Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=O.[C:12](=[O:15])([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH:12]([C:6]1[CH:7]=[CH:8][C:3]([C:1]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)=[CH:4][CH:5]=1)=[O:15]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccc(-c2ccccc2)cc1
Reaction time: 24 h

Procedure:
The bromoresin 1-Scheme 10 (1 g, 1 mmol) was swelled in toluene (10 mL) and ethanol (4 mL). To this was added 4-formylphenylboronic acid (450 mg, 3 mmol), aqueous sodium carbonate (2M, 3 mL, 6 mmol) and tetrakistriphenylphosphine palladium (200 mg). The reaction mixture was heated under Argon ("Ar") with stirring for 24 h., cooled and filtered through a sintered glass funnel. Washed the resin with methylene chloride, methanol, methanol-water (1:1), methanol, methylene chloride and finally with methanol. Dried in vacuo to give colorless 4-formylbiphenyl resin 2-Scheme 10. IR (KBr) 1701 cm-1 (CHO).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([OH:13])=[CH:6][C:5]=1[CH3:14].[CH3:15]I.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][CH3:15])=[CH:6][C:5]=1[CH3:14]
Reactant: CI
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)c(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a suspension of sodium hydride (1.2 mmol) in DMF (6 mL), 4-chloro 3-methyl 6-nitrophenol (1.0 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 15 minute then methyliodide was added at 0° C. and the mixture was stirred for 4 hours at room temperature. Water (60 mL) was added and the mixture extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica using 5-8% EtOAc in hexane to give the title compound (87%) as a solid.
Reaction SMILES: N12CCN(CC1)CC2.[SH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[CH2:20][OH:21])=[CH:17][C:16]([O:22][CH3:23])=[CH:15][CH:14]=2.[CH2:24]([O:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH3:25]>>[CH2:24]([O:26][C:27]([CH:28]1[CH:20]([OH:21])[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[N:12]=[CH:11][C:10]=2[S:9][CH2:29]1)=[O:30])[CH3:25]
Reactant: C=CC(=O)OCC
Reactant: COc1ccc2ncc(S)c(CO)c2c1
Agent: C1CN2CCN1CC2
Product: CCOC(=O)C1CSc2cnc3ccc(OC)cc3c2C1O
Temperature: 25 °C
Yield: 99.5 %

Procedure:
1,4-diazabicyclo[2.2.2]octane (1.04 g, 9.26 mmol) is added at room temperature to a stirred solution of (3-mercapto-6-methoxy-quinoline-4-yl)-methanol and its corresponding dimer (2.02 g) in acrylic acid ethyl ester (21.7 mL, 203.72 mmol). The reaction mixture is heated under reflux for 2 hours, cooled down to room temperature and concentrated to afford 4-hydroxy-6-methoxy-3,4-dihydro-2H-1-thia-9-aza-phenanthrene-3-carboxylic acid ethyl ester as a dark brown solid (1.47 g, 99.5% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:23]=[CH:22][C:10]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][O:21][C:15]=4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][NH:25][CH3:26].[CH2:27]=O>C(O)(=O)C>[CH3:24][N:25]([CH2:27][C:20]1[O:21][C:15]2[CH2:14][N:13]([C:11](=[O:12])[C:10]3[CH:9]=[CH:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:23][CH:22]=3)[CH2:18][CH2:17][C:16]=2[CH:19]=1)[CH3:26]
Reactant: C=O
Reactant: O=C(c1ccc(-c2ccccc2)cc1)N1CCc2ccoc2C1
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)c1ccc(-c3ccccc3)cc1)CC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.250 g (0.824 mmol) of 6-(4-phenylbenzoyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 20 ml of acetic acid, 0.112 ml (1.24 mmol) of 50% aqueous dimethylamine and 0.101 ml (1.24 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 60 minutes. Additionally, 0.075 ml (0.82 mmol) of 50% aqueous dimethylamine and 0.067 ml (0.82 mmol) of 37% aqueous formaldehyde were added, followed by stirring for 20 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous solution of sodium hydrogen carbonate and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform to chloroform/methanol 50/1 to =25/1) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1nccc2ccccc12
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1cccc(Cl)c1)C1CCN(c2nccc3ccccc23)CC1
Yield: 2.7 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 1-chloroisoquinoline (131 mg, 0.76 mmol), DIEA (0.2 ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title compound (4 mg), a beige solid, in 3% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O-])=O.C[N+](C)(C)C.[C:17](#N)[CH3:18].[C:20]([O:24][CH2:25]C)(=[O:23])[CH:21]=C>O>[C:20]([O:24][CH3:25])(=[O:23])[CH2:21][CH2:17][CH2:18][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:11]
Reactant: COC(=O)CCCCC(=O)[O-]
Reactant: C=CC(=O)OCC
Reactant: CC#N
Agent: C[N+](C)(C)C
Solvent: O
Product: COC(=O)CCCCCCCCC(=O)OC
Yield: 87 %

