Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=O.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH2:7][N:12]1[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1occc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2occc2Br)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
To a solution of 3-bromofuran-2-carbaldehyde (500 mg, 2.85 mmol) and tert-butyl piperazine-1-carboxylate (1.1 g, 5.71 mmol) in CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (1.2 g, 5.71 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (100 mL). The organic phase was washed with aqueous NaHCO3 and brine then dried (MgSO4), filtered and concentrated to dryness. The residue was purified by column chromatography (silica, 0-10% MeOH in CH2Cl2) to afford the sub-title compound (910 mg, 92%).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([N:8]2[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N:11][N:10]=[C:9]2[CH2:24]O)=[C:5]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH:4]=1)[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([C:3]1[S:7][C:6]2[N:8]3[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[N:11][N:10]=[C:9]3[CH2:24][O:35][CH:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCCCCCCCCCCc1nnc(CO)n1-c1sc(CC)cc1C(=O)c1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCc1nnc2n1-c1sc(CC)cc1C(c1ccc(OC)cc1)OC2
Yield: 38.5 %

Procedure:
5-Ethyl-3-(4-methoxybenzoyl)-2-(3-hydroxymethyl-5-undecyl-1,2,4-triazol-4-yl)thiophene (4.4 g) obtained in Example 20 was dissolved in ethanol (100 ml). Thereto was added sodium borohydride (0.16 g) with stirring and the mixture was stirred at room temperature for 1 hour. After the ethanol was distilled away, 5% aqueous sodium hydrogencarbonate was added thereto and the liberated oily substance was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and toluene (100 ml) was added to the residue. The mixture was refluxed under heating with stirring and sulfuric acid was gradually added dropwise until the reaction ended. After cooling, 5% aqueous sodium hydrogencarbonate was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, the residue was concentrated under reduced pressure and the residue was purified by silica gel column chromatography. The oily substance obtained was crystallized from hexane to give 1.64 g of 2-ethyl-4-(4-methoxyphenyl)-9-undecyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine as white crystals, melting point 91°-93° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](Cl)=[O:15])[CH:10]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH:11]([C:14](=[O:15])[C:18]3[S:19][CH:20]=[CH:21][C:17]=32)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCN(Cc2ccccc2)CC1c1ccsc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1c2sccc2C2CN(Cc3ccccc3)CCC12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 46 %

Procedure:
A solution of the product from step e) (4.9 g, 13.8 mmol) in CH2Cl2 (21 ml) was added dropwise to a slurry of AlCl3 (5.51 g, 41.4 mmol) in CH2Cl2 (47 ml) at 22° C. After 45 minutes, the reaction mixture was poured into ice cold 2 M NaOH (100 ml) and extracted with CH2Cl2 (300 ml). The organic extract was dried (MgSO4), solvent evaporated in vacuo and residue purified by silica-gel chromatography using a ethyl acetate/hexanes gradient (0% to 50% ethyl acetate) to give the subtitle compound (1.8 g, 46%). MS calculated for C17H17NOS+H 284, observed 284.
Reaction SMILES: O=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[CH:16][C:3]1=2.Cl.O>C1(C)C=CC=CC=1>[CH:16]1[C:3]2[CH2:2][CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C:4]=2[CH:13]=[C:14]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=1
Reactant: CCOC(=O)C(C)c1ccc2c(c1)Sc1ccccc1CC2=O
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)c1ccc2c(c1)Sc1ccccc1CC2
Yield: 15.8 %

Procedure:
To 172 mg of ethyl 2-(10,11-dihydro-11-oxo dibenzo [b,f]-thiepin-3-yl)-propionate in 1 ml of toluene were added a small amount of zinc-amalgam, 0.5 ml of conc. hydrochloric acid and 0.4 ml of water and the mixture was refluxed for 4 hours. After cooling, the mixture was filtered and the filtrate was extracted with benezene. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain yellow oil, which was subjected to thin-layer chromatography and there was obtained 26 mg of ethyl 2-(10,11-dihydro dibenzo[b,f]thiepin-3-yl)-propionate as pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:5](=[O:12])[CH2:6][C:7](=[O:11])[CH2:8][O:9][CH3:10].COC(OC)N(C)C.CN>>[CH3:10][O:9][CH2:8][C:7]([C:6]1[C:5](=[O:12])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:14]=2)=[CH:3][N:2]([CH3:1])[CH:23]=1)=[O:11]
Reactant: COCC(=O)CC(=O)C(=CN(C)C)c1cccc(C(F)(F)F)c1
Agent: CN
Agent: COC(OC)N(C)C
Product: COCC(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
A 1 g. portion of impure 1-dimethylamino-6-methoxy-2-(3-trifluoromethylphenyl)-1-hexene-3,5-dione was reacted with 10 ml. of N,N-dimethylformamide dimethyl acetal, and then with 5 ml. of 40% aqueous methylamine, as described in Example 15. The product was purified as described in that example, except that 1:1 ethyl acetate:dichloromethane was used as the eluent, to obtain 0.13 g. of the desired product, m.p. 140°, dec. Nmr analysis in DMSOd6 showed peaks at δ7.6-8.5 (m, 6H, aromatic); 4.8 (s, 2H, COCH2); 3.9 (s, 3H, N--CH3); 3.4 (s, 3H, OCH3).
