Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:25]2[CH2:30][CH2:29][N:28]([CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH2:27][CH2:26]2)=[C:21]([CH:24]=1)[C:22]#[N:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[CH2:27][CH2:26]4)=[C:21]([C:22]#[N:23])[CH:24]=3)=[O:15])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Reactant: O=C(O)c1ccn(-c2ccc(Cl)cc2)c1
Product: N#Cc1cc(NC(=O)c2ccn(-c3ccc(Cl)cc3)c2)ccc1N1CCN(C2CCOCC2)CC1
Yield: 36.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)pyrrole-3-carboxylic acid (0.5 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (0.7 g), the title compound (0.4 g) was obtained, melting point: 224° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.O[C@H:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[NH:39][CH2:38][CH2:37][CH2:36]2>C(Cl)Cl>[Cl:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[N:39]([C@@H:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])[CH2:38][CH2:37][CH2:36]2
Reactant: Clc1ccc2c(c1)CCCN2
Reactant: O=C1NCC[C@@H]1O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1NCC[C@H]1N1CCCc2cc(Cl)ccc21
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
Prepared using general procedure 57. Under an N2 atmosphere at −20° C., N,N-diisopropylethylamine (1.74 mL, 10.0 mmol) was added dropwise to a solution of (S)-3-hydroxypyrrolidin-2-one (500 mg, 5.0 mmol) in CH2Cl2 (8 mL). Trifluoromethanesulfonic anhydride (0.88 mL, 5.25 mmol) was added dropwise to this solution. Upon completion of addition, the mixture was stirred at −20° C. for 30 min. 6-Chloro-1,2,3,4-tetrahydroquinoline (1.26 g, 7.5 mmol) was added in one portion. The reaction was allowed to warm up to RT overnight. After 18 h, the reaction mixture was washed with saturated aqueous sodium bicarbonate (2×20 mL), brine (20 mL), dried over magnesium sulfate, and concentrated. Purification via silica gel chromatography using 0-30% ethyl acetate in hexane gave (R)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)pyrrolidin-2-one as a colorless oil (150 mg, 12%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=251.3; tR=2.77 min.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][O:11][CH3:12].[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[CH3:12][O:11][CH2:10][CH2:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:13]([OH:18])[OH:14]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCCOc1ccccc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COCCOc1ccccc1B(O)O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 49.4 %

Procedure:
To a solution of the compound of step 1 (2.20 g, 7.91 mmol) in toluene (20 ml) and THF (4 ml) was added triisopropyl borate (2.19 ml, 9.49 mmol), and the mixture was cooled to −78° C. n-Butyllithium (3.79 ml, 9.49 mmol, 2.5 M in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 1.5 h. The cooling bath was removed and the reaction mixture was allowed to warm to −20° C. Then 2 N hydrochloric acid (7 ml) was added. When the mixture had reached room temperature, water and EA were added. The organic layer was separated, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography (EA/HEP 1:4). 766 mg of the title compound were obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][C:8]2=[O:19])[CH2:2]1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])([O-])=O.[K+].[K+].[I-].[K+]>O.C(Cl)(Cl)Cl>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][C:8]2=[O:19])[CH2:2]1)[CH3:26]
Reactant: O=c1[nH]c2cnc3[nH]ccc3c2n1C1CCCNC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN1CCCC(n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Temperature: 90 °C

