Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:38])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](B4OC(C)(C)C(C)(C)O4)=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:40]1[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[N:41]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:38])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:40]4[CH:45]=[CH:44][N:43]=[C:42]([CH3:46])[N:41]=4)=[C:21]([C:34]([F:36])([F:35])[F:37])[CH:20]=3)=[N:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: Cc1nccc(Cl)n1
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(B4OC(C)(C)C(C)(C)O4)c(C(F)(F)F)c3)nc2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C)n4)c(C(F)(F)F)c3)nc2)CC1
Temperature: 100 °C

Procedure:
A mixture of N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phenyl)acetamide 192-3 (53 mg, 0.1 mmol), 4-chloro-2-methylpyrimidine 192-4 (18 mg, 0.14 mmol) Pd(PPh3)4 (11 mg, 0.01 mmol) and K3PO4 (42 mg, 0.2 mmol) in dioaxane (1.0 mL) was flushed with nitrogen and heated to 100° C. for 2 hours. The salt was removed by filtration and the filtrate was taken to dryness by rotary evaporation. The residue was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-methylpyrimidin-4-yl)-3-(trifluoromethyl)phenyl)acetamide 192. MS m/z 499.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ10.58 (s, 1H), 8.77 (d, 1H), 8.02 (s, 1H), 7.89 (m, 2H), 7.73 (d, 1H), 7.54 (d, 1H), 7.42 (m, 2H), 3.76 (s, 2H), 3.66 (b, 4H), 3.14 (b, 2H), 3.07 (b, 2H), 2.64 (s, 3H), 2.03 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH2:11][CH3:12])=[CH:9][N:8]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:6]=2[N:7]=1.Cl.[OH-:24].[Na+]>>[NH2:1][C:2]1[NH:3][C:4](=[O:24])[C:5]2[C:10]([CH2:11][CH3:12])=[CH:9][N:8]([C@@H:13]3[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@H:14]3[OH:15])[C:6]=2[N:7]=1
Reactant: CCc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)nc(Cl)c12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CCc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)[nH]c(=O)c12

Procedure:
A mixture of the compound from Step B (104 mg, 0.32 mmol) in 2N aqueous NaOH (10 mL) was stirred at reflux temperature for 15 min. The solution was cooled in ice bath, neutralized with 2 N aqueous HCl, and evaporated to dryness. The residue was suspended in MeOH, mixed with silica gel, and evaporated. The solid residue was placed onto a silica gel column (packed in a solvent mixture of CH2Cl2/MeOH: 10/1) which was eluted with a solvent system of CH2Cl2/MeOH: 10/1 and 5/1. The fractions containing the product were collected and evaporated to dryness to yield the title compound (48 mg) as a white solid.
Reaction SMILES: [BH4-].[Na+].CS(O)(=O)=O.[O:8]=[C:9]([N:23]1[CH2:28][CH2:27][N:26]2[C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=[C:25]2[CH2:24]1)[CH:10]=[C:11]([NH2:22])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21].N.[F-].[K+]>O.CC(O)C.C1COCC1>[O:8]=[C:9]([N:23]1[CH2:28][CH2:27][N:26]2[C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][N:31]=[C:25]2[CH2:24]1)[CH2:10][CH:11]([NH2:22])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: CS(=O)(=O)O
Agent: N
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: -12.5 °C
Reaction time: 0.75 h

Procedure:
In a 2 L round bottom flask dry THF (450 mL) was taken. It was cooled to −15 to −10° C. and NaBH4 (11.2 g) was added. After that methanesulfonic acid (71.1 g) was added dropwise at −15 to −5° C. over a period of 2.5 h. Separately, 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (40.0 g) was mixed in a solvent mixture of dry THF (100 mL) and IPA (44 mL) and added into the reaction mixture over a period of 45-60 min. at −10 to −5° C. It was stirred for 30-60 min. at −10 to −5° C. Reaction mixture was poured into cold water. It was basified by adding 25% aq. ammonia solution. Product was extracted in an ethyl acetate. The organic layer was collected and combined. It was washed with water and brine solution. It was dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-41.5 g; % Y-100%; % Purity by HPLC-94.5%; % H2O by KF-4.58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8](I)[N:7]([CH3:11])[C:6]=2[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][CH:30]=[C:31]([CH:34]=2)[CH:32]=[O:33])O1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:27]3[CH:28]=[N:29][CH:30]=[C:31]([CH:34]=3)[CH:32]=[O:33])[N:7]([CH3:11])[C:6]=2[CH:12]=1
Reactant: Cn1c(I)nc2ccc(Cl)cc21
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(-c2cncc(C=O)c2)nc2ccc(Cl)cc21
Temperature: 160 °C