Reaction SMILES: [ClH:1].Cl.C([N:7]([CH2:11][C@H:12]([OH:62])[CH2:13][C@@H:14]1[NH:32][C:31](=[O:33])[C@@H:30]([NH:34]C(OC(C)(C)C)=O)[CH2:29][C:28]2[CH:42]=[C:24]([CH:25]=[CH:26][C:27]=2[OH:43])[C:23]2=[CH:44][C:19](=[C:20]([OH:45])[CH:21]=[CH:22]2)[CH2:18][C@@H:17]([C:46]([NH:48][C@H:49]([C:55]([NH:57][CH2:58][CH2:59][NH2:60])=[O:56])[CH2:50][C@@H:51]([OH:54])[CH2:52][NH2:53])=[O:47])[NH:16][C:15]1=[O:61])C(=O)O)(C)(C)C.Cl>O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[NH2:34][C@H:30]1[CH2:29][C:28]2[CH:42]=[C:24]([CH:25]=[CH:26][C:27]=2[OH:43])[C:23]2=[CH:44][C:19](=[C:20]([OH:45])[CH:21]=[CH:22]2)[CH2:18][C@@H:17]([C:46]([NH:48][C@H:49]([C:55]([NH:57][CH2:58][CH2:59][NH2:60])=[O:56])[CH2:50][C@@H:51]([OH:54])[CH2:52][NH2:53])=[O:47])[NH:16][C:15](=[O:61])[C@H:14]([CH2:13][C@@H:12]([OH:62])[CH2:11][NH2:7])[NH:32][C:31]1=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@@H](C(=O)N[C@@H](C[C@@H](O)CN)C(=O)NCCN)NC(=O)[C@H](C[C@@H](O)CN(C(=O)O)C(C)(C)C)NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: NCCNC(=O)[C@H](C[C@@H](O)CN)NC(=O)[C@@H]1Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@H](N)C(=O)N[C@@H](C[C@@H](O)CN)C(=O)N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
16 mg (0.02 mmol) of the compound from Example 172A are provided in 0.5 ml of dioxane and cooled to 0° C., and 1 ml of 4N hydrogen chloride in dioxane is added. The mixture is allowed to warm to room temperature and is stirred for 1 h. The mixture is then concentrated in vacuo and the residue is dried under high vacuum. Stirring with acetonitrile and collecting the precipitate which has separated out by filtration results in the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>>[Cl:21][C:22]1[N:23]=[CH:24][C:25]([C:13]2[CH:12]=[N:11][C:7]3[NH:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]4[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:2]=4[Cl:1])[C:6]=3[CH:14]=2)=[CH:26][CH:27]=1
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Product: Clc1ccc(Cl)c(CN2CCNc3ncc(-c4ccc(Cl)nc4)cc32)c1
Yield: 54 %

Procedure:
1-(2,5-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (115 mg) was reacted with 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine as in General Procedure 4B to give the title compound as a yellow solid (54% yield). M.p.=205° C., LCMS: m/z=405.57 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.50 (2H, t, J=4.8 Hz), 3.67 (2H, m), 4.49 (2H, s), 5.10 (1H, bs), 6.52 (1H, s), 7.21 (1H, dd, J=8.3, 2.3 Hz), 7.29 (2H, m), 7.35 (1H, d, J=8.3 Hz), 7.55 (2H, m), 8.36 (1H, d, J=2.5 Hz).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1>CN(C)C=O.Cl>[CH2:11]([O:10][C:8](=[O:9])[C:7]([NH:6][C:3](=[O:5])[CH3:4])([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)c1ccc([N+](=O)[O-])cn1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a stirred slurry of sodium hydride (46 g, 1 mol, 50% oil dispersion) in dimethylformamide (500 mL, distilled from calcium oxide) was slowly added a solution of diethyl acetamidomalonate (217 g, 1 mol) in dimethylformamide (1200 mL). After the initial reaction, the slurry was heated to 45° C. for 1.5 hours and then 2-chloro-5-nitropyridine (159 g, 1 mol) in DMF (800 mL) was added. The mixture became dark brown during addition of the 2-chloro-5-nitropyridine. The mixture was stirred at 45° C. overnight. After cooling, the mixture was diluted with 1000 mL hydrochloric acid (0.2 N), and then extracted with dichloromethane (3×1200 mL). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated to give a dark brown oil. The oil was dry-loaded on silica gel and chromatographed on a dry-packed silica gel column. The column was eluted with petroleum ether-ethyl acetate (8:1 and then 5:1). Fractions containing the indicated compound were combined and concentrated to give pale yellow solid. Mp 82-83° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)=[O:11])=[CH:6][C:5]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:19][C:14]1[CH:13]=[C:12]([CH:10]2[O:11][C:2]3=[N:3][CH:4]=[C:5]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=[C:7]3[CH2:8][CH2:9]2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CS(=O)(=O)c1cnc(Cl)c(CCC(=O)c2ccc(Cl)c(Cl)c2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cnc2c(c1)CCC(c1ccc(Cl)c(Cl)c1)O2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 0.39 g of 3-[2-chloro-5-(methylsulfonyl)-3-pyridinyl]-1-(3,4-dichlorophenyl)propan-1-one in 15 ml of methylene chloride was cooled to -70° C. under nitrogen and then a solution of 1.0 ml of 1.5M diisobutylaluminum hydride/toluene was added dropwise over 3 minutes while keeping the temperature below -65° C. After an additional 5 minutes, the mixture was quenched by careful addition of 1.5 ml of a mixture consisting of 10% water, 40% acetic acid and 50% ether. The reaction mixture was then allowed to warm to 0° C. and was partitioned between water and methylene chloride. The methylene chloride layer was washed with aqueous saturated sodium bicarbonate solution, dried over magnesium sulfate and filtered, and the filtrate was concentrated to a colorless solid, 3-[2-chloro-5-(methylsulfonyl)-3-pyridinyl]-1-(3,4-dichlorophenyl)propan-1-ol. This solid was dissolved in 2 ml of anhydrous dimethyl sulfoxide and added to a stirred suspension of 0.07 g of 50% sodium hydride (previously freed of oil by washing with hexane) in 10 ml of dimethyl sulfoxide under nitrogen. Gas evolution took place and the mixture first became lavender and then cherry red. After 15 minutes, it was partitioned between ethyl acetate and 1N hydrochloric acid. The yellow ethyl acetate layer was washed with water and then twice with aqueous saturated sodium chloride solution, dried over magnesium sulfate and filtered and the filtrate was concentrated to leave a pale yellow solid. This solid was recrystallized from a mixture of 2-propanol and ethyl acetate to give 2-(3,4-dichlorophenyl)-3,4-dihydro-6-(methylsulfonyl)-2H-pyrano[2,3-b]pyridine melting at about 171.5°-172.5° C. This material exhibited the same spectral characteristics as the material prepared by the procedure described in Example 17. This compound has the following structural formula: ##STR7##
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[N:12]1([C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[NH:24][N:25]=[C:26]([O:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:19]=23)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:33]([O:37][C:38]([N:40]([CH:53]([CH3:55])[CH3:54])[CH2:41][C@H:42]([C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[C:43](O)=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:52][C:49]1[CH:50]=[CH:51][C:46]([C@H:42]([C:43]([N:15]2[CH2:16][CH2:17][N:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[NH:24][N:25]=[C:26]([O:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:19]=34)[CH2:13][CH2:14]2)=[O:44])[CH2:41][N:40]([CH:53]([CH3:54])[CH3:55])[C:38](=[O:39])[O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:47][CH:48]=1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: OCC(O)COc1n[nH]c2nccc(N3CCNCC3)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2ccnc3[nH]nc(OCC(O)CO)c23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DIEA (0.0514 mL, 0.295 mmol) was added to 3-(4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)propane-1,2-diol