Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[C:6]([F:16])[C:5]([CH:17](O)[CH2:18][CH3:19])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:41]>C(Cl)Cl>[Br:41][CH:17]([C:5]1[C:6]([F:16])=[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:18][CH3:19]
Reactant: BrC(Br)(Br)Br
Reactant: CCC(O)c1ccc(Cl)c(C(=O)c2ccccc2)c1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(Br)c1ccc(Cl)c(C(=O)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
Step 2 [6-Chloro-2-fluoro-3-(1-hydroxy-propyl)-phenyl]-phenyl-methanone (760 mg; 2.6 mmol) was dissolved in DCM (20 ml), treated with triphenylphosphine (1.095 g; 1.6 equiv.) and carbon tetrabromide (1.275 g; 1.5 equiv.) and stirred at room temperature overnight. The reaction mixture was evaporated then purified by flash column chromatography eluting with 0 to 20% EtOAc/petroleum ether. Product containing fractions were combined and evaporated to give 650 mg of [3-(1-Bromo-propyl)-6-chloro-2-fluoro-phenyl]-phenyl-methanone as a colourless gum. 1H NMR (400 MHz, DMSO-d6): 7.89-7.69 (4H, m), 7.69-7.54 (3H, m), 5.34 (1H, dd), 2.38-2.12 (2H, m), 0.99 (3H, t).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=3)=[CH:11][C:10]([NH2:28])=[N:9]2)=[CH:4][CH:3]=1.[O:29]=[C:30]1[NH:34][CH2:33][C@@H:32]([C:35](O)=[O:36])[CH2:31]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:24])([F:25])[F:23])[CH:16]=[C:15]([F:27])[CH:14]=3)=[CH:11][C:10]([NH:28][C:35]([C@H:32]3[CH2:31][C:30](=[O:29])[NH:34][CH2:33]3)=[O:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: O=C1C[C@H](C(=O)O)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](OCc1cc(F)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of 1-(4-fluorophenyl)-5-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine prepared in the previous step (about 0.125 mmol) in dimethylformamide (0.5 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (18 mg) prepared according to the same procedures as Preparation 14 and WSC.HCl (29 mg) at room temperature, and the mixture was stirred for 3 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (31 mg).
Reaction SMILES: O=C([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)CCC[Cl:6].[I-].[Na+].C1OC2C=CC(N3CCNCC3)=CC=2O1.C1CCN2C(=NCCC2)CC1.C(=O)([O-])O.[Na+].Cl>CS(C)=O.CO>[ClH:6].[NH:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:16][CH:15]=2)[CH2:10][CH2:11][C:12]1=[O:17]
Reactant: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CS(C)=O
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCc2ccccc2N1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2.7 Grams of 6-(1-oxo-4-chlorobutyl)-3,4-dihydrocarbostyril and 1.5 g of sodium iodide were mixed in 30 ml of dimethyl sulfoxide and the mixture was stirred at 50° C. for 2 hours. Then to the reaction mixture were added 2.0 g of 4-(3,4-methylenedioxyphenyl)-piperazine and 3 g of DBU and the reaction mixture was stirred at 70°-80° C. for 5 hours. After the reaction was completed, the reaction mixture was poured into 10 ml of 2%-sodium hydrogencarbonate and the organic layer was extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation. To the residue thus obtained were added 50 ml of methanol and 5 ml of concentrated hydrochloric acid and the mixture was concentrated under a reduced pressure to dryness. The residue thus obtained was crystallized by adding ethanol-acetone to obtain crude crystals, and the crude crystals were recrystallized from ethanol-water. 2.1 Grams of 6-{1-oxo-4-(3,4-methylenedioxy-phenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril monohydrochloride in colorless powdery crystals were obtained.
