Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:19])=[CH:16][C:15]=1[O:33][CH3:34]>CN(C)C=O>[CH:26]1([N:20]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:18](=[O:19])[C:17]2[CH:31]=[CH:32][C:14]([CH2:13][N:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2][N:3]=[C:4]34)=[C:15]([O:33][CH3:34])[CH:16]=2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: c1cnc2nc[nH]c2c1
Reactant: COc1cc(C(=O)N(C2CCCC2)C2CCCC2)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C2CCCC2)C2CCCC2)ccc1Cn1cccc2ncnc1-2
Reaction time: 2 h

Procedure:
To a stirred solution of imidazo[4,5-b]pyridine (350 mg, 2.94 mmol) in N,N-dimethylformamide (25 mL), sodium hydride (118 mg, 60% dispersion in mineral oil, 2.94 mmol) was added. After stirring for 2 hr, 4-bromomethyl-3-methoxy-N,N-dicyclopentyl benzamide (1.4 g, 3.57 mmol) was added in small installments over 10 min. The reaction mixture was stirred under argon at 25° C. After 18h, the reaction was quenched by adding acetic acid (0.5 mL) and the solvent was removed under reduced pressure at <45° C. The crude mixture (2 g) was chromatographed (silica gel, CH2Cl2 -MeOH-NH4OH 90-10-1) to give the title compound. (145 mg, 12%) mp 223°-224° C.; Anal calcd. for C25H30N4O2.1.0H2O: C, 68.78; H, 7.39; N, 12.83. Found C, 68.88; H, 7.13; N, 12.55.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]=O)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH:18]1([O:23][C:24](=[O:33])[C@@H:25]([NH2:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH:18]1([O:23][C:24](=[O:33])[C@@H:25]([NH:32][CH2:15][CH:12]2[CH2:13][CH2:14][CH:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])[CH2:10][CH2:11]2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: N[C@H](C(=O)OC1CCCC1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCC(CN[C@H](C(=O)OC2CCCC2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 31.3 %

Procedure:
(4-Formyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (390 mg, 1.6 mmol) and (S)-amino-phenyl-acetic acid cyclopentyl ester (394 mg, 1.8 mmol) were stirred in DCE (6 ml) at r.t. for 25 min. Acetic acid (9.6 ul, 0.16 mmol) and sodium triacetoxy-borohydride (1.0 g, 4.8 mmol) were added and the resulting mixture was stirred for 1 h30 at r.t. DCM (10 ml) and a saturated solution of NaHCO3 (10 ml) were added and phases were separated. Aqueous were extracted with EtOAc (2×10 ml), the organics were dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was purified by column chromatography (8:2 heptane/EtOAc) to yield 223 mg of the pure amine (31% yield). LCMS purity 100%, m/z 445 [M++H]+.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([NH:36][NH2:37])=[CH:28][CH:27]=1>>[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:37]2)=[CH:28][CH:27]=1
Reactant: NNc1ccnc2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccnc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and quinolin-4-yl-hydrazine according to the method described for example 43. MS: M=450.1 (M+H)+
Reaction SMILES: C([O:8][N:9]1[C@@H:12]([CH3:13])[C@H:11]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[C:10]1=[O:25])C1C=CC=CC=1>C1COCC1.[Pd]>[OH:8][N:9]1[C@@H:12]([CH3:13])[C@H:11]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[C:10]1=[O:25]
Reactant: C[C@H]1[C@H](N2C(=O)c3ccccc3C2=O)C(=O)N1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: C[C@H]1[C@H](N2C(=O)c3ccccc3C2=O)C(=O)N1O
Yield: 98.4 %