dihydrochloride (0.030 g, 0.0737 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0252 g, 0.0737 mmol, see Example B) and TBTU (0.0284 g, 0.0885 mmol) in DCM (1 mL) and stirred at room temperature for 2 hours. The reaction was concentrated to dryness. The resulting residue was dissolved in THF:MeOH (2 mL, 1:1), and a LiOH solution (1 mL, 2M) was added. The solution was stirred for 30 minutes, followed by the addition of ether (20 mL). The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (ethyl acetate:MeOH, 20:1) to give tert-butyl(2S)-2-(4-chlorophenyl)-3-(4-(3-(2,3-dihydroxypropoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and 2N HCl in ether (1 mL) was added. The resulting solid was collected by filtration to give (2S)-2-(4-chlorophenyl)-1-(4-(3-(2,3-dihydroxypropoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one dihydrochloride (0.014 g, 33%). MS APCI (+) m/z 517.2 detected.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:13]2[N:14]=[C:15]([S:18][CH:19]([CH2:25][CH3:26])[C:20](OCC)=[O:21])[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1>CO>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:13]2[N:14]=[C:15]([S:18][CH:19]([CH2:25][CH3:26])[C:20]([NH2:1])=[O:21])[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1
Reactant: CCOC(=O)C(CC)Sc1ccc2nnc(-c3ccccc3F)n2n1
Reactant: N
Solvent: CO
Product: CCC(Sc1ccc2nnc(-c3ccccc3F)n2n1)C(N)=O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To 10 ml of dry methanol saturated with ammonia was added 0.5 mmol of ethyl 2-((3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)butanoate. The pressure tube was stoppered tightly, and the solution was stirred for 16 hours at 50° C. The white precipitate was collected and washed with cold methanol to give 2-((3-(2-fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)butanamide.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([OH:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.CO.O>C(Cl)(Cl)Cl>[Br:1][C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=2)(=[O:26])=[O:25])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(Br)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a slurry of methyl 5-bromo-8-hydroxy-1,6-naphthyridine-7-carboxylate (5.0 g, 17.66 mmol, prepared as in Example 113) in chloroform (20 mL) under nitrogen was added N,N,N-diisopropylethylamine (3.72 mL, 26.49 mmol). 4-Methylbenzenesulfonyl chloride (4.04 g, 21.20 mmol) was added over 5 minutes and the reaction was heated to 40 degrees C. and stirred one hour. The completed reaction was cooled to 25 degrees C. and 1:1 methanol:water was added to precipitate the product which was filtered, washed with more 1:1 methanol:water and dried in vacuo. This afforded the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[OH:4].[CH:11]([C:13]1(O)[CH2:16][CH2:15][CH2:14]1)=[CH2:12]>O1CCOCC1.C(OCC)(=O)C>[CH3:10][C:5]1[C:3]([OH:4])=[C:2]([CH3:1])[CH:8]=[C:7]2[C:6]=1[CH2:12][CH2:11][C:13]1([O:9]2)[CH2:16][CH2:15][CH2:14]1
Reactant: C=CC1(O)CCC1
Reactant: Cc1cc(O)cc(C)c1O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc2c(c(C)c1O)CCC1(CCC1)O2
Yield: 38.7 %

Procedure:
To a solution of 2,6-dimethylhydroquinone (2.36 g) and BF3-ether (4.47 mL) in dioxane (10 mL) was added 1-vinyl-cyclobutanol (1.58 g) in dioxane (5 mL) over 50 min at 110° C. under nitrogen. The reaction was refluxed for one additional hour. The solution was diluted with ethyl acetate and washed with water and brine, dried and evaporated. The residue was chromatographed (silica gel, hexane-ethyl acetate 1% to 5%) gave 1.36 g of 5,7-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol.
