Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][Mg+].[Br-]>C1COCC1>[CH3:15][C:12]1([OH:14])[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1(O)c2ccccc2-c2ccccc21
Temperature: 0 °C

Procedure:
In a glovebox, in a 50 mL round bottom flask, 9H-fluorene-9-one (5.458 g, 30.3 mmol) was dissolved in 20 mL of THF and cooled to 0° C. for 30 minutes. MeMgBr (1.2 eq.) was then slowly added via syringe while stirring. A slurry formed once all of the Grignard was added. The reaction was allowed to stir for 48 hours. The flask was then removed from the glovebox and 4 mL of 2M NaOH were added. The mixture was washed with brine and the organic portion collected and dried over MgSO4, filtered and the volatiles removed under a N2 stream. NMR of the resultant yellow solid showed pure 9-methyl-9H-fluoren-9-ol. Yield is 5.67 g (95 wt %).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[S:27][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:10]=2[CH:9]=1>>[CH3:1][C:2]1[N:3]([C:13]2[N:14]=[C:15]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:10]3[CH:9]=[CH:8][S:27][C:11]=3[N:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=[N+]([O-])c1cccc(CNc2ncnc3sc(Cl)cc23)c1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCc2cccc([N+](=O)[O-])c2)c2ccsc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 6-chloro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[N:14]=[C:13]([C:15]([NH2:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[CH2:20]([NH:1][CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[N:14]=[C:13]([C:15]([NH2:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCc1ccc(Oc2cccc(C(N)=O)n2)cc1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cccc(Oc2ccc(CCNCc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
Dissolve 6-[4-(2-aminoethyl)phenoxy]pyridine-2-carboxamide (0.0452 g, 0.176 mmol) in methanol (2.9 mL). Add benzaldehyde (0.018 mL) and 3 Å molecular sieves. Stir at room temperature overnight. Add NaBH4 (0.0066 g, 0.176 mmol). Stir for additional 6.5 hours before filtering and concentrating. Purify by reverse phase chromatography, eluting with 0-99% 0.1% TFA/acetonitrile and 0.1% TFA/water to give the title compound (9.4 mg, 15.4%): MS ES− 347.9 (M+H)+, HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min], tR=7.6 min, 100% purity.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]3=[CH:15][S:16][CH:17]=[C:13]3[CH:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([O:24]COC)=[CH:20][CH:19]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl.[OH-].[Na+]>C(O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]3=[CH:15][S:16][CH:17]=[C:13]3[CH:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(OCOC)cc3)cc3cscc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN1CCN(c2nc(-c3ccc(O)cc3)cc3cscc23)CC1
Yield: 11.4 %

Procedure:
4-(4-Ethylpiperazin-1-yl)-6-[4-(methoxymethoxy)phenyl]thieno[3,4-c]pyridine (695 mg) was dissolved in ethanol (10 ml), followed by the addition of a 5N aqueous solution of hydrochloric acid (1 ml), and the mixture was reacted for 1 hr with heating under reflux. The reaction solution was neutralized with a 1N aqueous solution of sodium hydroxide and then extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated, and then purified by silica gel column chromatography (dichloromethane/methanol system), to give 4-(4-ethylpiperazin-1-yl)-6-(4-hydroxyphenyl)thieno[3,4-c]pyridine as a yellow oil (70 mg, yield; 11%).
Reaction SMILES: [CH:1]([CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)=O.[CH2:18]([O:21][CH2:22]C[C@H]1CC[C@H](C2C=CC(C#N)=CC=2)CC1)[CH:19]=[CH2:20]>>[CH2:18]([O:21][CH2:22][CH2:1][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH:19]=[CH2:20]
Reactant: C=CCOCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1
Product: C=CCOCCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1