Reaction SMILES: [NH2:1][C:2](=[O:17])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1.[Br:18]Br>C(Cl)(Cl)Cl>[NH2:1][C:2](=[O:17])[CH2:3][O:4][C:5]1[C:14]([Br:18])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc(OCC(N)=O)cc1OC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)c(OCC(N)=O)cc1OC
Temperature: 0 °C
Yield: 104 %

Procedure:
To a 250 mL round-bottomed flask was added methyl 4-(2-amino-2-oxoethoxy)-2-methoxybenzoate (1.2 g, 5.14 mmol) and chloroform (40 mL). The mixture was placed under a nitrogen atmosphere and cooled to 0° C. Bromine (0.263 mL, 5.14 mmol) was added drop wise (in 3 mL of chloroform) and the solution was allowed to warm to room temperature overnight. The orange solid was cooled with an ice bath, filtered, washed sequentially with cold chloroform, then diethyl ether. The product was dried under vacuum giving 1.7 grams (91% yield) of methyl 4-(2-amino-2-oxoethoxy)-5-bromo-2-methoxybenzoate as an orange solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Waters Sunfire 5 μm C18, 4.6×30 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 2 minutes with a 1 minute hold at a rate of 4 mL/minute. 1H NMR (400 MHz, THF-d8) δ ppm 3.76 (s, 3H), 3.88 (s, 3H), 4.63 (s, 2H), 6.76 (s, 1H), 7.10 (br. s., 2H), 7.96 (s, 1H). LCMS Rt=1.793 min., m/z 319.1 (M+H), 90% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[F:31][C:32]1([F:45])[CH2:37][CH2:36][C@H:35]([OH:38])[C@@H:34]([C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)[CH2:33]1.[H-].[Na+]>CN(C=O)C>[F:45][C:32]1([F:31])[CH2:37][CH2:36][C@H:35]([O:38][C:13]2[CH:14]=[C:15]([F:16])[C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:3]=3[O:2][CH3:1])[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:8])=[O:9])=[C:11]([F:18])[CH:12]=2)[C@@H:34]([C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)[CH2:33]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(F)cc2F)c(OC)c1
Reactant: Cn1nccc1[C@H]1CC(F)(F)CC[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(O[C@H]3CCC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 48.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4,6-trifluoro-N-(pyrimidin-4-yl)benzenesulfonamide (150 mg, 0.34 mmol) prepared in Example 27a, the (1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (61.6 mg, 0.28 mmol) prepared in Example 88 g, sodium hydride (63%; 21.7 mg, 0.57 mmol) and DMF (2.0 mL), to yield the title compound (85.9 mg, 47%) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[C:11]=2[C:17]#[C:18][C:19]2[CH:20]=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C1COCC1>[NH2:25][C:22]1[N:21]=[CH:20][C:19]([C:18]#[C:17][C:11]2[C:12]([CH3:16])=[N:13][CH:14]=[CH:15][C:10]=2[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:26])=[O:2])=[CH:9][CH:8]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(-c2ccnc(C)c2C#Cc2ccc(N)nc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nccc(-c2ccc(C(=O)O)cc2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 2.0 g (5.8 mmol) 4-[3-(6-amino-pyridin-3-ylethynyl)-2-methyl-pyridin-4-yl]-benzoic acid methyl ester using 11.6 mL (11.6 mmoL) 1 N NaOH in 8 mL THF. After completion of the reaction the pH is adjusted to pH about 5 with 1.0 N HCl. The precipitate is collected by filtration, washed with water and dried under vacuum. The solid is taken up in iPrOH, stirred for a few minutes before the solid is isolated by filtration and dried at 40° C. under vacuum. Yield: 1.9 g (99%).
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:17]3[CH2:20][CH:19]([NH:21][C:22](=[NH:37])[CH2:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=4)=[O:25])[CH2:18]3)=[O:16])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>C1(OC)C=CC=CC=1>[SH:8][C@@H:9]1[CH2:13][N:12]([CH3:14])[C@H:11]([C:15]([N:17]2[CH2:20][CH:19]([NH:21][C:22](=[NH:37])[CH2:23][C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=3)=[O:25])[CH2:18]2)=[O:16])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(NC(=N)CC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CC(NC(=N)CC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h
Yield: 93.7 %

Procedure:
610 mg of (2S, 4S)-4-(4-methoxybenzylthio)-1-methyl-2-[3-(N-4-nitrobenzyloxycarbonylacetimidoylamino)azetidin-1-ylcarbonyl]pyrrolidine [prepared as described in step (a) above] were dissolved in 1.19 ml of anisole, and 4.23 ml of trifluoroacetic acid and 193 μl of trifluoromethanesulfonic acid were added to the resulting solution, whilst ice-cooling. The mixture was then stirred for 1 hour under the same conditions and then at room temperature for a further 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was washed with hexane and with diethyl ether and dried by evaporation under reduced pressure, to convert it to the trifluoromethanesulfonate in the form of a powder. Ethyl acetate was added to the whole of this compound, followed by sufficient of a saturated aqueous solution of sodium hydrogencarbonate to make it alkaline. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation under reduced pressure, to give 448 mg of the title compound as a powder.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][N+:14]=1[O-:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccc(Cl)[n+]([O-])c1
Temperature: 45 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
m-Chloroperbenzoic acid (7.46 g, 26.0 mmol) was added to a suspension of 6-chloronicotinic acid (3.14 g, 20.0 mmol) in chloroform (30 mL) at room temperature. The mixture was stirred for 24 h at 45° C. followed by cooling to 0° C. The resulting white precipitate was filtered off, washed with chloroform (10 mL), and air-dried to give 3.22 g, (93% yield) of the title compound: 1H NMR (DMSO-d6, 400 MHz) δ 8.72 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H); MS (EI) m/z 174 and 176 (M++1).
