Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][O:19][C:20]4[CH:24]=[CH:23][O:22][N:21]=4)[O:15][C:14]3=[O:25])=[CH:9][C:8]=2[F:26])[CH2:3]1.Cl.[NH2:28][OH:29].C([O-])(=O)C.[Na+]>ClCCl.CO.O>[N:28](=[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][O:19][C:20]4[CH:24]=[CH:23][O:22][N:21]=4)[O:15][C:14]3=[O:25])=[CH:9][C:8]=2[F:26])[CH2:3]1)[OH:29]
Reactant: NO
Reactant: O=C1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCC(=NO)C2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
3-(4-(3-Oxo-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (124 mg, 0.34 mmol) was dissolved in a mixture of dichloromethane (10 ml) and MeOH (10 ml), and treated with a solution of hydroxylamine hydrochloride (220 mg, 3.17 mmol) and sodium acetate (500 mg) in water (2 ml). After stirring at ambient temperature for 4 hours, solvents were evaporated, and the residue triturated with water (10 ml), solid filtered and dried to give the desired product (118 mg) as a single isomer of unknown geometry. MS (ESP): 377 (MH+) for C17H17FN4O5.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[C@@H:14]([NH2:18])([CH2:16][CH3:17])[CH3:15]>C(O)C>[C@@H:14]([NH:18][C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1)([CH2:16][CH3:17])[CH3:15]
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: CC[C@H](C)N
Solvent: CCO
Product: CC[C@H](C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Yield: 61.6 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (257 mg, 1.0 mmol) and (S)-(+)-sec-butylamine (0.31 ml, 3.0 mmol) was stirred in 10 ml of abs ethanol for 4 days at 80° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was stirred with water (10 ml) followed by adjustment to pH 2 with 4M hydrochloric acid. The initially formed gummy product was crystallized by stirring at 0° C. The precipitate was isolated by filtration, washed with water, and recrystallised from ethyl acetate/methanol followed by drying in vacuo at 30° C. over night to give 181 mg (62%) of the pure title compound; mp 228-230° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ0.88 (t, 3H, CH3), 1.14 (d, 3H, CH3), 1,49 (m, 2H, CH2), 3.68 (m, 1H, CH), 7.08 (s, 1H, H-5), 7.13 (br, 1H, NH), 10.73 (br s, 1H, NH); MS: m/e 293/295 (M+); (C9H12N3Cl1O2S2) calc. C, 36.79; H, 4.12; N, 14.30; found C, 36.9; H, 4.1; N, 14.2.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][C:31]=1[CH3:32])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1)(=O)C.[OH-].[Na+].C(Cl)[Cl:36]>CO>[ClH:36].[OH:4][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][C:31]=1[CH3:32])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccncc1
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(Nc3ccc(C)c(O)c3)ncnc2cc1OCc1ccncc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a solution of 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)quinazoline (93 mg, 0.2 mmol) in a mixture of methanol (6 ml) and methylene chloride (3 ml) was added at ambient temperature a 2M aqueous sodium hydroxide solution (0.3 ml, 0.6 mmol). The mixture was stirred for 10 minutes at ambient temperature, the solvents were partially evaporated, water was added to the residue and the solution was acidified with 0.1M hydrochloric acid to pH6. The precipitate was filtered off, washed with water and dried under vacuum to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)quinazoline hydrochloride (67 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:21]([OH:23])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[F:25][C:26]([F:35])([F:34])[C:27]1[N:31]=[C:30]([CH2:32][NH2:33])[O:29][N:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][C@@H:15]([CH3:20])[C:16]([F:18])([F:17])[F:19])=[CH:12][N:11]=[C:10]([C:21]([NH:33][CH2:32][C:30]3[O:29][N:28]=[C:27]([C:26]([F:35])([F:34])[F:25])[N:31]=3)=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: C[C@H](Oc1cnc(C(=O)O)nc1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: NCc1nc(C(F)(F)F)no1
Agent: Cl
Product: C[C@H](Oc1cnc(C(=O)NCc2nc(C(F)(F)F)no2)nc1-c1ccc(Cl)cc1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1, using (S)-4-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrimidine-2-carboxylic acid (Example AQ) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAN 944905-93-5; example AK) as starting materials. MS: 496.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25]Cl)=[N:23][N:24]=2)[CH:3]=1.[CH2:27]1[C:31]2([CH2:36][NH:35][CH2:34][CH2:33][O:32]2)[CH2:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[I-].[Na+]>C(#N)C.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:35]3[CH2:36][C:31]4([CH2:27][CH2:28][CH2:29][CH2:30]4)[O:32][CH2:33][CH2:34]3)=[N:23][N:24]=2)[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(Br)cc21
Reactant: C1CCC2(C1)CNCCO2
