Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C@@H:36](O)[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C@H:36]([O:28][C:21]1[CH:20]=[C:19]([N:18]2[C:12]3[CH:11]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[N:15]=[CH:14][C:13]=3[N:16]=[CH:17]2)[S:23][C:22]=1[C:24]([O:26][CH3:27])=[O:25])[CH3:37]
Reactant: C[C@H](O)c1ccccc1Br
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@H](C)c1ccccc1Br

Procedure:
In a similar manner as described for example B31, 1.68 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 960 mg of (1S)-1-(2-bromophenyl)ethanol, 2.67 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 1.842 g of di-tert-butyl azodicarboxylate in 50 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]#[CH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:20](=[N:22][OH:23])[CH3:21].Cl[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:9][CH2:10][C:11]1[O:23][N:22]=[C:20]([CH3:21])[CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=NO
Reactant: C#CCOC(=O)c1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(COC(=O)c2ccccc2)on1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A solution of prop-2-yn-1-yl benzoate (26.0 g, 162 mmol) in chloroform (598 mL) was treated with triethylamine (11.3 mL, 81.2 mmol) and acetaldoxime (14.4 g, 244 mmol). The reaction mixture was cooled to 0° C., treated with sodium hypochlorite (551 mL, 487 mmol) (commercial grade ˜5% aqueous), and stirred overnight at room temperature. The layers were separated and the aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (100% hexanes to 30% ethyl acetate/hexanes) gave the desired product (20.1 g, 57%). LCMS calculated for C12H12NO3 (M+H)+: m/z=218.1. found: 218.1.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:3]([OH:5])=[O:4])=[CH:7][CH:8]=1
Reactant: C1CCNCC1
Reactant: O=C(O)C(Br)c1ccc(Cl)cc1
Solvent: CC#N
Product: O=C(O)C(c1ccc(Cl)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.4 %

Procedure:
2-Bromo-2-(4-chlorophenyl)acetic acid (300 mg, 1.20 mmol), piperidine (125 μl, 1.26 mmol) and TEA (503 μl, 3.61 mmol) were dissolved in acetonitrile (6 ml). The resulting reaction was stirred at room temperature for 48 hours. Acetonitrile was evaporated, the residue was triturated with acetonitrile/petroleum ether (9/1) and filtered by suction filtration to collect 2-(4-chlorophenyl)-2-(piperidin-1-yl)acetic acid (190 mg, 62.3% yield) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([C:27]1[S:31][C:30]([S:32][CH3:33])=[N:29][CH:28]=1)=[C:7]2[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][C:40](Cl)=[O:41].C(N(CC)CC)C>O1CCCC1>[CH:14]([O:13][C:11]([C:7]1[N:8]2[CH:3]([S:4][CH2:5][C:6]=1[C:27]1[S:31][C:30]([S:32][CH3:33])=[N:29][CH:28]=1)[CH:2]([NH:1][C:40](=[O:41])[CH2:39][C:35]1[S:34][CH:38]=[CH:37][CH:36]=1)[C:9]2=[O:10])=[O:12])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CSc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)s1
Reactant: O=C(Cl)Cc1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4cccs4)C3SC2)s1

Procedure:
Crude 7-amino-2-benzhydryloxycarbonyl-3-(2-methylthiothiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (3.3 g) is dissolved in tetrahydrofuran (30 cc) and is then acylated with (thien-2-yl)-acetyl chloride (0.83 cc) in the presence of triethylamine (0.94 cc) in accordance with the working method described in Example 1. The crude product obtained is chromatographed on a column (height: 30 cm; diameter: 4 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 1 bar (100 kPa), with a 70:30 (by volume) mixture of cyclohexane and ethyl acetate, and 50 cc fractions being collected. Fractions 16 to 27, containing the pure product, are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C., and the residue is triturated with isopropyl ether (30 cc). 2-Benzhydryloxycarbonyl-3-(2-methylthio-thiazol-5-yl)-8-oxo-7-(thien-2-yl-acetamido)-5-thia- 1-azabicyclo[4.2.0]oct-2-ene (1.6 g) is obtained in the form of a yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][C:12](O)=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:15][C:16]1[C:17](=[O:36])[N:18]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:19](=[O:27])[N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[C:21]=1[NH2:22].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:23]([N:20]1[C:21]2[N:22]=[C:12]([CH2:11][C:8]3[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:10][CH:9]=3)[NH:15][C:16]=2[C:17](=[O:36])[N:18]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:19]1=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCn1c(N)c(N)c(=O)n(Cc2ccccc2F)c1=O
Reactant: CC(=O)Nc1ccc(CC(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(C)=O)nc3)nc21

