Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[O:25]1[CH:28]([CH3:29])[C:26]1([CH3:30])[CH3:27].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH:28]([C:26]([OH:25])([CH3:30])[CH3:27])[CH3:29])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: CC1OC1(C)C
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(n1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O)C(C)(C)O
Temperature: 85 °C
Reaction time: 48 h
Yield: 20.1 %

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (300 mg, 0.84 mmol), prepared as described in Example 1, in 0.6 mL of DMF was added 2,3-epoxy-2-methylbutane (4.8 mg, 0.056 mmol), followed by K2CO3 (15.5 mg, 0.112 mmol). The mixture was heated at 85° C. for 16 h. After this time, an additional 10 mg of K2CO3 and 2,3-epoxy-2-methylbutane (4.8 mg, 0.056 mmol) were added. The reaction was allowed to continue stirring at 85° C. for an additional 48 h. The reaction was cooled to RT and filtered. The collected solution was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give the title compound, 7,8-bis(4-chlorophenyl)-2-(3-hydroxy-3-methylbutan-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (5 mg, 20% yield) as a yellow oil. MS [M+H]+: found 443; 1H NMR (CDCl3, 400 MHz) δ 8.25 (s, 1H), 7.39-7.27 (m, 6H), 7.14 (dd, 2H), 4.55 (q, 1H), 1.52 (d, 3H), 1.34 (s, 1H), 1.23 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](OCC)(OCC)[CH:10]([NH2:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[C:23]([N:27]=[C:28]=S)[CH:22]=1>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[N:27]([C:23]3[CH:22]=[C:21]([CH3:30])[CH:26]=[CH:25][CH:24]=3)[CH:28]=[N:20][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N=C=S)c1
Reactant: CCOC1(OCC)CCN(Cc2ccccc2)CC1N
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-n2cnc3c2CCN(Cc2ccccc2)C3)c1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
A solution of 1-benzyl-4,4-diethoxy-piperidin-3-ylamine 16 (600 mg, 2.2 mmol), and m-tolyl isothiocyanate (328 mg, 2.2 mmol) in 10 mL chloroform was heated at 60° C. for 2 hr. The solvent was removed in vacuo, and the residue was treated with 10 mL each of 10% hydrochloric acid and dioxane and heated at reflux for 1 h. After removal of the solvent the residue was dissolved in 50 mL ethanol followed by addition of Raney Nickel (ca. 3.0 g). The suspension was heated at reflux for 2 h then allowed to cool to room temperature. The solids were removed by filtration. The solvent was evaporated in vacuo, and the residue was diluted with 10% sodium hydroxide solution and extracted into chloroform. The organic layer was dried over potassium carbonate, filtered and concentrated to provide 500 mg of 5-benzyl-1-m-tolyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine 17a as a light brown oil, [M+H]+=304.
Reaction SMILES: [NH:1]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C@H]2CC[C@H](CC(OC)=O)CC2)=[CH:9][CH:8]=1)=[O:5])[NH2:2].O=C(NC1C=C[C:35]([S:38](CCC)(=[O:40])=[O:39])=[CH:34][CH:33]=1)C(OC)=O>>[NH:1]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([S:38]([CH2:35][CH2:34][CH3:33])(=[O:40])=[O:39])=[CH:11][CH:12]=1)=[O:5])[NH2:2]
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Reactant: CCCS(=O)(=O)c1ccc(NC(=O)C(=O)OC)cc1
Product: CCCS(=O)(=O)c1ccc(NC(=O)C(=O)NN)cc1

Procedure:
The procedure described for Intermediate 43 (part iv) was followed starting with methyl oxo{[4-(propylsulphonyl)phenyl]amino}acetate to give the title compound (Intermediate 97); 1H NMR δ 0.85-0.97 (m, 3H), 1.46-1.65 (m, 2H), 3.18-3.27 (m, 2H), 4.77 (s, 2H), 7.85 (d, 2H), 8.10 (d, 2H), 10.44 (s, 1H), 11.09 (s, 1H); MS m/e MH+ 286.
Reaction SMILES: CN(C)C=O.Cl.Cl[CH:8]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[F:23])[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][CH:8]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:27][CH:26]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cc1cccnc1C(Cl)c1cc(F)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cccnc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a dimethylformamide (5 ml) solution of the 2-[chloro-(2,5-difluorophenyl)methyl]-3-methylpyridine hydrochloride (94 mg, 0.32 mmol) obtained in Referential Example 14 were added 4-chlorobenzenethiol (70 mg, 0.49 mmol) and potassium carbonate (265 mg, 1.92 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, diethyl ether (50 ml) was added to the reaction mixture. The resulting mixture was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane:ethyl acetate 10:1), whereby the title compound (103 mg, 89%) was obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:18]=3)=[C:15]3[N:10]([CH:11]=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:37][S:38]SC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:18]=3)=[C:15]3[N:10]([C:11]([S:38][CH3:37])=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2nn3cnccc3c2-c2ccnc(NC3CCCC3)n2)c1
Reactant: CSSC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3cccc(Cl)c3)nn12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 57.3 %

