Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)C=C.Cl[C:20]1[CH:25]=CC=C[C:21]=1Cl>>[F:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[C:10]([CH2:25][CH:20]=[CH2:21])[CH:9]=2)=[CH:17][CH:16]=1
Reactant: C=CCOc1ccc(Oc2ccc(F)cc2)cc1
Reactant: Clc1ccccc1Cl
Product: C=CCc1cc(Oc2ccc(F)cc2)ccc1O

Procedure:
4-(4-fluorophenoxy)phenyl allyl ether (4.00 g, 16.37 mmol) was taken up in 1,2-dichlorobenzene (50 mL) and refluxed for 48 h. After cooling, the solvent was removed in vacuo and the resulting crude oil was chromatographed on silica gel (15% ethyl acetate/hexane) to afford the title compound.
Reaction SMILES: [CH2:1]1[CH:3]2[CH2:4][C:5]3[C:6]([O:11][C:12]4[N:13]=[N:14][C:15]([Cl:19])=[CH:16][C:17]=4Cl)=[CH:7][CH:8]=[CH:9][C:10]=3[CH:2]12.[OH-:20].[Na+]>CS(C)=O>[CH2:1]1[CH:3]2[CH2:4][C:5]3[C:6]([O:11][C:12]4[N:13]=[N:14][C:15]([Cl:19])=[CH:16][C:17]=4[OH:20])=[CH:7][CH:8]=[CH:9][C:10]=3[CH:2]12
Reactant: [OH-]
Reactant: Clc1cc(Cl)c(Oc2cccc3c2CC2CC32)nn1
Agent: [Na+]
Solvent: CS(C)=O
Product: Oc1cc(Cl)nnc1Oc1cccc2c1CC1CC21
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
In dimethylsulfoxide (3 mL) was dissolved 32.6 mg (0.111 mmol) of 3-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yloxy)-4,6-dichloropyridazine obtained in Example 14(8), and 0.1 mL (0.2 mmol) of 2 mol/L aqueous sodium hydroxide solution was added to the solution and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice-cold 1 mol/L aqueous sodium hydroxide solution, and washed with ethyl acetate. The aqueous layer was separated, conc. hydrochloric acid was added thereto to adjust pH to 4 in an ice bath, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, dried over sodium sulfate. The solvent was distilled off and the obtained residue was purified by preparative thin-layer chromatography (available from Merck Co., 1.05744, 1 plate was used, developed by chloroform:methanol=10:1) to obtain 13.4 mg (0.0487 mmol, Yield: 43.9%) of 3-(1,1a,6,6a-tetrahydrocyclopropa[a]inden-5-yloxy)-6-chloro-4-pyridazinol (Compound No. 516).
Reaction SMILES: [CH2:1]([C:13]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)C.[Pt]=O>[CH2:1]([CH:13]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCC(=CC(=O)OCC)c1coc([Si](C)(C)C)c1
Agent: O=[Pt]
Solvent: CCO
Product: CCCCCCCCCCCCC(CC(=O)OCC)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 3-dodecyl-3-(2-trimethylsilyl-4-furyl)-2-propenoate (Compound 27, 141 mg, 0.35 mmol) and platinum oxide (28 mg) in ethanol (5 ml) was stirred under hydrogen at room temperature for 2 days. After the solvent and the catalyst were removed, the residue was purified by a silica column using 2% ethyl ether/hexane to give the title ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[Cl:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>O>[Cl:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([NH:8][C:9]3[N:14]=[C:13]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:12]=[CH:11][N:10]=3)[CH:7]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
In certain embodiments of the invention, after condensing N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine with 4-chloromethylbenzoyl chloride in the presence of an inorganic base to obtain 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide, water is added, and 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide is isolated by filtration.
Reaction SMILES: [CH3:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:11](Cl)=[O:12].S(=O)(=O)(O)O.[CH3:19]COCC>>[CH3:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:11](=[O:12])[CH3:19]
Reactant: C[C@@H]1c2ccccc2C[C@@H]1C(=O)Cl
Reactant: CCOCC
Agent: O=S(=O)(O)O
Product: CC(=O)[C@H]1Cc2ccccc2[C@H]1C
Yield: 92 %

