Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([SH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.C(Cl)(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:13][C:7]1[C:6]2[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1ccc2c(S)ccnc2c1
Reactant: BrCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: FC(F)(F)c1ccc2c(SCCCCCBr)ccnc2c1
Temperature: 20 °C
Reaction time: 48 h
Yield: 71.6 %

Procedure:
7-Trifluoromethyl-4-quinoline-thiol (5 g, 21.8 mmol), 1,5-dibromopentane (23.7 g, 98.1 mmol) and CHCl3 (60 mL) were charged in a 250 ml round-bottomed flask equipped with a magnetic stirrer. TBABr (0.7 g, 2.2 mmol) and water (40 mL) were added and the reaction mixture was stirred for 48 h at 20° C. The reaction mixture was poured in 100 mL of H2O with K2CO3 (3.0 g, 21.8 mmol) and extracted with CH2Cl2 (400 mL). The organic layer was washed with water (30 mL), brine (2×30 mL), dried over MgSO4, filtered and evaporated at 30° C. to dryness. The crude compound was purified by column chromatography (SiO2:CH2Cl2:MeOH=99.5:0.5 to 98:2) to give after evaporation 4-(5-bromopentylthio)-7-(trifluoromethyl)quinoline 25 (5.9 g, 72% yield) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCCl)c23)ccc1OCc1ccccn1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCOCC4)c23)ccc1OCc1ccccn1
Yield: 41 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and morpholine to give the title compound in 41% yield; NMR Spectrum: 2.26 (s, 3H), 2.51 (hidden by DMSO, 4H), 2.79 (t, 2H), 3.55 (t, 4H), 4.43 (t, 2H), 5.21 (s, 2H), 7.00 (d, 1H), 7.35 (t, 1H), 7.44 (m, 2H), 7.55 (d, 1H), 7.86 (t, 1H), 8.24 (s, 1H), 8.28 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 462 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:15][C:14]3[C:16](O)=[C:17]4[O:23][CH2:22][O:21][C:18]4=[C:19]([OH:20])[C:13]=3[C:11](=[O:12])[CH:10]=2)=[CH:5][CH:4]=1.C1OC2C=C3C(C(=O)C=C(C4C=CC(O)=CC=4)O3)=C(O)C=2O1.COS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:22]1[O:23][C:17]2[CH:16]=[C:14]3[C:13]([C:11](=[O:12])[CH:10]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[O:15]3)=[C:19]([OH:20])[C:18]=2[O:21]1
Reactant: COc1ccc(-c2cc(=O)c3c(O)c4c(c(O)c3o2)OCO4)cc1
Agent: O=C([O-])[O-]
Agent: O=c1cc(-c2ccc(O)cc2)oc2cc3c(c(O)c12)OCO3
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(-c2cc(=O)c3c(O)c4c(cc3o2)OCO4)cc1

Procedure:
A solution of Kanzakiflavone-1 or 6,7-methylenedioxy-5,4′-dihydroxyflavone (1.49 g, 5 mmol) [Manchanda, V. P.; Khanna, R. N. Curr. Sci. (1977), 46(13), 445-6.] and dimethylsulfate (1.02 g, 8 mmol) in acetone (20 ml) is refluxed in the presence of anyhyd. potassium carbonate (0.5 g) overnight. The reaction mixture is filtered off and the filtrate is evaporated to give a dark brown residue. The residue is taken up in ethyl acetate and washed with water followed by saturated brine solution and dried (MgSO4), thus giving the title compound, upon filtration and evaporation.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:25][CH:26]1[N:31]([CH2:32][C:33]([NH:35][NH2:36])=[O:34])[CH:30]([CH3:37])[CH2:29][O:28][CH2:27]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1.O>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:36][NH:35][C:33](=[O:34])[CH2:32][N:31]3[CH:26]([CH3:25])[CH2:27][O:28][CH2:29][CH:30]3[CH3:37])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CC1COCC(C)N1CC(=O)NN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC1COCC(C)N1CC(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reaction time: 2 h
Yield: 6.8 %

