Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][CH2:12][CH:13]=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[P:15]([O-:32])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([O:24][P:15]([CH:13]([OH:14])[CH2:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:32])[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=CCCc1cccc2ccccc12
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=P(OCc1ccccc1)(OCc1ccccc1)C(O)CCc1cccc2ccccc12
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(naphthalen-1-yl)propanal (2.3 g, 12.5 mmol) in DMF (6 mL) under nitrogen is added dibenzyl phosphite (3.3 g, 12.5 mmol), followed by potassium fluoride (0.94 g, 16.2 mmol). After 2 hours, the stirred suspension is diluted with ethyl acetate (60 mL) and washed with water (3×20 mL). The organic layer is dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel, eluting with a gradient of ethyl acetate in hexane (30% to 40% ). Concentration of the pure fractions in vacuo yields [1-hydroxy-3-(naphthalen-1-yl)-propyl]phosphonic acid dibenzyl ester as an oil which solidifies on standing.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([CH:10]([CH3:12])[CH3:11])[C:7](O)=[O:8])=[O:4].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.Cl.[CH3:26][O:27][C:28](=[O:76])[NH:29][CH:30]([C:34]([N:36]1[CH:42]([C:43]2[NH:44][C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:54]4[CH:63]=[CH:62][C:61]5[C:56](=[CH:57][CH:58]=[C:59]([C:64]6[NH:65][C:66]([CH:69]7[CH2:73][CH:72]([C:74]#[N:75])[CH2:71][NH:70]7)=[N:67][CH:68]=6)[CH:60]=5)[CH:55]=4)=[CH:50][CH:49]=3)=[CH:46][N:47]=2)[CH2:41][C:38]2([CH2:40][CH2:39]2)[CH2:37]1)=[O:35])[CH:31]([CH3:33])[CH3:32].CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH3:26][O:27][C:28](=[O:76])[NH:29][CH:30]([C:34]([N:36]1[CH:42]([C:43]2[NH:44][C:45]([C:48]3[CH:49]=[CH:50][C:51]([C:54]4[CH:63]=[CH:62][C:61]5[C:56](=[CH:57][CH:58]=[C:59]([C:64]6[NH:65][C:66]([CH:69]7[CH2:73][CH:72]([C:74]#[N:75])[CH2:71][N:70]7[C:7](=[O:8])[CH:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:10]([CH3:12])[CH3:11])=[N:67][CH:68]=6)[CH:60]=5)[CH:55]=4)=[CH:52][CH:53]=3)=[CH:46][N:47]=2)[CH2:41][C:38]2([CH2:39][CH2:40]2)[CH2:37]1)=[O:35])[CH:31]([CH3:33])[CH3:32]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC(C#N)CN6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)O)C(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC(=O)NC(C(=O)N1CC(C#N)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC7(CC7)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 11.3 %

Procedure:
2-Methoxycarbonylamino-3-methyl-butyric acid (40 mg, 0.227 mmol) EDC-HCl (44 mg, 0.227 mmol) and HOBt (32 mg, 0.237 mmol) were combined in DMF (2 mL) and stirred for 20 min at RT. (1-{6-[5-(4-{6-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester-tris-hydrochloride (150 mg, 0.189 mg) was added, the reaction mixture was cooled to 0° C. and NMM (0.104 mL, 0.947 mmol) was added dropwise. After 1.5 h, the reaction mixture was warmed to RT. 30 min later, the mixture was diluted with EtOAc and washed with NaHCO3, then 1:1 brine/5M NaOH. The organic phase was dried over MgSO4, then filtered and concentrated. The resulting residue was purified by HPLC to afford the title compound (18 mg, 11%). MS (ESI) m/z 840 [M+H]+.
Reaction SMILES: [N:1]1[N:2]=[C:3]([CH2:6][C:7]([O:9]CC)=O)[NH:4][CH:5]=1.[CH2:12]([C@@H:19]1[NH:24][CH2:23][CH2:22][N:21]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([CH2:37][CH3:38])=[N:30][N:31]3[CH:34]([CH3:36])[CH3:35])=[CH:27][CH:26]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C@H:19]1[CH2:20][N:21]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([CH2:37][CH3:38])=[N:30][N:31]3[CH:34]([CH3:35])[CH3:36])=[CH:27][CH:26]=2)[CH2:22][CH2:23][N:24]1[C:7](=[O:9])[CH2:6][C:3]1[NH:4][CH:5]=[N:1][N:2]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)Cc1nnc[nH]1
Reactant: CCc1nn(C(C)C)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Product: CCc1nn(C(C)C)c2cc(N3CCN(C(=O)Cc4nnc[nH]4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 39 %

