Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:12]([CH3:13])[CH:11]=[CH:10][C:5]2=[N:6][C:7]=1[C:8]#[N:9].[NH:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:18][CH:16]1[CH2:17][N:14]([C:2]2[CH:3]=[C:4]3[N:12]([CH3:13])[CH:11]=[CH:10][C:5]3=[N:6][C:7]=2[C:8]#[N:9])[CH2:15]1
Reactant: Cn1ccc2nc(C#N)c(Br)cc21
Reactant: OC1CNC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cn1ccc2nc(C#N)c(N3CC(O)C3)cc21
Temperature: 90 °C
Yield: 67.8 %

Procedure:
6-Bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (4.27 g, 18.1 mmol), azetidin-3-ol (2.36 g, 18.1 mmol), Xantphos (1.05 g, 1.81 mmol), Pd(OAc)2 (0.406 g, 1.81 mmol) and cesium carbonate (11.8 g, 36.2 mmol) in dioxane (100 mL) were combined in a flask to give an orange suspension. The flask was purged with N2, sealed, and heated to 90° C. for 3 hours. The crude material was diluted with EtOAc (25 mL) and filtered through a pad of Celite. The filtrate was washed with saturated aqueous NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was loaded onto a silica gel cartridge (ISCO®, 120 g) and eluted using an EtOAc/hexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a yellow solid (2.8 g, 67%). ESI-MS m/z [M+H]+ calc'd for C12H12N4O, 229; found 229.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:42][CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][CH:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:42][CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCN(CCOc2cc3nccc(Oc4cc5ccccc5nc4C)c3cc2OC)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and ethyl piperidine-4-carboxylate (60 mg), and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (48 mg, yield 73%).
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17](F)F)=[CH:12][CH:11]=1)=[O:9])[C:3]([O:5][CH3:6])=[O:4].[CH2:20](OCC)[CH3:21]>>[CH3:1][N:2]([CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:20][CH3:21])=[CH:12][CH:11]=1)=[O:9])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)N(C)CC(=O)c1ccc(OC(F)F)cc1
Reactant: CCOCC
Product: CCCOc1ccc(C(=O)CN(C)C(=O)OC)cc1

Procedure:
By substantially following the procedure given in Example 19b, substituting 2-(N-methyl-N-(methoxycarbonyl)amino)-4'-propoxyacetophenone for 2-(N-methyl-N-(methoxycarbonyl)amino)-4'-difluoromethoxyacetophenone and using diethyl ether as solvent and continuing with Example 19dii the expected compound, an oil, bp 150°-160° C. at 0.2 torr, was obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1([CH3:20])[C:18]2[CH:13]([O:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[S:11]1>ClCCl>[Br:1][C:16]1[CH:17]=[C:18]2[C:10]([CH3:20])([CH3:9])[S:11][C:12](=[O:19])[CH:13]2[O:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)SC(=O)C2OC=CC=C21
Solvent: ClCCl
Product: CC1(C)SC(=O)C2OC=C(Br)C=C21

Procedure:
N-Bromosuccinimide (15.0 g, 84.3 mmol) was added to a solution of 5,6-dihydro-5,5-dimethyl-7H-thieno-[3,4-b]pyran-7-one (15.0 g, 82.6 mmol) in dichloromethane (300 mL) at 0° C., and the resultant solution was stirred for 2 h at 0° C. The solution was washed with water and dried over magnesium sulfate. The solvent was evaporated in vacuo to give the product as a dark grey solid, 15.1 g (70%), mp 63°-72° C.; IR(neat): 1694, 1558 and 1438 cm-1 : MS: m/z 261 (MH+); 1H NMR(CDCl3): δ 1.47 (s, 6H), 2.63 (s, 2H),7.99 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:19]>CO>[CH3:17][CH:16]([CH3:18])[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:19])[C:11]=2[N:12]=[CH:13]1
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: N
Solvent: CO
Product: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 150 °C
Yield: 70 %

