Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27]N(C=O)C.[H-].[Na+].CI>O>[CH3:27][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12]1
Reactant: c1ccc(CN(CCc2c[nH]c3ccccc23)Cc2ccccc2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1cc(CCN(Cc2ccccc2)Cc2ccccc2)c2ccccc21
Reaction time: 0.25 h

Procedure:
N,N-dibenzyl-tryptamine (1.72 g) was added to an anhydrous DMF solution containing 0.24 g of NaH (60% nujol) and the mixture was stirred for 15 minutes. Methyl iodide (0.31 ml) was added and the mixture was stirred for one hour. Water was added and the solvent was evaporated off. The residue to which water was added was extracted with IPE, the extract was washed with water and the brine and dried over magnesium sulfate. The crude product was purified by column chromatography on silica gel. Eluates with ethyl acetate/hexane (1/9) afforded 1.58 g of the oily title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH2:10]Br)[CH:7]=[C:6]([CH3:12])[C:5]=1[N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34].N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH2:10][N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])[CH:7]=[C:6]([CH3:12])[C:5]=1[N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: CCNCC
Reactant: COC(=O)c1cc(CBr)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)Cc1cc(C)c(N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1

Procedure:
A solution of 518.4 mg (1.0 mmole) of the product of Example 279, 0.5 ml (4.8 mmol) of diethylamine and 0.172 ml (2.0 mmol) of pyridine in 10 ml of dichloromethane was stired at room temperature for 18 hr. The resulting mixture washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with 2% MeOH/CH2Cl2 as eluant to provide 425 mg (83%). Electrospray Mass Spec 511 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:25]([O:27]CC)=[CH2:26])CCC>C(OCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[C:10]([Cl:12])[N:11]=[C:2]([C:25](=[O:27])[CH3:26])[CH:3]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)nc(C(C)=O)c1
Reaction time: 8 h

Procedure:
Add methyl 2,6-dichloroisonicotinate (3.0 g, 15.0 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (105 mg, 0.15 mmol) and toluene (10 mL) in a previously nitrogen filled sealed vessel. Flush the reactants with nitrogen again. Add tributyl(1-ethoxyvinyl)tin (5.57 mL, 16.5 mmol) under nitrogen and heat the sealed mixture at 100° C. overnight with vigorous stirring. Cool the reaction to room temperature, dilute with diethyl ether and filter through a filtering agent. Concentrate to near dryness and dilute the residue with THF (10 mL). Add dropwise 5 N HCl (5 mL) and stir the mixture overnight. Concentrate to near dryness and extract the organic material by diethyl ether, partitioning with water. Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 10:90 ethyl acetate:hexanes) to give the title compound as a solid over two steps (47%).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[CH:10].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[CH:10]
Reactant: C#CCCCCCCCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C#CCCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a flame-dried round-bottomed flask was added 9-decyn-1-ol (1 equiv, 32.4 mmol, 5.00 g), dihydropyran (1.5 equiv, 48.6 mmol, 4.09 g, 4.5 mL), CH2Cl2 (50 mL), and PPTS (0.1 equiv, 3.24 mmol, 800 mg). The reaction was stirred for 16 h at rt and quenched with sat. aq. NaHCO3 (40 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic layers were washed with H2O (30 mL), dried with Na2SO4, concentrated in vacuo, and purified by flash column chromatography (5% EtOAc/Hex) to afford 9-Decyn-1-ol tetrahydropyranyl ether (7.55 g, 31.7 mmol, 98%). TLC Rf=0.30 (5% EtOAc/Hex); 1HNMR (600 MHz): δ 4.55-4.62 (1H), 3.83-3.91 (m, 1H), 3.70-3.78 (m, 1H), 3.48-3.55 (m, 1H), 3.36-3.43 (m, 1H), 2.19 (td, 2H, J1=7.1 Hz, J2=2.6 Hz), 1.95 (t, 1H, J=2.6), 1.80-1.89 (1H), 1.69-1.76 (1H), 1.50-1.63 (8H), 1.28-1.44 (8H); 13CNMR (150 MHz): δ 98.8, 84.7, 68.1, 67.6, 62.3, 30.8, 29.7, 29.3, 29.0, 28.7, 28.5, 26.2, 25.5, 19.7, 18.4.