Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([NH:10][S:11]([C:14]2[C:15](=[O:24])[S:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].NC1C=C(NS(C2C(=O)SC3C(C=2)=CC=CC=3)(=O)=O)C=CC=1F.BrC1C=CC(NS(C2C(=O)SC3C(C=2)=CC=CC=3)(=O)=O)=CC=1.ClC1C=C2C(C=C(S(NC3C=CC(OC)=CC=3)(=O)=O)C(=O)S2)=CC=1.ClC1C=C2C(C=C(S(NC3C=CC(OC)=C(O)C=3)(=O)=O)C(=O)S2)=CC=1.ClC1C=C2C(C=C(S(NC3C=CC(F)=C(N)C=3)(=O)=O)C(=O)S2)=CC=1.ClC1C=C2C(C=C(S(NC3C=CC(Br)=CC=3)(=O)=O)C(=O)S2)=CC=1.ClC1C=C2C(=CC=1)SC(=O)C(S(NC1C=CC(OC)=CC=1)(=O)=O)=C2.BrC1C=C2C(=CC=1)SC(=O)C(S(NC1C=CC(OC)=CC=1)(=O)=O)=C2.C(OC1C=CC=C2C=1SC(=O)C(S(NC1C=CC(OC)=CC=1)(=O)=O)=C2)C.ClC1C=C2C(=CC=1)SC(=O)C(S(NC1C=CC(OC)=C(O)C=1)(=O)=O)=C2.NC1C=C(NS(C2C(=O)SC3C(C=2)=CC=CC=3OCC)(=O)=O)C=CC=1F.NC1C=C(NS(C2C(=O)SC3C(C=2)=CC(OC)=CC=3)(=O)=O)C=CC=1F.BrC1C=CC(NS(C2C(=O)SC3C(C=2)=CC(OC)=CC=3)(=O)=O)=CC=1.BrC1C=CC(NS(C2C(=O)SC3C(C=2)=CC=CC=3Cl)(=O)=O)=CC=1.BrC1C=CC(NS(C2C(=O)SC3C(C=2)=CC=CC=3Br)(=O)=O)=CC=1>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:10][S:11]([C:14]2[C:15](=[O:24])[S:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:13])=[O:12])=[CH:3][CH:2]=1
Reactant: COc1ccc(NS(=O)(=O)c2cc3ccccc3sc2=O)cc1O
Agent: CCOc1cccc2cc(S(=O)(=O)Nc3ccc(F)c(N)c3)c(=O)sc12
Agent: CCOc1cccc2cc(S(=O)(=O)Nc3ccc(OC)cc3)c(=O)sc12
Agent: COc1ccc(NS(=O)(=O)c2cc3cc(Br)ccc3sc2=O)cc1
Product: COc1ccc(NS(=O)(=O)c2cc3ccccc3sc2=O)cc1

Procedure:
N-(3-hydroxy-4-methoxyphenyl)-2-oxo-2H-thiochromene-3-sulfonamide; N-(3-amino-4-fluorophenyl)-2-oxo-2H-thiochromene-3-sulfonamide; N-(4-bromophenyl)-2-oxo-2H-thiochromene-3-sulfonamide; 7-chloro-N-(4-methoxyphenyl)-2-oxo-2H-thiochromene-3-sulfonamide; 7-chloro-N-(3-hydroxy-4-methoxyphenyl)-2-oxo-2H-thiochromene-3-sulfonamide; 7-chloro-N-(3-amino-4-fluorophenyl)-2-oxo-2H-thiochromene-3-sulfonamide; 7-chloro-N-(4-bromophenyl)-2-oxo-2H-thiochromene-3-sulfonamide; 6-bromo-N-(4-methoxyphenyl)-2-oxo-2H-thiochromene-3-sulfonamide 6-chloro-N-(4-methoxyphenyl)-2-oxo-2H-thiochromene-3-sulfonamide; 8-ethoxy-N-(4-methoxyphenyl)-2-oxo-2H-thiochromene-3-sulfonamide; 6-chloro-N-(3-hydroxy-4-methoxyphenyl)-2-oxo-2H-thiochromene-3-sulfonamide; N-(3-amino-4-fluorophenyl)-8-ethoxy-2-oxo-2H-thiochromene-3-sulfonamide; N-(3-amino-4-fluorophenyl)-6-methoxy-2-oxo-2H-thiochromene-3-sulfonamide; N-(4-bromophenyl)-6-methoxy-2-oxo-2H-thiochromene-3-sulfonamide; 8-ethoxy-N-(4-methoxyphenyl)-2-oxo-2H-thiochromene-3-sulfonamide; N-(4-bromo-phenyl)-8-chloro-2-oxo-2H-thiochromene-3-sulfonamide; N-(4-bromophenyl)-8-bromo-2-oxo-2H-thiochromene-3-sulfonamide; mixtures thereof; and salts thereof.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[N:3]=1>[Pd].C(O)C>[NH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][C:4]1[N:3]=[C:2]([CH3:1])[NH:6][N:5]=1
Reactant: Cc1nc(Cc2ccccc2[N+](=O)[O-])n[nH]1
Agent: [Pd]
Solvent: CCO
Product: Cc1nc(Cc2ccccc2N)n[nH]1
Reaction time: 4 h

