Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[F:39])[CH:34]=O.O>C1COCC1.CCCCCCC>[CH3:2][O:3][CH2:4][CH2:34][C:33]1[CH:36]=[CH:37][C:38]([F:39])=[C:31]([F:30])[CH:32]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCCC
Product: COCCc1ccc(F)c(F)c1
Temperature: -30 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Into a 2 liter three-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a nitrogen gas tube, 133.7 g (390 mmol) of methoxymethyltriphenyl phosphonium chloride were charged in a nitrogen atmosphere and dried, and 450 ml of THF were added. The mixture was cooled to −30° C., 43.76 g (390 mmol) of potassium-t-butoxide were added and the mixture was stirred for 1 hr. To the mixture, a solution of 42.63 g (300 mmol) of 3,4-difluorobenzaldehyde in 150 ml of THF was added dropwise over a period of one and a half hours. The mixture was stirred as such over night and raised to room temperature. Water and heptane were added, the precipitate was filtered through Celite, and an organic layer and an aqueous layer were separated. The aqueous layer was extracted with heptane, an extract combined with the organic layer was washed with water, and the organic layer was dried over anhydrous magnesium sulfate. A solvent was distilled away from the solution, and the solution was condensed. The concentrate was purified by column chromatography (elution solvent: mixed solvent of toluene and heptane), the eluate was further purified by vacuum distillation to obtain 46.70 g of the title compound (91%, bp 98-100° C./15 Torr., cis:trans=1:1) as oily product.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][N:7]=1.[F:16][C:17]([F:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18][NH2:19].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:16][C:17]([F:26])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:18][NH:19][C:2]1[C:3](=[O:15])[N:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: NCC(F)(F)c1ccccc1
Reactant: CCOC(=O)Cn1c(C)cnc(Br)c1=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1c(C)cnc(NCC(F)(F)c2ccccc2)c1=O
Temperature: 110 °C

Procedure:
To a stirred suspension of 507 mg (1.843mmol) of 7-4 in 10 ml of toluene was added 578 mg (3.68 mmol) of 7-6 via pipet. The reaction mixture was heated to 110° C. overnight. The solution was allowed to cool to room temperature and ethyl acetate was added. The diluted reaction mixture was washed with 10% hydrochloric acid. Three ethyl acetate extractions were performed on the aqueous layer. The organic layers were combined, dried (sodium sulfate), and concentrated in vacuo to give 745 mg of an off white solid. The solid was purified using a 40 mm column, 6 inches of silica gel and a 1:1 ethyl acetate/hexane solvent system to give 7-7 as a colorless solid: H1NMR CDCl3): δ 1.25 (t, 3H, 6.2 Hz), 2.1 (s, 3H), 4.0-4.1 (m, 2H), 4.25 (q, 2H, 7.1 Hz), 4.72 (s, 2H), 6.15 (s 1H), 6.68 (s, 1H) 7.4-7.6 (m, 3H), 7.6-7.8 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:24](=[O:25])[C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[N:21]=[N:20]3)[CH2:14][CH:15]=2)=[CH:2]1.I[CH3:31]>>[CH3:31][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:24](=[O:25])[C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[N:21]=[N:20]3)[CH2:12][CH:11]=2)=[CH:2]1
Reactant: O=c1c2ccccc2nnn1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Reactant: CI
Product: Cn1cc(C2=CCN(CCCn3nnc4ccccc4c3=O)CC2)c2ccccc21
Yield: 35.3 %

Procedure:
Starting from 3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-1,2,3-benzotriazin-4(3H)-one (0.83 g, 2.2 mmol) and iodomethane (0.14 mL, 2.2 mmol), and following the same procedure as in example 21, 0.31 g of 3-[3-(4-(1-methyl-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-1,2,3-benzotriazin-4(3H)-one was isolated as an orange solid. Yield 35%; mp 70° C.; MS: 400.3 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 2.20 (m, 2H), 2.54 (m, 2H), 2.66 (t, 2H), 2.72 (t, 2H), 3.21 (m, 2H), 3.75 (s, 3H), 4.60 (t, J=5.34 Hz, 2H), 6.11 (t, 1H), 6.99 (s, 1H), 7.16 (t, 1H), 7.22 (t, 1H), 7.27 (m, 2H), 7.75 (t, 1H), 7.87 (m, 1H), 8.12 (d, 1H), 8.36 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][C:4]2[C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][NH:17][C:3]1=2.FC(F)(F)C(O)=O.C(Cl)[Cl:31]>>[ClH:31].[CH3:1][C:2]1([CH3:22])[CH2:7][NH:6][CH2:5][C:4]2[C:15]([C:18]([F:21])([F:19])[F:20])=[N:16][NH:17][C:3]1=2