Procedure:
The compound (iii) of Example 7 was subjected to the procedures of (ii), (iii), (iv) and (v) of Example 7 in this order to obtain the captioned compound. M.P.: 12.0° C.,N-I point: 5.9° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)=[C:7]([CH:10]=1)[C:8]#[N:9].[CH3:17][N+:18]([CH3:20])=[CH2:19].[I-]>CN(C=O)C>[CH3:17][N:18]([CH2:20][C:15]1[N:11]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:10][C:7]=2[C:8]#[N:9])[CH:12]=[N:13][C:14]=1[CH3:16])[CH3:19]
Reactant: C=[N+](C)C
Reactant: COc1ccc(-n2cnc(C)c2)c(C#N)c1
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(-n2cnc(C)c2CN(C)C)c(C#N)c1
Yield: 83 %

Procedure:
As described for example 84b, 5-methoxy-2-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 16 h at 70° C. Evaporation of the solvent, aqueous workup and chromatography afforded the title compound as an oil (yield: 83%). MS: m/e=271.4 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21]CC)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Na+].Cl>ClCCl>[C:30]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([OH:21])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Yield: 83.6 %

Procedure:
To a suspension of ethyl 6-[(2,2-diphenylethyl)amino]-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2-carboxylate (0.55 g, 1.16 mmol) (Preparation 27) in industrial methylated spirits (2.2 ml) was added deionised water (0.08 ml) followed by 10 M aqueous sodium hydroxide solution (0.23 ml, 2.3 mmol). The resultant mixture was stirred at 65° C. for 30 minutes and then at ambient temperature for 18 hours during which time a thick paste was formed. To this mixture was added dichloromethane (10 ml) and the pH was adjusted to 2 by the addition of dilute aqueous hydrochloric acid solution. The phases were separated and the aqueous layer was extracted with dichloromethane (10 ml). The combined organic phases were then dried (MgSO4) and the solvent was removed under reduced pressure to give the title compound as a tan coloured foam (0.43 g) that was identical by 1H-NMR, high performance liquid chromatography, mass spectrometry and thin-layer chromatography to the compound prepared in Preparation 21.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5](=[O:11])[NH:4][CH:3]=1.[H-].[Na+].[CH3:14]I.O>CN(C=O)C.C(Cl)Cl.CC(O)C>[Br:1][C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5](=[O:11])[N:4]([CH3:14])[CH:3]=1
Reactant: O=c1[nH]cc(Br)n2cnnc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: Cn1cc(Br)n2cnnc2c1=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To a solution of the title compound of step 1 (400 mg, 1.86 mmol) in DMF (4 mL) was added NaH (149 mg, 3.72 mmol, 60% in mineral oil) in portions at 0° C. under N2. The mixture was stirred at 20° C. for 1 h, and methyl iodide (792 mg, 5.58 mmol) was added. After stirring at 20° C. for 5 h, water was added. Methylene chloride:2-propanol (10:1) extractive work up gave the title compound (200 mg, yield: 47%) as a light yellow solid which was carried on without purification. 1H NMR (DMSO-d6, 400 MHz): δ 9.26 (s, 1H), 7.60 (s, 1H), 3.42 (s, 3H). LCMS: 228.9 (M+H)+
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:25]([N+:26]([O-])=O)=[CH:24][C:8]2[CH:9]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][C:11]([CH3:14])([CH3:13])[O:12][C:7]=2[CH:6]=1.C([OH:31])C>[C].[Pd]>[NH2:26][C:25]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C@@H:10]([OH:31])[C@H:9]([NH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH:24]=1
Reactant: CCO
Reactant: COCOc1cc2c(cc1[N+](=O)[O-])C(NCCc1ccccc1)CC(C)(C)O2
Agent: [Pd]
Product: COCOc1cc2c(cc1N)[C@@H](NCCc1ccccc1)[C@H](O)C(C)(C)O2
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 7-methoxymethoxy-2,2-dimethyl-6-nitro-4-(2-phenylethylamino)-3,4-dihydro-2H-1-benzopyrane (265 mg, 0.66 mmol) in ethanol (5 mL), 5% palladium-carbon (AER type, 13 mg) was added at room temperature, and the resulting mixture was stirred under hydrogen stream overnight. Upon the completion of the reaction, the resulting solution was filtered through celite, concentrated, and the aimed product was obtained (yield: 98%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-])=O)=[C:7]([CH3:15])[CH:6]=1)([O:3][CH3:4])=[O:2]>C(OCC)(=O)C.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([CH3:15])[C:8]([NH2:12])=[C:9]([CH3:11])[CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cc(C)c([N+](=O)[O-])c(C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)c(N)c(C)c1
Yield: 99.9 %

