Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Cl[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].[F-].[K+].O>CS(C)=O>[CH3:16][N:15]1[C:11]([N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[N:14]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(=O)CC1
Yield: 109.8 %

Procedure:
Three identical solutions of piperidin-4-one hydrochloride hydrate (1.84 g, 12.0 mmol), 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (1.3 g, 8.0 mmol) and potassium fluoride (1.86 g, 32 mmol) in dry DMSO (20 mL) were heated in a microwave at 100° C. for 12 hr. The mixtures were combined, poured into water (700 mL) and extracted into EtOAc (3×100 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a yellow solid (1.97 g, 36%). To a solution of this ketone in DMF (40 mL) was added NEt3 (3.05 mL, 21.9 mmol) and chlorotrimethylsilane (1.55 mL, 12.3 mmol). The reaction vessel was sealed and the mixture heated at 90° C. for 16 hr. The mixture was cooled and the product extracted into EtOAc (2×50 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% Et2O/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-4-(trimethylsilyloxy)-1,2,3,6-tetrahydropyridine as a yellow gum (1.53 g, 59%). This gum was dissolved in MeCN (130 mL) and cooled to 0° C. A solution of SelectFluor® (1.99 g, 5.61 mmol) in 2:1 MeCN:DMF (10 mL) was added dropwise over 20 min and the mixture stirred at between −5° C. and 0° C. for 2 hr. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (40 mL). The product was extracted into EtOAc (50 mL) and DCM (50 mL), and the combined organic layers passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 3-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a pale yellow solid (1.23 g, 99%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 5.04 (ddd, J=48.3, 8.2, 5.7 Hz, 1H), 3.89 (s, 3H), 3.77-3.64 (m, 2H), 3.64-3.51 (m, 1H), 3.50-3.43 (m, 1H), 2.88-2.72 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[NH2:23][CH2:24][CH2:25][N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28](C)[C:27]1=[O:36].CCN(C(C)C)C(C)C>C1COCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:23][CH2:24][CH2:25][N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[NH:28][C:27]3=[O:36])[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21]
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Reactant: Cn1c(=O)n(CCN)c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C[C@H](Nc2nc(NCCn3c(=O)[nH]c4ccccc43)ncc2C#N)CC[C@@H]1O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 27.3 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (100 mg, 0.308 mmol), 1-(2-amino-ethyl)-3-methyl-1,3-dihydro-benzoimidazol-2-one (140 mg, crude), and DIEA (85 mg, 0.66 mmol) in THF (3 mL) was stirred at 100° C. in a microwave reactor for 1.5 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by preparative standard methods to afford the title compound (36.7 mg, 0.084 mmol, 24% yield over 2 steps). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.08-7.94 (m, 1H), 7.11-7.08 (m, 4H), 4.26-4.10 (m, 3H), 3.89-3.66 (m, 2H), 3.40-3.35 (m, 4H), 1.96-1.51 (m, 6H), 1.05-0.99 (m, 6H). MS (ESI) m/z 436.2 [M+H]+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH:39][C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])=[CH:33][C:32]=2[CH3:50])=[C:28]([CH:51]([CH3:53])[CH3:52])[NH:27][N:26]=1)(=O)C.C[O-].[Na+]>CO>[CH2:43]([O:42][C:40]([NH:39][CH2:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:51]([CH3:53])[CH3:52])=[C:32]([CH3:50])[CH:33]=1)=[O:41])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCNC(=O)OCc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CCNC(=O)OCc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[2-(benzyloxycarbonylamino)ethyl]-2-methylphenyl}-methyl)-5-isopropyl-1H-pyrazole (20 mg) was dissolved in methanol (1 mL). To the solution was added sodium methoxide (28% methanol solution, 0.005 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give 4-({4-[2-(benzyloxycarbonylamino)ethyl]-2-methylphenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole. This material was dissolved in methanol (1 mL). To the solution was added 10% palladium-carbon powder (5 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (11 mg).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[F:33]>C1C=CC=CC=1.C(O)C.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>[Cl:26][C:27]1[CH:28]=[C:29]([C:2]2[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: OB(O)c1ccc(F)c(Cl)c1
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: CCO
Solvent: c1ccccc1
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccc(F)c(Cl)c2)C1=O
Yield: 25 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (112 mg) and tetrakis(triphenylphosphine)palladium(0) (54 mg) in 7 ml benzene and 1 ml ethanol, were added 2 M aqueous sodium carbonate (0.22 ml) and (3-chloro-4-fluorophenyl)boronic acid (82 mg). The reaction solution was kept at reflux for 24 hours. Then the solvent was evaporated off under reduced pressure. The resulting residue was extracted with 50 ml water and dichloromethane (50 ml×3). The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate) to yield 32 mg of 4-(3-chloro-4-fluorophenyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 162-164° C. NMR: δ1.58 (s, 6H), 3.09 (s, 3H), 7.13 (m, 2H), 7.40 (d, J=6.6 Hz, 1H), 7.83 (d, J=8.1 Hz, 2H), 7.97 (d, J=8.1 Hz, 2H). IR (cm−1): 2930, 1700, 1587, 1503, 1404, 1317, 1150, 1068, 913, 771, 744.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10]>>[CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:12][N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccc(C=O)o1
Product: Cc1ccc(C=C[N+](=O)[O-])o1
Yield: 88 %