Reaction SMILES: C1(C)C=C[C:4]([S:7](O)(=[O:9])=[O:8])=CC=1.[CH3:12][C:13]1([CH3:32])[CH:15]([CH:16](OS(C)(=O)=O)[C:17]([C:20]([F:23])([F:22])[F:21])([Br:19])[Cl:18])[CH:14]1[C:29]([O-:31])=[O:30]>C(Cl)Cl>[CH3:32][C:13]1([CH3:12])[CH:15]([CH:16]([S:7]([CH3:4])(=[O:9])=[O:8])[C:17]([C:20]([F:21])([F:22])[F:23])([Br:19])[Cl:18])[CH:14]1[C:29]([OH:31])=[O:30]
Reactant: CC1(C)C(C(=O)[O-])C1C(OS(C)(=O)=O)C(Cl)(Br)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC1(C)C(C(=O)O)C1C(C(Cl)(Br)C(F)(F)F)S(C)(=O)=O
Temperature: 40 °C

Procedure:
30 mg of p-toluene sulfonic acid were added at 40° C. to a solution of 1 g of the product of Step B and 10 ml of methylene chloride and the reaction mixture was heated for 5 hours at 40° C., then poured on to ice, and decanted. The organic phase was washed with water, dried on sodium sulfate and evaporated to dryness under reduced pressure to obtain 860 mg of [1R-[1α-, 3α-(RS*,RS*)]] 2,2-dimethyl-3-[2-trifluoromethyl-2-bromo-2-chloro-1-methylsulfonylethyl]-cyclopropane carboxylic acid melting at 138° C.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH:7]1([N:10]([CH:24]([CH2:28]O)[CH:25]([CH3:27])[CH3:26])[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])=[O:12])[CH2:9][CH2:8]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1>[CH:7]1([N:10]2[CH:24]([CH:25]([CH3:27])[CH3:26])[CH2:28][N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:23])([F:22])[F:21])[C:11]2=[O:12])[CH2:9][CH2:8]1
Reactant: CC(C)C(CO)N(C(=O)Nc1ccccc1C(F)(F)F)C1CC1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1CN(c2ccccc2C(F)(F)F)C(=O)N1C1CC1
Temperature: 0 °C
Reaction time: 12 h
Yield: 73.4 %

Procedure:
Following a procedure outlined in J. Org. Chem. 64, 1999, 2941-2943, sodium tert-butoxide (200 mg) and 1-cyclopropyl-1-(1-hydroxymethyl-2-methyl-propyl)-3-(2-trifluoromethyl-phenyl)-urea (245 mg) were added to THF (17 mL) and cooled to 0° C. To the mixture was added a solution of p-toluenesulfonyl chloride (170 mg) in THF (5 mL) slowly by syringe to give a suspension. The mixture was allowed to stir at RT for 12 hours and was then quenched by addition of ice cold water (15 mL). The mixture was extracted with ethyl acetate and the organic layer was separated, dried over Na2SO4 and evaporated. The crude material was purified by flash chromatography using ethyl acetate/heptane 1:1 as an eluent to give the desired material as yellow oil (170 mg). MS (ESI): 313.3 (MH+).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][C:20]3[S:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=4)=[N:22][C:21]=3[CH3:36])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[CH3:36][C:21]1[N:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:29][CH:30]=2)[S:24][C:20]=1[CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:37])=[O:5])=[CH:12][CH:13]=1
Reactant: Cc1nc(-c2ccc(OC(F)(F)F)cc2)sc1CCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(OC(F)(F)F)cc2)sc1CCOc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], (6-{2-[4-methyl-2-(4-trifluoromethoxy-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester was treated with LiOH to obtain (6-{2-[4-methyl-2-(4-trifluoromethoxy-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid as orange solid.