Procedure:
4-Carbomethoxy-2,6-dimethylnitrobenzene (2 g, 9.5 mmol) was dissolved in in ethyl acetate (20 ml) and subjected catalytic hydrogenation using 10% palladium on carbon (300 mg) at 55 psi for 30 min. The catalyst was filtered and solvent removed to give 4-carbomethoxy-2,6-dimethylaniline as a solid (1.7 g, 100% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.CN1C(=O)CCC1.[CH2:33]([Mg]Br)[CH2:34][CH2:35][CH2:36][CH3:37].[Cl-].[NH4+]>C1COCC1.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Fe]>[CH2:33]([C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:17][CH2:18]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)cc3cccnc23)CC1
Reactant: CCCCC[Mg]Br
Agent: [Fe]
Agent: CC(=O)/C=C(/C)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCCCCc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2ncccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
1,1-Dimethylethyl 4-[(6-chloro-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as prepared for Intermediate 6) (2.73 g, 7.5 mmol) was dissolved in a mixture of THF (55 ml), NMP (5.6 ml) and iron (III) acetylacetonate (220 mg, 0.62 mmol) were added, and the mixture was cooled to 0° C. and stirred under a nitrogen atmosphere. n-Pentyl magnesium bromide (commercially available, for example, from TCI-Europe and/or Aldrich) was added dropwise over 9 min. The stirring was continued at 0° C. for 1 h, and the reaction was then allowed to warm to room temperature with stirring overnight. The reaction mixture was treated with aqueous ammonium chloride solution and extracted with EtOAc (×3). The combined organic extracts were filtered, dried (MgSO4), and concentrated in vacuo. The residue was purified by silica chromatography (2×100 g), eluting with 0-50% EtOAc-cyclohexane over 40 min. The relevant fractions were concentrated in vacuo to give the title compound as a yellow oil (2.2 g, 74%): LCMS RT=3.76 min, ES+ve m/z 399 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:31][CH:30]=3)=[O:18])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: O=C(O)/C=C/c1ccc(-c2ccc(Cl)cc2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(-c2ccc(Cl)cc2)cc1)Nc1ccc(CN2CCCCC2)cc1

Procedure:
Prepared analogously to Example 3.1.e. from [(E)-3-(4′-chlorobiphenyl-4-yl)acrylic acid and 4-piperidin-1-ylmethylphenylamine. Yield: 0.57 g (62.9% of theory); melting point: 265° C.-270° C.; C27H27ClN2O (M=430.98); calc.: molecular ion peak (M+H)+: 431/433; found: molecular ion peak (M+H)+: 431/433; Rf value: 0.31 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.I[C:14]1[CH:15]=[CH:16][C:17]2[S:21][CH:20]=[N:19][C:18]=2[CH:22]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:21]1[C:17]2[CH:16]=[CH:15][C:14]([N:9]3[CH2:10][CH2:11][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[C:8]3=[O:12])=[CH:22][C:18]=2[N:19]=[CH:20]1
Reactant: Ic1ccc2scnc2c1
Reactant: O=C1NCCN1c1cccnc1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2cccnc2)CCN1c1ccc2scnc2c1
Yield: 61.7 %

Procedure:
Using the same reaction conditions as in Example 1, 1-pyridin-3-yl-imidazolidin-2-one (I-1b: 93.67 mg, 0.5747 mmol) was reacted with 5-iodo-benzothiazole (150 mg, 0.5747 mmol), 1,4-dioxane (5 mL), copper iodide (10.9 mg, 0.05747 mmol), trans-1,2-diamino cyclohexane (19.65 mg, 0.1724 mmol) and potassium carbonate (159 mg, 1.1494 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform) afforded 105 mg of the product (61.76% yield).
Reaction SMILES: [CH3:1][N:2]1[C:8](=O)[O:7][C:5](=[O:6])[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12>C(O)CCCCCCC>[CH3:1][NH:2][C:3]1[C:4](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:5]([O:7][CH2:8][CH2:5][CH2:4][CH2:3][CH2:13][CH2:12][CH2:11][CH3:10])=[O:6]
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Solvent: CCCCCCCCO
Product: CCCCCCCCOC(=O)c1ccccc1NC
Temperature: 108 °C

