Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][OH:27]>CC(=O)CC>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:24][CH2:25][CH2:26][OH:27])=[CH:12][CH:11]=1
Reactant: Oc1ccc(CCOC2CCCCO2)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCCc1ccc(CCOC2CCCCO2)cc1
Yield: 73.6 %

Procedure:
To a solution of 4-(2-tetrahydropyran-2-yloxyethyl)phenol (9, 8.0 g, 36 mmoles) in 2-butanone (100 mL) were added K2CO3 (10.0 g, 72 mmoles) and 3-bromopropanol (6.5 mL, 72 mmoles). The solution was refluxed 18 hours with mechanical stirring. After cooling, the mixture was filtered and the solvent removed under reduced pressure to afford 13.0 g of crude oil. This was purified by flash chromatography on silica gel (solvent=80:20 ethyl acetate:heptane). The pure fractions were pooled and the solvent removed in vacuo to give 7.0 g of 1-[2-(tetrahydropyran-2-yloxy)ethyl]-4-(3-hydroxypropy)benzene (10). NMR (CDCl3)δppm: 7.0(q, 4H); 4.58(s, 1H)' 4.3-3.3(m, 8H); 3.06(s, 1H); 2.83(t, 2H); 1.83(m, 2H); 1.63(m, 6H). (Scheme II, Step 5.)
Reaction SMILES: [CH2:1]([N:7]([CH3:27])[C:8]([CH:10]1[CH2:14][CH:13]([OH:15])[CH2:12][CH:11]1[C:16]([NH:18][C:19]1([C:24]([OH:26])=[O:25])[CH2:21][CH:20]1[CH:22]=[CH2:23])=[O:17])=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[H-].[Na+].Cl[C:31]1[C:40]2[C:35](=[CH:36][C:37](OC)=[CH:38][CH:39]=2)[N:34]=[C:33]([C:43]2[S:44][CH:45]=[C:46]([CH:48]([CH3:50])[CH3:49])[N:47]=2)[N:32]=1.Cl>C1COCC1.CCOC(C)=O>[CH2:1]([N:7]([CH3:27])[C:8]([CH:10]1[CH2:14][CH:13]([O:15][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[C:33]([C:43]3[S:44][CH:45]=[C:46]([CH:48]([CH3:50])[CH3:49])[N:47]=3)[N:32]=2)[CH2:12][CH:11]1[C:16]([NH:18][C:19]1([C:24]([OH:26])=[O:25])[CH2:21][CH:20]1[CH:22]=[CH2:23])=[O:17])=[O:9])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: COc1ccc2c(Cl)nc(-c3nc(C(C)C)cs3)nc2c1
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)O)CC1C=C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCCCCN(C)C(=O)C1CC(Oc2nc(-c3nc(C(C)C)cs3)nc3ccccc23)CC1C(=O)NC1(C(=O)O)CC1C=C
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
Compound 37 (26 mg, 70 μmol) was dissolved in THF (3 mL, dried with mol. siev.). To this solution was added NaH (60% in oil, 8.2 mg, 210 μmol) and the reaction was incubated for 10 min at ambient temperature. To the reaction mixture was then added compound 39 (17.6 mg, 61 μmol) followed by incubation at ambient temperature for 16 h. To the reaction was then added 0.1 M HCl (aq) and EtOAc, the phases separated and the aqueous phase extracted with another portion of EtOAc. The pooled organic phases were dried (MgSO4), filtered and concentrated in vacuo which gave a crude product which was further purified by flash-chromatography (Silica; DCM:MeOH) to afford the title compound (30 mg, 78%). LC/MS>95%, m/z (ESI+)=632 (MH+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[N:1]1([CH2:7][CH2:8][C:9]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[CH:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(CCN1CCOCC1)NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccn2c(CCN3CCOCC3)ncc2c1
Temperature: 80 °C
Yield: 78 %

