Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>COCCOC.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:20][Si:21]([C:24]#[C:25][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])([CH3:23])[CH3:22]
Reactant: COC(=O)Cc1ccccc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: COC(=O)Cc1ccccc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.4 %

Procedure:
To a solution of ester 318 (7.50 g, 27.2 mmol) in dry DME (125 mL) at 0° C. was added triethylamine (6.0 mL, 4.3 g, 43 mmol), copper (I) iodide (1.00 g, 5.25 mmol), and bis(triphenylphosphine) palladium (II) chloride (0.65 g, 0.93 mmol). The mixture was degassed with a stream of N2 for 5 min, then trimethylsilylacetylene (5.8 mL, 4.1 g, 41 mmol) was added and the reaction mixture was warmed to room temperature and stirred for 24 h. It was concentrated under reduced pressure, partitioned between ethyl acetate and water, washed with brine, dried (anhydrous MgSO4), filtered and concentrated. Flash chromatography of the residue (eluent 4% ethyl acetate/hexanes) afforded title compound 319 (4.65 g, 69% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.22 (dd, J=7.4, 0.8 Hz, 1H); 7.07-6.95 (m, 3H); 3.58 (s, 2H); 3.45 (s, 3H); 0.00 (s, 9H). LCMS: (M+H) 247.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]2([CH3:14])[CH3:13].[I:15][CH2:16][CH3:17]>ClC1C=CC=CC=1Cl>[I-:15].[CH2:16]([N+:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6]([CH3:14])([CH3:13])[C:7]=1[CH3:12])[CH3:17]
Reactant: COc1ccc2c(c1)C(C)(C)C(C)=N2
Reactant: CCI
Solvent: Clc1ccccc1Cl
Product: CC[N+]1=C(C)C(C)(C)c2cc(OC)ccc21
Product: [I-]
Temperature: 80 °C