Procedure:
To 65 g. of 1-octanol heated at 108° C. there was added 53.1 g. of N-methylisatoic anhydride in portions during 3.5 hours and the reaction mixture was further heated at 108° C. for 1.75 hours after addition was completed. The reaction mixture was distilled to remove unreacted octanol and to afford the n-octyl N-methylanthranilate as the liquid distillate fraction, b.p. 160°-168° C. at less than 0.1 mm pressure.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[C:5]([O:25][CH3:26])=[C:6]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:3].Cl[C:28]1[N:36]=[CH:35][N:34]=[C:33]2[C:29]=1[N:30]=[CH:31][N:32]2[CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1.C(=O)(O)[O-].[Na+]>C(O)CCC>[Cl:10][C:8]1[C:7]([CH3:11])=[C:6]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]2)[C:5]([O:25][CH3:26])=[C:4]([CH:2]([NH:1][C:28]2[N:36]=[CH:35][N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][N:32]3[CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)[CH3:3])[CH:9]=1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 110 °C
Yield: 109 %

Procedure:
A mixture of tert-butyl 4-{3-[1-aminoethyl]-5-chloro-2-methoxy-6-methylphenyl}piperidine-1-carboxylate (150 mg, 0.392 mmol), 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (122 mg, 0.509 mmol), and sodium bicarbonate (35 mg, 0.41 mmol) in 1-butanol (4.7 mL) was degassed with N2 for ˜5 minutes. The mixture was heated at 110° C. for 3 h under nitrogen. The solvent was removed under reduced pressure and the resulting residue was diluted with EtOAc, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography eluting with 0 to 80% EtOAc in CH2Cl2 to provide the desired product (0.25 g). LCMS calculated for C30H42ClN6O4 (M+H)+: m/z=585.3. found: =585.3.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[N:20]=[N:19][C:18]=1[O:29]C)=O)(C)(C)C.C[Si](C)(C)Cl.Cl.CN(C=O)C.O>C(#N)C.O1CCOCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:29])[NH:19][N:20]=[C:21]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:22]=1
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=c1[nH]nc(-c2ccncc2)cc1-c1cc2ccccc2[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
25 mg of 2-(3-Methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester, 7.4 mg trimethylchlorosilane and 11.3 mg KI dissolved in 1 ml of acetonitrile are stirred for 2 h at 60° C. Subsequently, 0.5 ml of a 4N solution of hydrochloric acid in dioxane is added and stirred for 2 h at room temperature. The solution is diluted into DMF/water and directly purified by HPLC on a RP18 column giving 4.5 mg 4-(1H-Indol-2-yl)-6-pyridin-4-yl-2H-pyridazin-3-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].Cl>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH:9]1[CH3:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CC(O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1CC(OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The 4-hydroxy-2-methyl-pyrrolidine-1-carboxylic acid t-butyl ester (110.89 mg, 0.55 mmol) was dissolved in anhydrous DCM and triethylamine (166.96 mg, 1.65 mmol, 0.23 mL) was added under argon. The reaction mixture was cooled to 0EC and methanesulfonyl chloride (69.30 mg, 0.61 mmol, 0.05 mL) was added via syringe. The reaction was stirred at 0EC for 30 min and then allowed to warm to room temp and stir for 12 h. The reaction was slowly poured into a 1N HCl solution and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine then dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (3:1 hexane-ethyl acetate) Yield 135.21 mg. 1H NMR (CDCl3, 300 MHz): δ 1.27 (D, J=9 Hz, 3H), 1.48 (s, 9H), 1.81-1.92 (m, 1H), 2.43 (bs, 1H), 3.04 (s, 3H), 3.56 (dd, J=7.17 Hz, 1H), 3.84 (bs, 1H), 4.01 (bs, 1H), 5.17 (bs, 1H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([OH:20])[C:17]3[C:12](=[CH:13][C:14]([OH:21])=[CH:15][CH:16]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2].[CH3:22][CH:23]([Si:25](Cl)([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH3:24].N1C=CN=C1>CN(C=O)C>[CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([OH:20])[C:17]3[C:12](=[CH:13][C:14]([O:21][Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:24])[CH3:22])=[CH:15][CH:16]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1nc(-c2cc(O)c3ccc(O)cc3n2)cs1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)Nc1nc(-c2cc(O)c3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc3n2)cs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
To a solution of 2-(2-Isopropylamino-thiazol-4-yl)-quinoline-4,7-diol (1.27 g, 4.2 mmol) in 4 mL of DMF was added TIPSCl (2.67 mL, 12.6 mmol) followed by imidazole (2.86 g, 42 mmol). The solution was stirred for 5 min at rt, dissolved in 20 mL EtOAC, quenched by saturated solution of NH4Cl in H2O. The solution was extracted and evaporated under vacuo. The crude product was purified by silica gel chromatography using SiO2 (eluted with 5% to 20% MeOH/DCM) to give 2-(2-Isopropylamino-thiazol-4-yl)-7-triisopropylsilanyloxy-quinolin-4-ol as a dark orange solid (1.9 g, 99%). 1H-NMR (300 MHz, DMSO): δ 11.0 (bs, 1H), 7.93 (d, 1H), 7.70 (bs, 1H), 7.42 (s, 1H), 7.25 (s, 1H), 6.81 (dd, 1H), 6.49 (s, 1H), 3.97-3.87 (m, 1H), 1.38-1.25 (m, 1H), 1.22 (d, 6H), 1.07 (d, 6H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:16][CH3:17])=[N:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(OC(C)(C)C)=O>>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:10]=3)[C:6]([CH2:16][CH3:17])=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nn(C2CCCC2)c2cc(Br)ccc12
Product: CCc1nn(C2CCCC2)c2cc(N3CCNCC3)ccc12