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(F)(F)F)n[nH]c2C(C)(C)C1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCc2c(C(F)(F)F)n[nH]c21
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.37 g (0.52 mmol) of a mixture of tert. butyl 7,7-dimethyl-3-trifluoromethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylate and tert. butyl 4-hydrazone-3,3-dimethyl-5-(2,2,2-trifluoro-acetyl)-piperidine-1-carboxylate in 8.0 mL DCM was combined with 4.0 mL trifluoroacetic acid and stirred for 2 h at RT. Then the reaction mixture was evaporated down, the residue was dissolved in EtOH, mixed with 0.90 mL (1.1 mmol) of a 1.25 molar ethanolic hydrochloric acid and co-evaporated again. The residue was triturated with diethyl ether, suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25].[H-].[Na+].[CH3:32][O:33][CH2:34]Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[N:23]([CH2:32][O:33][CH3:34])[C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25]
Reactant: COCCl
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCNC(=O)N(COC)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18 %

Procedure:
N-{2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-phenyl}-N′-propylurea 100 mg) was dissolved in anhydrous tetrahydrofuran (30 ml), and sodium hydride (60 wt %, 88 mg) was added to the solution. The mixture was stirred at room temperature for 15 min. Next, chloromethyl methyl ether (67 μl) was added to the reaction solution, and the mixture was stirred at room temperature for additional 30 min. The solvent was removed by distillation under the reduced pressure, and water was added to the residue. The mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 18 mg (yield 18%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][CH2:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: Cc1ccnc(CCl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccnc(COc2cccnc2Br)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-bromo-3-pyridinol (commercially available, e.g. from Aldrich) (2.9 g) and potassium carbonate (6.94 g) in DMF (25 ml) was stirred for 20 min before adding 2-(chloromethyl)-4-methylpyridine hydrochloride (for preparation see WO 2008/141011) (3 g). This was stirred at room temperature overnight. The reaction mixture was poured into ice/water and the solid formed was collected by filtration, washed with hexane and dried to give the title compound, 2.87 g (61%).
Reaction SMILES: C([O:4][CH2:5][CH:6]([CH3:22])[CH:7]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[Cl:8])(=O)C.C[O-].[Na+].C(O)(=O)C>CO.C(OCC)(=O)C>[Cl:8][CH:7]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[CH:6]([CH3:22])[CH2:5][OH:4]
Reactant: CC(=O)OCC(C)C(Cl)c1ccc(Cc2cccnc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CC(CO)C(Cl)c1ccc(Cc2cccnc2)cc1
Yield: 62.3 %

Procedure:
In 10 ml of methanol was dissolved 740 mg of 3-[p-(3-acetoxy-1-chloro-2-methylpropyl)benzyl]pyridine, and to the resulting solution was added 40 mg of sodium methoxide with ice-cooling, after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. To the reaction mixture was added 0.1 ml of acetic acid, and the solvent was removed by distillation under reduced pressure, after which the residue thus obtained was dissolved in 10 ml of ethyl acetate. The resulting solution was washed with 5 ml of water and then dried over anhydrous magnesium sulfate. The residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (1:1 by volume)] to obtain 400 mg (yield 62.3%) of colorless, oily 3-[p-(1-chloro-3-hydroxy-2-methylpropyl)benzyl]pyridine.