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CN4CCOC5(CCCC5)C4)o3)cc(Br)cc21
Temperature: 70 °C
Yield: 30 %

Procedure:
6-Bromo-4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-(phenylsulfonyl)-1H-indazole (200 mg, 0.441 mmol) in acetonitrile (2 ml) was treated with 6-oxa-9-azaspiro[4.5]decane (160 mg, 0.793 mmol), DIPEA (0.154 ml, 0.8825 mmol) and sodium iodide (66 mg, 0.44 mmol). The reaction mixture was heated at 70° C. for 5 h, then cooled, diluted with DCM and washed with aqueous HCl. The organic layer was separated using a hydrophobic frit, washed with water and the solvent removed under a stream of nitrogen. The resulting residue was purified by loading onto a silica cartridge (20 g) and eluting with 0-100% ethyl acetate/cyclohexane over 40 mins. The appropriate fractions were combined and evaporated to give the title compound as a yellow solid (74 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([F:17])=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[N:8]=2)[CH2:3]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(OCC)C>C(Cl)(Cl)Cl>[C:27]([NH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([F:17])=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[N:8]=2)[CH2:3]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(F)c(N2CCC(N)C2)nc1Nc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Nc1ccc(F)cc1F
Yield: 99.4 %

Procedure:
In 6.5 ml of chloroform was dissolved 650 mg of methyl 6-(3-amino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate, and 190 mg of acetic anhydride was added to the resulting solution, after which the resulting mixture was subjected to reaction at room temperature for 10 minutes. The solvent was then removed by distillation under reduced pressure. To the crystalline material thus obtained was added 2 ml of diethyl ether, after which crystals were collected by filtration to obtain 720 mg (yield 99.4%) of methyl 6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate having a melting point of 199°-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][CH2:28][NH:29]3)=[CH:25][CH:24]=2)=[O:22])=[CH:16][C:15]=1[C:32]([F:35])([F:34])[F:33])#[N:13].N1C=CC=CC=1>ClCCl>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:31]=[C:30]3[C:26]([CH2:27][CH2:28][N:29]3[S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:9])=[CH:25][CH:24]=2)=[O:22])=[CH:16][C:15]=1[C:32]([F:35])([F:33])[F:34])#[N:13]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: N#Cc1ccc(NC(=O)c2ccc3c(c2)NCC3)cc1C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CC3)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
3-Chloro-benzenesulphonyl chloride (55 mg, 0.26 mmol, 1.1 equiv.) was added to a mixture of crude 2,3-dihydro-1H-indole-6-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (70 mg, 0.24 mmol, 1 equiv.) in dichloromethane (2 ml) and pyridine (0.15 mL, 1.9 mmol, 8 equiv.) and the mixture stirred at room temperature for 16 hours. The solvent was removed under a stream of N2 and the residue purified by column chromatography (SiO2, dichloromethane). Fractions were combined to afford 1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide, 81 mg (67% yield). LC @215 nm; Rt 1.74: 94%, m/z (ES+): 547 (M+H+.), δH (400 MHz; d6-DMSO) 11.04 (1H, s), 8.55 (1H, s), 8.36 (1H, d), 8.12-8.26 (5H, m), 7.92 (1H, t), 7.79 (1H, d), 7.45 (1H, d), 4.15 (2H, t), 3.07 (2H, t).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH2:19]C[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[H-].[Na+].CI>C1C=CC=CC=1>[C:1]1([C:7]2[NH:8][C:9]3[CH2:19][C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc3c([nH]2)CCc2ccccc2-3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CI
Solvent: CN(C)C=O
Product: c1ccc(-c2nc3c([nH]2)Cc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-phenyl-4,5-dihydro-naphtho[1,2-d]imidazole (2.46 g.) dissolved in 10 ml. of dimethylforamide, 0.5 g. of 55% NaH (mineral oil dispersion) and 1.41 g. of methyl iodide are added. After stirring for two hours at room temperature, and for one hour at 60° C., the mixture is poured into ice water. The resulting solid precipitate is dissolved in benzene and chromatographed through a silica gel column and eluted with benzene containing 10% of ethyl ether for separating the two methylated isomers. The first eluted isomer (1.66 g.) melts at 150° C. (from ethanol) while the second (0.79 g.) melts at 141°-3° C. By operating according to the procedure described in Example 1, utilizing as the starting material 2-bromo-1-indanone, 2-phenyl-1,8-dihydro-indeno[1,2-d]imidazole (m.p. 231-2) is obtained which is in turn methylated according to the procedure described above to give 1-methyl-2-phenyl-8H-indeno[1,2-d]-imidazole, 3-methyl-2-phenyl-8-indeno[1,2-d]imidazole.