Procedure:
Prepared by the method outlined for Example 275 using ethyl 2-(4H-1,2,4-triazol-3-yl)acetate and 6-((S)-3-benzyl-piperazin-1-yl)-1-isopropyl-3-ethyl-1H-indazole as starting materials. Product was obtained as an off-white solid (39%). LC/MS (Method B) 3.34 min, [M+1]+ 472.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:32]=[CH:31][C:11]([O:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C@H:21]([CH2:25][C:26]([O:28]CC)=[O:27])[CH2:20][CH2:19]4)=[C:10]([CH2:33][CH2:34][CH3:35])[CH:9]=2)[S:6][CH:7]=1)[CH3:2].O[Li].O>C1COCC1.O>[CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:32]=[CH:31][C:11]([O:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C@H:21]([CH2:25][C:26]([OH:28])=[O:27])[CH2:20][CH2:19]4)=[C:10]([CH2:33][CH2:34][CH3:35])[CH:9]=2)[S:6][CH:7]=1)[CH3:2]
Reactant: CCCc1cc(-c2nc(CC)cs2)ccc1OCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.8 %

Procedure:
To a solution of ethyl ((1S)-5-{2-[4-(4-ethyl-1,3-thiazol-2-yl)-2-propylphenoxy]ethoxy}-2,3-dihydro-1H-inden-1-yl)acetate (18 mg, 0.04 mmol) (Example 35) in THF (1.2 mL), was added a solution of LiOH.H2O (5 mg, 0.11 mmol) in H2O (0.4 mL). The mixture was stirred for 12 h at rt. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in a small volume of water. Then, HCl (1 N aqueous solution) was added until the solution was below pH 3. The aqueous layer was extracted with excess EtOAc, and the organic layer was dried, filtered and then concentrated to give the crude product. The residue was purified by HPLC (C18 reverse phase column, using 0-80% CH3CN in water) to give 2.2 mg (13%) of the title compound as a white solid. LC-MS: RT3.78 min; (M+H)+:466.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15](S(C)=O)SC)[C:5]2[O:9][CH:8]3[CH2:10][CH:11]=[CH:12][CH:7]3[C:6]=2[CH:13]=1.Cl.C[OH:23].[C:24](=O)([O-])[OH:25].[Na+]>CO>[CH3:24][O:25][C:15](=[O:23])[CH2:14][C:4]1[C:5]2[O:9][CH:8]3[CH2:10][CH:11]=[CH:12][CH:7]3[C:6]=2[CH:13]=[C:2]([Br:1])[CH:3]=1
Reactant: CO
Reactant: CSC(=Cc1cc(Br)cc2c1OC1CC=CC21)S(C)=O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: COC(=O)Cc1cc(Br)cc2c1OC1CC=CC21
Reaction time: 2 h
Yield: 99 %

Procedure:
(3aSR, 8bSR)-7-bromo-3a,8b-dihydro-5-(2-methylsulfinyl-2-methylthioethenyl)-3H-cyclopenta[b]benzofuran (5) (14.6 g) was dissolved in methanol (400 ml) followed by addition of a 5.24 N methanol hydrochloric acid solution (56 ml) while cooling with ice and stirring for 2 hours. Saturated sodium hydrogencarbonate solution was added to the reaction solution to neutralize followed by concentration. After extracting the residue with ethyl acetate (300 ml×2) and washing with water (50 ml) and brine (50 ml), it was dried with anhydrous magnesium sulfate and concentrated. The residue was then purified with column chromatography (silica gel: ethyl acetate/cyclohexane 1/20) to obtain the target compound (12.1 g, 99%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+].Cl>O.CO>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(O)c(C=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(O)c(CNc2ccccc2)c1
Reaction time: 20 h

