, water (10 ml) was added to the mixture which was extracted with CHCl3 (20 ml). The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was crystallized from AcOEt-Et2O to afford 230 mg of 1-(2-chloro-5-thiazolylmethyl)-3,3-dimethyl-2-nitro-1-phenoxythiocarbonylguanidine (Compound No. 44) as a white crystal, m.p. 161°-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:12][CH2:13][C:14]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:15]
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C(Cl)CCl
Product: O=C(CCl)Nc1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
The method described in Referential Example 502 was performed by use of 4-chloro-3-nitroaniline and chloroacetyl chloride, whereby the title compound was obtained.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([NH:8][C@@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][O:11][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](CO)NCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To methyl N-benzyl-D-serinate (1 eq.) in CH2Cl2 (0.3 M) at rt were added triethylamine (1 eq) and DMAP (0.05 eq). The reaction mixture was cooled to 0° C. and TBS-Cl (1.1 eq) was added. The reaction mixture was stirred at rt for 16 hrs, water was added and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with saturated aqueous NH4Cl, dried over Na2SO4, filtered and concentrated. The crude product was used as such for the next step.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[C:13]#N)=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[OH-:16].[Na+].[OH2:18]>CO>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[C:13]([OH:18])=[O:16])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: O
Reactant: [OH-]
Reactant: CC(C)=CCc1ccc(C(C)C#N)cc1
Agent: [Na+]
Solvent: CO
Product: CC(C)=CCc1ccc(C(C)C(=O)O)cc1
Reaction time: 8 h

Procedure:
A mixture of 16.4 g of 2-(p-prenylphenyl)propionitrile, 60 g of sodium hydroxide, 100 ml of water and 120 ml of methanol was stirred at 70°-75° C. for 8 hours. The resulting solution was concentrated and acidified with dilute hydrochloric acid, followed by extraction with ethyl ether and washing with water. The ethereal solution was extracted with 5% aqueous potassium hydroxide solution. The aqueous layer was acidified with dilute hydrochloric acid, and extracted with ether, which was then washed with water, dried over anhydrous magnesium sulfate and decolorized with activated charcoal. The ether was removed to give 15.5 g of 2-(p-prenylphenyl)propionic acid. ##STR1##
Reaction SMILES: C([O-])(=O)C.[Ni+2:5].C([O-])(=O)C.[CH2:10]([C:12]1[C:32]2[N:33]=[C:14]([CH:15]=[C:16]3[NH:43][C:19](=[CH:20][C:21]4[C:22]([CH2:41][CH3:42])=[C:23]([CH2:39][CH3:40])[C:24]([N:38]=4)=[CH:25][C:26]4[NH:30][C:29]([CH:31]=2)=[C:28]([CH2:34][CH3:35])[C:27]=4[CH2:36][CH3:37])[C:18]([CH2:44][CH3:45])=[C:17]3[CH2:46][CH3:47])[C:13]=1[CH2:48][CH3:49])[CH3:11]>>[Ni:5].[CH2:39]([C:23]1[C:24]2[N:38]=[C:21]([CH:20]=[C:19]3[NH:43][C:16](=[CH:15][C:14]4[C:13]([CH2:48][CH3:49])=[C:12]([CH2:10][CH3:11])[C:32]([N:33]=4)=[CH:31][C:29]4[NH:30][C:26]([CH:25]=2)=[C:27]([CH2:36][CH3:37])[C:28]=4[CH2:34][CH3:35])[C:17]([CH2:46][CH3:47])=[C:18]3[CH2:44][CH3:45])[C:22]=1[CH2:41][CH3:42])[CH3:40]
Reactant: [Ni+2]
Agent: CC(=O)[O-]
Agent: CCC1=C(CC)c2cc3[nH]c(cc4nc(cc5[nH]c(cc1n2)c(CC)c5CC)C(CC)=C4CC)c(CC)c3CC
Product: [Ni]
Temperature: 25 °C