Procedure:
To 5-methoxy-2,3,3-trimethyl-3H-indole (1.9 g) was added iodoethane (5 ml) and 1,2-dichlorobenzene (10 ml). The mixture was heated to 80° C. for 4 hours after which time the mixture was allowed to cool and the precipitate removed by filtration and washed sequentially with dichlorobenzene and diethyl ether. Drying in a vacuum oven gave the product (3 g).
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC(=O)[NH:14][CH:15]([C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][C:35]=1[S:42][CH3:43])[C:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:17]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)(C)(C)C>C(#N)C>[ClH:1].[NH2:14][CH:15]([C:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:17]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=1)[C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][C:35]=1[S:42][CH3:43]
Reactant: CSc1cc(C#N)ccc1C(NC(=O)OC(C)(C)C)C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: CSc1cc(C#N)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of hydrogen chloride in 1,4-dioxane (4 M, 4.5 mL, 18 mmol) is added to a mixture of {(4-cyano-2-methylsulfanyl-phenyl)-[6-oxo-2-(3-trifluoromethyl-phenylamino)cyclohex-1-enyl]-methyl}-carbamic acid tert-butyl ester (INTERMEDIATE 4, 2.16 g, 3.25 mmol) in acetonitrile (4.5 mL) and the mixture is stirred at room temperature for 1 h. The precipitate is filtered off, washed with acetonitrile and dried. Yield: 1.19 g. ESI mass spectrum: [M+H-NH3]+=415; Retention time HPLC: 0.88 min (Z018_S04).
Reaction SMILES: Cl[CH2:2][CH:3]=[O:4].[CH3:5][C:6]1[N:11]=[C:10]([NH:12][C:13](=[S:15])[S-:14])[CH:9]=[CH:8][CH:7]=1.C([NH+](CC)CC)C.C(O)C>O>[OH:4][CH:3]1[CH2:2][S:15][C:13](=[S:14])[N:12]1[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:5])[N:11]=1
Reactant: O=CCCl
Reactant: Cc1cccc(NC(=S)[S-])n1
Agent: CC[NH+](CC)CC
Solvent: O
Solvent: CCO
Product: Cc1cccc(N2C(=S)SCC2O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A 50% aqueous solution of chloroacetaldehyde (28.4 g) is added, at between 20° and 30° C., to a solution of triethylammonium 6-methylpyrid-2-yldithiocarbamate (51.5 g) in distilled water (225 cc). The reaction mixture is stirred for 2 hours at 25° C. The crude product is filtered off, washed five times with distilled water (total 125 cc) and dried in air. The product obtained (37.0 g; m.p. 128° C.) is dissolved in boiling ethanol (250 cc). After filtering the boiling solution and cooling the filtrate for 2 hours at 2° C., the resulting crystals are filtered off, washed three times with ice-cooled ethanol (total 30 cc) and dried under reduced pressure (0.2 mm Hg) at 40° C. 4-Hydroxy-3-(6-methylpyrid-2-yl)-thiazolidine-2-thione (29.8 g), melting at 128° C., is thus obtained.
Reaction SMILES: [CH3:1][C:2]([C:11]1[O:15][N:14]=[C:13]([NH:16][C:17](=[O:25])OC2C=CC=CC=2)[CH:12]=1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C([N:29](CC)C(C)C)(C)C.COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(C=CC=1)N>C1COCC1>[CH3:1][C:2]([C:11]1[O:15][N:14]=[C:13]([NH:16][C:17](=[O:25])[NH2:29])[CH:12]=1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CC(C)(CN1CCOCC1)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: CCN(C(C)C)C(C)C
Agent: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Product: CC(C)(CN1CCOCC1)c1cc(NC(N)=O)no1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A stirred solution of phenyl 5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-ylcarbamate (22 mg), N,N-diisopropylethylamine (12 mg, 0.093 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (15 mg, 0.051 mmol) in THF (0.5 mL) was heated at 60° C. for 15 h. The reaction mixture was cooled to rt and partitioned between saturated aqueous sodium carbonate and dichloromethane. The organic layer was separated and concentrated under reduced pressure to give the crude product. Purification via preparative TLC afforded 14346,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-yl)urea (5 mg, 1% over three steps) as a solid. 1H NMR (400 MHz, CDCl3) 89.35 (brs, 1H), 8.65 (brs, 2H), 7.66 (s, 1H), 7.57 (s, 1H), 7.29-7.41 (m, 3H), 7.01 (m, 1H), 6.10 (s, 1H), 4.09 (s, 6H), 3.63-3.66 (m, 4H), 2.40-2.70 (m, 6H), 1.32 (s, 6H); LC-MS (ESI) m/z 549 (M+H)+.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1)([CH3:5])([CH3:4])[CH3:3].[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O>[F:31][C:19]([F:18])([F:30])[C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:16][C@@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:7]([O:6][C:2]([CH3:3])([CH3:5])[CH3:4])=[O:17])=[CH:13][CH:12]=2)[CH3:15])(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H](N)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](NS(=O)(=O)c1ccc(C(F)(F)F)cc1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a vial containing tert-butyl-4-[(1R)-1-aminoethyl]benzoate hydrochloride from Step 1 was added N,N-dimethylaminopyridine (3.91 mg, 0.032 mmol), 4-(trifluoromethyl)benzenesulfonyl chloride (0.059 g, 0.24 mmol), N,N-dimethylformamide (2 mL), and triethylamine (0.18 mL, 1.28 mmol). The mixture was stirred at rt for 16 h, after which the solvent was fully evaporated. To the residue was added 1,2-dichloroethane (3 mL), sat. NaHCO3 solution (0.5 mL), and water (0.5 mL). After separation, the aqueous layer was extracted with 1,2-dichloroethane (2×3 mL). The combined organic phases were evaporated to dryness to give (R)-tert-butyl 4-(1-(4-(trifluoromethyl)phenylsulfonamido)ethyl)benzoate as a brown solid. LC-MS: (FA) ES+ 430.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]([NH:24][NH2:25])=[O:23])[N:19]=[C:18]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:43](N1C=CN=C1)(N1C=CN=C1)=[O:44]>C1COCC1.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]4[O:23][C:43](=[O:44])[NH:25][N:24]=4)[N:19]=[C:18]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:33])[F:34])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(C(=O)NN)nc3-c3ccccc3C(F)(F)F)cc2)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(-c4n[nH]c(=O)o4)nc3-c3ccccc3C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.8 %