Reaction SMILES: C(N(CC)CC)C.O.[OH:9]N1C2C=CC=CC=2N=N1.[CH:19]1([N:25]=[C:26]=[N:27][CH:28]2[CH2:33]C[CH2:31][CH2:30][CH2:29]2)CCCCC1.[NH2:34][CH:35]1[CH2:41][CH2:40][NH:39][C:37](=[O:38])[CH2:36]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:19][N:25]1[CH:33]=[C:28]([CH:29]=[CH:30][C:31]([NH:34][CH:35]2[CH2:41][CH2:40][NH:39][C:37](=[O:38])[CH2:36]2)=[O:9])[N:27]=[CH:26]1
Reactant: On1nnc2ccccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: NC1CCNC(=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cnc(C=CC(=O)NC2CCNC(=O)C2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To a solution of β-(1-methylimidazole-4-yl)acrylrate hydrochloride (7 g, 37.1 mmole) in dimethylformamide (60 ml) was added triethylamine (7.51 g, 74.2 mmole) and 1-hydroxybenzotriazole hydrate (6.25 g, 40.8 mmole) and the mixture was ice-cooled, and then a solution of dicyclohexylcarbodiimide (8.42 g, 40.8 mmole) in dimethylformamide (15 ml) was added dropwise. After stirring at 80° C. for 30 minutes, followed by at room temperature for 30 minutes, 3-amino-δ-valerolactam (5.08 g, 44.5 mmole) was added to the reaction mixture which was heated with stirring for 13 hours. After cooling to room temperature, a sodium bicarbonate solution was added to the mixture which was extracted with a chloroform-methanol mixed solvent. After drying over magnesium sulfate, the solvent was removed under reduced pressure. The residue was subjected to silica gel flash chromatography and then recrystallized from ethanol/chloroform to obtain the titled compound (6.72 g, 73.0%).
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH:9]=[CH:10][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:15][CH2:14]3)=[CH:12][C:7]2=[N:6][C:5]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)(=O)[CH3:2].[CH3:36]N(C(OC)OC)C.Cl.[NH2:45][C:46]([NH2:48])=[NH:47].C[O-].[Na+]>CO.C1(C)C=CC=CC=1>[NH2:47][C:46]1[N:48]=[C:1]([C:4]2[N:8]3[CH:9]=[CH:10][C:11]([CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[O:20])[CH2:17][CH2:18]4)=[CH:12][C:7]3=[N:6][C:5]=2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:2]=[CH:36][N:45]=1
Reactant: COC(OC)N(C)C
Reactant: N=C(N)N
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nc2cc(C3CCN(C(=O)OCc4ccccc4)CC3)ccn12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Nc1nccc(-c2c(-c3ccc(F)cc3)nc3cc(C4CCN(C(=O)OCc5ccccc5)CC4)ccn23)n1
Temperature: 100 °C

Procedure:
A 28 mL Pyrex Plus tube was charged with ketone 35 (420 mg, 0.89 mmol), DMFDMA (530 mg, 4.45 mmol) and toluene (10 mL). The reaction was heated to 100° C. for 7 hours, after which more DMFDMA (530 mg, 4.45 mmol) was added, and the reaction was allowed to heat at 100° C. for 12 more hours. The reaction was then concentrated under reduced pressure, and then dissolved in 1-propanol (20 mL). The reaction was then charged with guanidine-HCl (128 mg, 1.34 mmol) and sodium methoxide (305 □L of a 25% (w/w) solution in methanol, 1.34 mmol), and the reaction was heated to 80° C. for 18 hours. The reaction was then concentrated under reduced pressure, then dissolved in 10 mL CH2Cl2, then loaded onto a 40 g Isco RediSep normal phase silica cartridge, and purified on an Isco OptiX10 CombiFlash instrument using a gradient that started at 100% heptane and ended at 100% ethyl acetate. Fractions containing desired product were pooled and concentrated under reduced pressure. Yield of 37: 190 mg (41% over both steps). 1H NMR (400 MHz, CDCl3) δ 1.62 (m, 2H), 1.88 (m, 2H), 2.74 (m, 1H), 2.91 (m, 2H), 4.34 (bs, 2H), 5.14 (s, 2H), 5.21 (s, 2H), 6.48 (d, J=5.2 Hz, 1H), 6.74 (d, J=7.2 Hz, 1H), 7.09 (t, J=8.8 Hz, 2H), 7.34 (m, 5H), 7.44 (bs, 1H), 7.60 (m, 2H), 8.08 (d, J=5.2 Hz, 1H), 9.40 (d, J=7.2 Hz, 1H). MS (ESI+) 523.7.