Procedure:
The nickel acetate is added to the octaethylporphyrin solution; the mixturewhich results is refluxed for about 24 hours until the electronic spectrum of the reaction mixture indicates that chelation is complete. The reactionmixture is then concentrated to 7 mL and allowed to cool to room temperature of about 22°. Product which precipitates is recovered by filtration, dissolved in a mixed solvent composed of 5 mL dichloromethane and 2 mL methanol, and recrystallized, yielding Ni octaethylporphyrin.
Reaction SMILES: Br[C:2]1[S:6]/[C:5](=[CH:7]\[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])/[N:4]([CH2:19][CH2:20][CH2:21][CH3:22])[C:3]=1[CH3:23].[CH3:24][C:25]([OH:29])([C:27]#[CH:28])[CH3:26]>C(N(CC)CC)C.[Cu]I.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>[CH2:19]([N:4]1[C:3]([CH3:23])=[C:2]([C:28]#[C:27][C:25]([OH:29])([CH3:26])[CH3:24])[S:6]/[C:5]/1=[CH:7]\[C:8]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])=[O:9])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN1C(C)=C(Br)S/C1=C\C(=O)c1cc(Cl)ccc1OC
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCN1C(C)=C(C#CC(C)(C)O)S/C1=C\C(=O)c1cc(Cl)ccc1OC
Temperature: 100 °C
Yield: 59.5 %

Procedure:
A mixture of product from Example 13 (33 mg, 0.08 mmol), 2-methylbut-3-yn-2-ol (10 mg, 0.1 mmol), CuI (2 mg, 0.01 mmol and Pd(Ph3P)4 (30 mg, 0.03 mmol) in triethylamine (10 mL) was heated at 100° C. for 1 hour. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by chromatography (hexane-EtOAc 1:1) to afford 20 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.95 (t, J=7 Hz, 3H), 1.40 (sextet, J=7 Hz, 2H), 1.67 (quintet, J=7 Hz, 2H), 2.34 (s, 3H), 3.85 (s, 3H), 3.95 (t, J=7 Hz, 2H), 5.50 (s, 1H), 6.72 (s, 1H), 7.13 (d, J=9 Hz, 1H), 7.43 (dd, J=9 Hz, 3 Hz, 1H), 7.66 (d, J=3 Hz, 1H); MS (ESI) m/z 420 (M+H)+. Anal calcd for C22H26ClNO3S: C, 62.92; H, 6.24; N, 3.34. Found: C, 62.85; H, 6.28; N, 2.92.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH2:8][CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:7])=[C:4]([CH:20]=O)[CH:3]=1.C(O[K])(C)(C)C.O>C(O)(C)(C)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH3:7])[CH2:8][CH2:9][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:20][C:4]=2[CH:3]=1.[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH3:7])[CH2:8][CH2:9][C:10]([C:11]([OH:13])=[O:12])=[CH:20][C:4]=2[CH:3]=1
Reactant: CN(CCCC(=O)OC(C)(C)C)c1ccc(Br)cc1C=O
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CC(C)(C)O
Product: CN1CCC(C(=O)O)=Cc2cc(Br)ccc21
Product: CN1CCC(C(=O)OC(C)(C)C)=Cc2cc(Br)ccc21
Yield: 77 %
Yield: 17 %

Procedure:
In tert-butanol (250 ml) was dissolved tert-butyl 4-(4-bromo-2-formyl-N-methylanilino)butyrate (4.54 g) and tert-butoxy potassium (1.43 g), and the mixture was refluxed for 1 hour and cooled. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate (500 ml×2). The aqueous layer was made weakly acidic with 1N hydrochloric acid (about 12.5 ml), and the mixture was extracted with ethyl acetate (500 ml). Both of these organic layer was washed with saturated brine (250 ml) and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (200 g, hexane:ethyl acetate=10:1→1:1) to give tert-butyl 7-bromo-1-methyl-2,3-dihydro-1-benzoazepine-4-carboxylate (3.33 g, 77%) and 7-bromo-1-methyl-2,3-dihydro-1H-1-benzoazepine-4-carboxylic acid (0.60 g, 17%).
Reaction SMILES: C(OCCCC)CCC.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:13][CH:12]=1.BrBr.[CH2:23]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[K+]>CO.O>[CH3:19][CH:18]([N:33]1[CH2:34][CH2:35][CH:30]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:31][CH2:32]1)[CH:17]([OH:20])[C:14]1[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=1
Reactant: c1ccc(Cc2ccncc2)cc1
Reactant: CCC(=O)c1ccc(O)cc1
Agent: BrBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCCCOCCCC
Solvent: O
Solvent: CO
Product: CC(C(O)c1ccc(O)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 90 %