Procedure:
A mixture of 15.2 g 2-hydroxy-5-methoxy benzaldehyde, 93 g of aniline and 100 ml of methanol was stirred at 25° for 20 hours. The mixture was then cooled with an ice-bath and stirred, and 3.9 g of sodium borohydride was added slowly. The mixture was stirred for 1 hour at 25°, 150 ml of water was added and the pH was adjusted to 7.0 with 2.5N hydrochloric acid. The resultant solid was collected, washed with water and purified by chromatography on silica gel using 3:17 ethyl acetate:n-hexane as an eluant. A 17.7 g yield of N-(2-hydroxy-5-methoxybenzyl)aniline was obtained. M.p. 82°-84°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl>[C:25]([NH:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11]1)(=[O:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCN)C1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCN1CCC(CNC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)ethylamine (1 g) was dissolved in methylene chloride (10 ml) and triethylamine (0.86 ml) was added. Then, a solution of acetyl chloride (0.29 ml) in methylene chlride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 1 hr, and the reaction mixture was concentrated under reduced pressure to give 1-(2-acetylaminoethyl)-3-tert-butoxycarbonylaminomethylpyrrolidine.
Reaction SMILES: [Si]([O:8][CH:9]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=1)[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])(C(C)(C)C)(C)C.[SH:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C(Cl)(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[OH:8][CH:9]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][S:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:22][CH:23]=1)[CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: COC(=O)CCS
Reactant: CC(C)(C)OC(=O)CC(O[Si](C)(C)C(C)(C)C)c1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CCSCc1ccc(C(O)CC(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a solution (40 ml) of tert-butyl 3-(tert-butyldimethylsilyl)oxy-3-(4-chloromethylphenyl)propionate (3.25 g, 8.44 mmol) in chloroform were added methyl 3-mercaptopropionate (1.12 g, 9.32 mmol), triethylamine (2.4 ml, 17.29 mmol), and tetrabutylammonium iodide (156 mg, 0.42 mmol), and the mixture was stirred overnight at 50° C. The solvent was evaporated under reduced pressure and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure again. The obtained crude product was dissolved in THF (35 ml), 1M tetrabutylammonium fluoride-THF solution (8.5 ml, 8.50 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give the title compound (711 mg, 24%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]([F:15])([F:14])[F:13])[CH:9]=2)[NH:4][N:3]=1.[CH3:16]C([O-])(C)C.[K+].CI>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]([F:14])([F:13])[F:15])[CH:9]=2)[N:4]([CH3:16])[N:3]=1
Reactant: FC(F)(F)Oc1ccc2[nH]nc(I)c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2cc(OC(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a solution of 3-iodo-5-(trifluoromethoxy)-1H-indazole (178 mg, 543 μmol) in THF (5 mL) at 0° C. was added KOtBu (85.2 mg, 760 μmol) and the mixture stirred at 0° C. for 30 min then MeI (108 mg, 47.5 μL, 760 μmol) was added. The reaction mixture was stirred at 0° C. for 30 min then warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride in water and extracted with dichloromethane (3×30 mL). The combined organics were dried over MgSO4 and concentrated to a clear oil. Purification by chromatography (40 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 20 min) gave 3-iodo-1-methyl-5-(trifluoromethoxy)-1H-indazole (141 mg, 412 μmol, 76%) as a white solid. MS (M+H)+=342.8; 1H NMR (CDCl3) δ: 7.36-7.43 (m, 1H), 7.23-7.36 (m, 2H), 4.12 (s, 3H); LCMS ESI+ TIC MS showed 100% purity, [M+H]+=342.8. The regioisomer, 3-iodo-2-methyl-5-(trifluoromethoxy)-2H-indazole, (29 mg, 84.8 μmol, 16%) was also obtained as a waxy off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[C:4](=O)[CH2:5][CH:6]=[N:7]2.P(Cl)(Cl)([Cl:19])=O>[OH-].[NH4+]>[Cl:19][C:4]1[C:3]2[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=2[CH3:1])[N:7]=[CH:6][CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c1N=CCC2=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc([N+](=O)[O-])c(C)c2c(Cl)ccnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a flask is placed 5,8-dimethyl-6-nitro-4-quinolone (3.01 g, 13.8 mmol) with phosphorus oxychloride (41.3 g, 268 mmol). The mixture is refluxed under argon with stirring for 3 hours. After cooling to room temperature the mixture is poured on crushed ice, and concentrated ammonium hydroxide (100 mL) is added. Extraction with chloroform (2×200 mL), drying over potassium carbonate, filtration and solvent removal by rotary evaporation gives 4-chloro-5,8-dimethyl-6-nitroquinoline.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[NH:8]([CH2:12][CH2:13][OH:14])[CH2:9][CH2:10][OH:11].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[OH:11][CH2:10][CH2:9][N:8]([C:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:1]([OH:7])=[O:6])[C:3]([OH:5])=[O:4])[CH2:12][CH2:13][OH:14]
Reactant: O=C(O)CC(=O)O
Reactant: OCCNCCO
Reactant: O=Cc1ccccc1
Solvent: CO
Product: O=C(O)C(Cc1ccccc1)(C(=O)O)N(CCO)CCO
Temperature: 20 °C