Procedure:
To the solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.2 g, 0.569 mmol) and 2-(3,5-dimethylmorpholino)acetohydrazide (0.106 g, 0.569 mmol) in THF (10 mL) were added T3P (0.543 g, 0.854 mmol) followed by DIPEA (0.110 g, 0.854 mmol) at −60° C. and stirred for 2 h. The reaction mixture was transferred into 25 mL iced-water and extracted with ethyl acetate (2×25 mL) and the combined organic layers was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford the crude product, which was purified by chromatography (0-3% MeOH/CH2Cl2) to give 0.02 g of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(2-(3,5-dimethylmorpholino)acetyl)acrylohydrazide (Yield: 7%). 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.83 (s, 1H), 9.56 (s, 1H), 8.54-8.56 (m, 2H), 8.25-8.30 (m, 1H), 7.49-7.51 (d, J=10.4 Hz, 1H)), 6.01-6.04 (d, J=10.4 Hz, 1H), 3.44-3.57 (m, 2H), 3.28-3.34 (m, 2H), 3.21 (s, 1H), 3.15 (s, 1H), 2.84-2.88 (m, 2H), 0.93-1.04 (m, 6H): LCMS m/z 521.18 [M+H]+, tR 1.898 min.
Reaction SMILES: [Br:1][C:2]1[C:7]2[S:8][C:9]([C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])=[C:10]([Cl:11])[C:6]=2[CH:5]=[C:4]([O:20][CH3:21])[C:3]=1[OH:22].[CH:23](N(C(C)C)CC)(C)C.O>CN1CCCC1=O>[Br:1][C:2]1[C:7]2[S:8][C:9]([C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[O:13])=[C:10]([Cl:11])[C:6]=2[CH:5]=[C:4]([O:20][CH3:21])[C:3]=1[O:22][CH3:23]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1cc2c(Cl)c(C(=O)N3CCOCC3)sc2c(Br)c1O
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(Cl)c(C(=O)N3CCOCC3)sc2c(Br)c1OC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
(7-Bromo-3-chloro-6-hydroxy-5-methoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (7.0 g) was dissolved in 1-methyl-2-pyrrolidinone (35 ml) and di-isopropylethylamine was gradually added. The reaction solution was warmed at 80° C. for 3 hours. Then water (350 ml) was added. The reaction solution was stirred at room temperature for 30 minutes. The product was extracted into ethyl acetate. The organic phase was washed with 1M hydrochloric acid and a solution of sodium sulphate, evaporated and dried in vacuum. The product was purified by flash chromatography using heptane-ethyl acetate as an eluent.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[CH:16]=1.[N:24]1([CH2:30][CH2:31][NH2:32])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[CH:21]([C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][N:11]=[C:2]([NH:32][CH2:31][CH2:30][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1cccc(Nc2c(C#N)cnc3cnc(F)cc23)c1
Reactant: NCCN1CCOCC1
Solvent: c1ccncc1
Product: CC(C)c1cccc(Nc2c(C#N)cnc3cnc(NCCN4CCOCC4)cc23)c1
Yield: 54 %