Procedure:
A mixture of 1-piperidin-3-yl-3,6-dihydroimidazo[4,5-d]-pyrrolo[2,3-b]pyridin-2(1H)-one (0.030M solution in NMP, 1.00 mL), ethyl bromoacetate (6.7 mg), K2CO3(8.3 mg), potassium iodide (0.3 mg) was heated at 90° C. for 16 hours. Chloroform (4 mL) and water (2 mL) was added and was mixed with Bortex Mixer. The organic phase was separated with 1PS Filter Tube (from Whatman) and evaporated. Purification by preparative high performance liquid chromatography gave ethyl[3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidin-1-yl]acetate (2.8 mg).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[CH:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24].C([O-])([O-])=O.[K+].[K+]>C(O)C.C1(C)C=CC=CC=1.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>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:28]3[CH:29]=[CH:30][C:25]([CH:23]=[O:24])=[CH:26][CH:27]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
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: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccc(C=O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see intermediate 100) (1 g, 2.71 mmol) and 4-formylbenzeneboronic acid (0.487 g, 3.25 mmol) in ethanol (4.7 mL) and toluene (4.70 mL) was treated with K2CO3 (0.449 g, 3.25 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.156 g, 0.135 mmol). The resulting mixture was stirred under nitrogen at 90° C. for 16 h then was cooled to room temperature and concentrated in vacuovacuo. The residue was partitioned between water (8.5 mL) and EtOAc (3 mL) and the resulting biphasic mixture was stirred at room temperature for 30 min then the insoluble residue was filtered off and dried under house vacuo at 40° C. for 1 hr to give 1-methylethyl[(2S,4R)-1-acetyl-6-(4-formylphenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (1.0759 g, 2.59 mmol, 96% yield) as a light yellow solid.
Reaction SMILES: O1CCCCC1[N:7]1[C@@H:10]([CH2:11][CH2:12][O:13]C2CCCCO2)[C@H:9]([CH2:20][CH2:21][O:22][O:23][C:24]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:25])[C:8]1=[O:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.P([O-])([O-])([O-])=O>CO>[N+:33]([C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:24]([O:23][O:22][CH2:21][CH2:20][C@H:9]2[C@H:10]([CH2:11][CH2:12][OH:13])[NH:7][C:8]2=[O:36])=[O:25])=[CH:32][CH:31]=1)([O-:35])=[O:34]
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)OOCC[C@@H]1C(=O)N(C2CCCCO2)[C@H]1CCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)OOCC[C@@H]1C(=O)N[C@H]1CCO
Reaction time: 2 h

Procedure:
A solution of trans-1-(2-tetrahydropyranyl)-3-(1-p-nitrobenzylcarbonyldioxyethyl)-4-[2-(2-tetrahydropyranyl)oxyethyl]-2-azetidinone in methanol at 25° C. is treated with 0.1 molar equivalent of p-toluenesulfonic acid monohydrate. The solution is stirred for a period of 2 hours and then neutralized with 1M pH7 phosphate buffer. The product is extracted into ethyl acetate. The ethyl acetate solution is washed with brine, dried over magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure to give trans-3-(1-p-nitrobenzylcarbonyldioxyethyl)-4-(2-hydroxyethyl)-2-azetidinone. The cis diastereoisomers are obtained in an analogous manner.
Reaction SMILES: [Cl-].[OH:2][C@H:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C@@H:4]([NH3+:6])[CH3:5].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26](I)=[CH:27][CH:28]=3)[CH:23]=[N:22]2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([O:2][C@H:3]([CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:6])[CH3:5])=[CH:27][CH:28]=3)[CH:23]=[N:22]2)=[CH:19][CH:20]=1
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: C[C@H]([NH3+])[C@H](O)Cc1ccccc1
Agent: [Cl-]
Product: C[C@H](N)[C@@H](Cc1ccccc1)Oc1ccc2c(cnn2-c2ccc(F)cc2)c1

Procedure:
Prepared as described in Example 1 from (2S,3R)-3-hydroxy-4-phenylbutan-2-aminium chloride (290 mg, 1.44 mmol) and 1-(4-fluorophenyl)-5-iodoindazole (583 mg, 1.73 mmol). Yield 340 mg (63%).
Reaction SMILES: OC(C(F)(F)F)=O.[OH:8][NH:9][C:10]([C@H:12]1[CH2:17][C@H:16]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH2:15][N:14]([CH3:25])[C@@H:13]1[C:26]([N:28]1[CH2:33][CH:32]=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])=[O:11].[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[OH:8][NH:9][C:10]([C@H:12]1[CH2:17][C@H:16]([O:18][C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[CH2:15][N:14]([CH3:25])[C@@H:13]1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])=[O:11]
Reactant: [H][H]
Reactant: CN1C[C@@H](Oc2ccncc2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CC=C(c2ccccc2)CC1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CN1C[C@@H](Oc2ccncc2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCC(c2ccccc2)CC1
Yield: 91.2 %