Procedure:
To a cold (−78° C.) solution of 4-[2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentyl-2-pyrimidinamine (267 mg, 0.683 mmol) in tetrahydrofuran (8 mL) was added lithium diisopropylamide (12.8 mL, 0.16 M in tetrahydrofuran, 2.05 mmol, made from 5 mL n—BuLi (1.6 M in hexanes) and 1.19 mL diisopropylamine in 43.5 mL tetrahydrofuran at 0° C.) dropwise. The reaction mixture was stirred at −78° C. for 10 minutes followed by the addition of methyl disulfide (246 μL, 2.73 mmol). The resultant mixture was stirred at −78° C. for 10 minutes then quenched with water. Upon warming to room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 to 3:1 hexanes:ethyl acetate) provided 4-[2-(3-chlorophenyl)-7-(methylthio)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine (171 mg, 57%) as a white solid. Rf 0:10 (4:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.12 (d, 1H), 7.99–7.91 (m, 2H), 7.73 (s,1H), 7.51 (d, 1H), 7.48–7.34 (m, 2H), 6.35 (d,1H), 5.19 (d, 1H), 4.30 (m, 1H), 2.76 (s, 3H), 2.05 (m, 2H), 1.82–1.50 (m, 6H); MS m/z 437 (M+1).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Br:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1.[Cl-].[NH4+]>CN(C)C=O.O>[Br:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH2:21][CH2:22][O:23][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCOc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 79 %

Procedure:
tert-Butyldimethylchlorosilane (8.7 g) and imidazole (3.9 g) were added to a solution of 3-(4-bromophenoxy)propan-1-ol in N,N-dimethylformamide (193 mL) under ice-cooling, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was ice-cooled and water and a saturated ammonium chloride solution were added, followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:1). Pyrrolidine (4.82 mL) and triethylamine (8.86 mL) were added to a solution of the resulting crude product in tetrahydrofuran (145 mL) under ice-cooling, and the mixture was stirred at room temperature for 27 hours. The reaction solution was ice-cooled and a saturated ammonium chloride solution was added, followed by extraction with a mixture of hexane-chloroform (1:1). The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:1→80:1) to give the title compound (7.88 g, 79% (two steps)).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[Cl:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][Cl:22]>C(#N)C>[CH2:7]([N:19]([CH2:20][CH2:21][Cl:22])[CH2:18][CH2:17][Cl:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCCNCCCl
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: ClCCN(CCCl)Cc1ccccc1
Temperature: 60 °C
Yield: 65.4 %

Procedure:
21 g (152 mmol) of potassium carbonate and then 8 ml (67 mmol) of benzyl bromide are added to a solution of 10 g (56 mmol) of bis(2-chloroethyl)amine hydrochloride in 130 ml of acetonitrile, and then the reaction medium is heated at 60° C. for 24 h. After filtration, the filtrate is concentrated under vacuum. The crude residue is purified by chromatography on silica gel, elution being carried out with a 90/10 heptane/ethyl acetate mixture, to give 8.5 g (65%) of benzylbis(2-chloroethyl)amine.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(C)(C)C.C1COCC1.Cl>[OH-].[Na+].O>[C:24]([O:23][C:21]([NH:20][CH2:19][CH2:18][S:17][C:9]1[N:8]([CH2:7][C:6]([OH:28])=[O:5])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)Cn1c(SCCNC(=O)OC(C)(C)C)nc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCSc1nc2ccccc2n1CC(=O)O
Reaction time: 7 h
Yield: 77.2 %