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH2:6][NH:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:22][C:23]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:24]=1[CH2:25][N:5]1[CH2:6][C@H:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[C@@H:3]([CH:2]=[O:1])[CH2:4]1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: OC[C@H]1CNC[C@@H]1c1ccsc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C[C@H]1CN(Cc2ccc(Cl)cc2Cl)C[C@@H]1c1ccsc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.4 g (13.1 mmol) of 3-(R)-hydroxymethyl-4-(S)-(3-thienyl)pyrrolidine, 6.8 mL (39 mmol) of diisopropylethylamine, and 4.1 g (23.4 mmol) of 2,4-dichlorobenzaldehyde (Aldrich) in 60 mL of CH2Cl2 at rt was added 5.5 g (26 mmol) of sodium triacetoxyborohydride in several small portions and the reaction mixture was stirred at rt for 3 h. To the reaction was added 50 mL of sat'd NaHCO3 solution and the mixture was extracted with CH2Cl2. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:acetone, 4:1) to give the title compound. Mass Spectrum (ESI) m/e=342 (M+1 35Cl, 35Cl), 344 (M+1 35Cl, 37Cl), and 346 (M+1 37Cl, 37Cl). 1H-NMR (CDCl3, 500 MHz): 7.38 (m, 2H), 7.30 (m, 1H), 7.23 (m, 1H), 7.03 (m, 2H), 3.65-3.77 (m, 3H), 3.34 (m, 1H), 3.21 (t, J=8.5 Hz, 1H), 2.82 (m, 2H), 2.70 (m, 1H), 2.52 (t, J=8 Hz, 1H), 2.38 (m, 1H). 13C-NMR (CDCl3, 125 MHz): 145.0, 134.7, 134.6, 133.3, 131.3, 129.3, 127.0, 126.9, 126.0, 119.8, 66.2, 61.7, 57.8, 56.1, 48.0, 41.7.). [α]D=+3.0 (c=1.75, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[NH:8][C:9]([C:11]3[N:16]=[C:15]([C:17]4[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][C:20]5[O:24][C:23]([C:25]6[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=6)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=5[CH:36]=4)[CH:14]=[CH:13][C:12]=3[OH:43])=[CH:10][C:3]=12.[C:44]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:1][C:2]1[C:3]2[CH:10]=[C:9]3[C:11]4[N:16]=[C:15]([C:17]5[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:39])=[O:40])=[CH:19][C:20]6[O:24][C:23]([C:25]7[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=7)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=6[CH:36]=5)[CH:14]=[CH:13][C:12]=4[O:43][CH2:44][N:8]3[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(-c4cc5c(F)cncc5[nH]4)n3)cc12
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cncc5n3CO4)cc12
Yield: 28.7 %

Procedure:
To a stirring solution of 5-(6-(4-fluoro-1H-pyrrolo[2,3-c]pyridin-2-yl)-5-hydroxypyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.17 mmol) and Cs2CO3 (108 mg, 0.33 mmol) in DMF (3 mL) was added chloroidomethane (35 mg, 0.2 mmol) dropwise at 100° C. under N2. The mixture was heated for 8 hours. The mixture was diluted with H2O and extracted with EtOAc. The organics were washed with brine and dried over Na2SO4. The crude product was purified using prep-HPLC to obtain the product of Compound 46 (30 mg, yield: 30%). 1H-NMR (CDCl3, 400 MHz) δ 8.61 (s, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.95 (t, J=6.0 Hz, 2H), 7.65 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.53 (d J=8.0 Hz, 1H), 7.25˜7.19 (m, 3H), 6.10 (s, 2H), 5.99 (s, 1H), 3.37 (s, 3H), 3.00 (d, J=4.0 Hz, 3H), 2.80 (s, 3H). MS (M+H)+: 616.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7]O)[O:5][C@@H:4]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Se:27]C#N)([O-:20])=[O:19].O1CCCC1.C(P(CCCC)CCCC)CCC>C(OCC)(=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][Se:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N+:18]([O-:20])=[O:19])[O:5][C@@H:4]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1
Reactant: N#C[Se]c1ccccc1[N+](=O)[O-]
Reactant: Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cn([C@H]2C[C@H](F)[C@@H](C[Se]c3ccccc3[N+](=O)[O-])O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