Procedure:
cis-1-(2,3-Dihydro-1-methyl-1H-inden-2-yl)ethanone is prepared by the treatment of cis-2,3-dihydro-1-methyl-1H-indene-2-carboxylic acid chloride with ethoxymagnesiummalonic acid ethyl ester in dry ether and thereafter by the treatment of sulfuric acid according to the publication (Reynolds G. A. and Hauser, C. B., Org. Synth. 30 (1957) 70). The yield is 92%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:21]([Si:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)Cl)([CH3:24])([CH3:23])[CH3:22].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@@H:11]([O:14][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reaction time: 24 h

Procedure:
To a solution of tert-butyl(cis-4-hydroxycyclohexyl)carbamate (2.0 g) in dimethylformamide (40 mL), imidazole (756 mg) and t-butyldiphenylchlorosilane (2.86 mL) were added under ice cooling, and the mixture was stirred for 24 hours. Imidazole (226 mg) and t-butyldiphenylchlorosilane (858 μL) were further added thereto, and the mixture was stirred for 6 days. To the reaction solution, ethyl acetate was added, and the organic layer was washed three times with 10% sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. This residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=98/2-9/1) to obtain the title compound (5.09 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:22][C:23]([NH:25][C@H:26]([C:29]([OH:31])=[O:30])[CH2:27][NH2:28])=[O:24])=[CH:17][CH:16]=1>CCOCC.[OH-].[Na+]>[CH2:21]([O:22][C:23]([NH:25][C@H:26]([C:29]([OH:31])=[O:30])[CH2:27][NH:28][S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:13])=[O:12])=[O:24])[C:18]1[CH:17]=[CH:16][CH:15]=[CH:20][CH:19]=1
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(N[C@@H](CNS(=O)(=O)c1ccc2ccccc2c1)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 66.4 %

Procedure:
A solution of 21.4 g of 2-naphthylsulfonyl chloride in 200 ml of ether is added dropwise while stirring to a solution of 15 g of N-α-Z-L-2,3-diaminopropionic acid in 189 ml of 1N sodium hydroxide solution. The mixture is left to stir for a further 6 hours. Subsequently, the reaction mixture is poured into ice-cold 2N hydrochloric acid and extracted with ethyl acetate. The organic is washed with water, dried and evaporated. After chromatography of the residue on silica gel with methylene chloride/methanol/acetic acid (94:5:1 ) there are isolated 17.9 g of N-[(benzyloxy)carbonyl]-3-(2-naphthylsulfonamido)-L-alanine.
Reaction SMILES: [OH:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[Cl:9][CH2:10][CH2:11]O>>[OH:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([O:5][CH2:11][CH2:10][Cl:9])=[O:4]
Reactant: CC(C)C(O)C(=O)O
Reactant: OCCCl
Product: CC(C)C(O)C(=O)OCCCl

Procedure:
2-Chloroethyl 2-hydroxy-3-methylbutyrate was prepared from 2-hydroxy-3-methylbutyric acid and excess 2-chloroethanol essentially by the method described in Step 1 of Example 1: b.p. 137° C./20 mm Hg; 1H NMR δ0.90 (d, 3H, J=6.9 Hz), δ1.04 (d, 3H, J=6.9 Hz), δ2.12 (dqq, 1H, J=3.6, 6.9, 6.9 Hz), δ2.76 (d, 1H, J=6.4 Hz), δ3.72 (t, 2H, J=5.6 Hz), δ4.10 (dd, 1H, J=3.6 Hz, 6.3 Hz), δ4.36-4.53 (m, 2H); HRMS calcd for C6H9ClO3Tms (M-CH3) 237.0714, obsd 237.0677.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.C([Li])CCC.[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[CH2:17][CH2:16]2.Cl>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18]([CH:2]1[S:3][CH2:4][CH2:5][CH2:6][S:1]1)([OH:22])[CH2:17][CH2:16]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: C1CSCSC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(C2SCCCS2)CCc2cc(Br)ccc21
Temperature: -15 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of 1,3-dithiane (1.82 g, 14.7 mmol) in dry THF (20 ml) was added n-butyllithium (8.62 ml, 13.8 mmol, 1.6 M in hexane) dropwise at −30° C. The resulting mixture was stirred for 2 h at −15° C. Then, a solution of 5-bromo-2,3-dihydro-1H-inden-1-one (2 g, 9.19 mmol) in dry THF (24 ml) was added dropwise, maintaining the temperature between −15° C. and −6° C. After the addition was completed, the brown solution was allowed to warm to 0° C. and was then stored in the fridge overnight. Then, 1N HCl was added and the brown mixture was extracted two times with diethylether. The combined organic layers were washed with brine, dried with Na2SO4 and evaporated. The remaining residue was purified by chromatography (silica gel; heptane/EtOAc 90:10-75:25) to obtain the title compound as light yellow gum (2.167 g, 71%). MS: 330.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][C:6]#[N:7].[CH3:12][C:13]([CH3:15])=O.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](=[C:13]([CH3:15])[CH3:12])[C:6]#[N:7]
Reactant: CC(C)=O
Reactant: COc1ccccc1CC#N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1C(C#N)=C(C)C