Procedure:
tert-Butyl[2-(2-tert-butoxycarbonylamino-ethylsulfanyl)-benzoimidazol-1-yl]-acetate (Precursor V-02b, 28.5 mg, 0.07 mmol) is suspended in 0.2 M aqueous NaOH (2.1 ml), THF (3.95 ml) is then added and the initially turbid suspension becomes a clear solution. After 7 h, 1M aqueous HCl solution (420 μl) is added. The solution is diluted with water (10 ml) and extracted with dichloromethane (15 ml). The organic phase is dried over MgSO4 filtered over a fritted funnel and the solvents are evaporated in vacuo. Drying of the residue under high vacuum yields the title compound (19 mg) in 77% as a colourless solid: tR=1.74 min (LC-2), ESI-MS (pos.): m/z 352.17 [M+H]+, ESI-MS (neg.): m/z 350.20 [M−H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH:13]=O.Cl.[CH2:16]([O:18][C:19]([C:21]1[N:22]([CH3:27])[N:23]=[C:24]([NH2:26])[CH:25]=1)=[O:20])[CH3:17].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:27][N:22]1[C:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])=[CH:25][C:24]([NH:26][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:23]1
Reactant: Cc1onc(-c2ccccn2)c1C=O
Reactant: CCOC(=O)c1cc(N)nn1C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(NCc2c(-c3ccccn3)noc2C)nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a mixture of 5-methyl-3-(pyridin-2-yl)isoxazole-4-carbaldehyde (811 mg, 4.31 mmol) and 5-amino-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester hydrochloride (886 mg, 4.31 mmol) in MeOH (36 mL) was added molecular sieves (1.3 g). The reaction mixture was stirred at RT for 1 h. Then acetic acid (3.45 mL, 60.3 mmol) was added. After stirring for additional 5 min, sodium cyanoborohydride (542 mg, 8.62 mmol) was added in portions over 2 min and the reaction mixture was stirred at RT for 30 min, then evaporated. The residue was extracted with dichloromethane and then washed with a saturated solution of sodium hydrogen carbonate. The organic layers were washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, dichloromethane) afforded the title compound as a white solid (814 mg, 55%). MS: m/e=342.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[CH:11][N:12]([CH2:13][CH3:14])[C:4]=2[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[Cl:22].[F-].[Cs+]>COCCOC.CO.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>[CH2:13]([N:12]1[C:4]2[CH:3]=[C:2]([C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[C:21]([Cl:22])[CH:20]=3)[N:7]=[C:6]([C:8]#[N:9])[C:5]=2[N:10]=[CH:11]1)[CH3:14]
Reactant: CCn1cnc2c(C#N)nc(Cl)cc21
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: CCn1cnc2c(C#N)nc(-c3ccc(Cl)c(Cl)c3)cc21
Temperature: 80 °C
Yield: 46.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium (15 mg) was added under a nitrogen atmosphere to a mixture of 6-chloro-1-ethyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (42 mg), 3,4-dichloro-phenylboronic acid (152 mg) and cesium fluoride (100 mg) in DME (2mL) and methanol (1 mL). The mixture was heated at 80° C. for 24 hours then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by using preparative LC/MS (eluent: A: NH4HCO3 10 mM/B: CH3CN). to afford the title compound (30 mg) as a white solid. 1H NMR (CDCl3) δ: 8.20-8.15 (m, 2H); 7.94 (d, J=8 Hz, 1H); 7.91 (s, 1H); 7.58 (d, J=8 Hz, 1H); 4.37 (q, J=7 Hz, 2H); 1.65 (t, J=7 Hz, 3H). MS m/z: 317/ 319 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].[CH3:19]O.S(=O)(=O)(O)O>O>[Cl:1][C:2]1[C:3]([S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([O:7][CH3:19])=[O:6]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1Sc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(Cl)c(Cl)c1Sc1ccccc1

Procedure:
A mixture of 3,4-dichloro-2-phenylsulphenylbenzoic acid (25.0 g), methanol and concentrated sulphuric acid (5 ml) was heated at reflux for 22 hours. Water was added and the mixture concentrated. The residue was taken up in ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous magnesium sulphate and filtered. The solvent was evaporated and the oil purified by chromatography on silica, using a mixture of cyclohexane, ether and toluene to give methyl 3,4-dichloro-2-phenylsulphenylbenzoate (13.8 g) as a clear oil, 1H NMR (CDCl3) 3.7 (3H,s), 7.1 (SH,m), 7.4(2H, m).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[N+:12]([O-])([OH:14])=[O:13]>CC(O)=O>[N+:12]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[C:4]=1[OH:9])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccccc1C(F)(F)F
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44 %

Procedure:
To a solution of commercially available 2-trifluoromethylphenol (2.5 g, 15.42 mmol) in AcOH (3 mL) cooled to 0° C. was added dropwise concentrated HNO3 (1.5 mL). After the addition, the mixture was stirred at 0° C. for 5 min, at rt for 10 min, then poured into ice/water, and extracted with ether (3×). The combined ether extracts were washed with water, brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 0% to 10% EtOAc/hexane to yield the title compound (1.4 g, 44% yield).
Reaction SMILES: [NH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[N:3][C:2]1=S.O.[NH2:16][NH2:17]>>[NH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[N:3][C:2]1=[N:16][NH2:17]
Reactant: S=c1nnc2c([nH]1)[nH]c1ccccc12
Reactant: NN
Solvent: O
Product: NN=c1nnc2c([nH]1)[nH]c1ccccc12
Temperature: 120 °C