3'-Deoxy-3'-fluorothymidine (2.04 g, 8.34 mM) and o-nitrophenylselenocyanate (2.10 g, 9.20 mM) were placed in a flask under nitrogen. Tetrahydrofuran (dry) (50 mL) was added followed by 2.2 mL (8.83 mM) of tri-n-butylphosphine. The mixture was stirred at room temperature for 1.5 hours, diluted with 200 mL of ethyl acetate and washed with 200 mL of sat. sodium bicarbonate followed by 200 mL of brine. The extract was dried over magnesium sulfate and concentrated under reduced pressure to a yellow oil (6.3 g). Chromatographic purification of the yellow oil on silica gel with hexane:ethyl acetate (4:1 v/v) as eluent gave 2.79 g (6.51 mM; 78%) of 3',5'-di-deoxy-3'-fluoro-5'-[(2-nitrophenyl)selenyl]thymidine as an amorphous yellow solid.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C)C=O>[N:12]([CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)=[N+:13]=[N-:14]
Reactant: ClCCOCc1c[nH]cn1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCc1c[nH]cn1
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A stirred suspension of 4-(2-chloroethoxymethyl)imidazole hydrochloride (14.7 g.) and sodium azide (9.8 g.) in dry dimethylformamide (103 ml.) was maintained at 95° for 5 hours and then set aside overnight at room temperature. Following dilution with water and filtration, the filtrate was concentrated and the residue purified by chromatography on a dry column of alumina using ethanol. The product was basified with potassium carbonate (6.5 g.) in water (3 ml.) and the anhydrous residue was extracted with isopropyl alcohol (3×50 ml.). Concentration of the extracts afforded 4-(2-azidoethoxymethyl)imidazole (7.2 g.). Hydrogenation of the azido compound (7.2 g.) in isopropyl alcohol (142 ml.) over platinum oxide catalyst (3.0 g.) gave 4-(2-aminoethoxymethyl)imidazole (6.48 g.). A sample of the monopicrate monohydrochloride had m.p. 139°-140° (from nitromethane). (Found: C, 35.4; H, 3.8; N, 20.5; Cl, 8.8. C12H15ClN6O8 requires: C, 35.4; H, 3,7; N, 20.7; Cl, 8.7).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].O1[C:22]2([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[O:21]CC1>CS(C)=O.C(OCC)C>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([N:25]2[CH2:26][CH2:27][C:22](=[O:21])[CH2:23][CH2:24]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=C1CCN(c2ncccc2C(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2-Chloro-3-(trifluoromethyl)pyridine (11.92 g, 65.7 mmol)), K2CO3(19.10 g, 138 mmol), and 1,4-dioxa-8-azaspiro[4.5]decane (8.85 mL, 69.0 mmol) were combined in DMSO (65 mL) and stirred at 100° C. for 3 hours. The mixture was treated with additional 1,4-dioxa-8-azaspiro[4.5]decane (2.0 mL, 16 mmol), stirred for 2 hours, treated with additional 1,4-dioxa-8-azaspiro[4.5]decane (1.0 mL, 7.8 mmol), and stirred for 1 hour. The mixture was diluted with diethyl ether (200 mL), washed with water (250 mL), washed with brine (100 mL), dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in concentrated HCl (25 mL), stirred for 3 hours, basified with concentrated NH4OH, extracted with CH2Cl2, and the phases separated. The organic phase was dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified via flash chromatography (20% to 40% diethyl ether/hexanes) to provide the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1.Br[CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[N:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=3)[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: FC(F)(F)c1ccc(CCCBr)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCCc2ccc(C(F)(F)F)nc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
To a suspension of sodium hydride (0.014 g, 0.00054 mol) in dry DMF (3 mL), 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.00045 mol) was added at ice cold temp and stirred for 2 h at room temperature. Reaction mix was cooled to −20° C. and 5-(3-Bromo-propyl)-2-trifluoromethyl-pyridine (0.183 g, 0.00068 mol) was added, stirred for 1 h at 15° C., Reaction was monitor by TLC. After completion (TLC), reaction mix was cooled to 0° C. and water (10 mL) was added, extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (4% Methanol:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide desired compound as brown oil (0.06 g, 32% yield). 8-Chloro-2-methyl-5-[3-(6-trifluoromethyl-pyridin-3-yl)-propyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.06 g, 0.000147 mol) was dissolved in THF (1.0 mL), A solution of oxalic acid dihydrate (0.016 g, 0.000126 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.050 g, 68% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][N:7]=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]=[C:17]=[S:18])[N:5]=1.[N:19]#[C:20]Br.O>O1CCCC1>[CH3:3][C:4]1[N:5]=[C:6]2[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=[C:17]([S:18][C:20]#[N:19])[N:7]2[N:8]=1