Procedure:
To a solution of 1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazole-4-carbohydrazide (216 mg, 0.432 mmol), triethylamine (0.132 mL, 0.949 mmol) in 1 mL anhydrous THF was added carbonyldiimidazole (140 mg, 0.864 mmol). The reaction was stirred for 24 h at room temperature. The reaction was diluted with ethyl acetate, washed with water, brine, and dried with MgSO4. The residue was absorbed onto silica and purified by column chromatography using hexanes:ethyl acetate as eluents to afford 5-(1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)-1,3,4-oxadiazol-2(3H)-one (120 mgs, 52%) as a white solid. 1H-NMR (DMSO, 400 MHz) δ 12.48 (s, 1H), 8.39 (s, 1H), 8.15-8.14 (m, 1H), 8.04-8.01 (m, 1H), 7.93-7.90 (m, 1H) 7.87-7.82 (m, 3H), 7.75-7.70 (m, 3H), 7.66-7.64 (m, 1H), 7.38 (d, J=8.61 Hz, 2H), 3.28 (s, 3H); MS (ES): 527.3 [M+H]+ and 549.3 [M+Na]+.
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:13])[CH2:9][CH2:10][C:11]#[CH:12].[CH:14]1([Mg]Br)[CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>C1COCC1>[CH:14]1([C:8](=[O:13])[CH2:9][CH2:10][C:11]#[CH:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C#CCCC(=O)Sc1ccccn1
Reactant: Br[Mg]C1CCCC1
Agent: Cl
Solvent: C1CCOC1
Product: C#CCCC(=O)C1CCCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
To a solution of pent-4-ynethioic acid S-pyridin-2-yl ester (17.9 g, 94 mmol), dissolved in THF (900 mL) cooled to −78° C. was added cyclopentylmagnesium bromide (2.0 M, 94 mL, 188.5 mmol). The reaction was stirred for 15 minutes, and then warmed to −50° C. The reaction was poured into 500 mL 1 N HCl and the layers were separated. The aqueous layer was extracted with 2×200 mL diethyl ether and the organic layers were combined. The organics were then washed with 300 mL of 1 N NaOH. The organic layer was dried over Mg SO4, and the solids were removed by filtration. The solvent was removed by rotary evaporation to give the desired compound (14.0 g, 99% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17].Cl[C:20]1[S:24][N:23]=[C:22]([CH:25]([CH3:27])[CH3:26])[N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:20]3[S:24][N:23]=[C:22]([CH:25]([CH3:27])[CH3:26])[N:21]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17]
Reactant: COC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Reactant: CC(C)c1nsc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)NCc1cc(-c2ccn(-c3nc(C(C)C)ns3)n2)ccc1Cl
Temperature: 165 °C

Procedure:
A mixture of methyl N-[[2-chloro-5-(1H-pyrazol-3-yl)phenyl]methyl]carbamate (i.e. the product of Step B, Example 4) (0.02 g, 0.75 mmol), 5-chloro-3-(1-methylethyl)-1,2,4-thiadiazole (i.e. the product of Step A) (0.61 g, 3.75 mmol) and potassium carbonate (0.25 g, 1.5 mmol) in N-methyl-2-pyrrolidinone (2.5 mL) was heated in a Biotage Creator XM microwave apparatus at 165° C. for 15 minutes. The reaction mixture was poured into water (60 mL), and the aqueous mixture was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography (0 to 100% gradient of ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (0.5 g).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[NH:15][C:16](=[O:27])[C:17]2[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=2[N:19]=1)[CH3:6].[Br:28][CH2:29][C:30](Br)=[O:31].O>ClCCl>[Br:28][CH2:29][C:30]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:5][CH3:6])=[C:9]([C:14]2[NH:15][C:16](=[O:27])[C:17]3[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=3[N:19]=2)[CH:10]=1)=[O:31]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3OCC)nc12
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(C(=O)CBr)ccc3OCC)nc12
Reaction time: 18 h
Yield: 78.4 %