Procedure:
To a solution of 3-morpholin-4-yl-N-pyridin-2-ylmethyl-propionamide (5.4 g, 21.7 mmol) in 1,2-dichloroethane (100 mL), cooled in an ice bath, was added POCl3 (12 mL). The mixture was heated to 80° C. for 3 h. After this time the mixture was allowed to cool and poured slowly into 10% aqueous potassium carbonate (500 mL). The mixture was extracted with dichloromethane (200 mL) and ethyl acetate (200 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine (3.89, 78%).
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[O:4].C([O:8][C:9]([C:11]1([C:38](OCC)=[O:39])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:17]=[N:18][C:19]([O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[N:27]=[CH:26]3)=[CH:20][CH:21]=1)=O)C>C(O)C>[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([N:28]2[C:29]3[C:25](=[CH:24][C:23]([O:22][C:19]4[N:18]=[CH:17][C:16]([N:12]5[C:11]6([C:38](=[O:39])[NH:5][C:3](=[O:4])[NH:2][C:9]6=[O:8])[CH2:15][CH2:14][CH2:13]5)=[CH:21][CH:20]=4)=[CH:31][CH:30]=3)[CH:26]=[N:27]2)[CH:33]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc3c(cnn3-c3cccnc3)c2)nc1
Reactant: NC(N)=O
Agent: [Na]
Solvent: CCO
Product: O=C1NC(=O)C2(CCCN2c2ccc(Oc3ccc4c(cnn4-c4cccnc4)c3)nc2)C(=O)N1
Temperature: 80 °C

Procedure:
To a flame dried flask is added ethanol (6 mL) and freshly cut sodium metal (62.4 mg, 2.71 mmol). The solution is stirred until homogenous. Recrystallized urea (98 mg, 1.63 mmol) is added and the solution is stirred at room temperature for 5 minutes. 1-[6-(1-Pyridin-3-yl-1H-indazol-5-yloxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.54 mmol) is added, and the solution is heated to 80° C. for 30 minutes, then cooled to 50° C. and stirred for 16 hours. The reaction is then quenched by the addition of 10 mL water, and 1N hydrochloric acid is added to adjust the pH to 5. The aqueous layer is extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers are washed with saturated sodium chloride, dried with magnesium sulfate, filtered, and concentrated under vacuum to produce crude product. This material is chromatographed on silica gel (ISCO MPLC purification, 30 minutes, 50-100% ethyl acetate gradient, Biotage flash 40s column) to provide 1-[6-(1-Pyridin-3-yl-1H-indazol-5-yloxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5]decane-6,8,10-trione.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13].C(O)(=O)C.C(O)(=O)C.CO>CO>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Yield: 92 %

Procedure:
To a solution of 3.24 g of methyl 2-(2,6-dichloroanilino)-phenylglyoxylate in 50 ml of a 0.1 N acetic acid solution in methanol (hereinafter often referred to as "0.1 N acetic acid/methanol") was added 0.6 g of 5% Pt-carbon, and vigorous stirring was effected at room temperature under a hydrogen pressure of 2 atmospheres for 10 hours. The catalyst was filtered off and the filtrate was concentrated at room temperature under a reduced pressure of 10 mmHg. The crystalline substance thus deposited was recovered by filtration and recrystallized from ethanol to give 3.0 g of methyl 2-(2,6-dichloroanilino)phenylglycolate. m.p. 123°-124.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11].CO>O1CCCC1>[CH3:9][C:6]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:4][C:10]([CH3:11])=[O:12])[CH:5]=1
Reactant: Cc1ccc(C)c(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1cc(C)ccc1C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
2,5-Dimethylaniline 16 (5.0 gm, 0.041 moles) was dissolved in 30 ml tetrahydrofuran (THF) at room temperature under argon. Acetic anhydride (5.9 ml, 0.062 moles) was added. Within 15 minutes, solids formed and the mixture became a solid white mass after 1 hour. Methanol was added which dissolved the mass. The mixture was evaporated under reduced pressure, dissolved in hot DCM and purified by flash chromatography on silica gel, eluting with a mixture of methanol and DCM. 2,5-Dimethylacetanilide 17 (6.67 gm, 99% yield) was isolated after removing the solvent. NMR (CDCl3) δ 7.53, 1H, br s; 6.89-7.06, 3H, m; 2.30, 3H, s; 2.19, 3H, s; 2.17, 3H, s.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:12])=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(OC(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N)c(OC(C)C)c1