Procedure:
A mixture of 4-chloro-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (66 g), methanol (266 mL) and ammonia (46.2 g) was placed in a steel bomb and heated at 150° C. for 8 h. The resulting mixture was filtered, and the solid was washed with water and dried to afford the product 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine in 70% yield.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.[CH3:11][N:12]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21](C=O)[C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2.C(=O)([O-])O.[Na+].C(OCC)C>CO>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[C:21]1[C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:11])[C:25]=2[CH:24]=[CH:23][CH:22]=1)[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: CN1c2ccccc2Sc2c(C=O)cccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CCOC(OCC)c1cccc2c1Sc1ccccc1N2C
Temperature: 0 °C
Yield: 96.2 %

Procedure:
15.0 ml of triethyl orthoformate were added at room temperature to a solution of 4.90 g (20.3 mmol) of 10-methyl-phenothiazine-4-carbaldehyde and 50 mg of p-toluenesulphonic aci×1H2O in 15 ml of methanol. The reaction mixture was boiled at reflux for 45 minutes, cooled and poured into 30 g of ice, 30 ml of saturated aqueous sodium hydrogen carbonate solution and 100 ml of diethyl ether. The organic phase was washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The residue was chromatographed on 300 g of silica gel with diethyl ether/hexane (1:4), whereupon, after crystallization from diethyl ether/hexane in a refrigerator, 6.16 g (96.2%) of 4-diethoxymethyl-10-methyl-phenothiazine were obtained as a white solid of m.p. 44.6°-46.2°.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N+:22]([O-:24])=[O:23])=[C:8]2[C:12]=1[NH:11][C:10]([CH3:13])=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.[C:25]([O:29][C:30](=[O:33])[CH2:31]Br)([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[CH3:26][C:25]([O:29][C:30](=[O:33])[CH2:31][N:11]1[C:12]2[C:8](=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=[CH:5][C:4]=2[Br:3])[C:9]([O:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[C:10]1[CH3:13])([CH3:28])[CH3:27]
Reactant: Cc1[nH]c2c(Br)ccc([N+](=O)[O-])c2c1Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Oc2ccc(Cl)cc2)c2c([N+](=O)[O-])ccc(Br)c2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% disp. in oil) (0.043 g) was added to a stirred solution of the product from step (ii) (0.34 g) in THF (4 ml) at RT. After 1 h, tert-butylbromoacetate (170 ul) was added, the mixture stirred at RT for 16 h then quenched with water and extracted with diethylether. The organics were dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10% diethylether/iso-hexane. Yield 0.192 g
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC1C=CN=CC=1C1C=CC=C2C=1C=NN2>>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(-c2cnccc2Br)cc1
Agent: Cc1ccncc1-c1cccc2[nH]ncc12
Product: O=[N+]([O-])c1ccc(-c2cnccc2-c2ccccc2)cc1

Procedure:
Intermediate 13B was prepared from Intermediate 13A and phenylboronic acid by the procedure described for the preparation of Intermediate 1C. The crude material was purified by silica gel chromatography (12 g ISCO column, eluting with 0 to 40% EtOAc in CH2Cl2) to yield Intermediate 13B. MS (ES): m/z=277.0 [M+H]+.
Reaction SMILES: [CH:1]([Si:3]([CH:7]=[CH2:8])([CH:5]=[CH2:6])[Cl:4])=[CH2:2].[Cl:9][Si:10]([Cl:17])([Cl:16])[CH2:11][CH2:12][SiH:13]([Cl:15])[Cl:14]>>[Cl:14][Si:13]([Cl:15])([CH2:12][CH2:11][Si:10]([Cl:17])([Cl:16])[Cl:9])[CH2:2][CH2:1][Si:3]([CH2:7][CH2:8][Si:13]([Cl:15])([Cl:14])[CH2:12][CH2:11][Si:10]([Cl:17])([Cl:16])[Cl:9])([CH2:5][CH2:6][Si:13]([Cl:15])([Cl:14])[CH2:12][CH2:11][Si:10]([Cl:17])([Cl:16])[Cl:9])[Cl:4]
Reactant: C=C[Si](Cl)(C=C)C=C
Reactant: Cl[SiH](Cl)CC[Si](Cl)(Cl)Cl
Product: Cl[Si](Cl)(Cl)CC[Si](Cl)(Cl)CC[Si](Cl)(CC[Si](Cl)(Cl)CC[Si](Cl)(Cl)Cl)CC[Si](Cl)(Cl)CC[Si](Cl)(Cl)Cl
Temperature: 80 °C
Yield: 66 %