Procedure:
A mixture of (2S,3S,5S)—N-hydroxy-1-methyl-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)piperidine-3-carboxamide TFA salt (4 mg, 0.00001 mol) in 1 mL of MeOH was hydrogenated in the presence of 5% Pd/BaSO4, under balloon pressure of hydrogen, for 2 h. After filtered off the catalyst, the filtration was concentrated to dry to yield the titled compound (4 mg, 100%). MS (ESI): (M+H)+=439.2.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[CH2:33][CH2:32][C:31]([CH3:39])([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]4)=[N:26][CH:27]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]3[CH:27]=[N:26][C:25]([N:28]4[CH2:29][CH2:30][C:31]([CH3:39])([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]4)=[N:24][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(-c3ccccn3)c2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
To an ice-cold solution of ethyl 1-[5-[2-(ethylcarbamoylamino)-7-(2-pyridyl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (0.18 g, 0.33 mmol) in DMSO (2 mL) was added potassium tert-butoxide (0.184 g, 1.65 mmol) and the mixture stirred at rt for 2 h. After completion of reaction (by TLC), water (10 mL) was added followed by extraction with EtOAc (2×50 mL). The organic layer was discarded and the pH of the aqueous layer was adjusted up to 4-5 then extracted with hot EtOAc (3×100 mL). The combined organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue thus obtained was triturated with ether to afford the desired product as off-white solid (0.11 g, 65% yield). 1H NMR (DMSO-d6): δ 1.10 (t, J=7.20 Hz, 3H), 1.19 (s, 3H), 1.40 (m, 2H), 2.04 (m, 2H), 3.22 (q, J=7.20, 2H), 3.39 (m, 2H), 4.30 (m, 2H), 6.87 (br s, 1H, D2O exchangeable), 7.44 (m, 1H), 7.92 (s, 1H), 7.99 (m, 1H), 8.18 (s, 1H), 8.42 (d, J=8.0 Hz, 1H), 8.78 (d, (J=4.40 Hz, 1H), 8.85 (s, 2H), 10.54 (br s, 1H, D2O exchangeable) and 12.45 (br s, 1H, D2O exchangeable). MS: 518.27 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=1N)([O-:3])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[C:5]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Clc1ccc(Cl)cc1
Product: O=[N+]([O-])c1ccc(Cl)cc1-c1cc(Cl)ccc1Cl

Procedure:
2,5,5'-Trichloro-2'-nitrobiphenyl was prepared according to the procedure in Example 2A from 2-nitro-5-chloroaniline (2.6 g, 15 mmol) and 1,4-dichlorobenzene (29.5 g, 200 mmol). Purification was by filtration through silica gel (see Example 1A) eluting with hexanes/methylene chloride 80:20 yielding the title compound (830 mg). Mass spectrum: m/z at 301 for C12H6Cl3NO2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.Cl.[C:16]([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:16][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A solution of (4-bromo-2-nitro-phenyl)-acetic acid (5.00 g, 19.2 mmol) in methanol (100 mL) is treated with conc. HCl (1.0 mL). The mixture is stirred at 85° C. for 16 hours and cooled to room temperature. The mixture is neutralized with aqueous Na2CO3 and concentrated. The residue is extracted with ethyl acetate (50 mL×2), and the combined organic layers are dried over sodium sulfate and concentrated to provide (4-bromo-2-nitro-phenyl)-acetic acid methyl ester as a brown solid (5.27 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17](Br)=[CH:16][C:15]([CH3:19])=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.C1C[O:28][CH2:27]C1>>[CH2:1]([O:8][C:9]1[C:17]([CH:27]=[O:28])=[CH:16][C:15]([CH3:19])=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Cc1cc(Br)c(OCc2ccccc2)c2c1CCC2
Agent: [Li]CCCC
Product: Cc1cc(C=O)c(OCc2ccccc2)c2c1CCC2
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-benzyloxy-5-bromo-7-methylindan (5.87 g, 19.4 mmol) in THF (75 mL) at −78° C. is added dropwise n-BuLi (1.6 M in hexane, 13.3 mL, 21.3 mmol) and it is stirred at −78° C. for 1.5 h. DMF (freshly distilled from CaH2, 29 mL, 0.38 mol) is added dropwise and it is stirred at −78° C. for 4 h before slowly warmed to ambient temperature and stirred for 18 h. EtOAc is added and it is washed with 1N HCl and brine, dried and concentrated. The residue is purified by flash chromatography to give the title compound as a light yellow solid.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH3:16])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([N:7]2[C:11]3=[N:12][C:23]([C:20]4[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH3:16])[NH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nn(C2CCCCC2)c(N)c1C(N)=O
Reactant: O=Cc1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1[nH]n(C2CCCCC2)c2nc(-c3ccncc3)nc(=O)c1-2
Yield: 31.7 %