Procedure:
Bis-(hydroxyethyl) amino benzyl malonic acid was prepared conventionally in a flask equipped with a stirrer and reflux condenser by first charging 0.1 mol of malonic acid, 0.1 mol of diethanol amine and 100 cc methanol. The contents were warmed to a temperature of about 20° C. and then 0.1 mol benzaldehyde were added to the flask and the reaction commenced. After refluxing the reaction mixture for 1 hour, the methanol was removed from the reaction mixture by coupling the flask to a vacuum source and heating to a temperature of about 50° C. The residue remaining in the flask then was triturated in acetone and the resulting acid isolated by filtration.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:7][CH2:6]1.[CH2:21]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:28]([CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:7][CH2:6]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1ccccc1C(=O)NC1CCN(CCCCl)CC1
Reactant: c1ccc(CNc2ccccn2)cc1
Product: Cc1ccccc1C(=O)NC1CCN(CCCN(Cc2ccccc2)c2ccccn2)CC1

Procedure:
The title compound is prepared in a similar manner to Example 11 from 1-(3-chloropropyl)-4-(2-methylbenzamido)piperidine and 2-(benzylamino)pyridine.
Reaction SMILES: C(N(CC)[CH2:4][C:5]#[C:6][C@@H:7]([O:13][C:14](=[O:16])[CH3:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])C.N#C[Br:21]>CCOCC>[Br:21][CH2:4][C:5]#[C:6][C@@H:7]([O:13][C:14](=[O:16])[CH3:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: N#CBr
Reactant: CCCCC[C@@H](C#CCN(CC)CC)OC(C)=O
Solvent: CCOCC
Product: CCCCC[C@@H](C#CCBr)OC(C)=O
Reaction time: 18 h

Procedure:
A solution of 1-diethylamino-4(S)-acetoxy-2-nonyne (50.6 g., 0.20 mole) and cyanogen bromide (21.2 g., 0.20 mole) in ether (250 ml.) is allowed to stand at 25°-27° C. for 18 hours. The ether solution is washed with 5% hydrochloric acid solution, water, and brine and dried over sodium sulfate. The ether is evaporated and the residual oil distilled. After a forerun of diethylcyanamide, there is collected 34.1 g. (65%) of 1-bromo-4(S)-acetoxy-2-nonyne, b.p. 97°-105°/0.2 mm.; [α]D26 -83° (C 3.7, CHCl3).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+]>O>[OH:12][C:2]1[CH:3]=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cnc2ccsc2c1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cnc2ccsc2c1
Temperature: 0 °C

Procedure:
To a solution of 6-aminothieno[3,2-b]pyridine (2.5 g, 16.6 mmol) in water (22 ml) containing concentrated sulfuric acid (4.15 ml) and cooled at 0° C. was added dropwise with vigorous stirring a solution of sodium nitrite (1.26 g, 18.3 mmol) in water (7 ml) to give a copious yellow precipitate. This slurry was pipetted dropwise into 5% sulfuric acid (110 ml) maintained at 110° C. After an additional hour, the solution was cooled to room temperature and washed with methylene chloride. This aqueous solution was made basic with sodium hydroxide and washed again with methylene chloride to remove any unreacted starting material. The aqueous solution was then made neutral with hydrochloric acid and the precipitated product was extracted into chloroform/methanol, dried over anhydrous sodium sulfate and filtered through a pad of charcoal and the solvents were evaporated to give product (2.2 g) which was purified by crystallization from hot ethyl acetate/methanol to give pure product (1.81 g, 72% yield), m.p. 228°-230 ° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.[K].Br[CH2:36][C:37]1[C:38]([C:45]2[C:50]([Cl:51])=[CH:49][CH:48]=[CH:47][C:46]=2[Cl:52])=[N:39][O:40][C:41]=1[CH:42]1[CH2:44][CH2:43]1>C1COCC1.O.C(O)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15][CH2:36][C:37]2[C:38]([C:45]3[C:46]([Cl:52])=[CH:47][CH:48]=[CH:49][C:50]=3[Cl:51])=[N:39][O:40][C:41]=2[CH:42]2[CH2:44][CH2:43]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Reactant: CC(C)(C)OC(=O)N1CCCC(O)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 16.8 %