Procedure:
The O-benzyl derivative (51) (23.08 g) was taken up in THF (250 ml) and hydrogenolysed in the presence of 10% Pd/C until no starting material remained. The solution was filtered through Kieselguhr and the filtrate evaporated to give a white solid (52) (16.63 g), m.p. 94°-96° C. (from EtoAc--hexane), νmax (KBr) 3400, 1795, 1770, 1720, and 1400 cm-1, δ(CDCl3) 1.45(d, J6.5 Hz, 3H) (irradiation at 4.18 caused this signal to collapse to a s), 4.18 (dq, j6.5 and 2 Hz, 1H), 4.70(d, J2 Hz, 1H) (irradiation at 4.18 caused this signal to collapse to a s), 7.3-8.0 (m, 4H), and 7.7-8.7br (1H, exch.), m/e 246(M+) and 187 (base peak). (Found: C, 58.28; H, 4.11; N, 11.46; M+ 246.0647. C12H10N2O4 requires C, 58.54; H, 4.09; N, 11.38%, M, 246.0681).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[N:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:20][NH:21][C:22](=O)[O:23]C1C=CC=CC=1>CN(C)C=O>[CH3:20][NH:21][C:22]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:14]=[C:15]([NH2:19])[N:16]=[CH:17][N:18]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:23]
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ncn1
Reactant: CNC(=O)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3cc(N)ncn3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
Sodium hydride (199 mg, 4.97 mmol) was suspended in N,N-dimethylformamide (10 ml) under nitrogen atmosphere, 6-(1H-indol-5-yloxy)pyrimidin-4-ylamine (1.07 g, 4.73 mmol) synthesized in Production example 2-2 was gradually added while the reaction mixture was stirred at room temperature. After 30 minutes, the reaction mixture was cooled with an ice water bath, then phenyl N-methylcarbamate (751 mg, 4.97 mmol) synthesized in Production example 2-1 was added. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent; ethyl acetate) to yield the title compound (847 mg, 2.99 mmol, 63%) as white crystals.
Reaction SMILES: CS([CH2:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[CH:12]=[C:13]([C:19]#[N:20])[C:14](=[CH:17][CH:18]=2)[C:15]#[N:16])=[CH:8][CH:7]=1)(=O)=O.[Li+].[Br-:24]>C1COCC1>[Br:24][CH2:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[CH:12]=[C:13]([C:19]#[N:20])[C:14](=[CH:17][CH:18]=2)[C:15]#[N:16])=[CH:8][CH:7]=1
Reactant: [Br-]
Reactant: CS(=O)(=O)Cc1ccc(Oc2ccc(C#N)c(C#N)c2)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2ccc(CBr)cc2)cc1C#N
Temperature: 25 °C

Procedure:
To a solution of 4-[4-(methansulfonylmethyl)phenoxy]phthalonitrile (1.2 g, 3.3 mmol) prepared according to Example 2, in anhydrous THF (15 ml) kept in an inert atmosphere, LiBr (0.4 g, 4.6 mmol) was added. The solution was refluxed for 1 hour, during which a white precipitate formed, then it was allowed to cool at room temperature. The white precipitate was filtered off and the solvent was evaporated. From the crude mixture the desired product was isolated by filtration on silica gel (eluent: chloroform). (1.0 g, 95%)
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([C:9]([F:21])([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([I:22])[C:3]=1[NH2:4].[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])([O-:25])=[O:24]>>[I:1][C:2]1[CH:8]=[C:7]([C:9]([F:21])([C:14]([F:19])([F:20])[C:15]([F:16])([F:17])[F:18])[C:10]([F:11])([F:12])[F:13])[CH:6]=[C:5]([I:22])[C:3]=1[NH:4][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1I
Product: O=C(Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1I)c1cccc([N+](=O)[O-])c1

Procedure:
According to the method of 4-3 of Example 4, a target compound was prepared from 2,6-diiodo-4-(perfluorobutan-2-yl)aniline and 3-nitrobenzoyl chloride.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[O:10][C:11]2[C:18]([CH:19]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:20](OCC)=[O:21])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[CH3:14])[CH3:8].O.[OH-].[Na+]>O1CCCC1>[CH2:7]([C:9]1[O:10][C:11]2[C:18]([CH:19]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:20][OH:21])=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]=1[CH3:14])[CH3:8]
Reactant: CCOC(=O)C(c1cccc2c(C)c(CC)oc12)N(CC)CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1oc2c(C(CO)N(CC)CC)cccc2c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
300 mg (7.87 mmol) of lithium aluminium hydride and 10 ml of anhydrous tetrahydrofuran are introduced into a 100 ml round-bottomed flask. This suspension is cooled to 0° C. by an ice bath and a solution of 1 g (3.15 mmol) of ethyl 2-(2-ethyl-3-methylbenzofuran-7-yl)-2-(diethylamino)acetate in 20 ml of tetrahydrofuran is added dropwise. The reaction mixture is stirred for 1 hour at room temperature and then hydrolysed by the successive addition of 0.3 ml of water, 0.3 ml of a 15% sodium hydroxide solution and 0.9 ml of water. A white precipitate is formed which is filtered off and washed with 50 ml of ether. The filtrate is washed with 50 ml of water, dried over magnesium sulphate and concentrated under vacuum. The residue is purified by chromatography on a silica column (elution solvent: 2% methanol in dichloromethane). 0.83 g (Yield: 96%) of 2-ethyl-3-methyl-7-(1-diethylamino-2-hydroxyethyl)benzofuran is obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([C:25]5[CH2:26][CH2:27][N:28]([C:31](OC(C)(C)C)=[O:32])[CH2:29][CH:30]=5)=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:38])[O:4][N:3]=1.Cl.O1CCOC[CH2:41]1>CO>[C:31]([N:28]1[CH2:29][CH2:30][CH:25]([C:23]2[N:12]3[C@@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:14][O:15][C:16]4=[C:11]3[C:10](=[CH:9][CH:8]=[C:7]4[C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:38])[N:24]=2)[CH2:26][CH2:27]1)(=[O:32])[CH3:41]
Reactant: C1COCCO1
Reactant: Cc1noc(C)c1-c1ccc2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)n3c2c1OC[C@@H]3c1ccccn1
Agent: Cl
Solvent: CO
Product: CC(=O)N1CCC(c2nc3ccc(-c4c(C)noc4C)c4c3n2[C@@H](c2ccccn2)CO4)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.6 %