Procedure:
5-Methyl-1-(1-methylethoxy)-2-nitrobenzene, 17.7 g (91 mmol), is dissolved in methanol, palladium on charcoal is added and the mixture is exposed to hydrogen gas until the required amount of hydrogen is absorbed. The mixture is worked up in the usual manner to give 15 g of 4-methyl-2-(1-methylethoxy)benzenamine.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[CH2:12][CH2:13][CH2:14][N:15]=1>CO.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH:11]1[CH2:12][CH2:13][CH2:14][NH:15]1
Reactant: Fc1ccc(F)c(C2=NCCC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Fc1ccc(F)c(C2CCCN2)c1
Reaction time: 2 h
Yield: 79.8 %

Procedure:
NaBH4 (12 g, 314.9 mmol) was added to a solution of 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole (28.5 g, 157.4 mmol) in a mixture of MeOH:H2O (4:1, 250 mL) and stirring was continued at 25-35° C. for 2 h. The reaction mixture was quenched with 1N aqueous HCl solution and basified with 2N aqueous NaOH solution, extracted with DCM, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 23 g of the title compound. MS (ESI): m/z 184 (M+H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[CH:2]=[CH2:3].I[CH2:24][CH3:25].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:24][CH3:25])=[CH:7][C:6]=1[N:12]1[C:13](=[O:22])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]1=[O:21])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(O)cc1N1C(=O)c2ccccc2C1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(OCC)cc1N1C(=O)c2ccccc2C1=O

Procedure:
A mixture of Example 84A (0.63 g, 2.13 mmol), iodoethane (0.68 mL, 8.52 mmol) and K2CO3 (1.47 g, 10.65 mmol) in acetone (50 mL) were stirred, and refluxed for 3 hours, and cooled. The solution was filtered, and dried with silica gel powder (10 g). 15% Ethyl acetate in hexanes (1 L) and 20% ethyl acetate in hexanes (1 L) were used to run flash chromatography. The title compound was obtained (320 mg, 46%). MS (DCI) m/z 324.07 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 1.39 (t, J=7.12 Hz, 3 H) 4.00 (q, J=7.12 Hz, 2 H) 4.46–4.55 (m, 2 H) 5.07–5.30 (m, 2 H) 5.88 (m, 1 H) 6.82 (dd, J=2.54, 0.85 Hz, 1 H) 6.93–6.96 (m, 2 H) 7.75–7.80 (m, 2 H) 7.94 (dd, J=5.42, 3.05 Hz, 2 H).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:12](=[O:13])[N:11]2[C:14]([CH2:24][N:25]([CH3:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[N:16]=[C:10]2[N:9]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[CH:8]=1)=[O:6])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH2:49]([N:51]=[C:52]=[O:53])[CH3:50]>C1COCC1>[CH:1]([O:4][C:5]([C:7]1[C:12](=[O:13])[N:11]2[C:14]([CH2:24][N:25]([CH3:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:52]([NH:51][CH2:49][CH3:50])=[O:53])=[CH:21][CH:22]=3)[N:16]=[C:10]2[N:9]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cn(Cc2c(F)cccc2F)c2nc(-c3ccc(N)cc3)c(CN(C)Cc3ccccc3)n2c1=O
Reactant: CCN=C=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(-c2nc3n(Cc4c(F)cccc4F)cc(C(=O)OC(C)C)c(=O)n3c2CN(C)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of the compound obtained in Example 32 (1.37 g, 2.40 mmol) in THF (3 ml) is added pyridine (0.5 ml) and ethyl isocyanate (0.38 ml, 4.8 mmol). Then the mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure to give the residue, which triturated with isopropyl ether to afford a crystalline solid, which is recrystallized from chloroform-isopropyl ether to afford pale yellow crystals (1.20 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([CH2:16][CH2:17][CH3:18])[CH:8]=2)=[CH:4][CH:3]=1.[Br:21]Br>O1CCOCC1.C(OCC)(=O)C>[Br:21][CH2:14][C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][C:9]=1[CH2:16][CH2:17][CH3:18])=[O:15]
Reactant: BrBr
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(C)=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(=O)CBr
Reaction time: 2 h