Procedure:
According to the procedure described by Example 1, o-methoxybenzylcyanide (18.6 g, 127 mmol) is condensed with acetone (50 ml) under addition of methanol (6.5 ml) and KOH (3.33 g, 50 mmol) to yield, after workup and distillation at 106-110° C./0.05 mbar, 2-(2-methoxyphenyl)-3-methyl-but-2-ene nitrile (1.7 g, 7%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])O.[Na+].[C:15](Cl)(Cl)=[S:16]>O1CCCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:15]=[S:16])=[C:4]([CH3:9])[CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(Br)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1N=C=S
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a solution of 4-bromo-2-methylaniline (11.0 g, 59.0 mmol) and saturated aqueous sodium hydrogen carbonate (150 mL) in tetrahydrofuran (150 mL) was added thiophosgene (4.50 mL, 59.0 mmol), and the mixture was stirred at 0° C. for 30 min. The reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residual solid was collected by filtration and was washed with n-hexane to give the title compound as a brown powder (8.16 g, 35.8 mmol, 61%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.CCN(C(C)C)C(C)C>CC(O)C>[CH3:11][C:12]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15][N:14]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:13]1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC1(C(=O)O)CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC1(C(=O)O)CCCN(c2ccncc2[N+](=O)[O-])C1
Temperature: 60 °C

Procedure:
4-chloro-3-nitropyridine (1.1 eq) was added to a solution of 3-methylpiperidine-3-carboxylic acid (1 eq) and DIEA (3 eq) in iPrOH (0.1 M). The reaction mixture was heated in a 60° C. oil bath for 3 h then concentrated in vacuo. The crude residue was diluted with EtOAc and washed with 1.0 N NaOH. The combined aqueous washes were acidified to pH=4 with 1.0 N HCl and extracted with CH2Cl2. The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give 3-methyl-(3-nitropyridin-4-yl)piperidine-3-carboxylic acid. LC/MS (m/z): 266.2 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)(C)(C)C.[NH:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([S:36](Cl)(=[O:38])=[O:37])[C:30]=2[CH:29]=[CH:28]1>>[CH3:25][CH:22]1[CH2:21][CH2:20][N:19]([C:17]([CH:8]([NH:7][S:36]([C:31]2[C:30]3[CH:29]=[CH:28][NH:27][C:35]=3[CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:38])[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)=[O:18])[CH2:24][CH2:23]1
Reactant: CC1CCN(C(=O)C(CCc2ccncc2)NC(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(Cl)c1cccc2[nH]ccc12
Product: CC1CCN(C(=O)C(CCc2ccncc2)NS(=O)(=O)c2cccc3[nH]ccc23)CC1