Procedure:
To 10 ml of di-n-butyl ether were added 6.0 g of 4'-hydroxypropiophenone. 6.6 Grams of bromine were added dropwise to the mixture with stirring at room temperature, and the reaction liquid was stirred for an additional 10 minutes. To the reaction liquid were then added 7.5 g of 4-benzylpyridine, 4.0 g of potassium hydrogen carbonate, 1 ml of water and 50 ml of methanol, and the mixture was refluxed under heating for 5 hours. After stopping the heating, the reaction mixture was treated in the same manner as described in Example 46, whereby 11.7 g (76.0%) of ifenprodil were obtained as white crystals.
Reaction SMILES: N[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[OH:4].O=[C:14]([CH3:28])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1.C1C=CC=CC=1.C([BH3-])#[N:36].[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH:14]([CH2:2][C:3]([NH2:36])([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)[OH:4])[CH3:28])=[CH:18][CH:19]=1)=[O:25]
Reactant: [BH3-]C#N
Reactant: COc1cccc(C(O)CN)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)CC(N)(O)c2cccc(OC)c2)cc1
Yield: 55.7 %

Procedure:
Following a procedure similar to that described in Example 3, but using 2.5 g of 2-amino-1-(3-methoxyphenyl)ethanol (prepared as described in Preparation 43), 4.0 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 2.75 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.11 g of the title compound were obtained having an Rf=0.21 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([Cl:11])[C:5]=1[NH2:12].O.[OH-].[K+].Cl>C(O)C>[NH2:12][C:5]1[C:6]([Cl:11])=[N:7][C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([OH:13])=[O:2]
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1c(C(=O)O)cc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
3-Amino-2,6-dichloroisonicotinic acid methyl ester (460 mg) was dissolved in ethanol (8 mL), water (2 mL) and potassium hydroxide (234 mg) was added. The solution was stirred for 20 minutes at room temperature and for 1.5 hours under reflux. After cooling to room temperature, 2N hydrochloric acid was added to adjust the pH-value to −3 and the so-formed yellow precipitate was extracted 3× with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum to afford 420 mg of the title compound of the formula
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:21])[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[C:24](OC)([N:26]([CH3:28])[CH3:27])[CH3:25]>CN(C=O)C>[CH3:27][N:26]([CH3:28])[C:24]([CH3:25])=[CH:2][C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:21])[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1cn(CC)c2cc(C(C)=O)ccc2c1=O
Reactant: COC(C)(OC)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(C(=O)C=C(C)N(C)C)ccc2c1=O

Procedure:
A mixture of 32.6 g ethyl 7-acetyl-1,4-dihydro1-ethyl-4-oxo-3-quinolinecarboxylate, 24 ml dimethylacetamide dimethylacetal and 100 ml DMF was heated on a steam bath for 4 hrs. The reaction mixture was concentrated in vacuo and the solid residue triturated with ethyl acetate. The solid product was recrystallized from acetonitrile to give 20.9 g ethyl 7-[3-(dimethylamino)-1-oxo2-butenyl]-1-ethyl-1,4-dihydro-4-oxo-3-quinolinecarboxylate, yellowish-orange powder, m.p. 178-179.5° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:12]([C:13]([NH:15][OH:16])=[O:14])=[C:11]([Cl:17])[N:10]([CH3:18])[N:9]=1.[CH2:19](Br)[CH:20]=[CH2:21].Cl>O.C1(C)C=CC=CC=1>[CH2:21]([O:16][NH:15][C:13]([C:12]1[C:8]([Cl:7])=[N:9][N:10]([CH3:18])[C:11]=1[Cl:17])=[O:14])[CH:20]=[CH2:19]
Reactant: Cn1nc(Cl)c(C(=O)NO)c1Cl
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCONC(=O)c1c(Cl)nn(C)c1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 72.2 %