Procedure:
A mixture of 1.67 g of 5-methyl-3-(o-nitrobenzyl)-1,2,4-triazole, 42 mg of 10% palladium on charcoal and 15 ml of ethanol is hydrogenated at 3 atmospheres pressure for 4 hours, filtered, decolorized, evaporated to a small volume and diluted with ether to give 3-(o-aminobenzyl)-5-methyl-1,2,4-triazole, m.p. 143°-145°.
Reaction SMILES: [CH2:1]([C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:12])[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:2].[C:19]1(C)C=CC=CC=1>>[C:4]([C:3]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:1][O:2][CH2:19][O:12]1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccccc1
Reactant: O=C(c1ccccc1)C(O)(CO)c1ccccc1
Product: O=C(c1ccccc1)C1(c2ccccc2)COCO1

Procedure:
About 273 grams of crude, wet α-methylolbenzoin prepared as described in Example I was refluxed under a Dean-Stark trap with 0.50 liters toluene for about two hours to remove about 50 ml. water. The reaction mixture was allowed to cool and 35 grams paraformaldehyde and 10 grams p-toluenesulfonic acid were added. The reaction mixture was heated for 45 minutes under controlled conditions such that the solvent refluxed below the trap and no water was collected. The temperature of the reaction mixture was then increased and about 16 ml. water was collected over a three-hour period. The mixture was allowed to cool and then saturated with ammonia gas. The resulting salt precipitate was removed by filtration and benzene solvent removed under vacuum from the residual yellow solution containing the solid reaction product. The crude solid reaction product was recrystallized from 1.6 l. of boiling hexane. 156 grams of recrystallized produce having m.p. of 66°-66.5° C was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].[C:17](Cl)(=[O:19])[CH3:18]>C(OCC)(=O)C.O>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[NH:1][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: NC1Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NC1Cc2ccccc2C1

Procedure:
To a cooled mixture of 2-aminoindan (1.2 mol, 160.00 g) in ethyl acetate (1019 mL) at about 5-7° C. was added a solution of Na2CO3 (2.4 mol, 254.65 g) in water (1528 mL) while stirring, followed by the addition of a solution of acetyl chloride (1.32 mol, 109.19 g) slowly over 2 hours. The reaction temperature was maintained below 10° C. by adjusting the addition rate. During the addition, a suspension was formed. After the addition of acetyl chloride, the mixture was stirred at the room temperature for 1 hour. The precipitated solid was collected by vacuum filtration and the filter cake was washed with water (200 mL), EtOAc (200 mL), and air-dried for 48 hours. The first crop of the product was obtained as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH2:22]O)([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:7]3[C:12]([N:13]([CH3:16])[C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:22][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:12]=3[N:13]([CH3:16])[C:14]=2[CH:15]=1
Reactant: CN(C)CCC1(CO)c2ccccc2N(C)c2cc(Cl)ccc21
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CN(C)CCC1=Cc2ccccc2N(C)c2cc(Cl)ccc21
Yield: 87.8 %

Procedure:
A mixture of 5 gm of 3-chloro-9-hydroxymethyl-9(β-dimethylaminoethyl)-10-methyl-acridane, 200 cc of xylene and 25 gm of phosphoric acid anhydride was refluxed for 3 hours with stirring and after cooling, the reaction mixture was poured over ice. The resulting mixture was made alkaline by the addition of 50 cc of sodium hydroxide solution and was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and distilled to dryness in vacuo. The residue was subjected to chromatography over silica gel with elution with a 6-3-1 mixture of cyclohexane-chloroform-triethylamine. Evaporation of the solvent gave 4.15 gm of 7-chloro-5-methyl-10-(β-dimethylaminoethyl)-dibenzo (b,f) azepine. The product was amorphous and was soluble in alcohols, chlorinated solvents, ether and benzene and insoluble in water.
Reaction SMILES: CS(O[C:6]1[C:23](=[O:24])[CH2:22][CH2:21][C@@:20]2([CH3:25])[C:7]=1[CH2:8][CH2:9][C@@H:10]1[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]1[CH2:12][CH2:13][C:14]2=[O:26])(=O)=O.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C)C=O.O>[N:27]([C:6]1[C:23](=[O:24])[CH2:22][CH2:21][C@@:20]2([CH3:25])[C:7]=1[CH2:8][CH2:9][C@@H:10]1[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]1[CH2:12][CH2:13][C:14]2=[O:26])=[N+:28]=[N-:29]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@]12CCC(=O)C(OS(C)(=O)=O)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12CCC(=O)C(N=[N+]=[N-])=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 60 °C
Yield: 60.4 %