Procedure:
1-Cyclohexyl-3-methyl-5-amino-1H-pyrazole-4-carboxamide (1.2 g, 5.4 mmol), 4-pyridinecarboxaldehyde (0.87 g, 8.1 mmol), toluene (125 ml) and p-toluenesulfonic acid monohydrate were combined and heated to reflux for 24 hours. The solvent was removed in vacuo and the residue was poured into water (450 ml). The obtained precipitate was collected by filtration, recrystallized from isopropanol (200 ml) and dried for 24 hours in high vacuum to afford 0.53 g (32%) of 1-cyclohexyl-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as a cream colored solid, m.p. 292°-293° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([NH:20][C:21]([NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[S:22])[CH:16]=[CH:17][C:18]=2[CH3:19])[C:3]1=[O:32].[OH-].[Na+].[CH3:35]I>C(Cl)Cl>[C:24](/[N:23]=[C:21](\[S:22][CH3:35])/[NH:20][C:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([C:4]2[C:3](=[O:32])[N:2]([CH3:1])[C:11]3[C:6]([CH:5]=2)=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=3)[CH:14]=1)(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cc2c(cn1)cc(-c1cc(NC(=S)NC(=O)c3ccccc3)ccc1C)c(=O)n2C
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS/C(=N\C(=O)c1ccccc1)Nc1ccc(C)c(-c2cc3cnc(C)cc3n(C)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenylcarbamothioyl)benzamide 20 (22 mg, 0.05 mmol) in DCM (0.5 mL) was added solid powder of NaOH (20 mg, 0.5 mmol) and MeI (7 mg, 0.05 mmol). The mixture was stirred at rt for 1 h to yield (Z)-methyl N′-benzoyl-N-(3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenyl)carbamimidothioate 21 after removal of DCM. The crude 21 was used without further purification. MS m/z 457.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@H:10]2[OH:17])[CH:3]=1.[I-:18].[Na+]>I>[OH:15][CH2:14][C@H:12]1[CH2:13][C@@H:9]([NH:8][C:4]2[CH:3]=[C:2]([I:18])[N:7]=[CH:6][N:5]=2)[C@H:10]([OH:17])[C@@H:11]1[OH:16]
Reactant: [I-]
Reactant: OC[C@H]1C[C@@H](Nc2cc(Cl)ncn2)[C@H](O)[C@@H]1O
Agent: I
Agent: [Na+]
Product: OC[C@H]1C[C@@H](Nc2cc(I)ncn2)[C@H](O)[C@@H]1O
Temperature: 70 °C
Yield: 944.2 %