Procedure:
To a solution of the product from Step 7 (1.2 g, 4.2 mmol) in dioxane (20 mL) at room temperature was added dropwise bromine (0.25 mL, 5.0 mmol). After 2 h at room temperature, the reaction mixture was diluted with ethyl acetate, washed with an aqueous solution of sodium thiosulfate and dried over magnesium sulfate. Removal of the solvent gave a residue which was purified by chromatography on silica gel to give the title product.
Reaction SMILES: [O:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[O:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[CH:23]=[O:24])=[CH:8][CH:7]=2)=[N:2]1
Reactant: O=Cc1ccc(-c2ncon2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-c2ncon2)cc1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 4-(1,2,4-oxadiazol-3-yl)benzaldehyde (prepared as described in Reference Example 75) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 201 (M+H)+.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[NH:4][C:3]=1[C:15](=[O:18])[CH2:16][CH3:17].C(O)C.[NH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>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>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[NH:4][C:3]([C:15](=[O:18])[CH2:16][CH3:17])=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([S:23]([NH2:22])(=[O:25])=[O:24])=[CH:27][CH:28]=3)[C:6]=2[CH3:7])=[CH:9][CH:10]=1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCC(=O)c1[nH]c(-c2ccc(Cl)cc2)c(C)c1Br
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: CCC(=O)c1[nH]c(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 6.7 %

Procedure:
To the solution of 1-(3-bromo-5-(4-chlorophenyl)-4-methyl-1H-pyrrol-2-yl)propan-1-one (compound 53b, 1.0 g, 3.06 mmol) in a mixture of toluene: ethanol (5:15 ml) was added 4-aminosulfonylbenzene boronic acid (0.67 g, 3.37 mmol) and potassium carbonate (1.26 g, 9.19 mmol) at a temperature of about 25° C. in a sealed tube and a nitrogen gas was bubbled through the resulting reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.153 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 90° C. to 95° C. for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with 10% methanol in dichloromethane (3×25 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.082 g, 6.65%).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH2:30]([OH:33])[CH2:31][CH3:32]>O1CCOCC1.CN(C=O)C>[CH3:25][O:24][C:14]1[C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:26]=[CH:27][C:2]([O:33][CH2:30][CH2:31][CH3:32])=[N:3][CH:4]=3)[S:10][C:11]=2[C:17]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:16][CH:15]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Reactant: CCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCCOc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cn1

Procedure:
From 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide with sodium hydride and propanol in dioxane and DMF. ES-MS m/e (%): 429 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH3:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccccc1)c1ccc(O)cc1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCCOc1ccc(C(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of phenyl 4-hydroxybenzoate (2.1 g, 9.8 mmol) in tetrahydrofuran (40 mL) was added a 60% suspension of sodium hydride in mineral oil (408 mg, 10.2 mmol) and the mixture was stirred at room temperature for about 30 minutes. Then 1-bromo-2-(2-methoxyethoxy)ethane (2.5 g, 13.7 mmol) was added and stirring was continued for about 5 days. The mixture was poured into saturated aqueous sodium carbonate and was extracted with ethyl acetate, the combined organic extracts were washed with saturated aqueous sodium carbonate, dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (10:1) as eluent to provide the desired product. 1H NMR (500 MHz, CDCl3) δ 3.40 (s, 3H), 3.60 (m, 2H), 3.76 (m, 2H), 3.92 (t, J=8 Hz, 2H), 4.22 (t, J=8 Hz, 2H), 7.00 (d, J=8 Hz, 2H), 7.22 (m, 3H), 7.42 (d, J=8 Hz, 2H), 8.17 (d, J=8 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH2:14][OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][C:24]=1[CH3:30].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:18][O:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:15][CH2:14][C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:16])([F:1])[F:17])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[CH:25][C:24]=1[CH3:30]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1C
Reaction time: 8 h

