Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[OH:23]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:23][C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[F:15])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Oc1ccc(F)cc1F
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Product: COC(=O)c1cc(Cl)ccc1COc1ccc(F)cc1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 2,4-difluorophenol:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1C=CC=CC=1.C(OC(=O)C)(=[O:24])C.C([O-])(=O)C.[Na+]>[Pd].C1(C)C=CC=CC=1>[C:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:19])[NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])(=[O:24])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2c(=O)[nH]cnc2cc1OC(C)=O
Reaction time: 3 h
Yield: 27 %

Procedure:
A mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (5.0 g, mmol), (prepared as described for the starting material in Example 4), acetic anhydride (200 ml), sodium acetate (12 g), 10% palladium-on-charcoal catalyst (1.5 g) in toluene (100 ml) was stirred under an atmosphere of hydrogen for 3 hours. The mixture was filtered and the filtrate was evaporated. The residue was partitioned between a mixture of ethyl acetate (500 ml), methanol (20 ml) and water (300 ml). The organic phase was separated, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with hexane to give 7-acetoxy-6-methoxy-3,4-dihydroquinazolin-4-one (1.1 g, 27%).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13](OC)=[O:14])[C@H:11]([C:17](O)=[O:18])[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].B(F)(F)F.CCOCC.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:20]([N:10]1[C@H:11]2[CH2:17][O:18][C:13](=[O:14])[C@H:12]2[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@@H]1[C@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
To a solution of (4R,5S)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (mp., 149°-150° C., [α]36525 =+27.4° at c=1 in DMF, 1.84 g) in tetrahydrofuran (15 ml) were added sodium borohydride (226 mg) in small portions at -20° C., and boron trifluoride etherate (1.06 g). The obtained mixture was stirred at the same temperature for 1 hour and at room temperature for 3 hours, poured into ice-water (50 ml), stirred further at room temperature, adjusted to pH 9 with aqueous potassium carbonate and extracted twice with ethyl acetate (50 ml). Organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel column to give (3aS,6aR)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione (0.80 g). M.P., 114°-118° C. [α]D 20 =+59.8° (c=1, CHCl3).
Reaction SMILES: [OH-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]#[C:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14].Cl>C(O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]#[C:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)CCC#Cc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCC#Cc1ccccn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 132.6 %

Procedure:
To a aqueous solution of 1M NaOH (9.9 mL) heated at 50° C., was added slowly a solution of ethyl 5-(pyridin-2-yl)pent-4-ynoate (2 g, 9.90 mmol) in 3 mL of ethanol. The reaction mixture was stirred 1 h 30 at 50° C. and cooled to room temperature. An aqueous 1N HCl (9.9 mL, 9.90 mmol) was then added and the solvent was removed under pressure to afford 2.3 g of 5-(pyridin-2-yl)pent-4-ynoic acid (Yield: 99%) as a brown solid which can be used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:4]3[CH2:22][CH:5]3[C:6](=[O:21])[N:7](CC3C=CC(OC)=CC=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[Br:1][C:2]1[C:3]2[CH:4]3[CH2:22][CH:5]3[C:6](=[O:21])[NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(CN2C(=O)C3CC3c3c(Br)cccc32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: O=C1Nc2cccc(Br)c2C2CC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a suspension of 7-bromo-3-(4-methoxybenzyl)-3,7b-dihydro-1H-cyclopropa[c]quinolin-2(1aH)-one (0.300 g, 0.837 mmol) in 9:1 acetonitrile/water (5.5 mL) was added CAN (0.459 g, 0.837 mmol) at room temperature. After stirring at room temperature overnight, the reaction mixture was quenched with water (10 mL) and adjusted pH to 7-9 by using saturated Na2CO3. The resulting mixture was extracted with EtOAc. The combined organic layer was concentrated and purified by flash chromatography (0 to 50% ethyl acetate:hexanes) to afford the title compound (0.18 g, 95% yield) as a pale yellow solid. LCMS, [M+H]+=237.9. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.24 (d, J=7.7 Hz, 1H), 7.00 (t, J=7.7 Hz, 1H), 6.69 (d, J=7.7 Hz, 1H), 2.84 (td, J=8.1, 5.2 Hz, 1H), 2.22-2.13 (m, 1H), 1.76 (td, J=9.2, 4.7 Hz, 1H), 0.75 (dd, J=10.0, 5.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]#[CH:24]>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]#[C:24][C:2]1[O:6][C:5]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1
Reactant: C#CCOCCCCCCBr
Reactant: CCN(CC)C(=O)c1ccc(Br)o1
Product: CCN(CC)C(=O)c1ccc(C#CCOCCCCCCBr)o1
Reaction time: 4 h
Yield: 95.4 %