Procedure:
A flask was charged with 6-chloro-2-iodo-1-methyl-1H-benzo[d]imidazole (627 mg, 2.145 mmol), DMF (10 mL), 2M aqueous sodium carbonate (2.145 mL, 4.29 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehyde (1 g, 4.29 mmol). Nitrogen was bubbled through the mixture for 10 min and polymer bound Pd(PPh3)4 (1.19 g, 0.107 mmol) was added. The mixture was heated to 160° C. under micro-wave irradiation for 30 min. The mixture was filtered through a thin pad of celite, which was washed with EtOAc (100 mL). The filtrate was poured into water (200 mL) and extracted with EtOAc (500 mL). The organic phase was washed with water (50 mL), dried over Na2SO4 and concentrated. The residue was purified by silica chromatography eluting with 20 to 100% EtOAc in heptane to give 5-(6-chloro-1-methyl-1H-benzo[d]imidazol-2-yl)nicotinaldehyde. ESI-MS: m/z 272.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][NH:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: NCc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CNCc1ccccc1

Procedure:
Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.263 g, 1.0 mmol) and benzylamine (0.11 mL, 1.0 mmol) gives the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CC1(C)C(C)(C)OB([C:29]2[O:33][C:32]([Si](C(C)C)(C(C)C)C(C)C)=[N:31][CH:30]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:13]1[N:14]=[C:3]2[C:2]([C:29]3[O:33][CH:32]=[N:31][CH:30]=3)=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]2[C:12]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Reactant: CCOC(=O)c1c(C)nc2c(Cl)cc(C(F)(F)F)cn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1c(C)nc2c(-c3cnco3)cc(C(F)(F)F)cn12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
A mixture of ethyl 8-chloro-2-methyl-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate (380 mg), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazole (479 mg), tetrakis(triphenylphosphine)palladium(0) (143 mg) and potassium carbonate (343 mg) in DME/water (8/2 mL) was stirred with microwave irradiation at 120° C. for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (12 mL), and 1N hydrochloric acid (4 mL) was added thereto. The reaction mixture was stirred at room temperature for 2 hr, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (78 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>CN(C)C=O.C(OCC)(=O)C>[C:19]([CH2:18][NH:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([O:21][CH3:22])=[O:20]
Reactant: N#Cc1ccc(Cl)cc1N
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CNc1cc(Cl)ccc1C#N
Yield: 36.7 %

Procedure:
Dissolve 2-amino-4-chlorobenzonitrile (12.9 g, 85 mmol) in anhydrous dimethylformamide (15 mL). Add potassium carbonate (7.6 g, 90 mmol) and methyl bromoacetate (7.8 mL, 90 mmol) and stir at 70° C. for 5 days. Add additional methyl bromoacetate (78 mL, 90 mmol) and continue heating for 1 day. Dilute with ethyl acetate (300 mL), wash with water, separate the organic phase and dry (MgSO4). Evaporate the solvent in vacuo and purify by flash chromatography (25% ethyl acetate/hexane). Recrystallize (hexane) to give the title compound (7 g, 36%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.[Cl-].[Na+].O>[CH3:17][O:15][C:14]([CH:9]1[CH:10]([OH:13])[CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1C(O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution containing 3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (16 g, 71 mmol. See: Hodges, J. A.; Raines, R. T. J. Am. Chem. Soc. 2005, 45, 15923) in DMF (100 mL) was cooled to 0° C. To this solution was added K2CO3 (16 g, 116 mmol) followed by iodomethane (5.4 mL, 87 mmol). The reaction mixture was slowly warmed to ambient temperature over 1 h at which time it became a yellow heterogeneous solution. This mixture was heated at 90° C. for 1 h and then cooled to ambient temperature. The solution was diluted with brine, extracted with diethyl ether, dried over anhydrous Na2SO4, filtered, and concentrated to afford 14.8 g (87%) of 3-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a yellow oil (See: Demange, L.; Cluzeau, J.; Menez, A.; Dugave, C. Tetrahedron Lett. 2001, 42, 651).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].Br[C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[C:30]([C:45]1[CH:52]=[CH:51][C:48]([CH:49]=[O:50])=[CH:47][CH:46]=1)[N:31]2[S:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:38])=[O:37]>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[C:30]([C:45]2[CH:46]=[CH:47][C:48]([CH:49]=[O:50])=[CH:51][CH:52]=2)[N:31]3[S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:38])=[O:37])[C:5]([C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: O=Cc1ccc(-c2cc3c(Br)cccc3n2S(=O)(=O)c2ccccc2)cc1
Product: CCn1cc(-c2cccc3c2cc(-c2ccc(C=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 100 using 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-[4-bromo-1-(phenylsulfonyl)-1H-indol-2-yl]benzaldehyde provided the title compound. ESMS [M+H]+:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][C:10]=2[OH:20])=[CH:4][CH:3]=1.[SH:22][CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([S:22][CH2:23][CH2:24][OH:25])=[CH:3][CH:4]=2)=[O:21])=[C:10]([OH:20])[CH:11]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCOc1ccc(C(=O)c2ccc(Cl)cc2)c(O)c1
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOc1ccc(C(=O)c2ccc(SCCO)cc2)c(O)c1