Reaction SMILES: Cl.[N:2]1[N:3]=[CH:4][N:5]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=12.C[CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15].[CH3:18]C(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[N:13]1([CH2:12][C:4]2[N:5]3[CH2:10][CH2:9][NH:8][CH2:7][C:6]3=[N:2][N:3]=2)[CH2:16][CH2:17][CH2:18][CH2:15][CH2:14]1
Reactant: c1nnc2n1CCNC2
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: C1CCN(Cc2nnc3n2CCNC3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (1.0 g, 6.23 mmol) in CH2Cl2 (25 mL) were added Et3N (2.17 mL, 15.57 mmol) and Boc2O (1.52 mL, 6.54 mmol) and the reaction was stirred at room temperature overnight. The mixture was extracted with aqueous 0.25 M KHSO4 (50 mL). The organic layer was dried (Na2SO4) and evaporated to dryness to afford compound A48-1 (1.29 g, 92%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([N+:17]([O-])=O)=[CH:10][CH:9]=3)[CH2:6]1)(=[O:4])=[O:3].[H][H]>CCO.C(Cl)Cl.[Pd]>[CH3:1][S:2]([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([NH2:17])=[CH:10][CH:9]=3)[CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CC2CC(C1)c1cc([N+](=O)[O-])ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CS(=O)(=O)N1CC2CC(C1)c1cc(N)ccc12
Yield: 103.7 %

Procedure:
10-methanesulfonyl-4-nitro-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (170 mg, 0.60 mmol) in 8 ml EtOH and 2 ml methylene chloride in a Parr bottle was treated with 50 mg 10% Pd/C and subjected to hydrogen (g) at 40 psi for 2 h. The suspension was filtered and the solvent removed under reduced pressure to yield 10-methanesulfonyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (157 mg, 99%). 1H-NMR (CDCl3) δ 7.03, (d, J=7.8 Hz, 1H), 6.64 (s, 1H), 6.52 (dd, J=7.8, 2.3 Hz, 1H), 3.77-3.68 (m, 1H), 3.67-3.54 (m, 3H), 3.36 (dd, J=12.6, 6.8 Hz, 2H), 3.13-3.05 (m, 2H), 2.38-2.28 (m, 1H), 2.03 (s, 3H), 1.78 (d, J=10.9 Hz, 1H), 1.24 (t, J=7.0 Hz, 3H); LC/MS (ESI+): 253 (M+H).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12](=[O:33])[C@@H:13]([C@H:23](O)[C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:10][O:11][C:12](=[O:33])[C@@H:13]([C@@H:23]([F:7])[C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CCCc1ccccc1)[C@@H](F)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
(Diethylamino) sulfur trifluoride (2.0 ml, 15.2 mmol) was added to a ice cold solution of (R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid methyl ester (4a) (0.85 g, 2.5 mmol) in dry methylene chloride (15 ml) and the reaction mixture was stirred overnight while warming to room temperature. The reaction was quenched with aqueous NaHCO3 solution and extracted with methylene chloride. The organic extracts were dried over Na2SO4 and concentrated under reduced pressure. Column chromatography on silica eluting with a mixture of ethyl acetate and methylene chloride gave the title compound as an off-white solid (230 mg). 1H NMR (CDCl3) δ 1.90–1.58 (m, 4H), 2.78–2.57 (m, 2H), 3.28–3.10 (m, 1H), 3.75 (s, 3H), 3.74–3.45 (m, 8H), 5.40–5.12 (m, 1H), 7.35–7.18 (m, 5H); MS: 338(MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[CH2:16][CH2:17][OH:18].O1CCCC1.C(O)(C)(C)C.[K]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1([C:7]2[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=2)[O:18][CH2:17][CH2:16][O:14]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(Br)cc1
Reactant: OCCCl
Agent: [K]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: CCOC(=O)C1(c2ccc(Br)cc2)OCCO1
Temperature: -60 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