Procedure:
5-Bromo-N,N-diethyl-2-furancarboxamide (2.0 g) was treated with 3-[(6-bromohexyl)oxy]-1-propyne (1.87 g) according to the method of Intermediate 9 except that the reaction mixture was stirred under nitrogen at 60° for 4 h, and hexane-ether (5:1 then 2:1 then 1:1) was used as the eluant for FCC. This afforded the title compound as a dark yellow oil (2.98 g), t.l.c. (diethyl ether) Rf 0.35.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH2:17][CH2:18][CH2:19][CH2:20][Si:21]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24].C(N(CC)CC)C>C(OCC)C>[CH2:26]([O:25][Si:21]([O:28][CH2:29][CH3:30])([O:22][CH2:23][CH3:24])[CH2:20][CH2:19][CH2:18][NH:17][C:8](=[O:10])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)[CH3:27]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCO[Si](CCCNC(=O)c1ccc([N+](=O)[O-])cc1)(OCC)OCC
Reaction time: 2 h

Procedure:
p-nitrobenzoic acid (10 g; 60 mmol) was added to 15 g thionylchloride. This mixture was heated during 2 h under reflux. Subsequently the thionylchloride was removed at reduced pressure. To the remainder γ-aminopropyltriethoxysilane (13,3 g; 60 mmol) was added, dissolved in 50 ml diethylether with 10 g triethylamine. After 2 h agitation at room temperature, the mixture was filtered. The filtrate was evaporated at reduced pressure. The remainder was washed in water, filtered, and dried at reduced pressure over KOH. Yield: 9,5 g (43%). Melting point 99° . . . 105° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:23]=1[CH:24]=[O:25].O>C(OCC)C.O1CCCC1>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:23]=1[CH:24]([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)[OH:25]
Reactant: Cc1ccnc(Br)c1
Reactant: COc1cc([N+](=O)[O-])ccc1C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1C(O)c1cc(C)ccn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2-bromo-4-methylpyridine (1.5 ml) was dissolved in diethylether (50 ml), and the mixture was cooled to −78° C. under argon atmosphere. 1.6M n-butyllithium hexane solution (8.3 ml) was added dropwise, and the mixture was stirred for 1 hour. The reaction solution was added dropwise to a solution of 2-methoxy-4-nitrobenzaldehyde (2 g) in tetrahydrofuran (300 ml) under argon atmosphere at −78° C. The mixture was allowed to be at room temperature and stirred overnight, and water was added to the mixture. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give (2-methoxy-4-nitrophenyl)(4-methylpyridin-2-yl)methanol (2.2 g) as pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([S:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[C:7]1[CH3:11])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(CC(=O)O)c1
Product: Cc1c(Sc2cccc(CC(=O)O)c2)c2ccc(Cl)cc2n1Cc1ccccc1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: [3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid and benzyl bromide.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([N:15]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:14])[CH:3]=1.N1C=CC=CC=1.[Cl:58][C:59]1[C:64]([Cl:65])=[CH:63][C:62]([S:66](Cl)(=[O:68])=[O:67])=[CH:61][N:60]=1.S(Cl)(Cl)(=O)=O>O1CCCC1>[Cl:58][C:59]1[C:64]([Cl:65])=[CH:63][C:62]([S:66]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:12])=[C:4]([C:13]([N:15]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:14])[CH:3]=2)(=[O:68])=[O:67])=[CH:61][N:60]=1
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Cl)c1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(N)c2ccccc2c1O
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cc(NS(=O)(=O)c2cnc(Cl)c(Cl)c2)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A solution of 22.5 g (0.0318 mole) 4-amino-1-hydroxy-N,N-dioctadecyl-2-naphthamide and 4.0 g (0.5 mole) pyridine in 300 ml tetrahydrofuran (THF) under nitrogen was stirred at room temperature and a solution of 9.0 g (0.036 mole) 2,3-dichloropyridine-5-sulfonyl chloride in 50 ml THF was added. The mixture was stirred 2 hours at room temperature. A thin-layer Chromogram on silica gel sheets indicated unreacted amine, so an additional 1.0 g of the sulfonyl chloride was added followed by 0.5 ml pyridine and stirring for an additional hour. Since a thin-layer chromatogram indicated no more amine, the mixture was concentrated to a small volume on a rotary evaporator, slurried in water several times with the water layer decanted off each time. The oil was dissolved in ether, water was separated, and the extract was dried with anhydrous Na2SO4. The ether layer was removed to leave a reddish oil which solidified on standing. The oil was extracted several times with boiling acetonitrile to leave a purplish black residue. The extracts were chilled and the precipitate was reextracted; chilling the extracts gave 25.7 g (88 percent) of product as a beige powder with a m.p. 88°-9° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([CH:28]=1)[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>C1(C)C=CC=CC=1>[Cl:13][C:5]1[C:4]([Cl:14])=[C:3]([Cl:15])[C:2]([Cl:1])=[C:7]([C:8]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:28]=2)=[O:9])[C:6]=1[C:11]([OH:10])=[O:12]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: CC(C)OC(=O)c1cc(N)ccc1Cl
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1cc(NC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)ccc1Cl
Reaction time: 8 h
Yield: 70 %