Procedure:
This compound was prepared by the method similar to that described in example 11 (method 1) except that the hydrochloride salt of (6-acetylamino-pyridin-3-yl)-acetic acid was used in place of N-acetyl-4-aminophenylacetic acid and the coupling to 5,6-diamino-1-butyl-3-(2-fluorobenzyl)-1H-pyrimidine-2,4-dione was performed with O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate and diisopropylethyl amine in N,N-dimethylformamide. MS, m/z(M+)=464.1971.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:16]([C:21]1[CH:22]=[C:23](OS(C(F)(F)F)(=O)=O)[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:26]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:45][C:46]([F:57])([F:56])[C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:15])[CH:16]([C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:24]=[C:23]([C:50]2[CH:51]=[CH:52][C:47]([C:46]([F:57])([F:56])[F:45])=[CH:48][CH:49]=2)[CH:22]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 95 °C
Yield: 79.8 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 5-[1-(4-benzyl-2-oxo-oxazolidine-3-carbonyl)-3-methyl-butyl]-4′-trifluoromethyl-biphenyl-3-yl ester (4.03 g, 6.27 mmol), 4-(trifluoromethyl)phenylboronic acid (1.34 g, 7.05 mmol), 1,2-dimethoxyethane (24 mL) and aqueous Na2CO3 (2 M, 3.2 mL, 6.4 mmol) was stirred while purging N2 at room temperature for 10 min. To this system was added Pd(Ph3)4 (1.45 g, 1.25 mmol) and heated to reflux (95° C.) for 1 h. The red-brown mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 solution (3×50 mL) and brine (2×50 mL). The organic fraction was dried (Na2SO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 4-benzyl-3-[2-(4,4″-bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-5′-yl)-4-methyl-pentanoyl]-oxazolidin-2-one (3.2 g, 79%).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3]1.[C:15]([NH:17][C:18]([NH2:20])=[NH:19])#[N:16].NC1N=C(N)C2C[C@@H](C3C=CC=CC=3)[C@H](C)CC=2N=1>C(O)C>[NH2:16][C:15]1[C:3]2[CH:2]([CH3:1])[CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][CH2:5][C:4]=2[N:19]=[C:18]([NH2:20])[N:17]=1
Reactant: CC1CC(=O)CCC1c1ccccc1
Reactant: N#CNC(=N)N
Agent: C[C@@H]1Cc2nc(N)nc(N)c2C[C@H]1c1ccccc1
Solvent: CCO
Product: CC1c2c(N)nc(N)nc2CCC1c1ccccc1
Yield: 13.8 %