Procedure:
In a solution of potassium carbonate (15.8 g, 114 mmol) in water (60 ml), a solution of 3,5-dichloro-1-methylpyrazole-4-carbohydroxamic acid (20.0 g, 95.2 mmol) and allyl bromide (13.8 g, 114 mmol) in toluene (60 ml) was added, and stirred at 50° C. for 3 hours. After cooling to room temperature, the mixture was adjusted to pH 1 by adding 35% hydrochloric acid, precipitated solid was filtered off, washed with water and toluene in that order, and dried to obtain the aimed product (17.2 g). Melting point 96-97° C. Proton nuclear magnetic resonance chemical shift values δ (ppm) (in CDCl3) 3.84 (s, 3H), 4.51 (d, J=6.3 Hz, 2H), 5.3-5.46 (m, 2H), 5.94-6.13 (m, 1H), 8.80 (brs, 1H).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]=1.[Cl-:30].[NH4+:31]>CO>[ClH:30].[NH:31]=[C:3]1[NH:9][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: [Cl-]
Reactant: CCOC(=O)C(CCCC1CCCCC(OC)=N1)NC(=O)OCc1ccccc1
Reactant: [NH4+]
Solvent: CO
Product: CCOC(=O)C(CCCC1CCCCC(=N)N1)NC(=O)OCc1ccccc1
Product: Cl

Procedure:
The product of EXAMPLE 248 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=1>COCCOCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:14]=[C:13]([Br:12])[CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Brc1cccc(Br)c1
Reactant: Oc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: Clc1ccc(Oc2cccc(Br)c2)cc1
Temperature: 165 °C
Reaction time: 21 h
Yield: 29.9 %

Procedure:
Under a nitrogen atmosphere, a solution of 13.6 grams (0.106 mole) of 4-chlorophenol in 50 mL of diglyme was stirred, and 24.1 mL (0.106 mole) of methanolic 25% sodium methoxide was added dropwise. Upon completion of addition, the reaction mixture was heated to about 165° C. to remove methanol. After the methanol was removed, the heating was ceased, and 25.0 grams (0.106 mole) of 1,3-dibromobenzene and 1.3 grams of cuprous bromide were added. Upon completion of the additions, the reaction mixture was heated to reflux where it was stirred for about 21 hours. The reaction mixture was then cooled and filtered. The filter cake was washed with diethyl ether, and the wash was combined with the filtrate. The combination was extracted with two 20 mL portions of aqueous 20% sodium hydroxide and then with two 75 mL portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under vacuum, yielding about 9.0 grams of 3-(4-chlorophenoxy)phenyl bromide, bp 110° C./0.5 mm Hg. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][O:9]2)[N:5]=[CH:4][C:3]=1[C:11]#[N:12].[OH:13][C@H:14]([C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[O:27][CH2:28][C:24]=2[C:23]=1[CH3:32])[CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CCO>[OH:9][CH:8]([C:6]1[N:5]=[CH:4][C:3]([C:11]#[N:12])=[C:2]([CH3:1])[CH:7]=1)[CH2:10][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C@H:14]([OH:13])[C:22]2[CH:31]=[CH:30][C:25]3[C:26](=[O:29])[O:27][CH2:28][C:24]=3[C:23]=2[CH3:32])[CH2:17][CH2:18]1
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Reactant: Cc1cc(C2CO2)ncc1C#N
Solvent: CCO
Product: Cc1cc(C(O)CN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2)ncc1C#N
Temperature: 140 °C

Procedure:
To a microwave tube were added 4-methyl-6-(oxiran-2-yl)pyridine-3-carbonitrile (40 mg, 0.25 mmol), 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one (69 mg, 0.25 mmol, as a free base), and EtOH (3.0 mL). The mixture was heated in the microwave for 60 min at 140° C. The solvent was evaporated and the crude product was purified by chiral prep SFC (30% MeOH (0.1% DEA)/CO2 on OJ column) to provide 6-(1-hydroxy-2-{4-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methylpyridine-3-carbonitrile as individual isomers. Further, the products were treated with 1 M HCl in diethyl ether to give the final products as HCl salts.