Procedure:
A mixture of tetrachlorophthalic anhydride (2.97 g, 0.010 mole), 1-methylethyl 5-amino-2-chlorobenzoate (2.22 g, 0.010 mole) and toluene (100 ml) was heated slowly to reflux with stirring, then left overnight at room temperature. Filtration of the reaction mixture gave the title compound, m.p. 178°-179° C. (3.45 g, 70% yield).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=[O:17])[C:9]2=[O:12])=[CH:4][CH:3]=1.Cl.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[OH-].[Na+]>CC(C)=O>[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=[O:17])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(O)cc2c1=O
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(OCCN(C)C)cc2c1=O
Reaction time: 0.33 h
Yield: 39.8 %

Procedure:
3-(7-Hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzoic acid (0.47 g), 2-dimethylaminoethyl chloride hydrochloride (0.69 g), potassium carbonate (2.21 g), and sodium iodide (24 mg) were stirred in acetone (25 ml) at 60° C. for 17 hours. 2N NaOH (5 ml) was added, the reaction stirred for 20 minutes and the acetone removed by evaporation. The residue was acidified with concentrated hydrochloric acid and the solution was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 3-[7-[2-(dimethylamino)ethoxy]-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoic acid as an oil (232 mg); Mass Spectrum: M+H+ 367.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[N:24]1C(=O)C(=CC2C=CC=CC=2)S[C:25]1=[S:37])(=O)C.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CO>[C@@H:6]1([NH:24][C:25]([NH:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[S:37])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](N2C(=O)C(=Cc3ccccc3)SC2=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCc1ccccc1
Solvent: CO
Product: OC[C@H]1O[C@@H](NC(=S)NCc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 23 h

Procedure:
N-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-5-benzylidenerhodanine (2.204 g., 0.004 mole) was added to a solution of benzylamine (2.58 g., 0.024 mole) in 50 ml. of methanol in a pressure bottle. The reaction mixture was stirred at room temperature for 23 hours in the pressure bottle with the stopper well closed. The mixture was filtered, and the filtrate was evaporated to a sticky syrup below 30° in vacuo. The residual syrup was dissolved in the minimum ammount of acetone, and anhydrous ether was added to the solution to give a yellow sticky solid. The supernatant was decanted, and the residual sticky solid was dissolved in the minimum amount of acetone. Benzene was added to the solution to give a precipitate. The precipitate was filtered, partially dissolved in ethyl acetate, and then chromatographed on a column of silica gel (1×20 cm) using ethyl acetate as the first solvent and acetone as the second solvent. Fifty ml. of ethyl acetate effluent was collected in the first Erlenmeyer flask and 75 ml. of acetone effluent was collected in the second Erlenmeyer flask. The volume of the acetone effluent was reduced ca. 25 ml. and was set aside at 5° for 16 hours. The white precipitate was filtered, washed with acetone, and dried at room temperature in vacuo, yielding 0.99 g. (64.2%); m.p. 97°-100° (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: N#Cc1c(N)nc2ccccc2c1Cl
Reactant: NCc1ccccc1
Solvent: O
Product: N#Cc1c(N)nc2ccccc2c1NCc1ccccc1
Temperature: 130 °C

Procedure:
5 g of 2-amino-3-cyano-4-chloroquinoline and 11 ml of benzylamine are heated under stirring at 130° C. The reaction mixture is poured onto 50 ml of water, the resulting precipitate is filtered off, washed with 50 ml of water. The pale-yellow precipitate is recrystallized from 25 ml of dimethylformamide to obtain 5.2 g of the title compound. Mp.: 206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:22]=[CH:21][N:20]=[CH:19][C:7]=3[CH2:8][N+:9]([O-])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[C:25]([O:28]C(=O)C)(=[O:27])[CH3:26]>>[C:25]([O:28][CH:8]1[C:7]2[CH:19]=[N:20][CH:21]=[N:22][C:6]=2[C:5]2[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:9]1)(=[O:27])[CH3:26]
Reactant: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2-c2ncncc2C1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1N=C(c2ccccc2F)c2cc(Cl)ccc2-c2ncncc21