Procedure:
To a stirred solution of 1.0 g of 4-methanesulfonyloxyandrost-4-en-3,17-dione in 5 ml of dimethylformamide are added 220 mg of powdered sodium azide dissolved in 3 ml of water. The resulting mixture is heated at 60° C. for 1 hour, cooled, poured into 250 ml of cold water and extracted with ethyl acetate (4×50 ml). The combined extracts are washed with saturated NaCl aqueous solution, dried over Na2SO4 and evaporated in vacuo to yield a residue which is purified by flash column chromatography on neutral Al2O3. Elution with n-hexane:diethyl ether 1:1 gives 0.52 g of the title compound, m.p. 142°-143° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:40])[C:20]=2[N:21]2[CH2:26][CH2:25][N:24]([C:27]([CH:29]3[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]3)=[O:28])[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:40])[C:20]=2[N:21]2[CH2:22][CH2:23][N:24]([C:27]([CH:29]3[CH2:30][NH:31][CH2:32]3)=[O:28])[CH2:25][CH2:26]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N2CCN(c3c(F)cncc3NC(=O)c3c(N)nn4cc(F)cnc34)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCN(C(=O)C2CNC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl 3-(4-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperazine-1-carbonyl)azetidine-1-carboxylate (73 mg, 0.1309 mmol) (prepared using a procedure similar to Example 8) was dissolved in DCM (219.0 μL). TFA (298.5 mg, 201.7 μL, 2.618 mmol) was added and the mixture was stirred at RT for 2 hr. The reaction mixture was concentrated in vacuo and the residue was purified by fractionlynx yielding 2-amino-N-(4-(4-(azetidine-3-carbonyl)piperazin-1-yl)-5-fluoropyridin-3-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide as a cream solid. MS (ES+) 458.1.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1>CCCCO>[CH:22]1([NH:27][C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: NC1CCCC1
Solvent: CCCCO
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(NC3CCCC3)nc2c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Into an 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (200 mg, 0.58 mmol, 1.00 equiv), cyclopentanamine (246.8 mg, 2.90 mmol, 5.00 equiv), and n-BuOH (2 mL). The resulting solution was stirred for 4 hrs at 100° C. in an oil bath. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:50) resulting in 214.1 mg (crude) of methyl 3-(cyclopentylamino)-2-phenylquinoxaline-6-carboxylate as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:7](=[CH:8][CH:9]=1)[CH:6]([C:10]#[N:11])[CH2:5]2.ClCCl.C(N(CC)CC)C.[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25]>O>[CH3:22][N:23]([CH3:28])[S:24](=[O:26])(=[O:25])[O:1][C:2]1[CH:3]=[C:4]2[C:7](=[CH:8][CH:9]=1)[CH:6]([C:10]#[N:11])[CH2:5]2
Reactant: N#CC1Cc2cc(O)ccc21
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN(C)S(=O)(=O)Oc1ccc2c(c1)CC2C#N
Reaction time: 96 h

Procedure:
2 g (13.8 mmoles) of 3-hydroxy-bicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile are mixed into 40 mL of dichloromethane, 3.9 g (2 equivalents) of triethylamine and 1.63 mL (1. 1 equivalents) of dimethylsulphamoyl chloride. Stirring is carried out at 25° C. for 4 days. The reaction mixture is poured into water, extracted with dichloromethane, dried over MgSO4, filtered and evaporated to obtain an oil. This residue is purified by flash chromatography over 70 g of silica (eluant: dichloromethane/toluene: 50/50). The expected product is obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C@@H:8]2[C@H:13]3[CH2:14][C@H:10]([CH2:11][CH2:12]3)[C@@H:9]2[C:15](OC)=[O:16])=[CH:4][CH:3]=1.[CH3:21][S:22]([NH:25][C:26]1[CH:41]=[CH:40][C:29]2[NH:30][C:31]([CH2:36][C:37](O)=[O:38])=[N:32][S:33](=[O:35])(=[O:34])[C:28]=2[CH:27]=1)(=[O:24])=[O:23].CN1CCOCC1.Cl.C(N=C=N)C.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:37](=[O:38])[C:36]([C:31]3[NH:30][C:29]4[CH:40]=[CH:41][C:26]([NH:25][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:27][C:28]=4[S:33](=[O:35])(=[O:34])[N:32]=3)=[C:15]([OH:16])[C@@H:9]3[C@H:8]2[C@H:13]2[CH2:14][C@@H:10]3[CH2:11][CH2:12]2)=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H]1[C@H]2CC[C@H](C2)[C@H]1NCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: CN1CCOCC1
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@H]3[C@H]4CC[C@H](C4)[C@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Yield: 46.3 %