Procedure:
Following the procedure of Example 2, the title compound is prepared by reacting equimolar amounts of 4′-chloro-2-hydroxy-4-butoxybenzophenone and 2-mercaptoethanol in the presence of potassium carbonate.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[N:8]2)=[CH:4][CH:3]=1.FC1C=CC(CN2C=C(C(O)=O)C=N2)=CC=1.S(Cl)([Cl:35])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]([Cl:35])=[O:13])[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(Cn2cc(C(=O)O)cn2)cc1
Agent: O=C(O)c1cnn(Cc2ccc(F)cc2)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(Cn2cc(C(=O)Cl)cn2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
1-(4-Methyl-benzyl)-1H-pyrazole-4-carboxylic acid (0.618 g, 2.86 mmol), which had been prepared according to the protocol described for intermediate (6e), in Example 21, was stirred in toluene (20 mL) at RT and thionyl chloride (681 mg, 0.42 mL, 5.72 mmol) was added. The reaction mixture was slowly heated to 90° C. and heating continued for 3 hrs. After cooling the reaction was concentrated in vacuo. Toluene was added to the residue and concentrated in vacuo. This was repeated a further three times and the crude solid obtained was triturated using isohexane. The solids were separated by filtration washed with isohexane and dried in vacuo to afford 1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl chloride as a white solid, 0.67 g, quant.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7](Cl)=[O:8].[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([NH:17][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:8]
Reactant: O=C(Cl)C=Cc1cccc(Cl)c1
Reactant: CC(C)CN
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)CNC(=O)/C=C/c1cccc(Cl)c1
Reaction time: 24 h

Procedure:
A solution of 3-chlorocinnamoyl chloride (4g) in dry toluene (75 ml) was added with stirring to a solution of isobutylamine (12 ml) in dry benzene (200 ml). The reaction mixture was allowed to stand for 24 hours. The solvent was evaporated under reduced pressure and the residue thoroughly triturated with water, washed with dilute hydrochloric acid and then with water. The resulting crude product was recrystallized from ethanol-water (1:10) to give trans 3-chloro-N-isobutylcinnamamide (3.9 g), m.p. 111.5°-112.5° C. Elemental analysis, nmr and ir data were all consistent with the assigned structure. TLC gave one spot run on silica gel with 5:1 and 3:1 hexane:ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[N+:15]([C:11]1[C:2]([Br:1])=[C:3]2[C:8](=[CH:9][C:10]=1[Br:12])[NH:7][C:6](=[O:13])[C:5](=[O:14])[NH:4]2)([O-:17])=[O:16]
Reactant: O=c1[nH]c2cc(Br)cc(Br)c2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Br)c([N+](=O)[O-])c(Br)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
The method of Cheeseman, supra. was adapted. 5,7-Dibromo-1,4-dihydroquinoxaline-2,3-dione (74 mg, 0.23 mMol) was dissolved in concentrated H2SO4 (1 mL) at 0° C. for 30 mins., and then KNO3 (28 mg, 0.27 mMol, Baker) was added to this solution. The mixture was stirred at 0° C. for 3 h and then at room temperature for 30 h. It was poured into ice water (8 g) and the precipitate was collected by filtration, was dissolved into 1N KOH (5 mL), and the red precipitate was removed by filtration. The solution then was acidified to pH=2 with 4N HCl to obtain a cream precipitate, which was collected by filtration, then was dried in the air at 50° C. for 4 h, affording the pure 6-nitro-5,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (71 mg, 84.5% ), as a yellow powder; mp: 318°-20° C. (dec.). IR (KBr, cm-1): 3468, 3131, 3062, 2931, 1712, 1593, 1537. NMR (1H, DMSO-d6): δ7.392 (s, 1H), 11.566 (s, 1H), 12.274 (s, 1H). HRMS: calcd. for C8H3N3O4Br2 m/z: 362.8489, found: 362.8478.
Reaction SMILES: [F:1][C:2]1([F:14])[C:4]2([CH2:7][C:6]([CH3:13])([C:8]([O:10]CC)=[O:9])[CH2:5]2)[CH2:3]1.[OH-].[Na+]>C1COCC1.O>[F:1][C:2]1([F:14])[C:4]2([CH2:5][C:6]([CH3:13])([C:8]([OH:10])=[O:9])[CH2:7]2)[CH2:3]1
Reactant: CCOC(=O)C1(C)CC2(C1)CC2(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C(=O)O)CC2(C1)CC2(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Intermediate 326A (0.5 g, 2.448 mmol) in THF (10 mL) and water (5 mL) was added NaOH (0.245 g, 6.12 mmol) and the reaction mixture was stirred at RT for 16 h. The volatiles were removed from the reaction mixture and the pH of the resulting residue was adjusted to ˜3 using a 1.0 N aq. solution of HCl. The aqueous layer was extracted with EtOAc (3×10 mL) The combined organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated to afford Intermediate 326B (0.35 g, 81%, a mixture of cis and trans isomers) as a yellow liquid used directly in the next step without purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.39 (br. s., 1H), 2.55-2.63 (m, 2H), 1.89-2.02 (m, 2H), 1.34-1.45 (m, 3H), 1.14-1.23 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH:5]=[CH:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=O)[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].Cl.[NH2:30][OH:31]>N1C=CC=CC=1>[CH3:1][CH:2]([CH2:4][CH:5]=[CH:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[N:30][OH:31])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3]
Reactant: CC(C)CC=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)CC=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=NO)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 50 %