Procedure:
In operation of the cell, anolyte was pumped by means of a syringe pump to the anolyte channel and through the porous anode and catholyte was pumped by means of another syringe pump to the cathode cavity of the cell and through the porous cathode. The anolyte consisted of a 0.1 M solution of tetramethyl ammonium monomethyl adipate ##STR5## in a solution composed of 90% by volume of acetonitrile and 10% by volume of water. The catholyte consisted of a 0.1 M solution of the same amine as above in a solution of 90% by volume of acetonitrile and 10% by volume of water to which solution was added 10% by volume of ethyl acrylate. Both anolyte and catholyte were caused to flow through their respective electrodes at the rate of 6 milliliters (mls) per minute. In carrying out the electrolytic reaction 1 Ampere of current was supplied to the anode--providing 0.2 A/geometric cm2. At the start of and during the course of the electrolytic reaction a solvent-electrolyte consisting of the above amine in 9cetonitrile and water solution was pumped upward through the channel between the anode and cathode at the rate of 20 mls/min., thus effectively preventing the anolyte from contacting the cathode and the catholyte from contacting the anode. The liquid exiting from the cell was collected and analyzed, and it was found that an 87% yield of dimethyl sebacate (from the monomethyl adipate) was obtained at 35% current efficiency. Also, an 84% yield of diethyl adipate (from the ethyl acrylate) was obtained at 61% current efficiency. No radical adducts were noted in the effluent from the cell.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=2)[N:3]=1.[F:25][C:26]1([F:41])[O:30][C:29]2[CH:31]=[CH:32][C:33]([C:35]3([C:38](Cl)=[O:39])[CH2:37][CH2:36]3)=[CH:34][C:28]=2[O:27]1>N1C=CC=CC=1.C(Cl)Cl>[C:21]([O:20][C:18]([C:14]1[CH:13]=[C:12]([C:4]2[N:3]=[C:2]([NH:1][C:38]([C:35]3([C:33]4[CH:32]=[CH:31][C:29]5[O:30][C:26]([F:41])([F:25])[O:27][C:28]=5[CH:34]=4)[CH2:37][CH2:36]3)=[O:39])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH:17]=[CH:16][CH:15]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: COC(=O)c1ccc(N)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Reaction time: 7 h
Yield: 67.9 %

Procedure:
A solution of methyl 6-amino-2-(3-(tert-butoxycarbonyl)phenyl)nicotinate (400 mg, 1.2 mmol) and 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (630 mg, 2.4 mmol) in pyridine (12 mL) was stirred at room temperature for 3 days and then at 90° C. for 7 hours. Additional 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (320 mg, 1.2 mmol) was added and the reaction was heated at 90° C. for 12 hours until the amine was completely consumed. The reaction mixture was concentrated and the residue was purified by column chromatography (0-40% ethyl acetate—hexanes). The material obtained was dissolved in CH2Cl2 and was washed with 1N HCl (×3) and saturated aq. NaHCO3 (×3), dried (MgSO4) and concentrated to yield methyl 2-(3-(tert-butoxycarbonyl)phenyl)-6-(1-(2,2-difluorobenzo [d][1,3]dioxol-5-yl)cyclopropanecarboxamido)nicotinate as a cream colored solid (450 mg, 67%). ESI-MS m/z calc. 552.2, found 553.3 (M+1)+. Retention time 2.49 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.24 (d, J=8.7 Hz, 1H), 8.12 (d, J=8.7 Hz, 1H), 7.95-7.91 (m, 2H), 7.64 (d, J=7.9 Hz, 1H), 7.57-7.51 (m, 2H), 7.39 (d, J=8.3 Hz, 1H), 7.34 (dd, J=1.6, 8.3 Hz, 1H), 3.63 (s, 3H), 1.54 (m, 11H), 1.22-1.19 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2.[CH2:12]([Li])[CH2:13][CH2:14][CH3:15].C[C:18]1[CH:26]=[CH:25][C:24](C)=[C:23]2[C:19]=1[CH:20]=[CH:21][CH:22]2[Li].BrCCBr>O1CCCC1.O>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4]([CH2:15][CH2:14][C:13]1[C:12]3[C:20](=[C:19]([CH3:23])[CH:18]=[CH:26][C:25]=3[CH3:24])[CH2:21][CH:22]=1)=[CH:5][CH2:6]2
Reactant: Cc1ccc(C)c2c1C=CC2
Reactant: [Li]CCCC
Reactant: [Li]C1C=Cc2c(C)ccc(C)c21
Solvent: O
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Cc1ccc(C)c2c1CC=C2CCC1=CCc2c(C)ccc(C)c21
Temperature: 0 °C
Yield: 48 %