Procedure:
The mixture of these isomers was prepared in a manner analogous to that of Example 1, using 7.0 grams (0.037 mole) of 3-methyl-4-phenylcyclohexanone and 3.4 grams (0.040 mole) of cyanoguanidine in ethoxyethoxy)ethanoethoxyethoxy)ethanol, yielding 1.3 grams of diamino-5-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline and cis/trans-2,4-diamino-7-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline. The NMR spectrum was consistent with the proposed structures. The cis/trans -2,4-diamino-5-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline is separated from cis/trans-2,4-diamino-7-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline by reverse phase high pressure liquid chromatography. The cis and trans geometric isomers of 2,4-diamino-5-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline and the cis and trans geometric isomers of 2,4-diamino-7-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline are also separated by reverse phase high pressure liquid chromatography.
Reaction SMILES: [H-].[Na+].[CH2:3]1COCC1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]3[C:30](=[O:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=[N:26]3)[CH2:19][CH2:18]2)=[CH:9]1.IC>O>[CH3:3][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]3[C:30](=[O:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[N:27]=[N:26]3)[CH2:19][CH2:18]2)=[CH:9]1
Reactant: O=c1c2ccccc2nnn1CCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1cc(C2CCN(CCn3nnc4ccccc4c3=O)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
A dried flask under nitrogen was loaded with sodium hydride (0.015 g, 0.37 mmol) and THF (10 mL). At 0° C. 3-{2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl}-1,2,3-benzotriazin-4(3H)-one (0.07 g, 0.19 mmol), was added and the mixture stirred for 15 minutes. Keeping the reaction temperature at 0° C., the iodomethane was added dropwise (0.01 mL, 0.19 mmol). This was allowed to warm to room temperature and stir overnight. Water was slowly added to the mixture to quench and the organics were extracted in chloroform, washed with water and dried over Na2SO4, filtered and concentrated. The residue was chromatograhed using silica and a 2% methanol:chloroform system. 0.03 g of 3-{2-[4-(1-methyl-1H-indol-3-yl)-1-piperidinyl]ethyl}-1,2,3-benzotriazin-4(3H)-one was isolated as an orange solid. Yield 41%; MS: 388.3 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 1.80 (q, 2H), 2.03 (d, 2H), 2.31 (t, 2H), 2.81 (m, 1H), 2.96 (t, 2H), 3.16 (d, 2H), 3.73 (s, 3H), 4.68 (t, J=5.19 Hz, 2H), 6.79 (s, 1H), 7.06 (t, 1H), 7.20 (t, 1H), 7.28 (m, 1H), 7.60 (d, 1H), 7.81 (t, 1H), 7.95 (t, 1H), 8.16 (d, 1H), 8.37 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.[NH2:18][CH:19]([C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([OH:27])[CH:26]=1)[CH3:20].C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:18][CH:19]([C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([OH:27])[CH:26]=1)[CH3:20]
Reactant: COc1ccc(C(C)N)cc1O
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(C)N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Yield: 73 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.10 g, 0.35 mmol) and 5-(1-amino-ethyl)-2-methoxyphenol hydrochloride (excess) were coupled in N,N-dimethylformamide (2 mL) with triethylamine (0.15 mL). The solid material is collected by Buchner filtration, washed with diethyl ether and acetonitrile, and then dried under house vacuum to give (4Z)-6-bromo-4-({[1-(3-hydroxy-4-methoxyphenyl)ethyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione as a light tan powder (0.11 g, 73%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[S:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH:26]O>C(O)(=O)C>[ClH:2].[Cl:2][C:3]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[S:5](=[O:26])[C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)CCN1C(=O)C(Cl)=C(c2ccccc2)Sc2ccccc21
Reactant: OO
Agent: Cl
Solvent: CC(=O)O
Product: CN(C)CCN1C(=O)C(Cl)=C(c2ccccc2)S(=O)c2ccccc21
Reaction time: 16 h

Procedure:
3-Chloro-5-[2-(dimethylamino)ethyl]-2-phenyl-1,5-benzothiazepin-4(5H)-one, hydrochloride (prepared as described in Example 1) is treated with one equivalent of hydrogen peroxide in dilute acetic acid, and allowed to stand for about 16 hours. Solvent removal yields the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](=[O:21])[NH:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.N1C=CC=CC=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>ClCCl>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([O:21][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCC[C@@H]3C)nc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)nc2c1
Temperature: 0 °C

Procedure:
To a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.70 mmol) in dichloromethane (30 mL) was added pyridine (220 mg, 2.78 mmol) and then Tf2O (393 mg, 1.39 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature and then quenched by the addition of ice-water (20 mL), extracted with dichloromethane (3×20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (300 mg, crude).
Reaction SMILES: COC1C=C(C=C(OC)C=1OC)C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:45]=[C:46]=[O:47])[CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42].[NH2:48][C:49]1[CH:50]=[N:51][C:52]2[C:57]([C:58]=1[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=1[Cl:65])=[CH:56][C:55]([CH3:66])=[CH:54][C:53]=2[CH3:67]>O1CCOCC1.C(N(CC)CC)C>[Cl:65][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=1[C:58]1[C:57]2[C:52](=[C:53]([CH3:67])[CH:54]=[C:55]([CH3:66])[CH:56]=2)[N:51]=[CH:50][C:49]=1[NH:48][C:46]([NH:45][C:37]1[CH:36]=[C:35]([O:34][CH3:33])[C:40]([O:41][CH3:42])=[C:39]([O:43][CH3:44])[CH:38]=1)=[O:47]
Reactant: Cc1cc(C)c2ncc(N)c(-c3ccccc3Cl)c2c1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Agent: COc1cc(C(=O)O)cc(OC)c1OC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)Nc2cnc3c(C)cc(C)cc3c2-c2ccccc2Cl)cc(OC)c1OC
Reaction time: 0.67 h