Procedure:
11.00 g (0.076 mol) trivinylchlorosilane was added to a 100 ml vessel followed by 2 ml 1,1,1,4,4-pentachloro-1,4-disilabutane. The solution was heated to 80° C. and 15 μL of a 10% H2PtCl6/IPA-solution was added. Strong exothermic reaction was observed and heat was switched off. Rest of 1,1,1,4,4-pentachloro-1,4-disilabutane was added slowly during 30 min keeping the temperature of the solution below 130° C. The total amount of 1,1,1,4,4-pentachloro-1,4-disilabutane was 61.50 g (0.234 mol, 2.6% excess). After addition heat was again switched on and solution was stirred for an hour at 110° C. After that solution was distilled yielding 47.08 g (66%) tris(3,3,6,6,6-pentachloro-3,6-disilahexyl)chlorosilane. B.p. 264° C./<0.5 mbar.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:14])[N:5]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:6]=[CH:7][C:8]=1Cl)[CH3:2].C(N)C1C=CC=CC=1.[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[CH2:1]([C:3]1[C:4](=[O:14])[N:5]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:6]=[CH:7][C:8]=1[NH:29][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([CH3:23])=[CH:25][CH:26]=1)[CH3:2]
Reactant: CCc1c(Cl)cnn(C(C)(C)C)c1=O
Reactant: Cc1ccc(CN)cc1
Solvent: NCc1ccccc1
Product: CCc1c(NCc2ccc(C)cc2)cnn(C(C)(C)C)c1=O

Procedure:
The compound as identified in Table 14 was prepared in the synthetic manner and after-treatment similar to those in Example 7 except that the 4-alkyl-5-chloro-2-alkyl-3(2H)pyridazinone with R1 and R2 as identified in Table 14 was used instead of the starting 4-ethyl-5-chloro-2-t-butyl-3(2H)pyridazinone used in Example 7, and the benzylamine derivative with R3, Y1, Y2 and Y3 as identified in Table 14 was used instead of the starting 4-methylbenzylamine. In the NMR data, only the characteristic absorptions were given in Table 14.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.O>C(OCC)(=O)C>[F:17][C:18]([F:29])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[CH:11]3)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2ccc3[nH]ccc3c2)cc1
Yield: 57.9 %

Procedure:
A stirred slurry of 6.56 g (62 mmol) Na2CO3, 3.03 g (15.5 mmol) 5-bromoindole, 3.415 g (16.5 mmol) 4-(trifluoromethoxy)phenylboronic acid, and 0.50 g (0.43 mmol) tetrakistriphenylphosphine palladium was heated to reflux for 3 hr. The reaction mixture was allowed to cool and was then poured into 300 mL water and shaken with ethyl acetate. The combined aqueous and organic phases were filtered and the organic layer was separated, dried over MgSO4, and concentrated. The residue was chromatographed on silica (eluting with 20–33% EtOAc-hexane) to afford 2.49 g (58%) 5-[4-(trifluoromethoxy)phenyl]indole as a solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH2:19](Br)[CH:20]([CH3:22])[CH3:21]>>[CH2:19]([O:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: CC(C)CBr
Product: CC(=O)c1cc2c(cc1OCC(C)C)C(C)(C)CCC2(C)C
Yield: 105.4 %