Procedure:
38.2 g (265 mmol) of 4,7-dimethylindene was dissolved in 350 ml of tetrahydrofuran and the solution was cooled to 0° C. Then 165 ml of n-butyllithium (1,6M in hexane, 264 mmol) was added dropwise over 2.5 hours. After warming to room temperature and stirring for 4 hours a purple solution of 4,7-dimethylindenyl-lithium was obtained. This solution was cooled to -70° C. and treated dropwise with 25,3 g of 1,2-dibromoethane (135 mmol) in 15 ml of tetrahydrofuran over 35 min. After warming to room temperature, a pale yellow solution was obtained, and then water was added. The organic phase was collected and dried over Na2SO4. The solvent was removed by vacuum evaporation to provide 20 g of crude product (48% yield).
Reaction SMILES: O[N:2]=[C:3]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[C:4](=O)[CH3:5].[CH3:13][CH:14]1[CH2:19][C:18](=[O:20])[CH2:17][C:16](=O)[CH2:15]1.C(O)(=O)C.[OH-].[Na+]>[Zn].CCOC(C)=O.O>[CH3:5][C:4]1[C:17]2[C:18](=[O:20])[CH2:19][CH:14]([CH3:13])[CH2:15][C:16]=2[NH:2][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: CC1CC(=O)CC(=O)C1
Reactant: CC(=O)C(=NO)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1c(-c2ccncc2)[nH]c2c1C(=O)CC(C)C2
Temperature: 25 °C
Yield: 17 %

Procedure:
According to the literature procedure (Chiswell, B. Inorganica Chimica Acta. 1972, 629), a mixture of 1-hydroxyimino-1-(4-pyridyl)-2-propanone (Tanaka, A et. al., Chem. Pharm. Bull., 1992, 40, 3206) (0.49 g, 3.0 mmol), 5-methyl-1,3-cyclohexanedione (0.38 g, 3.0 mmol), glacial acetic acid (2.4 mL) and H2O (0.6 mL) was stirred vigorously at room temperature. To this flask, zinc dust (0.6 g) was added slowly keeping the temperature below 60° C. Afer addition, the resulting brown solution was heated under reflux condition for 2 hours. After cooling down to room temperature, the reaction mixture was basified by an addition of 2 M aqueous NaOH, then filtered. The filtrate was extracted with CH2Cl2 (20 mL×3), the combined organic layer was dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography (1-5:1 EtOAc-Hexane then EtOAc only) to give the desired product (0.12 g, 17% yield).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)(=O)=O.[I:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[N:24][C:25]=2[NH2:27])[NH:20][N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C.O>[NH2:27][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:20]([CH:6]3[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]3)[N:19]=[C:18]([I:17])[C:26]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(n2nc(I)c3c(N)ncnc32)C1

Procedure:
A suspension of tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate (1.32 g) obtained in Step 1 above, 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.37 g), and cesium carbonate (3.47 g) in DMF (10 ml) was stirred at 90° C. for 10 hours. Ethyl acetate and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow amorphous substance (482 mg). Physical properties: m/z [M+H]+ 417.0
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[N:13]=1.CC1(C)COB([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][CH3:36])=[N:32][CH:33]=2)OC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:28]3[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][CH3:36])=[N:32][CH:33]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: CCCc1ccc(B2OCC(C)(C)CO2)cn1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1