Procedure:
Triethylamine (0.37 ml) was added dropwise to a mixture of 3,4,5-trimethoxybenzoic acid (563 mg), diphenylphosphoryl azide (730 mg) and dioxane (10 ml) under stirring. The mixture was further stirred for 30 mins. at room temperature and then for 40 mins. under reflux to prepare a solution of 3,4,5-trimethoxyphenyl isocyanate. After cooling, to the resultant solution was added 3-amino-4-(2-chlorophenyl)-6,8-dimethylquinoline (500 mg), and the whole was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by a column chromatography on silica gel and recrystallized from dichloromethane to give 4-(2-chlorophenyl)-6,8-dimethyl-3-[3-(3,4,5-trimethoxyphenyl)ureido]-quinoline as colorless needles. Yield 490 mg (56.3%). m.p. 204°-206° C.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:31][CH:30]([CH3:32])[CH2:29][C@H:25]([NH:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([N:11]2[CH2:10][CH2:9][CH:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)=[CH:20][CH:19]=1)(=[O:23])=[O:22])[C:26]([OH:28])=[O:27]
Reactant: CC(C)C[C@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Product: CC(C)C[C@H](NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1)C(=O)O

Procedure:
In a manner similar to Example 3(b), 4-phenyl-piperidin hydrochloride was condensed with (S)-2-(4-fluoro-benzenesulfonylamino)-4-methyl-pentanoic acid to give the title compound, % C,H,N found: 63.96, 6.96, 6.44.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1)[CH2:6][C:7](OCC)=[O:8])([O-])=O.[H][H]>C(O)C.[Ni]>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=[C:12]1[CH:5]1[CH2:4][NH:1][C:7](=[O:8])[CH2:6]1
Reactant: CCOC(=O)CC(C[N+](=O)[O-])c1cc2ccccc2o1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: O=C1CC(c2cc3ccccc3o2)CN1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
Ester (IV) (81.5 g; 0.297 mole) obtained in b) is dissolved in 500 ml ethanol and hydrogenated at ordinary pressure at 55° C., in the presence of 10 g Raney Nickel. The hydrogen required for the reaction (14.8 l) is taken up within 7 hours. After filtration of the catalyst and evaporation of the ethanol, the oily residue is heated at 100° C. under the vacuum of a water pump, for 2 hours. On trituration with isopropyl ether, the product crystallizes. M.P. (inst.)=142° C. Weight: 47.9 g (80%).
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([NH:22][CH2:23][CH3:24])[N:15]=1.Cl>O.C(O)C>[CH2:7]([O:6][C:4]([C:3]1[C:2](=[O:10])[N:22]([CH2:23][CH3:24])[C:16]2[C:17]([C:18]=1[NH2:19])=[CH:20][CH:21]=[C:14]([Cl:13])[N:15]=2)=[O:5])[CH3:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCNc1nc(Cl)ccc1C#N
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(N)c2ccc(Cl)nc2n(CC)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2.07 g. (0.09 g. atom) of sodium in 75 ml. of ethanol is added 14.4 g. (0.09 mole) of diethyl malonate. The solution is stirred at room temperature for 5 minutes and then 5.4 g. (0.03 mole) of 6-chloro-2-ethylaminonicotinonitrile is added. The mixture is heated under reflux for about 6 hours. The mixture is cooled and diluted with 75 ml. of water and acidified with conc. hydrochloric acid. The precipitate which forms is collected and air dried to give the title compound.
Reaction SMILES: F[C:2]1[C:3]([CH3:23])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH:18]([CH3:21])[CH2:17][NH:16][C:15](=[O:22])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:24][NH2:25]>CS(C)=O.O>[CH3:21][CH:18]1[CH2:17][NH:16][C:15](=[O:22])[C:14]2[CH:13]=[C:12]([C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[N:11]=[C:2]([NH:25][CH3:24])[C:3]([CH3:23])=[N:4]4)[NH:20][C:19]1=2