Procedure:
A solution of 1,9-Dihydro-1,3,4,9-tetraaza-fluorene-2-thione 14c (56 mmol, 1 equiv.) in hydrazine hydrate (195 mL) is heated to reflux (120° C.) for 4 hours as disclosed in Joshr, K. C.; Dandia, A.; Bawbia, S. J. Ind Chem. Soc. (1989), 66, 690-693 and references therein. The mixture is allowed to cool to room temperature for 48 hours. The orange-yellow precipitate is filtered, washed with water and ethanol, and dried under vacuum for 15 hours to yield (1,9-Dihydro-1,3,4,9-tetraaza-fluoren-2-ylidene)-hydrazine 14d as a yellow powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.Cl.[C:10]([O:14][C:15](=[O:19])[C@H:16]([CH3:18])[NH2:17])([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[C:10]([O:14][C:15](=[O:19])[C@@H:16]([NH:17][C:6]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:8])[CH3:18])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C(O)c1ncc[nH]1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1ncc[nH]1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
To a solution of 1H-imidazole-2-carboxylic acid (0.179) in N,N-dimethylformamide (DMF) (3 mL) was added alanine tert-butyl ester hydrochloride (0.22 g), diisopropylethyl amine (0.27 mL) and HOBT (0.41 g) before cooling to 0° C. and the reaction mixture was then treated with EDC HCl (0.32 g). The cooling bath was removed and the reaction mixture was stirred at ambient temperature for 18 hrs before being diluted with ethyl acetate and washed with water and brine, dried (MgSO4) and concentrated at reduced pressure. The residue was purified by silica gel chromatography (30% ethyl acetate in hexanes) to afford the sub-title compound as a colourless oil (0.263 g, 73%): 1H NMR 400 MHz CDCl3 1.50 (9H, s), 1.51 (3H, d, J 7.2), 3.70 (1H, m), 7.28 (2H, s), 7.78 (1H, d, J 7.6), 11.49 (1H, br s).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:29](=[O:33])[C:30]([NH2:32])=[O:31])=[C:9]([CH3:28])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.CO.[Na]>[OH-].[Na+]>[NH2:32][C:30](=[O:31])[C:29]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:34])=[O:2])[N:10]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:9]=1[CH3:28])=[O:33]
Reactant: COC(=O)COc1cccc2c1c(C(=O)C(N)=O)c(C)n2Cc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccc(-c2ccccc2)cc1
Yield: 77.1 %

Procedure:
Using the procedure described in Example 2, Part E, 803 mg (1.8 mmol) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester was hydrolyzed in 10 mL of 1N NaOH and 20 mL of MeOH to give 614 mg (74% yield) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid, sodium salt, mp, >265° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].Cl.[NH2:16][CH:17]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:18]1=[O:19].C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:10]=[C:8]1[C:7]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=2)[C:11](=[O:12])[N:16]1[CH:17]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:18]1=[O:19]
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)C(=O)N1
Yield: 54.3 %

Procedure:
A mixture of 4-nitrophthalic anhydride (1.7 g, 8.5 mmol), α-aminoglutarimide hydrochloride (1.4 g, 8.5 mmol) and sodium acetate (0.7 g, 8.6 mmol) in glacial acetic acid (30 mL) was heated under reflux for 17 hours. The mixture was concentrated in vacuo and the residue was stirred with methylene chloride (40 mL) and water (30 mL). The aqueous layer was separated, extracted with methylene chloride (2×40 mL). The combined methylene chloride solutions were dried over magnesium sulfate and concentrated in vacuo to give 1.4 g (54%) of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-nitroisoindoline as a light brown solid. An analytical sample was obtained by recrystallization from methanol: mp 228.5-229.5° C.; 1H NMR (DMSO-d6) δ11.18(s, 1H), 8.69-8.65(d,d J=1.9 and 8.0 Hz, 1H), 8.56(d, J=1.9 Hz, 1H), 8.21(d, H=8.2 Hz, 1H), 5.28(d,d J=5.3 and 12.8 Hz, 1H), 2.93-2.07(m, 4H); 13C NMR (DMSO-d6) δ172.66, 169.47, 165.50, 165.23, 151.69, 135.70, 132.50, 130.05, 124.97, 118.34, 49.46, 30.85, 21.79; Anal. Calcd for C13H9N3O6: C, 51.49; H, 2.99; N, 13.86. Found: C, 51.59; H, 3.07; N, 13.73.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:35])[C:17]2[CH:22]=[N:21][C:20](S(C)(=O)=O)=[N:19][C:18]=2[N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:35])[C:17]2[CH:22]=[N:21][C:20]([NH:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:19][C:18]=2[N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:14])[CH3:11]
Reactant: NCCCN1CCCC1
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCCN3CCCC3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from 3-pyrrolidin-1-yl-propylamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (20 mg, 0.05 mmol). 8-Cyclohexyl-5-oxo-2-(3-pyrrolidin-1-yl-propylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (18 mg, 85%). Mass Spectrum (LCMS, ESI pos.) Calcd. For C23H33N5O3: 428.26 (M+H). Found: 428.3.