Procedure:
In close analogy to the procedure described above, 5-Methyl-furan-2-carbaldehyde is reacted with nitromethane to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][N:2]=1.S(=O)(=O)(O)O.[CH3:15]O>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:15])=[O:8])=[CH:3][N:2]=1
Reactant: O=C(O)c1ccnnc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccnnc1
Reaction time: 16 h

Procedure:
To a solution of pyridazine-4-carboxylic acid (Aldrich, 5.0 g, 40.3 mmol) in methanol (anhydrous, Aldrich, 100 mL) was added sulfuric acid (concentrated, Aldrich, 2 mL). The reaction mixture was then heated to reflux and stirred for 16 hours. The volatiles were removed under reduced pressure. The residue was basified to pH=8-9 with saturated sodium carbonate (20 mL) and then extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (2×20 mL) and dried over magnesium sulfate. The drying agent was filtered off and the organic solution was concentrated and dried to give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 3.34 (s, 3 H), 8.10 (dd, J=5.2, 2.4 Hz, 1 H), 9.52 (dd, J=5.2, 1.2 Hz, 1 H), 9.58 (dd, J=2.2, 1.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z 139 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[Br:16]Br.[OH-].[Na+]>O1CCOCC1>[Br:16][CH:9]([O:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)[C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C(=O)COc1cccc(Cl)n1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)C(Br)Oc1cccc(Cl)n1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
A stirred solution of 227.68 g (1.0 mole) of 1-(6-chloro-2-pyridinyloxy)-3,3-dimethyl-2-butanone, prepared above, in 1000 ml dioxane was heated to 65° C. The heat source was removed and 175.8 g (1.1 mole) bromine added dropwise. After the addition of the bromine, the solution was stirred for 10 minutes and then poured into 3 liters ice water containing 25 g sodium bisulfite. The mixture was made slightly basic with 50% NaOH and twice extracted with 500-ml portions of pentane. The pentane extracts were washed with 1000 ml of 5% NaOH and dried, giving 259 g (84% yield) of 1-bromo-1-(6-chloro-2-pyridinyloxy)-3,3-dimethyl-2-butanone. Crystallization from pentane gave a white solid melting at 50°-52° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: CN1CCNCC1
Product: COc1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
Heat 1-chloro-2-methoxy-4-nitro-benzene (1.0 g, 5.33 mmol) and 1-methylpiperazine (1.33 g, 13.30 mmol) at 100° C. in a sealed tube for 16 h. Cool the mixture to room temperature and partition between dichloromethane (50 mL) and water (50 mL). Separate the organic portion and extract the aqueous portion with dichlorormethane (2×20 mL). Dry the combined organic portions (Na2SO4), filter and concentrate in vacuo to give 1.05 g (78%) of the title compound. MS/ES m/z 252.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([F:30])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([CH3:31])[CH:3]=1.Cl.[NH2:33][OH:34].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([F:30])[CH:21]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:33]\[OH:34])=[C:4]([CH3:31])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(OC(C)C)c(F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(OC(C)C)c(F)c1

Procedure:
In analogy to example 151, step 3, 5-[3-(4-chloro-2-methyl-phenyl)-3-(3-fluoro-4-isopropoxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI+): m/z=457.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9]C)=O.[NH2:11][NH2:12]>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([NH:11][NH2:12])=[O:9]
Reactant: NN
Reactant: COC(=O)c1cnccn1
Product: NNC(=O)c1cnccn1
Reaction time: 4 h