Procedure:
To a solution of [5-(4-Trifluoromethyl-phenyl)-thiophen-2-yl]-methanol (0.063 g, 0.232 mmole) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.045 g, 0.232 mmole) in toluene (2 mL) at room temperature, is added tributylphosphine (0.087 mL, 0.348 mmole) followed by a solution of 1,1′-(azodicarbonyl)-dipiperidine (0.088 g, 0.348 mmole) in toluene (2 mL). The reaction is stirred overnight, and then diluted with hexane (10 mL). The precipitate is removed through filtration and the filtrate is concentrated, loaded to a silica gel column, eluted with ethyl acetate in hexane (0-15%) and concentrated to provide the titled compound as white solid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:8]=1[O:17][CH3:18].[I:19]I>C1COCC1>[I:19][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:8]=1[O:17][CH3:18]
Reactant: II
Reactant: CCCOc1ccc(Br)c(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCOc1ccc(I)c(OC)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
11.1 mL (17.8 mmol) BuLi (1.6M solution in hexane) are added to 3.64 g (14.9 mmol) 1-bromo-2-methoxy-4-propoxybenzene (XXVI.1) in 100 mL THF at −78° C. The mixture is stirred for 5 min at −78° C. After that time, 5.65 g (22.3 mmol) I2 in 10 mL THF are added. The mixture is allowed to reach rt. The solvent is removed in vacuo and the residue is purified by column chromatography (silica gel, heptane/EtOAc 1/1).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: Cc1ccnc(Br)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Product: Cc1ccnc(C(=O)c2cn(-c3cccc(-c4c(F)ccnc4F)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12j and 2-bromo-4-methylpyridine
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14](O)=[C:13]([Cl:18])[CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:18][C:13]1[CH:12]=[C:11]([NH2:10])[CH:16]=[CH:15][C:14]=1[O:9][CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cccc(CO)n1
Reactant: Nc1ccc(O)c(Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(COc2ccc(N)cc2Cl)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of (6-methyl-pyridin-2-yl)-methanol (280 mg, 2.29 mmol), 4-amino-2-chloro-phenol (359 mg, 2.5 mmol) and triphenylphosphine (0.655 mg, 2.5 mmol) in THF (8 ml) was added DIAD (0.49 ml, 2.5 mmol) and the mixture was stirred at rt for 20 h. The mixture was concentrated in vacuo, diluted with 1N HCl (30 ml), washed with EtOAc (3×20 ml) and basified to pH 12 by 1N NaOH. The mixture was extracted with EtOAc (4×40 ml); the combined EtOAc extracts were washed with brine (1×20 ml), dried (MgSO4), filtered and concentrated in vacuo to give 15A (?? mg, ??% pure)
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:29])[F:28].Br[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1.C(N(CC)C(C)C)(C)C>>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][N:22]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:28])[F:29]
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Reactant: Brc1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(c5ccccn5)C4)c3C2)cc1C(F)(F)F
Temperature: 160 °C
Yield: 25.1 %

Procedure:
To a glass vial was added 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine dihydrochloride (prepared using step 1 of example 91 from intermediate 13) (75 mg, 0.16 mmol), 2-bromopyridine (1 mL, 10.25 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.80 mmol). The vial was capped and the mixture heated in the microwave at 160° C. for 20 min. Purification by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions over PL-HCO3 MP to give 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-1-pyridin-2-yl-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine as a light brown solid (19 mg, 25% yield) 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.24-2.44 (m, 2 H) 2.92 (t, 2 H) 3.47-3.69 (m, 5 H) 3.77-3.85 (m, 1H) 3.88-3.93 (m, 3 H) 4.12-17 (m, 2 H) 5.73-5.81 (m, 1 H) 6.40-6.52 (d, 1 H) 6.56-6.58 (m, 1 H) 7.43-7.54 (m, 1 H) 7.77-7.84 (m, 1 H) 8.02-8.09 (m, 1 H) 8.13-8.20 (m, 1 H) 8.61-8.66 (m, 1 H) LCMS: [M+H]+=473.0, Rt(4)=0.85 min.