Procedure:
2-(2,6-Difluorophenyl)4-(4-bromophenyl)oxazoline (0.8 g, 2.4 mmol) was refluxed for 8 hours with dimethyl-2-(2-n-propylpyridin-5-yl)-1,3,2-dioxaborinane (0.72 g, 3.1 mmol), Pd(PPh3)4 (0.14 g, 0.12 mmol) and sodium carbonate (0.5 g) in tolune/ethanol/water 8:2:1 (11 ml). After extraction and chromatography, 2-(2,6-difluorophenyl)4-[4-(2-n-propylpyridin-5-yl)phenyl]oxazoline was obtained, 0.20 g, pale solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=O.[NH2:18][OH:19]>CC(N(C)C)=O.CO>[CH3:17][O:16][C:14]([C:11]1[CH:12]=[CH:13][C:7]2[CH:6]=[C:5]([C:3](=[O:2])[NH:18][OH:19])[S:9][C:8]=2[CH:10]=1)=[O:15]
Reactant: COC(=O)c1ccc2cc(C(=O)OC)sc2c1
Reactant: NO
Solvent: CO
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc2cc(C(=O)NO)sc2c1

Procedure:
To a solution of benzo[b]thiophene-2,6-dicarboxylic acid dimethyl ester (115 mg, 0.46 mmol) in DMA/MeOH (3/1 mL) NH2OH (50% aq., 1.5 mL). The solution was stilted until the disappearance of starting material as indicated by LC/MS. After removal of solvent, MeOH/H2O was added until a precipitate forms. The solid was filtered yielding the desired material. 1H NMR (DMSO-d6) δ 11.57 (br s, 1H), 9.36 (br s, 1H), 8.67 (s, 1H), 8.05-7.87 (m, 3H), 3.87 (s, 3H). MS (EI): cal'd (MH+) 252.07, exp (MH+), 252.20.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12](C)[CH:11]([CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1)=O)(C)(C)C>O1CCOCC1.C(O)C>[ClH:1].[ClH:1].[CH:16]([CH:11]1[CH2:10][NH:9][CH2:14][CH2:13][NH:12]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: c1ccc(C(c2ccccc2)C2CNCCN2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4N Hydrogen chloride in 1,4-dioxane (44 ml) was added to a solution of 4-tert-butoxycarbonyl-2-benzhydryl-1-methylpiperazine (6.5 g) in ethanol (33 ml) under ice-cooling over 30 minutes. The mixture was stirred at room temperature for 4 hours and evaporated under reduced pressure. The residue was triturated with diisopropyl ether and the resulting solid was collected by filtration to give 2-benzhydrylpiperazine dihydrochloride (6.02 g) as a powder.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]1([CH3:15])[C:9]([CH3:14])=[CH:10][CH:11]=[CH:12][CH:13]=1>>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:10][CH2:9][CH2:8][CH2:13][CH2:12][CH2:11][CH2:14][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:8][CH3:15].[C:4]1(=[O:5])[O:6][C:1](=[O:7])[CH:2]=[CH:3]1
Reactant: Cc1ccccc1C
Agent: O=C1C=CC(=O)O1
Product: C=CCCCCCCCCCCCCCCCC

Procedure:
5.6 g PA-18 (0.02 equivalents as maleic anhydride, hereinafter "anhydride equivalents") and 100 ml xylene were mixed in a 250 ml flask equipped with a nitrogen atmosphere and a Dean Stark trap. This mixture was refluxed for 30 minutes to dry the polymer. The mixture was cooled slightly and Flame Retardant A (of Example 1) (5.1 g, 0.01 mole) was added. The mixture was refluxed for 2 hours with azeotropic removal of water as it formed. The solvent was stripped using aspirator and high vacuum systems to yield 10.4 g of yellow crystals. The infrared spectrum of this compound showed the N-(acylamino)imide carbonyl bands merged at 1710 cm-1 and a small residual anhydride carbonyl band at 1770 cm-1. The hydrazide carbonyl for the starting material was not observed in the product spectrum.
Reaction SMILES: [C:1]([O:5][C:6](/[C:8](=[CH:13]\[C:14]1[CH:22]=[C:21]([F:23])[C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)/[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:14]1[CH:22]=[C:21]([F:23])[C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C(=C/c1cc(F)c2c(c1)OCO2)C(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)[C@H](Cc1cc(F)c2c(c1)OCO2)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 149.1 %