Procedure:
Aluminium trichloride (12.8 g, 0.096 mol) was added portionwise over 1 hour to a stirred solution of 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (10.0 g, 0.032 mol) and bromoacetyl bromide (5.6 ml, 0.064 mol) in dichloromethane (150 ml) at 0° C. After 18 hours at room temperature, the reaction mixture was poured into ice an water (400 g) and the resulting mixture stirred vigorously. The organic phase was separated and the aqueous phase further extracted with dichloromethane (2×100 ml). The organic solutions were combined, dried (Na2SO4) and evaporated under vacuum to give an off-white solid, trituration of which from ether gave the title compound as a white solid (10.87 g, 78%), m.p. 159°-160° C. Found C,52,54; H,4.88; N,12.78. C19H21BrN4O3 requires C,52.67; H,4,88; N,12.93%
Reaction SMILES: [F:1][C:2]1[C:3]([N:15]=CN(C)C)=[N:4][C:5](=[O:14])[N:6]([CH:8]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]2)[CH:7]=1.[CH:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>C(Cl)Cl.CN(C)C=O>[NH2:15][C:3]1[C:2]([F:1])=[CH:7][N:6]([CH:8]2[CH2:12][CH2:11][CH:10]([O:13][C:33](=[O:34])[NH:32][C:29]3[CH:28]=[CH:27][C:26]([C:23]4[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=4)=[CH:31][CH:30]=3)[CH2:9]2)[C:5](=[O:14])[N:4]=1
Reactant: CN(C)C=Nc1nc(=O)n(C2CCC(O)C2)cc1F
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1nc(=O)n(C2CCC(OC(=O)Nc3ccc(-c4ccccc4)cc3)C2)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.2 %

Procedure:
A solution of N′-[5-fluoro-1-(3-hydroxy-cyclopentyl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine (0.050 g, 0.186 mmol) in CH2Cl2 (2 mL) and anhydrous dimethylformamide (1 mL) was treated with 4-biphenyl isocyanate (0.039 g, 0.2 mmol). The mixture was stirred at room temperature under nitrogen for 5 hours, then quenched by the addition of acetic acid (0.5 mL) and stirred 10 minutes. The mixture was concentrated in vacuo, loaded on silica gel, and chromatographed on silica gel (10 g SiO2, 8:1 ethyl acetate/methanol) to afford biphenyl-4-yl-carbamic acid 3-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)-cyclopentyl ester 31 as a white solid (0.029 g, 38%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[O:14]=[C:11]1[NH:12][N:13]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:15](=[O:17])[CH3:16])[CH:7]=[CH:6][CH:5]=2)[CH:9]=[CH:10]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-c2ccc(=O)[nH]n2)c1
Product: CC(=O)Nc1cccc(-c2ccc(=O)[nH]n2)c1

Procedure:
A mixture of 37 G of 6-(3-aminophenyl)-3(2H)-pyridazinone and 500 ml of acetic anhydride was heated at 85°-90° C. for 8 hours. The solvent was removed in vacuo and the residue dissolved in 500 ml of methanol. To this solution was added portionwise 40 g of potassium hydroxide. The solution was refluxed for 3 hours and the solvent removed in vacuo. The residue was dissolved in water and the solution neutralized with hydrochloric acid. The resulting solid was collected and recrystallized from dichloromethane-methanol, giving 10.8 g of the desired compound as crystals, mp 250°-252° C. (dec.).
Reaction SMILES: [CH3:1][N:2]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].Cl.[CH:29](Cl)(Cl)[Cl:30]>C(O)(=O)C>[ClH:30].[CH3:1][N:2]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)[CH2:3][CH2:4][CH2:5][N:6]1[C:7](=[O:15])[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[O:10][CH2:29]1
Reactant: ClC(Cl)Cl
Reactant: COc1ccc(CCN(C)CCCNC(=O)c2ccccc2O)cc1OC
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(CCN(C)CCCN2COc3ccccc3C2=O)cc1OC

Procedure:
A solution of 2 g (5.37 mmol) of N-{3-[(methyl)(3,4-dimethoxyphenethyl)amino]propyl}salicylamide in 18 ml of chloroform and 1 ml of acetic acid is treated for 2 min with a stream of gaseous hydrochloric acid. 340 milligrams of trioxymethylene are then added to the above mixture, which is heated for 20 min to 70°-75° C. After return to room temperature, a stream of nitrogen is passed through for 30 min and the mixture is then filtered on a sinter and evaporated to dryness. The residue is taken up in toluene and re-evaporated to dryness in a rotary evaporator under vacuum. The solid residue (3.10 g) is ground in isopropyl ether and filtered. The cream powder obtained (m=2.1 g) is recrystallized in a 75:25 i-PrOH/EtOH mixture to give 1.53 g (yld=68%) of compound A of formula: ##STR6##
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[CH:13][C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[OH:34].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[Cl:23][C:12]1[CH:13]=[C:14]2[C:15](=[CH:20][C:11]=1[CH2:10][C:9]1[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[CH:25][CH:24]=1)[C:16](=[O:17])[N:27]([C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[OH:34])[CH2:21]2
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(Cl)cc1C=O
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2cc(Cc3ccc(-n4cccn4)cc3)c(Cl)cc2CN1[C@@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 0 %