Procedure:
Example 53 is prepared from 70 mg (0.19 mmol) of tert-butyl{1-[(4-methylpiperidin-1-yl)carbonyl]-3-pyridin-4-ylpropyl}carbamate and indole-4-sulfonyl chloride in the same manner as Example 49 (51 mg, 60% yield). ESI MS Calc. 440.2; Found: 441.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br[C:22]([CH3:28])([CH3:27])[C:23](C#N)=[O:24]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[O:18][C:22]([CH3:28])([CH3:27])[C:23](=[O:24])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(Br)C(=O)C#N
Reactant: CSc1ccc(C(=O)Cc2ccccc2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C2=C(c3ccccc3)C(=O)C(C)(C)O2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.05 g of 1-{2-chloro-4-(methylthio)phenyl}-2-phenyl-ethanone in 60 ml dry THF was stirred at 0° C. for 20 minutes in the presence of 95% oil dispersion of sodium hydride (1.0 g), which was followed by dropwise addition of α-bromoisobutyryl cyanide (2.5 ml) diluted in 50 ml THF. The reaction solution was allowed to warm slowly to room temperature and was stirred overnight. Then the solvent was removed in vacuo, which was followed by extraction with 30 ml water and diethylether (50 ml×3). The organic layer was concentrated under reduced pressure and was purified by column chromatography (hexane/ethylacetate=8:1) to yield 2.73 g of 5-{2-chloro-4-(methylthio)phenyl}-2,2-dimethyl-4-phenyl-3(2H)-furanone. NMR: δ1.56 (s, 6H), 2.48 (s, 3H), 7.10 (dd, J=8.4, 1.5 Hz, 1H), 7.24 (m, 3H), 7.26 (m, 3H), 7.37 (d, J=1.5 Hz, 1H). IR (cm−1): 1698, 1620, 1394, 1235, 1176, 1144.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH2:29][CH3:30]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH2:28][CH2:29][CH3:30]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Reactant: CCCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3CCC)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine and 1-iodopropane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([CH:11]2SCCCS2)=[CH:5][C:4]=1[CH:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][C:19]([O:21][CH3:22])=[O:20].C([SnH](CCCC)CCCC)CCC.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([CH3:11])=[CH:5][C:4]=1[CH:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: CCCCCC(CC(=O)OC)c1cc(C2SCCCS2)c(OC)cc1OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)OC)c1cc(C)c(OC)cc1OC
Temperature: 100 °C
Yield: 92.5 %

Procedure:
A solution of 558 mg (1.35 mmol) of methyl 3-[2,4-dimethoxy-5-(1,3-dithian-2-yl)phenyl]octanoate [prepared as described in step (i) above], 1.576 g (5.42 mmol) of tributyltin hydride and 15 mg of azobis(isobutyronitrile) in 20 ml of toluene was stirred whilst heating at 100° C. for 6.5 hours. At the end of this time, the reaction temperature was allowed to reduce to room temperature, and the reaction mixture was purified by column chromatography through 15 g of silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 6:0 to 6:1 by volume as the eluent, to give a mixture containing the reduced product. The mixture was further purified by column chromatography through 30 g of alumina, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 20:0 to 20:1 by volume as the eluent, to give 385 mg (yield 92%) of methyl 3-(2,4-dimethoxy-5-methylphenyl)octanoate as an oily substance.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([NH2:26])[CH:16]=[CH:17][C:18]=1[N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>CC(O)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:26][C:15]2[CH:16]=[CH:17][C:18]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[C:13]([F:12])[CH:14]=2)=[N:4][CH:3]=1
Reactant: CN1CCN(c2ccc(N)cc2F)CC1
Reactant: Brc1ncc(Br)n2ccnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2F)CC1
Yield: 4.8 %

Procedure:
Following the general procedure for amine displacement using 5,8-dibromoimidazo[1,2-a]pyrazine (0.50 g, 1.81 mmol), 3-fluoro-4-(4-methyl-piperazin-1-yl)-phenylamine (0.45 g, 2.17 mmol) and DIPEA (0.47 mL, 2.72 mmol) in iPrOH (5 mL). The crude material is purified by silica gel column chromatography eluting with 90:10 DCM:MeOH to give the title compound (35 mg, 5%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[NH:10][C:11]3([CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]3)[C:12]=2[OH:13])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[F:36].Cl>COCCOC>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([C:8]3[C:9](=[O:21])[NH:10][C:11]4([CH2:14][CH2:15][C:16]([F:20])([F:19])[CH2:17][CH2:18]4)[C:12]=3[OH:13])[CH:7]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: Cc1ccc(Br)cc1C1=C(O)C2(CCC(F)(F)CC2)NC1=O
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(F)c(F)c2)cc1C1=C(O)C2(CCC(F)(F)CC2)NC1=O