Procedure:
tert-Butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3,6-dihydropyridine-1(2H)-carboxylate (3 mg, 0.006 mmol) was dissolved in methanol (0.5 mL) at room temperature, followed by addition of 4.0 M hydrogen chloride in dioxane (0.5 mL, 2 mmol) [Aldrich, cat. #345547]. The resulting mixture was stirred at room temperature for 10 min. The solvents were removed under a flow of nitrogen gas. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) afforded the title compound (1.8 mg, 70%). LCMS for C24H26O2N5 (M+H)+: calculated m/z=416.2. found 416.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br-].[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Zn+])#[N:14].O>O1CCCC1.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>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[C:15]([C:13]#[N:14])=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: N#Cc1ccccc1[Zn+]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccccc1-c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (9.68 g, 44 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.53 g, 1.3 mmol) was treated with 2-cyanophenylzinc bromide (100 ml of a 0.5M solution in tetrahydrofuran, 50 mmol) then heated under reflux for 8 h. After cooling to ambient temperature the reaction mixture was poured into water (1000 ml). After stirring for 30 min the resulting solid was collected by filtration and dried under vacuum over phosphorus pentoxide to afford 4′-fluoro-3′-nitrobiphenyl-2-carbonitrile as a tan solid (10.7 g, 100%) which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31]CC)=[CH2:30])CCC>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:22]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)[CH3:12]
Reactant: CC(c1cc2cccnc2cc1F)c1nnc2ccc(Cl)nn12
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1ccc2nnc(C(C)c3cc4cccnc4cc3F)n2n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)-7-fluoroquinoline (100 mg, 0.305 mmol), PdCl2(PPh3)2 (21.4 mg, 0.031 mmol) and tributyl(1-ethoxyvinyl)stannane (220 mg, 0.61 mmol) in 5 mL of 1,4-dioxane was heated at 90° C. for 5 h under nitrogen. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in HOAc and 3 N HCl, and stirred at rt for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM, washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/MeOH gradient to afford the title compound as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.87 (d, 1H), 8.16 (d, 1H), 8.03 (d, 1H), 7.80 (d, 1H), 7.73 (d, 2H), 34 (dd, 1H), 5.39 (q, 1H), 2.62 (s, 3H), 2.09 (d, 3H). LCMS (method A): [MH]+=336, tR=4.95 min.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](NCC3C=CC=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH2:30]>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:30][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([F:25])[CH:27]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: NCc1cccc(F)c1
Agent: Cl
Product: Cc1nc(NCc2cccc(F)c2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using (3-fluorobenzyl)amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.08 (t, J=13.57 Hz, 1H), 1.19-1.31 (m, 4H), 1.58-1.70 (m, 5H), 1.87 (s, 3H), 2.22 (s, 3H), 3.82 (d, J=6.98 Hz, 1H), 4.53 (d, J=5.91 Hz, 2H), 7.01-7.11 (m, 2H), 7.14 (d, J=7.25 Hz, 2H), 7.32-7.39 (m, 1H), 7.56 (d, J=7.79 Hz, 1H), 8.35 (s, 1H), 12.47 (s, 1H); MS (ESI) m/z 329.0 (M+1)+.
Reaction SMILES: [N:1]1[C:2]2[C:3](=[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]3=O)[CH:4]=[CH:5][CH:6]=1.N1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1.C(#N)C=C.C(CCC(C1C=CC=CC=1)C(=O)C)#N.C(CCC(C1C=CC(F)=CC=1)C(=O)C)#N.CC(=O)CCC.CC1C(C2C=CC=CC=2)CCCN1.CC1C(C2C=CC(F)=CC=2)CCCN1>>[CH3:13][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=C1C=CC=C2C=c3ncccc3=C12
Agent: CC(=O)C(CCC#N)c1ccc(F)cc1
Agent: CC(=O)C(CCC#N)c1ccccc1
Agent: CC1NCCCC1c1ccc(F)cc1
Solvent: CCCC(C)=O
Solvent: C=CC#N
Product: Cc1ncccc1-c1ccccc1