Reactant: Cc1nc(Cc2ccccc2N=C=S)n[nH]1
Reactant: N#CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2n(n1)C(SC#N)=Nc1ccccc1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 0.91 g of sodium hydride in 27 ml of tetrahydrofuran is added dropwise a solution of 8.74 g of 5-methyl-3-(o-isothiocyanatobenzyl)-1,2,4-triazole in 60 ml of tetrahydrofuran over a period of 20 minutes. The mixture is stirred at room temperature for 2 hours. To the resulting suspension a solution of 4.02 g of cyanogen bromide in 35 ml of tetrahydrofuran is added dropwise at 0° over a period of 15 minutes. The mixture is stirred at 0° for 1.5 hours, poured into water and extracted three times with ethyl acetate. The organic extracts are dried over magnesium sulfate, decolorized with charcoal and evaporated to give 2-methyl-5-cyanothio-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine; IR 2150 cm-1.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[C:7]([NH2:9])[N:6]=[N:5]1.Br[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1.CC([O-])(C)C.[K+].CN(C=O)C>O>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([NH:9][C:7]2[N:6]=[N:5][N:4]([CH2:3][O:2][CH3:1])[CH:8]=2)=[N:12][CH:13]=1
Reactant: Brc1ccc(Br)nc1
Reactant: COCn1cc(N)nn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1cc(Nc2ccc(Br)cn2)nn1
Temperature: 70 °C
Reaction time: 72 h
Yield: 4 %

Procedure:
1-(methoxymethyl)-4-amino-1H-1,2,3-triazole (3.56 g, 27.784 mmol), 2,5-dibromopyridine (19.608 g, 82.773 mmol) and potassium tert-butylate (9.345 g, 83.252 mmol) were added into DMF (100 mL), heated to 70° C., and stirred for 72 hours. The reaction solution was poured into water, and extracted with ethyl acetate. The combined organic phase was washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column chromatograph (ethyl acetate:petroleum ether=1:30) to obtain 0.318 g of 5-bromo-N-(1-(methoxymethyl)-1H-1,2,3-triazol-4-yl)pyridine-2-amine as a yellow solid, at a yield of 4%.
Reaction SMILES: C[C:2]1[C@@H:19](OC([C@H](O)[C@@H](NC(C2C=CC=CC=2)=O)C2C=CC=CC=2)=O)[CH2:18][C@:14]2(O)[C:15](C)(C)[C:3]=1[C@@H:4]([O:59]C(C)=O)C([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1O)=O.C(O)(=O)C.[Cl:67]CCl>C(OCC)(=O)C>[C:4]([Cl:67])(=[O:59])[C:3]1[CH:15]=[CH:14][CH:18]=[CH:19][CH:2]=1
Reactant: ClCCl
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(Cl)c1ccccc1

Procedure:
Before the C-4 sidechain can be added to the C-7 Cbz protected paclitaxel analog (9), the analog (9) must undergo protection of the 2-OH. The protection step is carried out by treating the reaction mixture containing analog (9) with an acid, preferably acetic acid to neutralize the reaction mixture. The dichloromethane in the neutralized reaction mixture is exchanged for ethyl acetate or other ester or amide organic solvent, and the resulting solution of 9 is treated with a strong base, preferably Li t-butoxide, and a benzoyl protecting agent, preferably benzoyl chloride, to form the 2-benzoyl (Bz) 7-hydroxy protected paclitaxel (10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH:13]=[CH2:14])[CH:7]=[CH:8][N:9]=2)[N:4]=1.Cl.[CH3:16][NH2:17].CC(O)=O>CO>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][NH:17][CH3:16]
Reactant: C=Cc1ccnc2ccc(OC)nc12
Reactant: CN
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: CNCCc1ccnc2ccc(OC)nc12
Yield: 18.6 %

Procedure:
A solution of 2-methoxy-8-vinyl-[1,5]naphthyridine (prepared as in WO 02/08224; 0.28 g, 1.5 mmol) in MeOH (6 mL) was treated with methyl amine hydrochloride (0.1 g, 1 eq.) and heated in a sealed flask at reflux for 5 h. AcOH (0.9 mL) was added and the mixture heated at reflux overnight. The mixture was concentrated in vacuo, taken up in aq. ammonia and extracted with DCM/MeOH (9:1). The combined org. extracts were dried over MgSO4 and concentrated. The residue was purified by FC (DCM/MeOH 9:1+1% NH4OH) to give the title amine as a brown oil (0.06 g, 19% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[C:6]([N:14]=[C:15]=[S:16])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:15]([NH:14][C:6](=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[S:16]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COCCN
Solvent: ClCCl
Product: COCCNC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
2-Methoxyethylamine (17.7 mL, 202.2 mmol) was added dropwise over 30 minutes to a stirring solution of benzoylisothiocyanate (30.00 g, 183.8 mmol) in CH2Cl2 (300 mL) at room temperature under argon and the mixture was stirred at room temperature for 16 hours. The mixture was washed sequentially with 10% aqueous citric acid (75 mL), water (75 mL) and brine (75 mL), dried over MgSO4 and concentrated in vacuo. The resulting yellow oil solidified on standing to give the title compound (41.85 g, 96%). The material was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:37]N1C(=O)CCC1=O.ClCCCl>C(Cl)Cl>[Br:37][CH:2]([Cl:1])[C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CCl)c3c2)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(Cl)Br)c3c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
A mixture of 3-[3-(chloromethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (1.00 g, 0.00266 mol), azo-bis-isobutyronitrile (0.100 g), N-bromosuccinimide (0.712 g, 0.00400 mol) and 1,2-dichloroethane is stirred one hour at reflux. Additional azo-bis-isobutyronitrile (0.0500 g) and N-bromosuccinimide (0.100 g) are added and the mixture is stirred two hours at reflux, cooled to room temperature, diluted with methylene chloride, washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to an orange gum. Chromatography of the gum on silica gel with methylene chloride:ether gives the title compound as a white foam (0.950 g, 80.2%, mp 93-96° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]=[C:10]1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Br)(=[O:19])[CH3:18].C(N(CC)CC)C>CC(C)=O>[C:17]([N:11]1[CH:12]=[CH:13][C:14](=[O:15])[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]1[CH3:16])(=[O:19])[CH3:18]
Reactant: CC1=NC=CC(=O)C1OCc1ccccc1
Reactant: CC(=O)Br
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)n1ccc(=O)c(OCc2ccccc2)c1C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
3-Benzyloxy-2-methylpyrid-4-one (4 g) is dissolved in dry acetone (100 ml). Acetylbromide (3 g) and triethylamine (2.7 g) are added and the resulting mixture is mechanically stirred overnight. The mixture is then filtered and the filtrate is rotary evaporated to dryness. The residue is dissolved in methylene chloride and washed with dilute hydrochloric acid (pH 3.0), then twice with water, and is dried over Na2SO4 and rotary evaporated to yield a solid residue. Recrystallisation of this residue from an ethylacetate/hexane mixture gives 1-acetyl-3-benzyloxy-2-methylpyrid-4-one as an oil (3.1 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16]C)=O)=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1.[NH2:18][NH2:19].CO>O>[NH2:1][C:2]1[C:3]([C:14]([NH:18][NH2:19])=[O:16])=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(-c2cccnc2)cnc1N
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1nc(-c2cccnc2)cnc1N
Yield: 58.5 %

Procedure:
Methyl 3-amino-6-(3-pyridyl)pyrazine-2-carboxylate (2 g, 8.687 mmol) was heated in hydrazine (1.392 g, 1.363 mL, 43.43 mmol) with a minimal amount of MeOH (5 mL) added at 80° C. for 2 hours. The reaction was treated with water and the product collected by filtration, washed with methanol and dried to give the desired product as a brown solid (1.17 g, 58% Yield). 1H NMR (400.0 MHz, DMSO) d 7.43 (1H, m), 7.47 (2H, br s), 8.54 (2H, m), 8.90 (1H, s), 9.38 (1H, m), 10.16 (1H, br s); MS (ES+) 231.96