Procedure:
To a slurry of (Z)-methyl 2-(tert-butoxycarbonyl)-3-(7-fluorobenzo[d][1,3]dioxol-5-yl)acrylate (8000 mg) in 70 mL of methanol was added [(1S,1S′,2R,2R′) [Rh(duanphos)cod]BF4 (41.64 mg, 58.94 μmol; Strem). The mixture was purged with hydrogen 5 times and then sealed at 50 psi of H2 and stirred for 8 hours. Concentration and purification of the reaction crude by silica gel chromatography provided (S)-methyl 2-(tert-butoxycarbonyl)-3-(7-fluorobenzo[d][1,3]dioxol-5-yl)propanoate (12.0 g, 99.4%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:27])[C@@H:12]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:13]([OH:22])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.F[B-](F)(F)F.C[O+](C)C>ClCCCl>[CH2:1]([O:8][C:9]([N:11]([CH3:27])[C@@H:12]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:13]([O:22][CH3:28])[CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: CC[C@H](C)[C@@H]([C@H](O)CC(=O)OC(C)(C)C)N(C)C(=O)OCc1ccccc1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of #3 (8.4 g, 22 mmol, 1 eq.) in 1,2-dichloroethane (25 mL, 0.88 M) were added molecular sieves (4 Å, 0.7 g) and Proton sponge (1,8-bis(dimethylamino)naphthalene) (13.4 g, 59.2 mmol, 2.7 eq.), followed by trimethyloxonium tetrafluoroborate (9.10 g, 61.6 mmol, 2.8 eq.). After stirring overnight, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (Gradient: 0% to 40% 1:1 acetone:ethyl acetate in heptane) to give #@2 (8.7 g, 68%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers: δ 7.28-7.40 (m, 5H), 5.01-5.13 (m, 2H), 3.89-4.08 (br m, 1H), 3.70-3.82 (m, 1H), 3.18 and 3.26 (2 s, total 3H), 2.66 and 2.71 (2 br s, total 3H), 2.44-2.53 (m, 1H, assumed; partially obscured by solvent peak), 2.17-2.24 (m, 1H), 1.71-1.86 (br m, 1H), 1.39 and 1.39 (2 s, total 9H), 1.31-1.40 (m, 1H), 0.94-1.08 (m, 1H), 0.76-0.91 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22].[CH2:23](O)C>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH2:21][CH3:23])=[O:19])[C:3]=1[Cl:22]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl
Reactant: CCO
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CCOC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl

Procedure:
To a solution of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid, methyl ester (200 mg, 0.9 mmol) in ethanol (5 mL) was added a catalytic amount of titanium tetraisopropoxide and the solution heated under reflux for 2 hours. The solution was cooled and partitioned between ethyl acetate (10 mL) and water (10 mL) and the organic phase was dried (sodium sulfate) and concentrated. The residue was passed over a plug of silica gel (1:1 ethyl acetate:hexanes) to give 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid, ethyl ester (150 mg. 0.6 mmol): mp 74-75° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:14]3[CH:24]=[CH:25][CH:26]=[CH:27][C:13]=3[N:12]=2)[CH2:6][CH2:5]1.[N:28]([C:31]1[CH:40]=[CH:39][CH:38]=[CH:37][C:32]=1[C:33](OC)=[O:34])=[C:29]=[S:30]>O1CCCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]2[C:14]3[CH:24]=[CH:25][CH:26]=[CH:27][C:13]=3[N:12]=[C:11]2[NH:10][CH:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][N:1]3[C:33](=[O:34])[C:32]4[C:31](=[CH:40][CH:39]=[CH:38][CH:37]=4)[NH:28][C:29]3=[S:30])[CH2:5][CH2:6]2)=[CH:18][CH:19]=1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: COC(=O)c1ccccc1N=C=S
Solvent: C1CCOC1
Product: O=c1c2ccccc2[nH]c(=S)n1CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 10.9 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine in 150 parts of tetrahydrofuran was added dropwise a solution of 6 parts of methyl 2-isothiocyanatobenzoate in 30 parts of tetrahydrofuran at room temperature: slightly exothermic reaction, the temperature rose to 30° C. Upon completion, stirring at room temperature was continued for one hour. The reaction mixture was evaporated. The residue was stirred in trichloromethane. The formed precipitate was filtered off and crystallized from 2 -propanone. The product was filtered off and dried, yielding 5.2 parts of 3-[2-[4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl]ethyl]-1,2-dihydro-2-thioxo-4(3H)-quinazolinone; mp. 198.5° C. (compound 131)