Procedure:
1-(3-Hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl)-ethanone (0.250 g, 1.01 mmol) was alkylated with isobutylbromide (0.195 g, 1.42 mmol, 0.154 mL) as described in Example 21. Aqueous workup gave 1-[3-isobutyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalen-2-yl]-ethanone 0.322 g (crude) as an orange oil: 1H-NMR (400 MHz, CDCl3) δ 7.74 (s, 1H, Ar—H), 6.81 (s, 1H, Ar—H), 4.13 (d, J=6.2 Hz, 2H, OCH2), 2.62 (s, 3H, CH3), 2.16 (m, 1H, CH), 1.68 (app br d, 4H, 2CH2), 1.30 (s, 6H, 2CH3), 1.28 (s, 6H, 2CH3), 1.08 (d, J=6.7 Hz, 6H, 2CH3).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N+:2]=1[O-].P(Cl)(Cl)([Cl:14])=O>ClCCl>[Cl:14][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc2ccccc2c1
Solvent: ClCCl
Product: Clc1nccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of isoquinoline-N-oxide (5.52 g, 38 mmol) in dichloromethane (50 ml) was added over 15 minutes to a solution of phosphorus oxychloride (40 ml) in dichloromethane (50 ml) at room temperature. The mixture was stirred for 1 hour, then heated to reflux for 2 hours. After cooling to room temperature, the mixture was poured into ice water (500 ml). The mixture was then extracted with dichloromethane (2×250 ml) and the combined organic layers were washed with 10% aqueous potassium carbonate solution (200 ml), brine (200 ml) then dried (Na2SO4) and evaporated to give the title compound (5.0 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH:16][N+:17]([O-])=O)[CH:12]=[C:11]([O:20][CH3:21])[CH:10]=1>C1COCC1>[CH3:21][O:20][C:11]1[CH:12]=[C:13]([CH2:15][CH2:16][NH2:17])[CH:14]=[C:9]([O:8][CH3:7])[CH:10]=1
Reactant: COc1cc(C=C[N+](=O)[O-])cc(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CCN)cc(OC)c1
Reaction time: 0.5 h

Procedure:
To a suspension of LiAlH4 (1.76 g, 46.4 mmol) in THF (30 mL) is added at 0° C. dropwise a solution of 1,3-dimethoxy-5-(2-nitro-vinyl)-benzene (2.43 g, 11.6 mmol; Gairaud C B, Lappin G R, J Org Chem 1953, 18, 1) in THF (70 mL). The mixture is stirred for 30 min at this temperature and then at reflux for 4 h. The reaction mixture is quenched by the subsequent addition of 2 N NaOH (20 mL) and stirred for another 15 min at ambient temperature. The aqueous solution is extracted three times with EtOAc. The combined organic layers are dried with anhydrous MgSO4, filtered and concentrated to give the title compound as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH3:23][C:24]1[S:25][C:26]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[C:27]([C:29](O)=[O:30])[N:28]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:29]([C:27]3[N:28]=[C:24]([CH3:23])[S:25][C:26]=3[C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:37]=3)=[O:30])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(C(F)(F)F)cc2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-(4-trifluoromethyl-phenyl)thiazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:36]=[C:37]([C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)[CH3:38]>CN(C=O)C.[Cu]I>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:36]=[C:37](/[C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)\[CH3:38])[C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=CBr)c1ccncc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(CCCO)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(CCCO)CC2)c1ccncc1
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
3-(3,4-Dihydro-8-methyl-1H-pyrido[4,3-b]indol-2(5H)-yl)propan-1-ol (500 mg, 2.04 mmol) was dissolved in DMF (10 mL) and to this solution were added potassium phosphate (865 mg, 4.08 mmol), copper(I) iodide (38.76 mg, 0.204 mmol) and L-proline (46.92 mg, 0.408 mmol). The reaction mixture was stirred for 10 min. and 4-(1-bromoprop-1-en-2-yl)pyridine (600 mg, 3.06 mmol) in DMF (2 mL) was added dropwise. The reaction mixture was purged with nitrogen and heated overnight at 85° C. (prolonged heating was required some cases). DMF was evaporated; the residue was diluted with water and filtered. The solid was purified by silica gel chromatography (100-200 mesh, neutralized by aq. ammonia) eluting with 0-10% MeOH-DCM. The compound was further purified by HPLC. 1H NMR (CD3OD, di-HCl salt) δ (ppm): 8.70 (m, 2H), 7.98 (m, 2H), 7.56 (s, 1H), 7.38 (s, 1H), 7.10 (m, 2H), 4.40 (m, 1H), 4.0 (m, 1H), 3.78 (t, 2H), 3.60 (m, 1H), 3.50 (t, 2H), 3.40-3.20 (m, 3H), 2.42 (s, 3H), 2.15 (m, 2H), 2.10 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH2:8]([O:15][C@@H:16]1[C@@H](CO)[O:19][C@@H:18]([N:23]2[CH:30]=[C:29]([F:31])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH2:8]([O:15][C@@H:16]1[C@@H:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:19][C@@H:18]([N:23]2[CH:30]=[C:29]([F:31])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccccc1
Reaction time: 8 h
Yield: 81.5 %