Procedure:
Alternatively, 5H-indeno[2,1-b]pyridine-5-one (also called 1-azafluoren-9-one) and 5 to 8 position fluoro or chloro derivatives are prepared according to a general procedure of Urbina, Synthetic Comm., 9, 245 (1979). Where to a substituted or unsubstituted 1-phenyl-2-propanone (e.g., 1-(4'-fluorophenyl)-2-propanone) is added acrylonitrile producing a corresponding 5-cyano-3-phenyl-2-pentanone, e.g., 5-cyano-3-(4'-fluorophenyl)-2-pentanone. The pentanone product is hydrogenated and cyclized to the corresponding 2-methyl-3-phenylpiperidine, e.g., 2-methyl-3-(4'-fluorophenyl)piperidine. Aromatization of the 2-methyl-3-phenyl piperidine is carried out in vapor phase with catalyst K-16 (Prostakon, Mathew and Kurisher, Khim-Geterotsikl. Socd., 8v6 (1970)) at 380° to 420° C. to yield the corresponding 2-methyl-3-phenylpyridine. Alternatively, aromatization can be achieved with Pd/C. Dehydrocyclization of the methyl-3-phenylpyridine at 500° C. to 550° C. over K-16 will produce the appropriate 1-azafluorene, e.g., 7-fluoro-1-azafluorene. The 9H-indeno [2,1-b]pyridine and its derivatives (e.g., 7-fluoro-9H-indeno[2,1-b]pyridine) are converted in accordance with Method II, III and IV into spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide derivatives. The 9H-indeno[2,1-b]pyridine is oxidized according to general procedures cited in Method VII or potassium permanganate (Urbina, ibid). The resulting ketone, e.g., 7-fluoro-9H-indeno[2,1-b]pyridin-5-one, is derivatized in accordance with Method I to yield the spiro-hydantoin derivative, such as spiro-(7-fluoro-9H-indeno[2,1-b]pyridin-9,4'-imidazolidine)-2',5'-dione.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[NH:8][N:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:13]=[CH:12][C:11]([C:9]2[NH:8][N:7]=[C:6]([CH2:4][OH:3])[CH:10]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)[nH]n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(-c2ccc(C(F)(F)F)cc2)[nH]n1
Temperature: 0 °C
Yield: 58.9 %

Procedure:
A solution of 5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (160 mg, 0.56 mmol; PCT Int. Appl. (2003), WO 2004000785 A2) in tetrahydrofuran (2.5 ml) was added to a suspension of lithium aluminium hydride (43 mg, 1.13 mmol) in tetrahydrofuran (2.5 ml) under an argon atmosphere at ambient temperature within 5 min. The mixture was heated to reflux for 12 h, cooled to 0° C. and treated cautiously with water (2 ml) and 10% aqueous NaOH (0.5 ml). The reaction mixture was filtered over celite, ice water/ethyl acetate 1/1 was added and the layers were separated. The aqueous layer was extracted one more time with ethyl acetate, the combined organic layers were washed with ice water/brine 1/1 and dried over sodium sulfate. Removal of the solvent under reduced pressure gave 81 mg (0.33 mmol, 59%) of the title compound as white solid.
Reaction SMILES: Cl[C:2]1[N:14]([CH3:15])[C:5]2=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]2[N:3]=1.[CH2:16]([S:18][C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1)[CH3:17].[H-].[Na+].O>CN(C=O)C>[CH2:16]([S:18][C:19]1[N:20]([C:2]2[N:14]([CH3:15])[C:5]3=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]3[N:3]=2)[CH:21]=[CH:22][CH:23]=1)[CH3:17]
Reactant: Cn1c(Cl)nc2cc(C(F)(F)F)cnc21
Reactant: CCSc1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cccn1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.1 %