Reaction SMILES: [C:1]([C:4]1[C:12]2[S:11][C:10](=[O:13])[NH:9][C:8]=2[C:7]([OH:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.C(Cl)Cl.O>[C:29](=[O:30])([O:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:14][C:7]1[C:8]2[NH:9][C:10](=[O:13])[S:11][C:12]=2[C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)c1ccc(O)c2[nH]c(=O)sc12
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccc(OC(=O)OCc2ccccc2)c2[nH]c(=O)sc12
Temperature: -10 °C

Procedure:
A mixture of 7-acetyl-4-hydroxy-1,3-benzothiazol-2(3H)-one (209 mg) in dry THF (5 ml) and DCM (5 ml) with pyridine (0.2 ml), stirring under nitrogen, was cooled to −10° C. and benzylchloroformate (0.37 mls) was added. After 18 h stirring at room temperature, the mixture was diluted with water and extracted into DCM. The solution was dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified on a 10 g silica SPE cartridge, eluting with a stepped gradient of 25% to 100% ethyl acetate-cyclohexane mixtures, to give the title compound (280 mg). LCMS RT=3.19 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:5](=[CH:10][C:11]([CH2:14]Br)=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[C:17]([O:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[C:5](=[CH:10][C:11]([CH2:14][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(CBr)cc1C(=O)OC
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1ccc(Cc2ccccc2NC(=O)OC(C)(C)C)cc1C(=O)OC
Temperature: 90 °C

Procedure:
A mixture of 4-bromomethylphthalic acid dimethyl ester (3.1 g, 10.8 mmol), 2-(tert-butoxycarbonylamino)phenylboronic acid (4.3 g, 18.1 mmol), tetrakis(triphenylphosphine)-palladium(0) (0.6 g), 2 M aqueous sodium carbonate (20 ml), and 1,2-dimethoxyethane (40 ml) was heated at 90° C. for 19 hours. The reaction mixture was cooled to room temperature and partioned between water (60 ml) and methylene chloride (60 ml). The organic phase was isolated, washed with water (2×50 ml), dried over magnesium sulphate, and evaporated to dryness in vacuo. The crude product was purified on silica gel (eluent: methylene chloride:ethyl acetate (95:5) to give 4-[2-(tert-butoxycarbonylamino)benzyl]phthalic acid dimethyl ester as yellow crystals (yield: 1.49 g, (40%)). 1H—NMR (CDCl3) in ppm: δ 7.70 (1H,d); 7.67 (1H,d); 7.47 (1H,d); 7.22-7.33 (2H,m); 7.10 (2H,d); 6.05 (1H,s); 4.03 (2H,s); 3.9 (6H,2xs); 1.47 (9H,s).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:7][N+:8]([O-])=O)[CH2:3][C:4](=[O:6])[CH3:5].[N+](CC(=O)CCC)([O-])=O.N(C(OCC)=O)=NC(OCC)=O.C(P(CCCC)CCCC)CCC>>[CH3:1][C:2]([CH3:11])([CH2:3][C:4](=[O:6])[CH3:5])[C:7]#[N:8]
Reactant: CC(=O)CC(C)(C)C[N+](=O)[O-]
Agent: CCCC(=O)C[N+](=O)[O-]
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Product: CC(=O)CC(C)(C)C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4,4-Dimethyl-5-nitropentan-2-one was made according to the literature procedure; see Kloetzel, M. C. J. Am. Chem. Soc., 69, pp. 2271-2275 (1947). Under a nitrogen atmosphere, a solution of nitropentanone (9.55 g, 60.0 mmol) was cooled to 0° C. Diethyl azodicarboxylate (11.5 g, 66 mmol) and tributylphosphine (26.71 g, 132 mmol) were sequentially added. The reaction was stirred for one hour at 0° C. and then for one hour at room temperature. The solvent was removed under reduced pressure, and the residue was purified by chromatography on a HORIZON HPFC system (65I cartridge, eluting with dichloromethane). The resulting oil was treated with hexane; a precipitate formed and was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on a HORIZON HPFC system (65I cartridge, eluting with 45% to 55% ethyl acetate in hexane) to provide 5.17 g of 2,2-dimethyl-4-oxopentanenitrile as a pale yellow oil.