Procedure:
A 3.33 ml quantity of acetic anhydride was added to a solution of 3.95 g of 3'-O-benzyl-2'-deoxy-5-fluorouridine in 30 ml of pyridine, and the mixture was left to stand at 40° C. overnight. The solvent was distilled off and the residue was dissolved in 30 ml of ethyl acetate. The solution was washed twice with 15 ml of water. The ethyl acetate layer was dried on anhydrous sodium sulfate and concentrated. The concentrate was placed on a silica gel column and eluted with chloroform, giving 3.62 g of the title compound in a yield of 81.5%.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[CH2:6]([O:8][C:9]([C:11]1([CH2:24][CH2:25]CO)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[O:10])[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:6]([O:8][C:9]([C:11]1([CH2:24][CH2:25][CH2:1][Br:5])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[O:10])[CH3:7]
Reactant: CCOC(=O)C1(CCCO)CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C1(CCCBr)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Carbon tetrabromide (1.6 gm, 0.0048 mol) is added to a stirred solution of 4-(3-hydroxypropyl) piperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester (1.27 gm, 0.0040 mol) and triphenyl phosphine (1.6 gm, 0.0060 mol) in dichloromethane (15 mL) at 0-5° C. temperature. Reaction mixture is allowed to stir at room temperature for 30 minutes. Removal of solvent gives a crude residue which is purified by column chromatography (silica gel 230-400 mesh, ethyl acetate:n-hexane 3:7) to get 4-(3-bromopropyl)piperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=1>CCO>[I:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([CH:2]=[C:3]([CH3:4])[N:6]=2)[CH:9]=1
Reactant: Nc1ccc(I)cn1
Reactant: CC(=O)CCl
Solvent: CCO
Product: Cc1cn2cc(I)ccc2n1

Procedure:
Chloroacetone (3 mL) was added to a stirring solution of 2-amino-5-iodopyridine (2g) in EtOH (20 mL) and heated to reflux. The reaction progress (50% of unreacted 2-amino-5-iodopyridine) was analyzed after 12 h by LC/MS and TLC. Additional amount of chloroacetone (3 mL) was transferred to the reaction mixture and heated for additional 8 h to observe the >90% consumption of 2-amino-5-iodopyridine. The reaction mixture was cooled and concentrated to dryness. The crude residue was diluted with EtOAc (130 mL)/water (50 mL) and neutralized with 5% aq. NaOH (25 mL). Organic layer from the biphasic solution was separated and the aqueous phase was partitioned again with EtOAc (70 mL). Combined organic layers were dried over MgSO4, filtered and concentrated. The crude brown residue was purified by Combiflash® companion System® with RediSep® silica gel column [(80g), 50-75-100% EtOAC/hexanes as an eluting solvent gradient. The product fractions were concentrated to provide 2.2 g of 6-iodo-2-methylimidazo[1,2-a]pyridine (1.8 g) as an off-brown solid. 1H NMR (300 MHz, DMSO-d6) δ 8.81 (dd, J=1.7, 1.0 Hz, 1H), 7.62-7.55 (app s, 1H), 7.31 (dd, J=9.4, 1.7 Hz, 1H), 7.25 (dd, J=9.3, 0.8 Hz, 1H), 2.29 (s, 3H). See Helvetica Chimica Acta, 90(12), 2349-2367 (2007).