Reaction SMILES: FC(F)(F)C(O[C:6](=[O:11])[C:7](F)(F)F)=O.[Br:14][C:15]1C(C)=[N+:17]([O-])[CH:18]=[C:19]([F:22])[C:20]=1[CH3:21]>C(Cl)Cl.C(OCC)(=O)C>[Br:14][C:15]1[C:7]([CH2:6][OH:11])=[N:17][CH:18]=[C:19]([F:22])[C:20]=1[CH3:21]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1c(F)c[n+]([O-])c(C)c1Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(F)cnc(CO)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
Trifluoroacetic anhydride (0.35 mL, 2.5 mmol) was added dropwise to a solution of 3-bromo-5-fluoro-2,4-dimethylpyridine 1-oxide (220 mg; 1.0 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature overnight and then diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (4 g, Silica, 0-100% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a pale yellow oil (150 mg, 68%), which was used in the next step without further purification.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:23]=1[OH:24])=[N:21][C:20]([O:25][CH3:26])=[CH:19][CH:18]=2.[CH2:27](O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH2:27]([O:24][C:23]1[C:14]([Br:13])=[CH:15][N:16]=[C:17]2[C:22]=1[N:21]=[C:20]([O:25][CH3:26])[CH:19]=[CH:18]2)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc2ncc(Br)c(O)c2n1
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(Br)c(OCc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.9 %

Procedure:
Diethyl azodicarboxylate (1.37 g, 7.84 mmol, 2.0 eq) is added at room temperature to a stirred solution of 3-bromo-6-methoxy-[1,5]naphthyridin-4-ol (1.0 g, 3.92 mmol, 1.0 eq), benzyl alcohol (640 mg, 5.88 mmol, 1.5 eq) and triphenylphosphine (2.05 g, 7.84 mmol, 2.0 eq) in tetrahydrofuran (25 mL). After 15 hours stirring at room temperature, tetrahydrofuran is evaporated and the resulting crude product is purified by column chromatography (silica gel, eluent: petroleum ether: ethyl acetate, 10:1, v/v) to afford 8-benzyloxy-7-bromo-2-methoxy-[1,5]naphthyridine as a white solid (1.0 g, 74% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]23[O:16][CH2:15][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]2)[CH2:11][O:10]3)=[CH:5][CH:4]=1)#[CH:2].[CH3:20][N:21]=[C:22]=[S:23].CNC(=O)C#CC1C=CC(C23OCC(CCC)(CO2)CO3)=CC=1>>[CH3:20][NH:21][C:22](=[S:23])[C:2]#[C:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]23[O:10][CH2:11][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]2)[CH2:15][O:16]3)=[CH:7][CH:8]=1
Reactant: CN=C=S
Reactant: C#Cc1ccc(C23OCC(CCC)(CO2)CO3)cc1
Agent: CCCC12COC(c3ccc(C#CC(=O)NC)cc3)(OC1)OC2
Product: CCCC12COC(c3ccc(C#CC(=S)NC)cc3)(OC1)OC2

Procedure:
N-Methyl-3-[4-(4-n-propyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)phenyl]-prop-2-yn-thioamide was prepared from 1-(4ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2,2,2]octane and methyl isothiocyanate in a manner analogous to the synthesis of N-Methyl-3-[4-(4-n-propyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)phenyl]-prop-2-ynamide.