Procedure:
0.74 g (2.0 mmol) of the compound from Example 11A was initially charged in 5 ml of ethylene glycol dimethyl ether, 14.5 ml of 2M aqueous sodium carbonate solution were added dropwise and 10 mg of bis(trisphenylphosphine)palladium(II) chloride were added. 0.35 g (2.2 mmol) of 3,4-difluorophenylboronic acid was then added, and the mixture was stirred under reflux overnight. After cooling, the mixture was acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate, and the extract was dried and concentrated. Purification was carried out by MPLC separation on silica gel using the mobile phase hexane/ethyl acetate 1/1. This gave 0.7 g (70% of theory) of the title compound. 395 mg were then purified again by HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm; mobile phase: water/acetonitrile gradient with addition of 0.1% formic acid]. This gave 121 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=S)[CH3:2].Cl.Cl.[C:17]([C:19]1([NH:28][C:29](=[O:37])[CH:30]([NH2:36])[CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]1)#[N:18]>>[CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6](=[N:36][CH:30]([C:29](=[O:37])[NH:28][C:19]1([C:17]#[N:18])[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]1)[CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CC(C)(C)C)CC1
Reactant: CCOC(=O)NC(=S)N1CCOCC1
Agent: Cl
Product: CCCN1CCC(C#N)(NC(=O)C(CC(C)(C)C)N=C(NC(=O)OCC)N2CCOCC2)CC1

Procedure:
The title compound was prepared starting from (morpholine-4-carbothioyl)-carbamic acid ethyl ester and 2-amino -4,4-dimethyl-pentanoic acid (4-cyano-1-propyl-piperidin-4-yl)amide bis hydrochloride salt according to the procedure from Example 5. MS, m/z 460=M+1.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][NH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=4)=[O:20])[CH:14]=3)[C:9]2=[O:31])[CH2:6][CH2:5][C:4](=[O:32])[NH:3]1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CCO.O>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19]([NH:18][CH2:17][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:31])[N:8]([CH:7]2[CH2:6][CH2:5][C:4](=[O:32])[NH:3][C:2]2=[O:1])[CH2:16]3)=[O:20])=[CH:23][CH:24]=1
Reactant: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc([N+](=O)[O-])cc4)ccc3C2=O)C(=O)N1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 60 °C

Procedure:
To a stirred mixture of 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-nitrophenyl)urea (150 mg, 0.343 mmol) in EtOH (2 mL) was added sodium dithionite (597 mg, 3.43 mmol) in water (2 mL). The resulting mixture was heated to 60° C. for 20 min at which time LC-MS indicated complete disappearance of nitro starting material. The reaction mixture was combined with the crude product from a separate run and concentrated in mew). The residue was dissolved in minimal DMF and chromatographed on a C-18 preparative HPLC column equipped with mass triggered collection. The desired fractions were combined and concentrated in vacuo to provide 1-(4-amino-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a pale yellow solid (90 mg, 40% combined average yield from two separate runs): mp: >400° C.; LCMS: MH+=408.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N+:13]2[O-])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C.[CH3:35][OH:36]>>[CH3:35][O:36][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:13]=1
Reactant: CO
Reactant: CCOC(=O)c1ccc2ccc[n+]([O-])c2c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2ccc(OC)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a 0° C. solution of 7-(ethoxycarbonyl)quinoline 1-oxide (150 mg, 0.69 mmol) and toluene-4-sulphonyl chloride (171 mg, 0.89 mmol) in methanol (5 mL) was added triethylamine (0.19 mL, 1.4 mmol). The reaction was stirred at room temperature overnight. LCMS showed the reaction was incomplete. Additional triethylamine (0.05 mL) was added and the reaction was stirred for another 4 hours. The reaction was concentrated and the residue partitioned between ethyl acetate and saturated aqueous sodium carbonate. The layers were separated and the aqueous was extracted two more times with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-40% ethyl acetate/heptanes) gave the title compound (130 mg, 81%) as a pale yellow solid. +ESI (M+H) 232.2; 1H NMR (400 MHz, CDCl3, δ): 8.49-8.60 (m, 1H), 7.95-8.05 (m, 2H), 7.75 (d, J=8.19 Hz, 1H), 6.98 (d, J=8.78 Hz, 1H), 4.43 (q, J=7.22 Hz, 2H), 4.08 (s, 3H), 1.43 (t, J=7.12 Hz, 3H).