Procedure:
A solution of 0.49 g of 2-chloro-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine in DMF (2 ml) was added to a mixture of 0.24 g of 2-ethylthio-1H-pyrrole, 0.11 g of sodium hydride (60% oil-based) and 3 ml of DMF, and the mixture was stirred at room temperature for 1.5 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesiums sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.53 g of 2-(2-ethylthiopyrrol-1-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound of Present Invention (23)).
Reaction SMILES: C([O:5][C:6](=[O:35])[C@@H:7]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[NH:8][S:9]([C:12]1[CH:21]=[C:20]2[C:15]([C:16]([Cl:26])=[CH:17][N:18]=[C:19]2[NH:22][C:23]([NH2:25])=[NH:24])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(C)(C)C.CCOCC>CCOC(C)=O.Cl>[ClH:26].[Cl:26][C:16]1[C:15]2[C:20](=[CH:21][C:12]([S:9]([NH:8][C@@H:7]([C:6]([OH:35])=[O:5])[CH2:27][C:28]([OH:30])=[O:29])(=[O:11])=[O:10])=[CH:13][CH:14]=2)[C:19]([NH:22][C:23]([NH2:25])=[NH:24])=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@H](CC(=O)O)C(=O)O)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 130.5 %

Procedure:
N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-aspartic acid di-t-butyl ester (50 mg, 0.095 mmol) was dissolved in a solution of EtOAc saturated with HCl (10 mL) and the mixture stirred at room temperature for 4 h. The mixture was concentrated in vacuo and the residue triturated with PhMe and then Et2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-aspartic acid hydrochloride (29 mg, 0.062 mmol) as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1>C(O)CCC>[N+:17]([C:13]1[CH:12]=[C:11]([C:9]2[NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:8][C@@H:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH3:10])[C:3]=3[CH:10]=2)[CH:16]=[CH:15][CH:14]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cccc(-c2cc3c(Cl)ncnc3[nH]2)c1
Solvent: CCCCO
Product: C[C@@H](Nc1ncnc2[nH]c(-c3cccc([N+](=O)[O-])c3)cc12)c1ccccc1

Procedure:
Analogously to the method described in stage 19.4, boiling 20.0 g (700 mmol) of 4-chloro-6-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine (prepared analogously to stages 19.1 to 19.3) with 23.1 ml (168 mmol) of (R)-phenylethylamine in 23.1 ml of n-butanol gives (R)-6-(3-nitrophenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo-[2,3-d]pyrimidine as rust-brown crystals of m.p.>250° C.; MS: M+=359.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH2:10]([C:12]([CH2:19]OS(C)(=O)=O)([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]=[O:14])[CH3:11].SC(O)C1C=CC=CC=1.Cl>C(N(CC)CC)C.COCCOCCOC>[CH2:10]([C:12]([CH2:19][S:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])([CH:15]=[CH:16][CH2:17][CH3:18])[CH:13]=[O:14])[CH3:11]
Reactant: OCc1ccccc1S
Reactant: CCCCC(C=O)(CC)COS(C)(=O)=O
Agent: Cl
Agent: OC(S)c1ccccc1
Solvent: CCN(CC)CC
Solvent: COCCOCCOC
Product: CCC=CC(C=O)(CC)CSc1ccccc1CO
Yield: 107.8 %

Procedure:
A mixture of 5.0 g (0.036 mole) of 2-mercaptobenzyl alcohol, 6.4 g (0.032 mole) of 1, 3.6 g (0.036 mole) of triethylamine and 25 mL of 2-methoxyethyl ether was held at reflux for 7 h. Additional 1.1 g of mercaptobenzyl alcohol and 0.72 g of triethylamine was added to the reaction mixture and the mixture was held at reflux for additional 16 h. The reaction mixture was cooled and poured into 6N HCl and extracted with methylene chloride. The methylene chloride extract was washed twice with 10% NaOH, dried over MgSO4 and concentrated in vacuo to give 9.6 g of residue. Purification by HPLC (20% EtOAc-hexane) gave 3.7 g (41%) of 16 as an oil.