Procedure:
A mixture of 2.5 g (7.4 mmoles) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-6-oxide and 50 ml of acetic anhydride was heated on the steambath for 24 hours. The reaction mixture was concentrated at reduced pressure to dryness and the residue was crystallized from a mixture of methylene chloride and ether to give the crude product, m.p. 197°-198° C. Recrystallization from a mixture of methylene chloride and ether gave the pure product as cream colored prisms, m.p. 200°-201° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:16][C:17](=O)[CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=C(CN1CCOCC1)Nc1ccc2ncnc(Nc3ccc(F)c(F)c3)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Fc1ccc(Nc2ncnc3ccc(NCCN4CCOCC4)cc23)cc1F
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-(3',4'-difluoroanilino)-6-(2-morpholinoacetamido)quinazoline was reduced with lithium aluminium hydride to give 4-(3',4'-difluoroanilino)-6-(2-morpholinoethylamino)quinazoline in 58% yield;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH3:30])([N:17]2[CH2:22][CH2:21][CH:20]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10].[CH3:31][O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1>>[CH3:31][O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][N:23]([CH:20]2[CH2:21][CH2:22][N:17]([C:14]3([CH3:30])[CH2:15][CH2:16][N:11]([C:9](=[O:10])[C:3]4[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[CH2:12][CH2:13]3)[CH2:18][CH2:19]2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:36][CH:35]=1
Reactant: Cc1cccc(C)c1C(=O)N1CCC(C)(N2CCC(Nc3ccccc3)CC2)CC1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(CN(c2ccccc2)C2CCN(C3(C)CCN(C(=O)c4c(C)cccc4C)CC3)CC2)cc1

Procedure:
It is prepared from (2,6-dimethyl-phenyl)-(4′-methyl-4-phenylamino-[1,4′]-bipiperidinyl-1′-yl)-methanone and 4-bromomethyl-benzoic acid methyl ester using a procedure as described for Example 52 of PCT/EP02/03871. MS/ESI 554 [M+H]+. (2,6-Dimethyl-phenyl)-(4′-methyl-4-phenylamino-[1,4′]bipiperidinyl-1′-yl)-methanone used as starting material may be prepared using a procedure similar to that described in Example 51a-e of PCT/EP02/03871. MS/ESI 406 [M+H]+
Reaction SMILES: [ClH:1].[C:2](=[NH:12])(OCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27]>O.O1CCOCC1>[ClH:1].[C:26]([C:25]1[CH:24]=[C:23]([NH:22][C:2](=[NH:12])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:31]=[CH:30][CH:29]=1)([OH:28])=[O:27]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N=C(Nc1cccc(C(=O)O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 15.8 %

Procedure:
To ethyl benzimidate hydrochloride (3 g, 0.016 mole)(Fluka) and (2.1 g, 0.016 mole) diisopropylethylamine in H2O (15 ml) and dioxane (15 ml) was added 3-aminobenzoic acid (2.22 g, 0.016 mole) (Aldrich). The reaction mixture was stirred at room temperature for 4 days. The resulting precipitate was filtered, washed with dioxane/H2O and dried. The precipitate was slurried in H2O and acidified with concentrated HCl. The solvent was removed under vacuum and the residue was slurried in ether. The ether was decanted off and the residue dried under vacuum to yield N-(3-carboxyphenyl)benzamidine hydrochloride (700 mg) as a white solid. MS and NMR were consistent with the desired structure.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:20]=CC=C[CH:16]=1.CC(O)C.C(OC(N=NC(OC(C)C)=O)=O)(C)C>C1COCC1>[CH:15]([O:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])([CH3:20])[CH3:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
Methyl 2-hydroxy-5-nitrobenzoate (11.82 g, 60 mmol), triphenylphosphine (17.29 g, 66 mmol) and iPrOH (3.96 g, 5 ml, 66 mmol) were taken up in THF (150 ml) and cooled in ice. Di-isopropyl-azodicarboxylate (8.31 g, 10 ml, 66 mmol) was added carefully, and the reaction was stirred at RT overnight. The volatiles were removed in vacuo and the residue treated with EtOAc (50 ml). The solids that didn't dissolve were removed by filtration, and the filtrate evaporated to dryness in vacuo. The residue was purified by column chromatography to give methyl 2-isopropoxy-5-nitrobenzoate (6.92 g, 48.5%) as a yellow oil.