Procedure:
Following the procedure described above in Example 34, 6-fluoro-4-[(3-isopropylphenyl)amino]-1,7-naphthyridine-3-carbonitrile was reacted with 2-morpholin-4-yl-ethylamine in pyridine. The crude product was purified by flash column chromatography (1% methanol in methylene chloride) to give a yellow solid (0.15 g, 54%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (d, J=7.1 Hz, 6 H) 2.4 (m, 4 H) 2.6 (m, 2 H) 2.9 (dq, J=6.9 Hz, 1 H) 3.4 (m, 2 H) 3.6 (m, 4 H) 6.6 (t, J=5.4 Hz, 1 H) 7.1 (m, 4 H) 7.3 (t, J=8.0 Hz, 1 H) 8.2 (s, 1 H) 8.8 (s, 1 H) 9.6 (s, 1 H)
Reaction SMILES: C([O:8][C@H:9]([C@@H:11]([N:14]1[C:18](=[O:19])[N:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH:16]=[N:15]1)[CH2:12][CH3:13])[CH3:10])C1C=CC=CC=1.CS(C)=O.[OH-].[Na+].[N:45]1([CH2:50][C@@:51]2([C:68]3[CH:73]=[CH:72][C:71]([F:74])=[CH:70][C:69]=3[F:75])[O:55][CH2:54][C@@H:53]([CH2:56][O:57]S(C3C=CC(C)=CC=3)(=O)=O)[CH2:52]2)[CH:49]=[N:48][CH:47]=[N:46]1>C(O)(C)C.O>[CH3:13][CH2:12][C@H:11]([N:14]1[N:15]=[CH:16][N:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:27][CH2:28][N:29]([C:32]4[CH:33]=[CH:34][C:35]([O:57][CH2:56][C@@H:53]5[CH2:54][O:55][C@:51]([C:68]6[CH:73]=[CH:72][C:71]([F:74])=[CH:70][C:69]=6[F:75])([CH2:50][N:45]6[N:46]=[CH:47][N:48]=[CH:49]6)[CH2:52]5)=[CH:36][CH:37]=4)[CH2:30][CH2:31]3)=[CH:22][CH:21]=2)[C:18]1=[O:19])[C@@H:9]([OH:8])[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO[C@@](Cn3cncn3)(c3ccc(F)cc3F)C2)cc1
Reactant: CC[C@@H]([C@H](C)OCc1ccccc1)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CS(C)=O
Solvent: O
Product: CC[C@@H]([C@H](C)O)n1ncn(-c2ccc(N3CCN(c4ccc(OC[C@@H]5CO[C@@](Cn6cncn6)(c6ccc(F)cc6F)C5)cc4)CC3)cc2)c1=O
Temperature: 45 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
Added 1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-4-(4-(4-(4-hydroxyphenyl) piperazin-1-yl)phenyl)-1H-1,2,4-triazol-5(4H)-one compound of formula-20 (35 g) to a mixture of dimethylsulfoxide (350 ml) and sodium hydroxide (3.4 g) and water (7 ml) at 25-30° C. and stirred for 45 minutes at 25-30° C. ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl-4-methylbenzenesulfonate compound of formula-10 (31.5 g) was added to the above reaction mixture at 25-30° C. and heated the reaction mixture to 45° C. and stirred for 5 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to room temperature and water was added to the reaction mixture. The reaction mixture was extracted twice with ethyl acetate. Adjusted the pH of the reaction mixture with aqueous hydrochloric acid solution. The organic layers were washed with sodium chloride solution. Distilled off the solvent under reduced pressure to get the compound as residue. Dissolved the obtained residue in isopropanol (320 ml) at 45-50° C. Filtered the solid, washed with isopropanol and dried aerially to get the title compound. Yield: 98%; Purity by HPLC: 99.5%; M.R: 117° C.-119° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[CH:14])[CH:6]=[CH:7][C:8]=1[O:9][C:10](=[O:12])[CH3:11].[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18][SH:19].[Na]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][C:10](=[O:12])[CH3:11])/[CH:13]=[CH:14]\[CH:18]([S:19][CH:18](/[CH:14]=[CH:13]\[C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10](=[O:12])[CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:17]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:16]=1[Cl:15])[C:17]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:16]=1[Cl:15]
Reactant: C#Cc1ccc(OC(C)=O)c(OC)c1
Reactant: SCc1ccc(Cl)cc1Cl
Agent: [Na]
Product: COc1cc(/C=C\C(SC(/C=C\c2ccc(OC(C)=O)c(OC)c2)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc2Cl)ccc1OC(C)=O

Procedure:
A solution of 3-methoxy-4-acetoxyphenylacetylene (0.02 mol), 2,4-dichlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-3-methoxy-4-acetoxystyryl-2,4-dichlorobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\CCCCCCCC.C=C>[Ru]>[CH2:10]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: [Ru]
Agent: C=C
Product: C=CCCCCCCCC(=O)O

Procedure:
The ethenolysis of the nitrile of oleic acid is carried out at 60° C. under atmospheric pressure in the presence of a ruthenium-based catalyst, [RuCl2(═CHPh)(IMesH2)(PCy3)], using an excess of ethylene, to give 9-decenoic acid, CH2═CH—(CH2)7—COOH. The yields are determined by chromatographic analysis. At the end of the reaction, 6 hours, the C10 α-olefin is separated by vacuum distillation, to give the 9-decenoic nitrile CH2═CH—(CH2)7—CN. The yields are determined by chromatographic analysis. It is possible to measure a yield of 55%.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1OC1CC.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.[Pd]>[C:1]1([CH2:7][C@H:8]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH:9]=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: CCC1CO1
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 17 h