Procedure:
To a solution of (1R,2S,3R,5R)-3-[(6-chloropyrimidin-4-yl)amino]-5-(hydroxymethyl)cyclopentane-1,2-diol (1.880 g, 7.239 mmol) in hydroiodic acid (23.9 mL) was added sodium iodide (5.42 g, 36.2 mmol). The mixture heated to 70° C. for 10 min then concentrated and azeotroped using toluene (3×). The residue was dissolved in acetone and NaHCO3 was added. The suspension was filtered and the filtrate was concentrated in vacuo to obtain the title compound (24 g, >99%). LC/MS: Rt=0.76 min ES+ 352 (FA standard).
Reaction SMILES: [CH:1]1(O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([NH:12][CH:13]=[N:14]2)=[C:10]([Cl:17])[N:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:10]([Cl:17])[N:9]=1
Reactant: OC1CCCC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Temperature: 0 °C
Reaction time: 60 h

Procedure:
Dissolve cyclopentanol (260 mg, 3.02 mmol), 2,6-dichloropurine (680 mg, 3.60 mmol) and triphenyl phosphine (950 mg, 3.60 mmol) in dry THF (20 mL) and cool to 0° C. Add diethyl azodicarboxylate (570 μL, 3.60 mmol) dropwise over a period of 15 minutes under a nitrogen atmosphere. Stir the resulting solution for 60 hours at room temperature. Evaporate the solvent in vacuo, charge directly onto a silica gel column, and elute with methylene chloride to give the title compound as a crude mixture.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C:12](=[O:13])[CH2:11][C@@H:10]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:25]([O-])=O.CO.[H][H]>C1COCC1.[Ni]>[NH2:25][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[C:12](=[O:13])[CH2:11][C@@H:10]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:9]2)=[N:7][C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: Cc1nc(N2C[C@H](NC(=O)OCc3ccccc3)CC2=O)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(N2C[C@H](NC(=O)OCc3ccccc3)CC2=O)ccc1N

Procedure:
250 mg (0.68 mmol) benzyl (R)-[1-(6-methyl-5-nitro-pyridin-2-yl)-5-oxo-pyrrolidin-3-yl]-carbamate are dissolved in 4 ml THF and 5 mL methanol and combined with 50 mg Raney nickel. The mixture is hydrogenated in a Parr apparatus at ambient temperature at 1 bar hydrogen pressure for four hours. Then the catalyst is filtered off and the filtrate is evaporated down i. vac..
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C)nn1
Reactant: NCC(F)(F)F
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NCC(F)(F)F)nn1
Yield: 73 %

Procedure:
As described for example 59, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) was converted, using 2,2,2-trifluoroethylamine instead of aminomethylcyclopropane, to the title compound (119 mg, 73%) which was obtained as a white solid. MS: m/e=411.1 [M+H]+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11](Cl)=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2].[CH2:16]([NH2:19])[CH:17]=[CH2:18]>O1CCCC1.C(OCC)(=O)C>[CH2:16]([NH:19][C:11]([C:10]1[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]([S:14][CH3:15])=[N:8][CH:9]=1)=[O:12])[CH:17]=[CH2:18]
Reactant: C=CCN
Reactant: CSc1ncc(C(=O)Cl)c(NC(C)C)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCNC(=O)c1cnc(SC)nc1NC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a 0° C. suspension of 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylic acid chloride in 10 mL of tetrahydrofuran is added 3.5 mL (46.2 mmol) of allylamine and 20 mL of tetrahydrofuran. The reaction suspension is allowed to warm briefly to room temperature, then stored at 0° C. overnight. The reaction mixture is diluted with ethyl acetate, washed with 1N HCl, a saturated solution of sodium bicarbonate, and brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated to give 2.1 g (51%) of the title compound:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=1>>[CH3:25][C:21]1[CH:20]=[C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH:24]=[CH:23][N:22]=1
Reactant: Cc1cc(CCl)ccn1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Agent: Cl
Product: Cc1cc(Cn2cc(C#Cc3ccnc(Cl)c3)nc2C)ccn1

Procedure:
The title compound, MS: m/e=323.3 (M+H30), was prepared in accordance with the general method of example 1 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-chloromethyl-2-methyl-pyridine hydrochloride.