Procedure:
A solution of methyl pyrazinecarboxylate (600 mg, 4.34 mmol) in hydrazine (3 ml) was stirred overnight for 20 hours, then at 60° C. for 4 hours. Removal of excess hydrazine under high vacuum afforded pyrazine hydrazide intermediate 47 as a yellow solid (550 mg, 92%). 1H NMR: (CD3OD) δ 9.19 (d, J=1.5, 1H), 8.76 (d, J=2.4, 1H), 8.65 (app t, 1H); LC/MS: (ES+) m/z (M+H)+=139, HPLC Rt=0.087.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[C:16]([F:25])[CH:15]=3)=[CH:9][CH:10]=2)[N:5]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH2:4][CH2:3]1.[Li+].[OH-]>O1CCCC1.CO>[CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[C:16]([F:25])[CH:15]=3)=[CH:9][CH:10]=2)[N:5]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)N(c2ccc(C)cc2)CCC3(C)C)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(N2CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)c(F)c4)cc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98 %

Procedure:
To a solution of 0.088 g (0.19 mmol) of ethyl 4-(2-(4,4-dimethyl-1,2,3,4-tetrahydro-N-(4-methylphenyl) quinolin-7-yl)ethynyl)-2-fluorobenzoate (Compound 11) in 3.0 mL of tetrahydrofuran and 0.5 mL of methanol was added 0.5 mL (0.5 mmol) of 1.0M aqueous LiOH. The resulting solution was stirred at room temperature for 72 hours. The mixture was concentrated in vacuo, water was added, and the mixture was extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by recrystallization from acetonitrile to give the title compound as a solid (77 mg, 90%). PNMR (300 MHz, d6-acetone) d 1.36 (6 H, s), 1.40 (3 H, t, J=7.1 Hz), 1.86 (2 H, t, J=5.9 Hz), 2.34 (3 H, s), 3.62 (2 H, t, J=5.9 Hz), 6.64 (1 H, d, J=1.6 Hz), 6.86 (1 H, dd, J=8.0, 1.6 Hz), ), 7.17 (2 H, d, J=8.3 Hz), 7.25-7.37 (5 H, m), 7.92 (1 H, t, J=7.8 Hz).
Reaction SMILES: [CH2:1]([Si:3]([CH2:7][CH3:8])([CH2:5][CH3:6])Cl)[CH3:2].C(N(CC)CC)C.[N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:17]=1[NH:25][C:26]([O:28][CH3:29])=[O:27]>O1CCCC1>[CH2:1]([Si:3]([CH2:7][CH3:8])([CH2:5][CH3:6])[N:25]([C:17]1[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:16]=1)[C:26]([O:28][CH3:29])=[O:27])[CH3:2]
Reactant: CC[Si](Cl)(CC)CC
Reactant: COC(=O)Nc1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)N(C(=O)OC)c1nc2ccccc2[nH]1
Reaction time: 12 h

Procedure:
4.1 parts of triethylchlorosilane and 3.0 parts of triethylamine are separately added, in portions, to 5 parts of methyl benzimidazole-2-carbamate in 50 parts of tetrahydrofuran. After 12 hours, the mixture is filtered and the solvent is distilled from the filtrate under reduced pressure. 1.6 parts of methyl N-triethylsilyl-benzimidazole-2-carbamate are obtained; decomposition point >120° C. (active ingredient No. 1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.[CH:12]([Mg]Br)=[CH2:13]>>[F:11][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[C:7]2[C:6]=1[CH:12]=[CH:13][NH:8]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cc(F)cnc1Cl
Product: Fc1cnc(Cl)c2[nH]ccc12

Procedure:
The chemistry in Scheme 3 provided the derivatives which corresponds to general formula 5 and has a 6-aza ring and R2=F and R4=Cl. In particular, reaction of 2-chloro-5-fluoro-3-nitro pyridine with 3 equivalents of vinyl Magnesium bromide using the typical conditions described herein will provide 4-fluoro-7-chloro-6-azaindole in high yield. Addition of this compound to a solution of aluminum trichloride in dichloromethane stirring at ambident temperature followed 30 minutes later with chloromethyl or chloroethyl oxalate provided an ester. Hydrolysis with KOH as in the standard procedures herein provided an acid salt which reacted with piperazines 4 (for example 1-benzoyl piperazine) in the presence of DEPBT under the standard conditions described herein to provide the compound 5 described just above. The compound with the benzoyl piperazine is N-(benzoyl)-N′-[(4-fluoro-7-chloro-6-azaindol-3-yl)-oxoacetyl]-piperazine and is compound 5av. The compound with the (R)-methyl benzoyl piperazine is 5 av′(R)-N-(benzoyl)-3-methyl-N′-[(4-fluoro-7-chloro-6-azaindol-3-yl)-oxoacetyl]-piperazine and is compound 5av′
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH:27]([NH:30][C:31]([CH:33]1[CH2:38][O:37][CH2:36][CH2:35][NH:34]1)=[O:32])([CH3:29])[CH3:28]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[C:4]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:3]([CH2:2][N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH:33]2[C:31](=[O:32])[NH:30][CH:27]([CH3:28])[CH3:29])[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: CC(C)NC(=O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)NC(C)C)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 29.4 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.57 g, 1.2 mmol) was reacted with N-isopropylmorpholine-3-carboxamide (0.21 g, 1.2 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (0.2 g, 30%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].[NH:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1>>[NH2:45][CH:42]1[CH2:43][CH2:44][N:39]([C:16]2[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[CH:33]=[CH:32][S:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]3[CH:12]=[CH:11][C:10](=[O:38])[N:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[C:14]=3[N:15]=2)[CH2:40][CH2:41]1
Reactant: NC1CCNCC1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1nc(N2CCC(N)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 32 %