To a solution of ethyl-4-bromobenzoylformate (940 mg) and 2-chloroethanol (0.360 mL) in a 2:1 mixture of dimethylformamide:tetrahydrofuran (2.1 mL) was added dropwise at −60° C. a solution of potassium tert-butanol (0.597 mg) in dimethylformamide (2 mL). The reaction mixture was stirred at −60° C. for 4 h then allowed to warm up to room temperature and stirred at room temperature overnight. The reaction mixture was partitioned between an aqueous solution of ammonium chloride and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layer were washed with brine. The crude mixture was concentrated to dryness and purified by chromatography on silica gel to yield the title compound as a colorless liquid (616 mg; 58%). MS (ESI): m/z=300.8 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH2:7](O)[C:8]([CH3:11])([CH3:10])[CH3:9].[C:13]1(C)C=CC=CC=1>S(=O)(=O)(O)O.O>[C:1]([C:3](=[CH2:13])[C:4]([O:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5])#[N:2]
Reactant: N#CCC(=O)O
Reactant: Cc1ccccc1
Reactant: CC(C)(C)CO
Agent: O=S(=O)(O)O
Solvent: O
Product: C=C(C#N)C(=O)OCC(C)(C)C
Temperature: 25 °C
Yield: 86.8 %

Procedure:
51 g (0.6 mole) of cyanoacetic acid, 74 g (0.84 mole) of neopentyl alcohol, 1 g of sulfuric acid and 100 g of toluene were reacted under reflux and water produced was removed by azeotropic distillation. Thereafter, the mixture thus produced was cooled to a room temperature and filtered to remove insoluble matter. The filtrate was washed with water and dried overnight with magensium sulfate. Then, the desiccant was filtered off and the solvent was removed under a reduced pressure, followed by vacuum distillation to afford 87.1 g of neopentyl α-cyanoacrylate (b.p. 79°-81° C./3 mmHg, yield 94%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH2:20]Br)=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(O)C>[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:20][C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[O:19])[CH:8]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Cn2cc(Cl)cnc2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5-chloropyrimidin-2-one hydrochloride (502 mg), α-bromo-4-methoxyacetophenone (687 mg), triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 2 hours, during which the suspension formed a solution from which a solid crystallised out. The solid was crystallised from acetone to give the title pyrimidinone: yield. 449 mg; m.p. 212°-214° C.: λmaxEtOH 222.5 nm (ε 19850), 277 nm (ε 18000), 330 nm (ε 3725).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[C:11]4[CH:17]=[CH:18][CH:19]=[CH:20][C:10]4=[CH:9][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([OH:21])[CH:3]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>CC(C)=O>[O:26]1[CH2:25][CH:24]1[CH2:22][O:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[CH:12]=[C:11]4[CH:17]=[CH:18][CH:19]=[CH:20][C:10]4=[CH:9][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([O:21][CH2:22][CH:24]2[CH2:25][O:26]2)[CH:3]=1
Reactant: O=c1c2cc3ccccc3cc2oc2cc(O)cc(O)c12
Reactant: ClCC1CO1
Solvent: CC(C)=O
Product: O=c1c2cc3ccccc3cc2oc2cc(OCC3CO3)cc(OCC3CO3)c12
Temperature: 57.5 °C
Yield: 7.3 %

Procedure:
1,3-dihydroxy-12H-benzo[b]xanthen-12-one (0.15 g, 0.54 mmol) synthesized in Step 1 of Example 18, CS2CO3 (0.53 g, 1.62 mmol), and anhydrous acetone (30 mL) were charged to a dry round-bottom flask, and epichlorohydrin (0.25 g, 2.7 mmol) was added thereto with stirring using a syringe. The reaction mixture was stirred with reflux under a nitrogen atmosphere (55 to 60° C., overnight). Solid of the reaction mixture was filtered and removed, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:3 (v/v)) to give the title compound (15.3 mg, 21.8%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH3:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[OH-].[K+].[CH2:15](Br)[CH3:16]>CS(C)=O>[CH2:15]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)[C:2]([CH3:1])=[CH:3]1)[CH3:16]
Reactant: COc1ccc2c(C)c[nH]c2c1
Reactant: CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCn1cc(C)c2ccc(OC)cc21