Procedure:
Prepared by the method outlined for Example 1 using 6-bromo-1-cyclopentyl-3-ethyl-1H-indazole (CAS [199172-02-6]) as the aryl halide and N BOC-piperazine as the amine component. Oil and gum (88% for two steps). LC/MS 4.56 min, [M+1]+ 299.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:13](I)[CH3:14].C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O.O>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:14]
Reactant: CCI
Reactant: COC(=O)c1cc(O)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccc(C)c(C(=O)OC)c1
Temperature: 100 °C
Yield: 99.3 %

Procedure:
To a mixture of methyl 5-hydroxy-2-methylbenzoate (134a, 0.600 g, 3.63 mmol) and ethyl iodide (1.13 g, 7.26 mmol) in CH3CN (10 mL) was added K2CO3 (1.00 g, 7.26 mmol) at room temperature. The resulting mixture was heated at 100° C. for 12 hours. The reaction mixture was diluted with EtOAc (25 mL) and H2O (10 mL). The organic layer was separated and washed with NaOH (2 N, 5 mL), H2O (5 mL) and brine (5 mL), dried over Na2SO4 and concentrated under vacuum to give methyl 5-ethoxy-2-methylbenzoate (134b, 0.7 g, 99%) as yellow liquid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:15][C:16]#[N:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.O1CCOCC1.O>[C:18]1([CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14][CH2:15][CH2:16][NH2:17])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#CCCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: NCCCC(c1ccccc1)c1ccccc1

Procedure:
To a suspension of lithium aluminum hydride (23 g) in ether (1 L) is added a solution of 4,4-diphenylbutyronitrile in dioxane (6.25 L), dropwise, at a rate causing gentle reflux. The reaction is maintained at reflux for one hour, and then a solution of potassium carbonate (200 g) in water (300 mL) is added dropwise with stirring. The mixture is filtered with a 1/1 dioxane/ether wash, and evaporation in vacuo of the filtrate followed by distillation affords the title compound (76 g), bp 145°-150° C. at 0.6 mm. The free amine is generally converted to the hydrobromide salt prior to use.