Reaction SMILES: O[C:2]1([CH2:8][CH:9]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CN(S(F)(F)[F:35])C.O>C(Cl)Cl>[F:35][C:2]1([CH2:8][CH:9]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)NC(CN(C)C(=O)OC(C)(C)C)CC2(O)CCCCC2)cc1
Reactant: CN(C)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)NC(CN(C)C(=O)OC(C)(C)C)CC2(F)CCCCC2)cc1
Yield: 19.9 %

Procedure:
To a solution of tert-butyl 3-(1-hydroxycyclohexyl)-2-(4-methylphenylsulfonamido)-propyl(methyl)carbamate (9.23 g, 21 mmol) in dry CH2Cl2 (100 mL) at −78° C. was added (dimethylamino)sulfur trifluoride (4.2 g, 32 mmol). The reaction mixture was poured into water (80 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica eluted with 10:90 hexanes/EtOAc to afford a light yellow solid. The crude product was purified further by preparative HPLC to give tert-butyl 3-(1-fluorocyclohexyl)-2-(4-methylphenylsulfonamido)propyl(methyl)carbamate (1.85 g). 1H NMR (400 MHz, CDCl3): 1.24-1.52 (m, 19H), 1.74-1.79 (m, 3H), 2.42 (s, 3H), 2.50 (s, 3H), 3.15 (m, 1H), 3.40 (m, 2H), 7.30 (d, 2H), 7.72 (d, J=8.4, 2H). MS (E/Z): 443 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][SH:5].F[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O>C1COCC1.CS(C)=O.O>[CH3:10][C:11]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:5][C:4]=1[C:3]([O:7][CH3:8])=[O:6]
Reactant: O=C(CF)c1ccccc1
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COC(=O)c1sc2ccccc2c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
To a suspension of 55% sodium hydride (390 mg, 9.69 mmol) in THF (7 mL)-DMSO (20 mL) was added methyl thioglycolate (0.64 ml) under N2 atmosphere. After ceasing of bubbling, the mixture was stirred for 15 minutes at room temperature, to which was added slowly a solution of 2-fluoroacetophenone (0.89 mL, 6.46 mmol) in DMSO (5 mL). The mixture was stirred at room temperature for 1 hour, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from ethyl acetate/hexane to give the titled compound as a white crystal (533 mg, 36%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C([Sn](CCCC)(CCCC)[CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])CCC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C1(C)C=CC=CC=1>[CH:30]([C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)=[CH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCC=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=Cc1cc(Br)cs1
Agent: [Pd]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC=Cc1csc(C=O)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 4-bromo-2-thiophenecarboxaldehyde (35.0), tetrakis(triphenylphosphine)palladium(O) (4.23 g), 2,6-di-t-butyl-4-methylphenol (a few milligrams) and dry toluene (150 ml) was added tri-n-butyl-1-dodecenylstannane (92.0 g), dropwise at room temperature, under nitrogen. The solution was heated under reflux for four hrs, with stirring. After cooling to room temperature, the solution was filtered through a bed of celite, and the filter cake was washed with ether. The filtrate was evaporated and the residue purified by flash chromatography (silica; 5% ethyl acetate-hexane). The appropriate fractions were collected and concentrated. The residue was distilled in a kugelrohr oven (170° C./0.3 mm mercury) to give 46.7 g (92%) of product, as an oil (ca. 4:1-trans:cis).
Reaction SMILES: C([O:3][CH2:4]C[N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1CCCCN1CCNCC1)C.ClCC1N(CC[O:38]CC)C2=NC=CC=C2N=1.[C:41](=[O:44])([O-:43])[O-].[Na+].[Na+]>CN(C)C(=O)C>[C:4]([OH:3])(=[O:38])[C:41]([OH:43])=[O:44].[N:8]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:6][CH:7]=1
Reactant: CCOCCn1c(CCCCN2CCNCC2)nc2cccnc21
Reactant: CCOCCn1c(CCl)nc2cccnc21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(O)C(=O)O
Product: c1cnc2[nH]cnc2c1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A mixture of 3.3 parts of 3-(2-ethoxyethyl)-2-[4-(1-piperazinyl)butyl]-3H-imidazo[4,5-b]pyridine, 2.9 parts of 2-(chloromethyl)-3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridine, 1.2 parts of sodium carbonate and 22.5 parts of N,N-dimethylacetamide was stirred for 6 hours at 70° C. The reaction mixture was evaporated and the residue was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was converted into the ethanedioate salt in 2-propanol. The salt was filtered off and crystallized from 2-propanol. The product was filtered off and dried, yielding 0.7 parts (6.8%) of 3-(2-ethoxyethyl)-2-[[4-[4-[3-(2-ethoxyethyl)-3H-imidazo-4,5-b]pyridin-2-yl]butyl]-1-piperazinyl]methyl]-3H-imidazo[4,5-b]pyridine ethanedioate(1:6); mp. 121.9° C. (compound 24).