Procedure:
The title compound was prepared from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-3-thiophenecarboxamide and 4-piperidinamine according to General Procedure for Sulfoxide/Sulfone Displacement, described above. The concentrated reaction mixture was purified via reversed-phase HPLC to give the desired compound as a light tan powder (0.041 g, 32%). HPLC indicated the material to be >95% pure (m.p. 183.8-187.9): LC-MS m/z 573 (M+H)+, 1.79 min (ret time).
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[S:14])=[CH:8][CH:7]=1>C(O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:3][C:2]#[N:1])=[S:14])=[CH:8][CH:7]=1
Reactant: N#CN
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
The suspension of monosodium cyanamide (1.9 g, 29.4 mmol) in absolute ethanol (5 mL) was slowly treated with 4-chlorophenylisothiocyanate (5.0 g, 29.4 mmol). The reaction was allowed to stir at room temperature for one hour and then heated at 75° C. for four hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title compound (5.4 g), mp>250° C.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[N+:15]([C:18]1[CH:24]=[C:23]([CH2:25][C:26]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:27])[CH:22]=[CH:21][C:19]=1[NH2:20])([O-])=O>O.CO>[N:28]1([C:26]([CH2:25][C:23]2[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([NH2:15])[CH:24]=2)=[O:27])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1ccc(CC(=O)N2CCCC2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(CC(=O)N2CCCC2)cc1N

Procedure:
A mixture of sodium dithionite (245 g) and sodium carbonate (196 g) in water (1129 ml) and methanol (1029 ml) was stirred and 2-nitro-4-pyrrolidin-1-ylcarbonylmethylaniline (30.5 g) was added over a period of five minutes. A further portion of water (1468 ml) was added and the solution was heated under reflux for 65 minutes. The volume was reduced in vacuo in several stages with any solid material removed by filtration between each stage. Any solid so removed was washed with methanol and the washings combined with the final filtrate. The resulting solution was evaporated to dryness and the residue dried by azeotropic distillation with toluene and then ethanol. The dried residue was extracted with boiling ethanol and the solution filtered to give a solution which yielded 4-pyrrolidin-1-ylcarbonylmethyl-o-phenylenediamine (m.p. 105°-108° C.) on evaporation.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[CH2:26]([N:25]([CH3:24])[C:1](=[O:8])[CH2:2][CH2:3][C:4](=[O:5])[CH3:6])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)CCC(=O)O
Reactant: CNCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)CCC(=O)N(C)Cc1ccccc1
Yield: 88.6 %

Procedure:
A! Starting from 10 g (0.086 mole) of levulinic acid, 11.8 ml (0.086 mole) of triethylamine, 11.2 ml (0.086 mole) of isobutyl chloroformate and 13.3 ml (0.103 mole) of N-methyl-benzylamine in 200 ml of acetone, and following the procedure of Example 6,B!, there were obtained 16.7 g (yield: 88%) of N-benzyl-N-methyl-4-oxo-pentanamide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH2:36]>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:36][CH2:35][CH2:34][CH2:33][N:32]([CH3:37])[CH3:31])=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCCN
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Product: CN(C)CCCNC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1

Procedure:
A solution of 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 2 mL of dioxane and 35 μl of N,N-dimethyl-1,3-propanediamine is heated by microwave at 130° C. for 15 minutes. The reaction mixture is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane/methanol/aqueous ammonia (75/23/2 by volume) to give 72 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-3-[3-(dimethylamino)propyl]urea, the characteristics of which are as follows: