Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[NH4+:5].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=O)[CH:7]=1.C(O)(=O)CC(O)=O.CO>C(O)C>[CH:10]1[CH:11]=[N:6][CH:7]=[C:8]([CH:12]([NH2:5])[CH2:2][C:1]([OH:4])=[O:3])[CH:9]=1
Reactant: [NH4+]
Reactant: CC(=O)[O-]
Reactant: O=Cc1cccnc1
Agent: O=C(O)CC(=O)O
Solvent: CCO
Solvent: CO
Product: NC(CC(=O)O)c1cccnc1
Temperature: 78 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
Ammonium acetate (194.28 g, 2.52 mol) was suspended in ethanol (285 g). A solution of pyridine-3-carbaldehyde (62.9 g, 1.68 mol) in ethanol (80 g) was added to the suspension within 10 min at 15° C.-20° C. The reaction mixture was stirred for 1 h until a clear yellowish solution was formed. A suspension of malonic acid (174.86 g, 1.68 mol) in ethanol (235 g) was then added (within 30 min.) After stirring for 30 min at ambient temperature the reaction mixture was heated for 5 h to reflux (78° C.). Gas evolution was observed. After 3-4 h a white solid started to precipitate. The orange colored suspension was cooled to 15° C.-20° C., and a thick slurry was obtained. To this slurry was added methanol (80 g) and the reaction mixture was again heated to reflux (65° C.). The suspension was filtered hot, and the filtercake was washed with three portions of hot methanol (120 g) (at a temperature of 55° C.-65° C.). The wet product was dried in vacuo at 70° C.-80° C. to yield the product as a colorless solid (137.73 g, 49.3%). LC purity 95.8%
Reaction SMILES: CS([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][N:6]=1)(=O)=O.[NH2:15][NH2:16].[ClH:17]>C(O)C>[ClH:17].[NH:15]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][N:6]=1)[NH2:16]
Reactant: NN
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(NN)nc1
Temperature: 25 °C

Procedure:
The 2,5-bis-methanesulfonyl-pyridine and anhydrous hydrazine are stirred in ethanol for two hours between room temperature and reflux temperature. After cooling to room temperature the mixture is concentrated. The residual solid is washed with aqueous saturated NaHCO3 and water and collected by filtration to give a pale yellow solid. The solid is treated with 10% methanolic HCl and the precipitate is collected by filtration to give the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].O[Li].O.Cl>CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([OH:28])=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Temperature: 80 °C
Yield: 71.1 %

Procedure:
To the solution of methyl 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoate (0.29 g, 0.623 mmol) in MeOH/H2O (2/1 mL) was added LiOH.H2O (0.131 g, 3.12 mmol). The mixture was heated with a microwave at 80° C. for 30 min. Then HCl (1 N) was added to adjust the about pH 4˜5. The solvent was removed. The residue was washed with H2O and a little EtOAc and dried under vacuum to afford the title compound 0.20 g (70%). LC-MS m/z 452 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].S(Cl)([Cl:18])=O.CN(C=O)C>C(Cl)Cl>[OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([Cl:18])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1O
Temperature: 10 °C
Reaction time: 16 h

Procedure:
A suspension of compound of Example 1a (1.0 eq) in DCM (approx 4.5 vol) is treated with thionyl chloride (1.0-1.2 eq, for example 1.1 eq) and catalytic amount (0.0055 eq) of DMF and the mixture is stirred for 16 h at reflux. Unreacted thionylchloride is distilled off with DCM and the residue after distillation is diluted with THF (approx 1.8 vol) and cooled to 10° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[Cl-].[NH4+:10].[OH-].[Na+]>CO.O>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][NH2:10])=[CH:4][CH:5]=1
Reactant: C=Cc1ccncc1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NCCc1ccncc1
Temperature: 0 °C
Yield: 29.5 %

Procedure:
4-Vinylpyridine (5.26 ml, 50 mmol) and ammonium chloride (5.35 g, 100 mmol, 2.0 eq) were dissolved in methanol (2.5 ml) and water (15 ml), and the mixture was stirred with reflux for 23 hours. This reaction mixture was poured into ice water, and a 15% aqueous sodium hydroxide solution was added to make the same strong alkaline. The mixture was extracted 3 times with chloroform (50 ml). The organic layers were combined, washed with saturated brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was distilled under reduced pressure to give 2-(4-pyridyl)ethylamine (1) (1.80 g, 30%; 87° C./6 mmHg) as a colorless oil. The residue from the distillation was subjected to column chromatography (chloroform/methanol=30/1-9/1) to give bis[2-(4-pyridyl)ethyl]amine (2) (1.11 g, 20%) as a pale-yellow oil.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:15][CH2:16][CH2:17][CH2:18]Br.Cl>C1(C)C=CC=CC=1>[CH2:15]1[C:8]2([CH2:9][CH2:10][CH2:11][CH2:12][C:7]2=[O:13])[CH2:18][CH2:17][CH2:16]1
Reactant: BrCCCCBr
Reactant: O=C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCCCC12CCCC2
Temperature: 25 °C
Yield: 51.5 %

Procedure:
To a suspension of potassium tert-butoxide (22.4 g) in toluene (120 mL) was added a solution of cyclohexanone (9.82 g) and 1,4-dibromobutane (21.6 g) in toluene (30 mL) while stirring, followed by stirring the reaction mixture at 95° C. for 3.5 hours. After cooling down to room temperature and adding ice-cold water (100 mL) and 2N aqueous hydrochloric acid solution (50 mL) to the reaction mixture, the organic layer was separated. Then, after the aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried and concentrated. The residue was distilled in vacuo (90 to 100° C./3 to 4 mmHg) to give spiro[4.5]decan-6-one (7.85 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl.[Br:30]Br>C(Cl)Cl>[Br:30][CH:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:20]
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Reactant: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1

Procedure:
To 1-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)ethanone (1.00 g) in CH2Cl2 containing CHCl3 (1.0 mL) and CCl4 (1.0 mL) was added bromine (0.614 g). After shining light for 1 h, the reaction was quenched with Na2S2O4, extracted with CH2Cl2, dried over Na2SO4 and evaporated to yield the title compound which was used as such for the next step (1.10 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Br:21]Br>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:21][CH:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:20]
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Yield: 75.4 %

Procedure:
A mixture of 1-(4-fluorophenyl)-2-(4-methylsulfonyl phenyl)ethanone (14.6 g, 50 mmol) in 210 mL of chloroform and 826 mL of CCl4. A solution of 8.0 g (50 mmol) of bromine in CCl4 was added dropwise to the mixture. When the loss of the bromine colour was complete, the organic layer was washed with 5% aqueous sodium bicarbonate solution and with brine. It was dried over anhydrous sodium sulfate. The drying agent was filtered, and the filtrate concentrated in vacuum to give 14.0 g (70%) of the desired product as a solid.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:13]([OH:16])([OH:15])=[O:14])([P:9]([OH:12])([OH:11])=[O:10])[OH:8])[CH:2]=1.[OH-:17].[Na+:18]>O>[CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:9]([O-:12])([OH:11])=[O:10])([P:13]([O-:15])([OH:16])=[O:14])[OH:8])[CH:2]=1.[OH2:17].[OH2:8].[OH2:8].[OH2:8].[Na+:18].[Na+:18]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=P([O-])(O)C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 92 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A 0.5 liter reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, was loaded with Zoledronic acid form I (10.0 g) and water (130 ml). The suspension was heated to reflux temperature (92° C.) to obtain a clear solution. A 40% aqueous solution of Sodium hydroxide (6.9 g) was added drop-wise. The solution was then cooled to 25° C. was stirred at this temperature for about 16 hours. The solution was then concentrated to half of its volume to obtain a precipitate. The white precipitate was filtered and dried in a vacuum oven at 50° C. for 18.5 hours to obtain 2.8 g (23%) of Zoledronate disodium crystal form VII (LOD by TGA=10.2%). Purity by HPLC 100.0%.
Reaction SMILES: [CH2:1]([C:5]1([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:13][C:12]2[C:7](=[C:8]([Cl:16])[C:9]([Cl:15])=[C:10]([OH:14])[CH:11]=2)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]([F:36])([F:35])[S:31](Cl)(=[O:33])=[O:32]>CN(C)C=O>[CH2:1]([C:5]1([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:13][C:12]2[C:7](=[C:8]([Cl:16])[C:9]([Cl:15])=[C:10]([O:14][S:31]([C:30]([F:36])([F:35])[F:29])(=[O:33])=[O:32])[CH:11]=2)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCCCC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC1(C2CCCC2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O

Procedure:
The starting material, 2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-one, dissolved in dimethylformamide was treated with potassium carbonate and trifluoromethanesulfonyl chloride to form (2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)trifluoromethanesulfonate (Step 1). This material was subjected to triflate displacement by reaction with diethyl malonate to form diethyl-5-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)malonate (Step 2). The malonate of Step 2 was then alkylated with ethyl 4-bromobutyrate to form diethyl 2-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-2-(ethoxycarbonyl)-1,6-hexanedioate (Step 3). Upon hydrolysis the hexanedioic acid is formed (Step 4) which undergoes monodecarboxylation by treatment with copper in quinoline to form a compound of the present invention such as 5-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)pentanoic acid (Step 5). The starting materials used in these examples is obtained as shown in the Journal of Medicinal Chemistry, 20, 1400 (1977); and 21, 437 (1978). This synthetic route is illustrated below: ##STR3##
Reaction SMILES: CC(C[AlH]C[CH:7]([CH3:9])[CH3:8])C.[Li+:10].[CH3:11][CH:12]([N-:14][CH:15]([CH3:17])[CH3:16])[CH3:13]>C1COCC1>[Li:10][CH2:11][CH2:9][CH2:7][CH3:8].[CH:12]([NH:14][CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:11]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)C[AlH]CC(C)C
Reactant: [Li+]
Solvent: C1CCOC1
Product: CC(C)NC(C)C
Product: [Li]CCCC

Procedure:
Synthesis of Hydroxy Acids 33 and 34 as illustrated in FIG. 6. Aldol Condensation of Acid 21 with Aldehyde 7. A solution of keto acid 21 (752 mg, 4.42 mmol, 1.0 equiv) in THF (22 mL) was added dropwise at −78° C. to a freshly prepared solution of LDA [formed by addition of n-BuLi (6.49 mL, 1.6 M solution in hexanes, 10.4 mmol, 2.35 equiv) to a solution of diisopropylamine (1.43 mL, 10.2 mmol, 2.3 equiv) in THF (44 mL) at −10° C. and stirring for 30 min]. After stirring for 15 min the reaction mixture was allowed to warm to −30° C. and stirred at that temperature for 1.5 h. The reaction mixture was cooled back to −78° C. and a solution of aldehyde 7 (0.891 g, 7.07 mmol, 1.6 equiv) in THF (22 mL) was added via cannula. The resulting mixture was stirred for 15 min at −78° C., then warmed to −40° C. and stirred for 1 h, cooled to −78° C. and quenched by slow addition of saturated aqueous NH4Cl (10 mL) solution. The reaction mixture was warmed to 0° C., and acetic acid (1.26 mL, 22.1 mmol, 5.0 equiv) was added, followed by warming to 25° C. Extractions with EtOAc (6×15 mL), filtration through a short plug of silica gel and concentration afforded, in high yield, a mixture of aldol products 33 and 34 along with unreacted starting acid 21 in a 35:50:15 ratio (1H NMR). This crude material was used without further purification.
Reaction SMILES: N1C(C)=CC=CC=1C.[Br:9][C:10]1[CH:11]=[C:12]([N+:20]([O-:22])=[O:21])[C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH2:15]O.[Br-:23].[Li+].CS(OS(C)(=O)=O)(=O)=O>O1CCCC1>[Br:9][C:10]1[CH:11]=[C:12]([N+:20]([O-:22])=[O:21])[C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH2:15][Br:23]
Reactant: COc1c(CO)cc(Br)cc1[N+](=O)[O-]
Reactant: [Br-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: COc1c(CBr)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 118.6 %

Procedure:
2,6-Lutidine (10.5 mL) was added to a stirring solution of 5-bromo-2-methoxy-3-nitrobenzyl alcohol (13.6 g) and lithium bromide (11.75 g) in anhydrous tetrahydrofuran (200 mL) at 0° C. A solution of methanesulfonic anhydride (11.8 g) in anhydrous tetrahydrofuran (20 mL) was added dropwise. The resulting mixture was left to stir at room temperature for 16 h. It was partitioned between diethyl ether (250 mL) and saturated sodium hydrogen carbonate (150 mL). The organic layer was dried (sodium sulfate) and evaporated in vacuo. Silica gel chromatography of the crude residue eluting with diethyl ether in petroleum ether gave the title compound (20 g) as an amber oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BrH:26]>>[Br:26][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(CO)cc2)cc1
Reactant: Br
Product: CCCCCCCCCCOc1ccc(-c2ccc(CBr)cc2)cc1
Reaction time: 3 h

Procedure:
To 0.81 g (2.51 mmol) of 4-hydroxymethyl-4'-decyloxybiphenyl was added 15 ml of an aqueous solution containing 47% HBr, and then healed at 115° C. for 3 hours. After completion of the reaction, the resultant mixture was extracted with ether and washed with water, which was further washed with an aqueous solution containing saturated NaHCO3 and washed again with water. The reaction product was concentrated and, then, separated by colomun chromatography, to thereby obtain 0.92 g of 4'-bromomethyl-4-decyloxybiphenyl.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[O:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]([NH2:18])[C:11]3=[CH:10][C:9]=2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:4]([Cl:28])[CH:3]=1.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[O:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]([NH:18][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:11]3=[CH:10][C:9]=2[C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[C:4]([Cl:28])[CH:3]=1
Reactant: CC1(C)CC(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Br)cc3Cl)nc2O1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Br)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the 7-(4-bromo-2-chlorophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine (536.2 mg, 1.12 mmol) in 10 mL of CH2Cl2 at 0° C. was added pivaloyl chloride (166 μL, 1.34 mmol) and NEt3 (313 μL, 2.24 mmol). After stirring at rt for 1 h, the reaction mixture was concentrated. Chromatography on a Biotage 40+M cartridge using 1:3 v/v EtOAc/hexanes as the eluant afforded the product: 1H NMR δ 1.26 (s, 9H), 1.47 (s, 3H), 1.55 (s, 3H), 1.82 (t, J=12.3, 1H), 2.26 (dd, J=6.2, 13.3, 1H), 5.48 (m, 1H), 5.81 (br. s, 1H), 6.97 (d, J=8.5, 2H), 7.16-7.20 (m, 3H), 7.33-7.42 (m, 2H), 7.55 (s, 1H).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:29](=[O:30])[C:28]([CH3:31])=[C:21]2[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]2[C:19]1=[O:32].[I-].[Na+]>CN(C)C=O.O>[N:12]1[CH:11]=[CH:10][N:9]2[C:4]([S:3][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:29](=[O:30])[C:28]([CH3:31])=[C:21]4[S:22](=[O:27])(=[O:26])[CH2:23][CH2:24][CH2:25][N:20]4[C:19]3=[O:32])=[CH:5][CH:6]=[CH:7][C:8]=12
Reactant: Sc1cccc2nccn12
Reactant: Cc1c2n(c(=O)n(CCCCCl)c1=O)CCCS2(=O)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c2n(c(=O)n(CCCCSc3cccc4nccn34)c1=O)CCCS2(=O)=O
Reaction time: 0.5 h

Procedure:
To a suspension of 0.26 g (6.5 mmol) of 60% oily sodium hydride in 30 ml of N,N-dimethylformamide, 0.98 g (6.5 mmol) of 5-mercaptoimidazo[1,2-a]pyridine was added at room temperature, followed by stirring for 30 minutes. To this mixture, 1.92 g (6 mmol) of 7-(4-chlorobutyl)-1,1-dioxo-9-methyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 0.97 g (6.5 mmol) of sodium iodide were added, followed by stirring at 100° C. for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate 3 times. The organic layer was washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=25/1) to yield 1.61 g (61.8%, white powder) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][C:5]2([F:13])[F:12].[C:14]([N:22]=C=O)(=[O:21])C1C=CC=CC=1.CCO.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C:14]([NH2:22])=[O:21])[CH2:7][CH2:6][C:5]2([F:12])[F:13]
Reactant: FC1(F)CCNc2ncc(Br)cc21
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: NC(=O)N1CCC(F)(F)c2cc(Br)cnc21
Temperature: 50 °C
Yield: 87.6 %

Procedure:
A mixture of 6-bromo-4,4-difluoro-1,2,3,4-tetrahydro-[1,8]naphthyridine (86.2 mg, 0.35 mmol) and benzoyl isocyanate (85.9 mg, 0.51 mmol, 90%) in 5 mL CH2Cl2 is heated at 50° C. for 2 hrs. The mixture is concentrated the dryness. The residue is dissolved into 5 mL of EtOH, K2CO3 (81.2 mg, 0.59 mmol) is added and the mixture is heated at 50° C. for 2 h. The mixture is concentrated to dryness. The residue is dissolved into 20 ml of H2O and neutralized by the addition of AcOH. This is extracted with 60 mL EtOAc, washed with 2×20 mL of H2O and 1×20 mL of brine. The organic phase is dried with MgSO4, filtered and concentrated. The residue is applied to a silica preparative TLC plate and eluted (75% EtOAc/hexanes) to give 89.6 mg of 6-bromo-4,4-difluoro-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH:9]([OH:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1.[OH-].[Na+].O>C(#N)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH:9]([O:11][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: COc1ccc(OCC(C)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1ccc(OCC(C)Oc2ccc(OC)cc2)cc1
Yield: 76.4 %

Procedure:
In 500 ml of acetonitrile were dissolved 168 g of 1-p-methoxyphenoxy-2-propanol and 62 g of p-methoxyphenol. To the solution was added 50 g of a 48% sodium hydroxide aqueous solution, and the mixture was allowed to react at 80° C for 3 hours while stirring. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration and recrystallized from methanol to obtain 110 g of 1,2-bis(4-methoxyphenoxy)propane having a melting point of 84 to 84.5° C.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.CSSC.Cl.[Br:28][CH2:29][C:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:31]>C1COCC1>[Br:28][CH2:29][C@H:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[OH:31]
Reactant: O=C(CBr)c1cccnc1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: Cl
Solvent: CSSC
Solvent: C1CCOC1
Product: O[C@H](CBr)c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
(S)-2-Methyl-CBS-oxazaborolidine (1M in toluene, 189 μL, 0.18 mmol) and borane-methyldisulfide complex (2M in toluene, 100 μL) in THF (11 mL) was allowed to stir at room temperature for 10 min. Then, the rest of BH3—S(CH3)2 (2M in toluene, 1.33 mL, 2.85 mmol) was added to the reaction solution followed by a suspension of 3-(bromoacetyl)pyridine hydrochloride (0.5 g, 1.78 mmol) in THF (11 mL). The heterogeneous reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then cooled to 0° C. and quenched with MeOH (1.5 mL). After 5 min of stirring, the solvent was removed and the resulting residue was diluted with CH2Cl2. The solution was treated with saturated NaHCO3 and the organic phase was separated. The aqueous phase was re-extracted with CH2Cl2. The combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 0.24 g of (S)-2-bromo-1-pyridin-3-yl-ethanol as a colorless oil (66%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:6]([O:32][CH3:33])=[CH:7][C:8]2[C:9]([CH:31]=1)=[N:10][C:11]1[N:12]=[CH:13][C:14]([C:29]#[N:30])=[C:15]([NH:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([Cl:27])=[CH:21][C:20]=3[Cl:28])[C:16]=1[CH:17]=2.[I].[Na].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[Cl:28][C:20]1[CH:21]=[C:22]([Cl:27])[C:23]([O:25][CH3:26])=[CH:24][C:19]=1[NH:18][C:15]1[C:16]2[CH:17]=[C:8]3[CH:7]=[C:6]([O:32][CH3:33])[C:5]([O:4][CH2:3][CH2:2][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:31][C:9]3=[N:10][C:11]=2[N:12]=[CH:13][C:14]=1[C:29]#[N:30]
Reactant: COc1cc(Nc2c(C#N)cnc3nc4cc(OCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Reactant: C1COCCN1
Agent: [I]
Agent: [Na]
Product: COc1cc(Nc2c(C#N)cnc3nc4cc(OCCN5CCOCC5)c(OC)cc4cc23)c(Cl)cc1Cl
Yield: 47 %

Procedure:
A mixture of 8-(2-chloroethoxy)-4-(2,4-dichloro-5-methoxyanilino)-7-methoxybenzo[b][1,8]naphthyridine-3-carbonitrile (202 mg, 0.40 mmol) and sodium iodine (70 mg, 0.47 mmol) in 4 mL of morpholine is heated at reflux for 2 hours. The reaction mixture is concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer is washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. Ethyl acetate is added to the residue and the orange solid is collected by filtration to provide 105 mg (47%) of 4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-[2-(4-morpholinyl)ethoxy]benzo[b][1,8]naphthyridine-3-carbonitrile, mp 242–244° C. dec. MS 553.8, 555.8 (M+H)+ Analysis for C27H25Cl2N5O4 Calcd: C, 58.49; H, 4.54; N, 12.63. Found: C, 58.41; H, 4.23; N, 12.48.