Procedure:
Methyl (1S,2S,3R,4R)-3-[(4-fluorobenzyl)amino]bicyclo[2.2.1]heptane-2-carboxylate (0.087 g, 0 3 mmol) was dissolved in anhydrous N,N-dimethylformamide (2.8 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 0.1 g, 0.3 mmol) was added followed by N-methylmorpholine (0.07 mL, 0.63 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 143-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.061 g, 0.315 mmol) was added and the mixture was stirred at 25° C. for 4 h. Triethylamine (0.126 mL, 0.9 mmol) was added and the mixture was stirred at 50° C. for 16 h. Upon cooling to 25° C., the solution was diluted with ethyl acetate (25 mL) and washed with 1.0 M aqueous hydrochloric acid solution (2×25 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The oil was dissolved in methanol (4 mL) and the product was precipitated by the addition of 1.0 M aqueous hydrochloric acid solution (4 mL) while stirring. The solid was collected by vacuum filtration and further dried in vacuo to afford the desired product, N-{3-[(1R,2R,7S,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.0781 g, 0.139 mmol, 46%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.23-1.48 (6H, m), 2.67-2.68 (2H, m), 3.06 (3H, s), 3.24 (1H, d, J=15.0 Hz), 3.72 (1H, d, J=11.9 Hz), 4.07 (1H, d, J=15.6 Hz), 5.12 (1H, d, J=15.7 Hz), 7.14 (2H, t, J=8.4 Hz), 7.39 (2H, dd, J1=8.2 Hz, J2=5.8 Hz), 7.51 (1H, dd, J1=8.4 Hz, J2=2.3 Hz), 7.57-7.60 (2H, m), 10.18 (1H, s). LC-MS (ESI) calcd for C25H25FN4O6S2 560.12, found 561.3 [M+H+]. ee=99% [HPLC-analysis: Chiralpak AS-RH 4.6×250 mm, 5 micron at r.t., Solvent A-Solvent B (see table for gradient), 0.8 mL/min, 310 nm, t1=7.58 min, t2=10.08 min (major)].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:12](=O)[CH:13]=O>CCO>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[N:10]=[CH:13][CH:12]=[N:11]2)([O-:3])=[O:2]
Reactant: O=CC=O
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: CCO
Product: O=[N+]([O-])c1ccc2nccnc2c1
Yield: 97.1 %

Procedure:
A suspension of 4-nitrobenzene-1,2-diamine (15.3 g, 0.1 mol) and oxalaldehyde (40% in water, 17.4 g, 0.12 mol) in EtOH (150 mL) was stirred at reflux for 16 h. The mixture was then filtered, and the solid was collected to give 6-nitroquinoxaline as a yellow solid (17.0 g, yield 97%). ESI MS: m/z 176.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:15]=[CH:14][C:13]([I:16])=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][C:3]=1[F:19].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.BrC1C(F)=C2C(=CC=1)OC1=NC=C(I)C=C1C2=O>>[Br:1][C:2]1[CH:18]=[C:17]2[C:5](=[CH:4][C:3]=1[F:19])[O:6][C:7]1=[N:15][CH:14]=[C:13]([I:16])[CH:12]=[C:8]1[C:9]2=[O:11]
Reactant: O=C(O)c1cc(I)cnc1Oc1ccc(Br)c(F)c1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=c1c2cc(I)cnc2oc2ccc(Br)c(F)c12
Product: O=c1c2cc(Br)c(F)cc2oc2ncc(I)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
A flask charged with 2-(4-bromo-3-fluorophenoxy)-5-iodonicotinic acid (109 g, 249 mmol) and phosphorus pentoxide (70.6 g, 497 mmol) was treated with methanesulfonic acid (484 mL, 7460 mmol). After stirring for 30 minutes at room temperature, the reaction mixture was heated to 120° C. for 18 h. The reaction mixture was allowed to cool to room temperature and was poured into 1 L of ice water. After stirring for one hour, the resulting solid was filtered and subsequently washed sequentially with water and MeOH. The solid was dried to provide a 1:4 mixture of 7-bromo-6-fluoro-3-iodo-5H-chromeno[2,3-b]pyridin-5-one and 7-bromo-8-fluoro-3-iodo-5H-chromeno[2,3-b]pyridin-5-one (81.92 g, 195 mmol, 78% yield) as an off white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH:16]([CH3:21])[CH2:17][C:18](O)=[O:19])=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:27][NH2:28].C(O)(=O)C>C(O)C>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH3:21])[CH2:17][C:18](=[O:19])[NH:27][N:28]=2)=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
4-(4-Benzylamino-3-nitro-phenyl)-3-methyl-4-oxo-butyric acid E-4.1″ (939 mg; 2.74 mmol) is placed in 7 ml ethanol and treated with hydrazine hydrate (0.16 ml; 3.29 mmol) and acetic acid (78.58 μl; 1.37 mmol). The reaction mixture is heated up to 100° C. for 2 hours. Another portion of hydrazine hydrate (0.08 ml; 1.65 mmol) and 40 μl acetic acid are added and stirred for 2 hours at 100° C. After letting the reaction cooling to RT, the product precipitates. It is filtered off and washed with methanol and dried under reduced pressure.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3]
Reactant: COC(=O)c1ccc(C(C)O)cc1
Reactant: Oc1ccccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(C)Oc2ccccc2F)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 32.8 %