Procedure:
To a solution of 4-hydroxy-azepane-1-carboxylic acid tert-butyl ester (1.88 g, 8.73 mmol) in anhydrous THF (15 mL) at 0° C. is added 18-crown-6 (2.3 g, 8.70 mmol) and tert-butyl alcohol, potassium derivative (8.8 mL, 1.0 M, 8.80 mmol). The mixture is stirred at room temperature for 20 minutes following which 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (1.8 g, 5.19 mmol) in THF is added over 2 minutes. The mixture is stirred for 2 h and water (10 mL) is added. The mixture is concentrated under reduced pressure and extracted with ethyl acetate (3×). The combined ethyl acetate layers are dried (MgSO4), concentrated, and purified via flash chromatography (120 g silica) eluting with a gradient of ethyl acetate in heptane (0 to 60%) to provide the title compound (420 mg, 17%).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14].Cl.N1C=CC=CC=1>O>[OH:9][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[O:15][C:13](=[O:14])[CH:12]=[CH:11]2
Reactant: COc1ccc(OC)c(/C=C/C(=O)O)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=c1ccc2cc(O)ccc2o1
Yield: 49 %

Procedure:
The carboxylic acid (1.97 g; prepared in reference example 24) and pyridine hydrochloride (12 g) were heated to 180°-190° C. The mixture was reacted for 3.5 hr. The reaction mixture was cooled and then dissolved in water. The solution was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then evaporated. The residue was purified by column chromatography on silica gel (n-hexane: ethyl acetate=3:1→1:1). The obtained crystals were washed with a mixture of n-hexane and ethyl acetate (3:1→1:1) to give the title compound (751 mg) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([O:16][CH2:17][CH3:18])=[N:12][C:13](Cl)=[N:14][C:5]=3[C:4]=2[CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]([O:16][CH2:17][CH3:18])=[N:12][C:13]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[N:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C1CNCCN1
Reactant: CCOc1nc(Cl)nc2c1[nH]c1ccc(Br)cc12
Solvent: Cc1cc(C)cc(C)c1
Product: CCOc1nc(N2CCNCC2)nc2c1[nH]c1ccc(Br)cc12
Yield: 59.6 %

Procedure:
920 mg (2.9 mmol) 8-bromo-2-chloro-4-ethoxy-5H-pyrimido[5,4-b]indole and 813 mg (9.5 mmol) piperazine were heated in 10 ml mesitylene to 150° C. for 18 h. Then, the solvent was removed and the residue was suspended in water and sucked off. 650 mg (60%) 8-bromo-4-ethoxy-2-(piperazin-1-yl)-5H-pyrimido[5,4-b]indole was obtained. ESI-MS [m/z]: 376, 378 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:17][CH:18]1[O:22][CH:21]([CH2:23][CH2:24][CH3:25])[CH2:20][O:19]1>>[CH2:23]([CH:21]1[CH2:20][O:19][CH:18]([CH2:17][NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[O:2][CH3:1])[O:22]1)[CH2:24][CH3:25]
Reactant: CCCC1COC(CBr)O1
Reactant: COc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCC1COC(CNc2ccccc2OC)O1

Procedure:
2-Methoxyaniline (0.05 mole) and sodium carbonate (30 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Bromomethyl-4-propyl-1,3-dioxolane (0.55 mole) is slowly added and the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and additional sodium carbonate (5 grams) is added to the filtrate. The mixture is then distilled under reduced pressure to yield the desired product N-(4-propyl-1,3-dioxolan-2-ylmethyl)-2-methoxyaniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:25])=[C:17]([CH:24]=1)[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.O1CCOCC1>[Cl:25][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[CH:24][C:17]=1[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CC(C)OC(=O)c1cc(N)ccc1Cl
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccccc1C(=O)Nc1ccc(Cl)c(C(=O)OC(C)C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.2 %

Procedure:
2-Methoxybenzoyl chloride (8.8 g, 0.05 mole) was added at room temperature under a dry nitrogen atmosphere to a stirred mixture of 1-methylethyl 5-amino-2-chlorobenzoate (10.7 g, 0.05 mole), triethylamine (5.6 g, 0.055 mole) and 4-(N,N,-dimethylamino)pyridine (catalyst, 0.2 g) dissolved in dry p-dioxane (100 ml). A solid precipitate formed. Following the initial exothermic reaction (temperature increased to about 45° C.), the reaction mixture was stirred under nitrogen at room temperature for 20 hours. Next, the reaction mixture was added to water (500 ml), resulting in the precipitation of a solid product, which was collected by vacuum filtration, washed with water (500 ml), and dried to yield 16.2 g of the title compound, m.p. 94°-96° C.