Yield: 72.2 %

Procedure:
3.12 g of 4.4'-bis-dimethylaminobenzophenone-2-carboxylic acid and 1.9 g of 1-ethyl-3-methyl-6-methoxyindol are stirred at 40° C. in 30 ml of acetic anhydride for 3 hours. The reaction mixture is poured onto ice, the resulting mixture is basified with NaOH and extracted with toluene. The organic phase is separated off, and treated with active carbon, dried and evaporated. The residue is decrystallized once from diethyl ether and once from toluene to give 3.35 g of 3-(4-dimethylaminophenyl)-3-(1-ethyl-3-methyl-6-methoxyindol-2-yl)-6-dimethylaminophthalide of the formula ##STR113## melting point 224°-225° C. On acid clay this compound produces a blue colour. The 1-ethyl-3-methyl-6-methoxyindol used is prepared as follows: 4.6 g of 3-methyl-6-methoxyindole [Chem ber 98, 1727 (1965)]are presented in 29 ml of dimethyl sulfoxide. 6.6 ml of 10 n aqueous KOH are then added, and 3.25 g of ethyl bromide are added dropwise at 20° C. in the course of 30'. 1 hour later the reaction mixture is poured onto water and extracted with toluene. Chromatography over silica gel (hexane/ether 5:1) gives 3.9 g of 1-ethyl-3-methyl-6-methoxyindol in the form of an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[F:16][C:17]([F:26])([F:27])[C:18]1[CH:19]=[CH:20][C:21]([C:22](=[NH:23])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:24][CH:25]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(NC(=N)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (10 mmol) in toluene (100 mL), trimethylaluminum (2M solution in toluene, 15 mmol) is added over 15 minutes. The reaction mixture is warmed to room temperature and stirred for 2.5 hours. A solution of 4-trifluoromethylbenzonitrile (20 mmol) in toluene (50 mL) is added over 10 minutes and the reaction mixture is heated to 80-85° C. After 20 hours, the reaction mixture is cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue is washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates are concentrated in vacuo and the resulting yellowish solid is stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate is filtered and washed with more of hexane/ether (2/1). The pale yellow solid 4-(trifluoromethyl)-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide is used in the next reaction without further purification.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[BH3-]C#N.[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([CH2:18][C:19]([N:21]2[CH:30]3[CH:25]([CH2:26][CH2:27][CH2:28][CH:29]3[N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:24][CH2:23][CH2:22]2)=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17].C([O-])([O-])=O.[Na+].[Na+]>CO.C(O)(=O)C>[CH2:1]([N:24]1[CH:25]2[CH:30]([CH:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:28][CH2:27][CH2:26]2)[N:21]([C:19](=[O:20])[CH2:18][C:13]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=2)[CH2:22][CH2:23]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC=O
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCN1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Butyraldehyde (93 mg, 1.3 mmol) was dissolved in 5 ml of MeOH and NaBH3CN (82 mg, 1.3 mmol) was added. The pH was adjusted to 5 with concentrated acetic acid. 2-(3,4-Dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (101 mg, 0.25 mmol), dissolved in MeOH (15 ml), was then added to the mixture and the mixture was stirred at room temperature overnight. After addition of saturated Na2CO3 solution (15 ml), the mixture was stirred at room temperature for 15 minutes. The precipitate formed was filtered off. The aqueous phase of the filtrate was extracted three times with CH2Cl2 and the combined organic phases were dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9.5:0.5:0.1, l=15 cm, V=5 ml). A colorless resin was isolated.