Reaction SMILES: S([O-])(OC(C)(C)S(OC1C=CC(O)=CC=1)(=O)=O)(=O)=O.[C:20]([OH:39])(=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:55][C@@H:56]([C:59]([OH:61])=[O:60])[CH2:57][OH:58].C(N(CC)CC)C>C(#N)C.O>[C:20]([NH:55][C@@H:56]([C:59]([OH:61])=[O:60])[CH2:57][OH:58])(=[O:39])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: N[C@H](CO)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(OS(=O)(=O)[O-])S(=O)(=O)Oc1ccc(O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@H](CO)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
4-hydroxyphenyldimethylsulfomethyl sulfate 2.66 g (0.01 mol) was heated and dissolved in 40 ml of acetonitrile. Oleic acid 2.82 g (0.01 mol) was added to the solution obtained, and the mixture was stirred at 0° C. To the mixture solution, dicyclohexyl carbodiimide 2.06 g (0.01 mol) was added little by little, and the solution was stirred for 2 hours at 0° C. and then for 2 hours at room temperature. The solution reacted was filtered to remove dicyclohexyl urea, and the filtrate was distilled in vacuo to obtain oily residue. D-serine 1.05 g (0.01 mol) and triethyl amine 1.4 ml (0.01 mol) were added to 10 ml of water. An acetonitrile solution of the above oily residue was added to the mixture with stirring, and stirred for 10 hours at room temperature. After reaction, the reaction mixture was concentrated under reduced pressure. The concentrate was adjusted to pH 2 or 3 with 6N-HCl, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium acetate, and freed of solvent in vacuo. The oily residue obtained was purified by column chromatography (column: 2.5×15 cm) on 50 g of silica gel and N-oleoyl-D-serine 1.5 g was obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=5)[C:24]([O:26]C)=[O:25])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>CO.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=5)[C:24]([OH:26])=[O:25])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.2 %

Procedure:
To a solution of example 53 (0.190 g, 0.480 mmol) in methanol (2.7 ml), lithium hydroxide (0.201 g, 4.80 mmol) in water (0.75 ml) was added and stirred at RT. After 12 h, the pH was adjusted to 7-7.5 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as brown solid (0.070 g, 38%). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 13.39 (s, 1H), 8.87 (d, J=2.6 Hz, 1H), 8.77 (s, 1H), 8.68 (d, J=8.7 Hz, 1H), 8.39 (m, 2H), 8.16 (d, J=8.7 Hz, 1H), 8.07 (m, 3H), 7.85 (dd, J=8.7, 1.5 Hz, 1H), 7.66 (t, J=7.8 Hz, 1H), 7.52 (dd, J=8.3, 4.1 Hz, 1H), 6.22 (s, 2H).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:8]=1[O:9][CH2:10][CH2:11][OH:12]>>[Cl:6][C:7]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:8]=1[O:9][CH2:10][CH2:11][O:12][S:1](=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCCOc1ccc(Cl)cc1Cl
Product: NS(=O)(=O)OCCOc1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared by the procedures of Example 28 from sulfamoyl chloride and 2-(2,4-dichlorophenoxy)ethanol. The viscous oil obtained solidified and was recrystallized from isopropyl ether to give the solid title compound, mp 75°-77° C., in 35% yield.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[S:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>CN(C=O)C.C1COCC1>[CH3:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([S:11][C:12]2[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)=[C:2]1[CH3:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1[nH]c2ccccc2c1Sc1cccc(CC(=O)O)c1
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(Sc2cccc(CC(=O)O)c2)c2ccccc2n1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
[3-(2-Methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid (0.050 g, 0.17 mmol) was dissolved in DMF:THF (1:1, 4 mL) and cooled to 0° C. Lithium bis(trimethylsilyl)amide solution (0.370 mL, 0.37 mmol, 1.0M in hexanes) was added. After 5 minutes iodomethane (11 μL, 0.18 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was stirred for an additional 5 minutes then submitted to aqueous workup. Purification by preparatory HPLC (10-100% ACN in H2O) provided the title compound.