Procedure:
A solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-formylbenzoate (0.12 g), trans-2-aminocyclohexanol hydrochloride (0.05 g), triethylamine (0.05 mL) and anhydrous magnesium sulfate (0.08 g) in THF (2.50 mL) was stirred at room temperature for 1 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (2.50 mL) and THF (2.50 mL), sodium triacetoxyborohydride (0.15 g) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.05 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]2[CH2:6][CH2:5][N:4]1[CH2:22][CH2:23][OH:24].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28]>C1(C)C=CC=CC=1>[CH2:3]1[CH:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]2[CH2:6][CH2:5][N:4]1[CH2:22][CH2:23][O:24][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: OCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)COCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 40 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
0.478 g of a 55% w/w dispersion of sodium hydride in mineral oil was added to a solution of 1.5 g of 2-(1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepin-2-yl)ethanol [prepared as described in step (a) or (c) above] dissolved in 20 ml of toluene, under an atmosphere of nitrogen. The mixture was then stirred at 40° C. for 2 hours, after which 0.924 g of methyl bromoacetate was added, whilst ice-cooling; the mixture was then stirred at 40° C. for a further 4 hours. At the end of this time, the reaction mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 0.58 g (31% yield) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([C:29](O)=[O:30])[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:18][C:17]3=[O:28])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[NH:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([C:29]([N:32]3[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]3)=[O:30])[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[CH:18][C:17]3=[O:28])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(Nc1ccc(F)c(Cl)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: OC1CCNCC1
Product: CC(Nc1ccc(F)c(Cl)c1)c1cc(C(=O)N2CCC(O)CC2)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 74.1 %

Procedure:
8-(1-(3-chloro-4-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (125 mg, 0.28 mmol) was reacted with piperidin-4-ol (34.0 mg, 0.34 mmol) using a procedure similar to the one described in Example 2.00 to afford 8-(1-(3-chloro-4-fluorophenylamino)ethyl)-6-(4-hydroxypiperidine-1-carbonyl)-2-morpholino-4H-chromen-4-one (110 mg, 74.2%) as a white solid. Mass Spectrum: M+H+ 530. NMR Spectrum: (DMSOd6) at 323° K: 1.24 (bs, 2H), 1.51 (d, 3H), 2.99 (bs, 2H), 3.30 (bs, 2H), 3.37 (bs, 2H), 3.49-3.63 (m, 4H), 3.63-3.72 (m, 1H), 3.72-3.82 (m, 4H), 4.62 (d, 1H), 4.92-5.02 (m, 1H), 5.56 (s, 1H), 6.36-6.46 (m, 2H), 6.59 (dd, 1H), 7.01 (dd, 1H), 7.51 (d, 1H), 7.76 (d, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]=[O:16]>>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]1[CH2:15][OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncn(Cc2ccccc2)c1C
Reactant: C=O
Product: Cc1nc(CO)n(Cc2ccccc2)c1C
Temperature: 150 °C

Procedure:
A mixture of 8 g (43 mmol) of 1-benzyl-4,5-dimethylimidazole and 60 ml of 40% aqueous formaldehyde solution was heated in a sealed autoclave at 150° C. for 20 hours. The mixture was evaporated and the semi-solid residue was chromatographed on a column of 300 g of silica gel using a 20% solution of methanol in chloroform for the elution. Evaporation of the eluate yielded 6 g of 1-benzyl-4,5-dimethyl-2-hydroxymethylimidazole of melting point 156°-158° C. After recrystallization from methylcyclohexane, the melting point was 160°-162° C. A portion of the product was treated with a solution of hydrogen chloride in ethanol. Addition of diethyl ether precipitated 1-benzyl-4,5-dimethyl-2-hydroxymethylimidazole hydrochloride of melting point 162°-163° C.