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)C(C)CNC4=O)c2nc1F
Reactant: CN
Solvent: O
Solvent: CS(C)=O
Product: CNc1nc2c(-c3cc4c([nH]3)C(C)CNC4=O)cccc2nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
A solution of rac-2-(3-fluoro-2-methylquinoxalin-5-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 156; 32.7 mg, 0.105 mmol) and methylamine (2.0M in THF; 0.158 mL, 0.316 mmol) in DMSO (0.8 mL) was stirred under argon in a sealed flask at 25° C. for 10 min, then at 60° C. for 1 h. The reaction was cooled to 25° C. and diluted with water (10 mL). The precipitated solid was collected by vacuum filtration, washed with water (2×5 mL), and dried in vacuo to provide rac-7-methyl-2-(2-methyl-3-(methylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (21.0 mg, 0.065 mmol, 62% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.24 (1H, br. s.), 7.93 (1H, d, J=7.4 Hz), 7.57 (1H, d, J=7.8 Hz), 7.45 (1H, d, J=4.3 Hz), 7.32 (1H, t, J=7.8 Hz), 7.04 (1H, s), 6.99 (1H, br. s.), 3.43 (1H, dt, J=11.0, 4.0 Hz), 3.09-3.21 (2H, m), 3.07 (3H, s), 2.52 (3H, s), 1.30 (3H, d, J=6.5 Hz). m/z (ESI, +ve) 322.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1)[NH2:30].CC1C=CC(C)=CC=1>C(Cl)Cl>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:30][C:2]2[C:3]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)(=[O:15])=[O:14])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1
Reactant: COc1cc(N)cc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Solvent: Cc1ccc(C)cc1
Solvent: ClCCl
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc([N+](=O)[O-])c1
Temperature: 140 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide (700 mg, 1.92 mmol), 3-methoxy-5-nitroaniline (645 mg, 3.84 mmol) and p-xylene (7 mL) were combined and heated to 140° C., then stirred for 16 hours at 130° C. The reaction was allowed to cool, placed in a sep. funnel, diluted with DCM, and washed with 2M HCl and brine and concentrated in vacuo. The resulting solid was washed with Et2O to give N-(3-(3-methoxy-5-nitro-phenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide (400 mg, 42%). MS (EI) m/z for C21H16N6O7S: 496.94 (MH+).
Reaction SMILES: O=[C:2]([CH2:16][CH2:17][C:18]([O-:20])=[O:19])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4].[CH2:21]([O:28][C:29]([NH:31][C@@H:32]1[CH2:36][O:35][NH:34][C:33]1=[O:37])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>ClCCl>[CH2:21]([O:28][C:29]([NH:31][C@@H:32]1[CH2:36][O:35][N:34]([C:2]2([C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=3)=[O:4])[CH2:16][CH2:17][C:18](=[O:19])[O:20]2)[C:33]1=[O:37])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C([O-])CCC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(N[C@@H]1CONC1=O)OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(C(=O)OCc2ccc([N+](=O)[O-])cc2)(N2OC[C@@H](NC(=O)OCc3ccccc3)C2=O)O1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 24.4 %

Procedure:
In 2 ml of dichloromethane were dissolved 85 mg of Compound (1) and 60 mg of (4R)-4-benzyloxycarbonylamino-3-isoxazolidinone. To the solution were added 77 mg of 2-chloro-1-methylpyridinium iodide and 84 μ1 of triethylamine. The mixture was stirred at room temperature for 40 minutes, followed by concentration under reduced pressure. The residue was dissolved in ethyl acetate, followed by conducting workup similar to that in Example 8(a) to give 31 mg of the subject Compound (8).