Reaction SMILES: [I:1][C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl.O>CN(C=O)C>[I:1][C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[CH:3]=1
Reactant: Ic1c[nH]c2ncncc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(I)c2cncnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a stirred solution of 5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 201, 735 mg, 3.00 mmol) in DMF (5 mL) at 0° C. was added to sodium hydride (132 mg, 3.30 mmol, 60% in oil). The mixture was stirred at room temperature for 30 minutes, cooled to −20° C. and 2-(trimethylsilyl)ethoxymethyl chloride (0.58 mL, 3.30 mmol) added. The reaction mixture was stirred at −20° C. for 3 hours then water (30 mL) was added. The mixture was extracted with EtOAc (2×50 mL) and the combined organic phases were dried over magnesium sulphate and evaporated under reduced pressure. The crude solid was purified by column chromatography on silica gel, eluting with a gradient of heptane:EtOAc 100:0 to 50:50), to afford the title compound as a white solid in 61% yield, 691 mg.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]([O:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:67])[CH2:23][CH2:24][C:25](=[O:66])[N:26]([O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:57])[CH2:34][CH2:35][C:36](=[O:56])[N:37]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH3:47])=O)(C)(C)C.C(ON(C(=O)CCC(=O)NCCCCCNOCC1C=CC=CC=1)CCCCC#N)C1C=CC=CC=1>C(Cl)Cl>[CH2:49]([O:48][N:37]([C:36](=[O:56])[CH2:35][CH2:34][C:33](=[O:57])[NH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][N:26]([O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:25](=[O:66])[CH2:24][CH2:23][C:22](=[O:67])[NH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][O:68][CH2:69][C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH3:47])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: COCCOCCOCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)OC(C)(C)C
Agent: N#CCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOCCOCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Temperature: 25 °C

Procedure:
11,22,33-Tris(benzyloxy)-12,15,23,26-tetraoxo-11,16,22,27,33-pentaaza-2,5,8-trioxatritriacontane (21) was prepared by adding excess TFA to (20) (2.05 g, 2.16 mmol) in CH2Cl2 at 0° C. The solution was stirred at room temperature and worked up by the method of (9) to give 1.91 g (quantitative) of (21) as a waxy solid: NMR δ 1.18-1.70 (m, 12 H), 2.32-3.33 (m, 18 H), 3.39-3.80 (m, 14 H), 4.64 (s, 2 H), 4.80 (s, 2 H), 4.87 (s, 2 H), 6.23 (br s, 2 H), 7.2-7.4 (m, 15 H). Analysis: (C46H67N5O10.H2O) C, H, N.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][N:16]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]2.O.[CH3:26]O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][N:16]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:26])=[O:12])=[CH:7]2
Reactant: CO
Reactant: CS(=O)(=O)c1ccc(Oc2cc(O)c3[nH]c(C(=O)O)cc3c2)nc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(O)c2[nH]1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a suspension of 7-hydroxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylic acid (8.71 g) in a mixture of methanol (300 mL) and toluene (300 mL) was added dropwise 2M trimethylsilyldiazomethane diethyl ether solution (12.5 mL) at 0° C., and the mixture was stirred at 0° C. for 1.5 h. Furthermore 2M trimethylsilyldiazomethane diethyl ether solution (10 mL) was added to the mixture and the mixture was stirred at 0° C. for 1 h, which was repeated three times. And then 2M trimethylsilyldiazomethane diethyl ether solution (5 mL) was added and the mixture was stirred at 0° C. for 30 min, which was repeated two times. To quench the reaction, 1M hydrochloric acid (80 mL) was added to the mixture. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with diethyl ether to give the title compound (8.25 g, 92%) as a purple solid. MS 363 (MH+).
Reaction SMILES: [C:1]([CH:6]1[CH2:15][CH2:14][C:13]2[N:12]=[C:11]([Cl:16])[N:10]=[C:9](Cl)[C:8]=2[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].CC(O)C.[OH-].[NH4+:23]>O>[NH2:23][C:9]1[C:8]2[CH2:7][CH:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:15][CH2:14][C:13]=2[N:12]=[C:11]([Cl:16])[N:10]=1
Reactant: CCOC(=O)C1CCc2nc(Cl)nc(Cl)c2C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)C1CCc2nc(Cl)nc(N)c2C1
Temperature: 130 °C

Procedure:
A mixture of 6-Carboethoxy-2,4-dichloro-5,6,7,8-tetrahydroquinazoline (7.68 g), 2-propanol (7 mL) and 30% ammonium hydroxide (12 mL) was heated in a sealed tube at 130° C. for 20 min. The tube was cooled and 20 mL of H2O was added to the mixture. The solid which precipitated was collected and dried to yield 4-Amino-6-carboethoxy-2-chloro-5,6,7,8-tetrahydroquinazoline.