Procedure:
To a solution of methyl 4-(1-hydroxyethyl)benzoate (0.9 g, 5 mmol), 2-fluorophenol (627 mg, 5.6 mmol), triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0° C. The mixture was stirred at 20° C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 4-(1-(2-fluorophenoxy)ethyl)benzoate (450 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[Cl:17][C:18]1[CH:46]=[CH:45][C:21]([CH:22]([N:30]2[C:38]3[C:33](=[CH:34][C:35](/[C:39](/[CH3:44])=[CH:40]/[C:41](O)=[O:42])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH:22]([N:30]2[C:38]3[C:33](=[CH:34][C:35](/[C:39](/[CH3:44])=[CH:40]/[C:41]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:42])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:21]2[CH:45]=[CH:46][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:24][CH:25]=1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)c1

Procedure:
217 mg of compound 61 was obtained in a similar manner to those described in the Examples 1 and 2 using 438 mg of ethyl 4-(2-aminophenoxy)butyrate and 429 mg of 3-[1-(4,4'-dichlorobenzhydryl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [Si]([O:8][CH2:9][C@:10]1([CH3:35])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO.O1CCOCC1>[CH3:35][C@@:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cn1cc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO)C5)CC3)cc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
The compound (403 mg, 0.79 mmol) obtained in Example 34-1) was dissolved in methanol (4 mL). A 4 N solution (1.98 mL) of hydrochloric acid in dioxane was added to the solution, and the mixture was stirred at room temperature for 1 h. The solvent was distilled off, the residue was dissolved in a mixed solvent of methylene chloride (50 mL) and methanol (2 mL), and the mixture was separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate (20 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0% to 50%) to obtain the title compound (228 mg, 73%) in a colorless solid form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]#[N:22])=[C:6]([C:8]2[C:13]([F:14])=[CH:12][N:11]([CH:15]([CH3:19])[C:16](O)=[O:17])[C:10](=[O:20])[CH:9]=2)[CH:7]=1.[NH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]#[N:22])=[C:6]([C:8]2[C:13]([F:14])=[CH:12][N:11]([CH:15]([CH3:19])[C:16]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[CH:26][CH:25]=3)=[O:17])[C:10](=[O:20])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1cc(F)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
54 mg (purity 90%, 0.15 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 51 mg (67% of theory)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH2:13](O)[CH3:14]>Cl>[CH2:13]([O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:14]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CCc1ccc(O)cc1
Temperature: 145 °C

Procedure:
4 drops of concentrated HCl are added, under stirring, to a solution of commercial 3-(4 Hydroxy-phenyl)-propionic acid (13.08 g; 78.79 mmol) in 100 mL of ethanol. The reaction medium is heated to reflux in a bath at 145° C. overnight. The ethanol is evaporated off and ethyl acetate is added. The organic phase is washed with a saturated NaHCO3 solution and with a NaCl solution. After drying over MgSO4 and evaporation, an oil is obtained. This latter is distilled by Kugelrohr (150-175° C.; 1.2 mmbar). A transparent oil which crystallizes is obtained in order to produce the expected compound 4′-1 (13.8 g; 71.1 mmol; 90%) in the form of a white solid.