Procedure:
The solution containing the 3-phenyl-2(S)-phthalimidopropionyl chloride is diluted with 500 ml of toluene and treated with 72.11 g of 1,2-butylene oxide. 23.5 g of palladium-on-charcoal (5%) and 100 ml of toluene are added to the solution. The suspension is hydrogenated for 17 hours while stirring and then filtered, and the residue is washed with 200 ml of toluene. The filtrate and washings are combined and treated while stirring with a solution of 0.5 mol of sodium pyrosulfite in water. The phases are separated after 4.5 hours. The aqueous phase is washed with toluene. The toluene phases are washed with water. The combined aqueous phases are treated with toluene and 3N sulphuric acid and stirred at 60°. Thereafter, the phases are separated and the aqueous phase is extracted with toluene. The toluene phases are washed with water, combined, dried and evaporated. 3-Phenyl-2(S)-phthalimido-propan-1-al is obtained as a white solid, melting point 115°-117°, [a]D20 -200° (1% in ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]([CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)=[O:11].[H-].[Na+].I[CH3:26]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]([CH3:26])[C:10]([CH:12]1[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]1)=[O:11]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)Nc2cc(Cl)ccc2Br)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)C1CN(C(=O)OC(C)(C)C)C1)c1cc(Cl)ccc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
A solution of tert-butyl 3-((2-bromo-5-chlorophenyl)carbamoyl)azetidine-1-carboxylate 7.56 (400 mg, 1.03 mmol) in THF (3 mL) was cooled 0° C. Sodium hydride (60%, 63 mg, 1.58 mmol) was added and mixture stirred at 0° C. for 15 minutes. Iodomethane (0.45 mL, 7.23 mmol) was then added dropwise and the mixture was warmed to rt and stirred overnight. Reaction mixture was quenched with water and taken up in EtOAc. Layers were separated, and aqueous was extracted with ethyl acetate. Combined organics were washed with brine, dried (Na2SO4), filtered, concentrated under reduced pressure. The resulting residue was purified via silica gel column chromatography (0-35% ethyl acetate/hexanes) to yield tert-butyl 3-((2-bromo-5-chlorophenyl)(methyl)carbamoyl)azetidine-1-carboxylate 7.57 (393 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C16H21BrClN2O3: 402.03; found: 402.75.
Reaction SMILES: [C:1]([CH:5]1[CH2:9][S:8][CH2:7][C:6]1=O)(OC)=[O:2].C(O)(=O)C.[CH:15]([NH2:17])=[NH:16].[O-]CC.[Na+]>CCO>[N:16]1[C:6]2[CH2:7][S:8][CH2:9][C:5]=2[C:1](=[O:2])[NH:17][CH:15]=1
Reactant: N=CN
Reactant: COC(=O)C1CSCC1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c1CSC2
Temperature: 90 °C

Procedure:
Commercially available 4-carbomethoxytetrahydro-3-thiophenone (5 g, 31.2 mmol) is dissolved in EtOH (284 mL). Formamidine acetate (22 g, 211 mmol) is then added followed by sodium ethoxide (45 mL, 121 mmol, 21% w/w) and the mixture is heated at 90° C. for 14 hours. Reaction is cooled to room temperature and concentrated to a residue which is absorbed onto silica and separated via FCC (0-10% Methanol:CH2Cl2) to give the title compound as a solid. MS (ESI) m/z 155.14 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[H-].[Na+].[C:14]([O:18][C:19]([NH:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24]Cl)=[O:20])([CH3:17])([CH3:16])[CH3:15]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:14]([O:18][C:19]([NH:21][C:22]([CH3:26])([CH3:27])[CH2:23][CH2:24][N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(CCCl)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(CCn1ccc2cc(C#N)ccc21)NC(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
Under a nitrogen atmosphere 4.07 g (16.9 mmol) 5-cyanoindole are dissolved in 30 ml DMF, and 0.73 g (18.3 mmol) sodium hydride (60% dispersion in mineral oil) are added batchwise while cooling with ice and with stirring. Then the mixture is stirred for 30 minutes at ambient temperature. It is heated to 50° C., 0.41 g (1.1 mmol) tetrabutylammonium iodide are added and over a period of 5 hours a solution of N-tert-butoxycarbonyl-3-chloro-1,1-dimethyl-propylamine is added dropwise. Then the mixture is stirred for 18 hours at ambient temperature. Then the reaction solution is poured onto water and extracted with ethyl acetate. The organic phases are combined, dried on sodium sulphate and freed from the solvent in vacuo. The residue is chromatographed on silica gel (petroleum ether/ethyl acetate=100:0→70:30). The product fractions are combined and freed from the solvent in vacuo. The residue is dissolved in 5 ml of methanol and poured onto 50 ml hot water. The precipitate thus obtained is suction filtered and dried in vacuo and reacted further without any further purification.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:16]=2)=[N:2]1.N1C=CC=CC=1.C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44].[OH-].[NH4+]>>[NH:2]1[C:3]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][N:10]=[C:9]3[C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:43](=[O:45])[CH3:44])[CH2:26][CH2:25]2)=[N:4][CH:5]=[N:1]1
Reactant: c1cc(OCCN2CCNCC2)cc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Reactant: CC(=O)OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(=O)N1CCN(CCOc2cccc(-c3n[nH]c4ccc(-c5ncn[nH]5)cc34)c2)CC1
Reaction time: 2 h
Yield: 8.8 %