Procedure:
10 mg of 4,22-cholestadien-3-one (0.026 mmol) is solubilized in 5 ml of pyridine in a 10 ml flask, then 100 mg of hydroxylamine hydrochloride is added. Stirring is maintained for 24 hours at ambient temperature, and the solvent is evaporated off under reduced pressure. Water then ethyl acetate are added in order to carry out an extraction. Then the organic phase is washed with an acidified aqueous solution (HCl 1%). The ethyl acetate is evaporated off under reduced pressure. A white powder is obtained with a yield greater than 50%.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:29][CH2:28]1.[OH-].[Na+]>CN(C=O)C.CO>[O:27]1[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][C:35]2[CH:41]=[CH:40][C:38]([NH:39]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:37][CH:36]=2)[CH2:31][CH2:32]1
Reactant: Nc1ccc(CCN2CCOCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(CCN2CCOCC2)cc1)c1ccccc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-morpholinoethyl)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH2:1]([NH:9][C:10]([NH:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CS(O)(=O)=[O:22].OO>>[CH2:1]([NH:9][C:10]([NH:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:18][OH:22])=[O:17])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CS(=O)(=O)O
Reactant: CCCCCCCCNC(=O)NC(=O)CCC(=O)O
Agent: OO
Product: CCCCCCCCNC(=O)NC(=O)CCC(=O)OO

Procedure:
13.6 g (0.05 mol) of N-(N'-octylcarbamoyl)succinamic acid, 50 g of methanesulfonic acid and 6 g (0.15 mol) of hydrogen peroxide (85% strength by weight) are reacted and worked up as described in Example 3.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[N:6]=[C:5]2[N:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1.[CH2:30]([OH:32])[CH3:31]>>[CH2:30]([O:32][C:2]1[N:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[N:6]=[C:5]2[N:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1)[CH3:31]
Reactant: CCO
Reactant: Clc1nc2c(N3CCSCC3)nc(N3CCNCC3)nc2nc1N1CCSCC1
Product: CCOc1nc2c(N3CCSCC3)nc(N3CCNCC3)nc2nc1N1CCSCC1

Procedure:
This compound was prepared analogous to Example 3 from 6-chloro-2-piperazino-4,7-bis-(thiomorpholino)pteridine and ethanol.
Reaction SMILES: [F:1][C:2]1[C:3]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[C:6](Br)[CH:7]=1.[Cu](C#N)[C:32]#[N:33].CN1CCCC1=O>O>[F:1][C:2]1[C:3]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[C:6]([C:32]#[N:33])[CH:7]=1
Reactant: COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Br)c1
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2C#N)c1
Temperature: 175 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
A mixture of 75 mg of 5-fluoro-2-(3-methoxyphenoxy)-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]bromobenzene, 27 mg of copper cyanide and 0.5 ml of N-methyl-2-pyrrolidone was stirred at 170 to 180° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 57 mg of 5-fluoro-2-(3-methoxyphenoxy)-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]cyanobenzene.