Procedure:
1-(5-(1H-1,2,4-triazol-3-yl)(1H-indazol-3-yl))-3-(2-piperazinylethoxy)benzene (0.066 g, 0.169 mmol) was stirred with pyridine (0.50 mL, 6.18 mmol), triethylamine (0.10 mL, 0.717 mmol) and acetic anhydride (0.10 mL, 1.06 mmol) at ambient temperature. After 2 h, ammonium hydroxide (0.50 mL) was added and the mixture stirred for 1 h. The mixture was evaporated and gave the title compound (0.0064 g, 9% yield). 1H NMR (CD3OD) δ 8.71 (s, 1H), 8.35 (s, 1H), 8.08 (dd, 1H), 7.66 (d, 1H), 7.61 (dt, 1H), 7.55 (m, 1H), 7.44 (t, 1H), 7.01 (m, 1H), 4.25 (t, 2H), 3.58 (dt, 4H), 2.85 (t, 2H), 2.60 (dt, 4H), 2.08 (s, 3H). ES-MS (m/z) 432 [M+1]+
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[C:42]1[N:47]2[CH:48]=[CH:49][N:50]=[C:46]2[CH:45]=[CH:44][CH:43]=1>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].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>[N:50]1[CH:49]=[CH:48][N:47]2[C:42]([C:5]3[N:4]=[C:3]4[C:8]([N:9]=[C:10]([CH2:11][N:12]5[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:19])[CH3:20])[CH2:16][CH2:17]5)[N:2]4[CH3:1])=[C:7]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:6]=3)=[CH:43][CH:44]=[CH:45][C:46]=12
Reactant: Brc1cccc2nccn12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3cccc4nccn34)nc21
Yield: 57.8 %

Procedure:
A mixture of 2-[1-(9-methyl-6-morpholin-4-yl-2-(tributylstannanyl)-9H-purin-8-ylmethyl)piperidin-4-yl]propan-2-ol (0.2 g, 0.30 mmol), 5-bromoimidazo[1,2-a]pyridine (0.066 g, 0.33 mmol), copper(I) 2-thiophene carboxylate (0.018 g, 0.09 mmol) and Pd(PPh3)4 (0.052 g, 0.045 mmol) in dioxane (5 mL) was subjected to microwave irradiation at 150° C. for 60 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The eluent was concentrated in vacuo and the resultant residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 94:6) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 698 as a yellow powder (0.085 g, 58%). LCMS: RT=4.17 min, [M+H]+ 491.2. 1H NMR (CDCl3, 400 MHz) δ 9.26 (d, J=1.2 Hz, 1 H); 7.96 (dd, J=8.2, 1.2 Hz, 1 H); 7.76-7.73 (m, 2 H); 7.31 (dd, J=8.2, 5.2 Hz, 1 H); 4.38 (t, J=4.6 Hz, 4 H); 3.96 (s, 3 H); 3.89 (t, J=4.6 Hz, 4 H); 3.75 (s, 2 H); 2.96 (d, J=11.0 Hz, 2 H); 2.11 (t, J=11.0 Hz, 2 H); 1.76 (d, J=11.0 Hz, 2 H); 1.44-1.29 (m, 3 H); 1.18 (s, 6 H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)[N:8]=[N:7][C:6]=1[C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22].[Cl:27][CH2:28][CH2:29][N:30]=[C:31]=[O:32]>C1COCC1>[Cl:27][CH2:28][CH2:29][NH:30][C:31]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:15]=2)[N:8]=[N:7][C:6]=1[C:21]([NH:23][CH:24]1[CH2:26][CH2:25]1)=[O:22])=[O:32]
Reactant: O=C=NCCCl
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCN)cc1
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCNC(=O)NCCCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To a solution of 5-(3-aminopropyl)-N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (356 mg, 1 mmol) obtained in Example 1202 in THF (5 ml) was added 1-chloro-2-isocyanatoethane (106 mg, 1 mmol) at room temperature, and the mixture was stirred at room temperature for 30 min. The precipitated crystals were collected by filtration and dried to give the title compound as a white powder (450 mg, 97.4%).