Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=2)[C:8]([O:19][CH2:20][O:21][CH3:22])=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[O:30])[CH:24]=2)[CH:6]=1)C.[OH-].[K+]>CO.Cl.O>[CH:17]([C:13]1[CH:12]=[C:11]([C:9]2[CH:10]=[C:5]([CH:6]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[O:30])[CH:24]=3)[C:8]=2[O:19][CH2:20][O:21][CH3:22])[C:4]([OH:31])=[O:3])[CH:16]=[CH:15][CH:14]=1)=[O:18]
Reactant: CCOC(=O)c1cc(-c2cccc(C=O)c2)c(OCOC)c(-c2cccc(C=O)c2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCOc1c(-c2cccc(C=O)c2)cc(C(=O)O)cc1-c1cccc(C=O)c1
Yield: 78.5 %

Procedure:
To a solution of 3,5-bis-(3-formylphenyl)-4-methoxymethoxybenzoic acid ethyl ester (960 mg, 2.12 mmol) in 3 mL MeOH was added 3 mL H2O and solid KOH (179 mg, 3.18 mmol). The reaction was refluxed for 5 to 6 hours then the cooled reaction mixture was diluted with 2N HCl and water. The aqueous solution was extracted with EtOAc (3×) and the combined organic layers were dried over Na2SO4. The solvent was removed in vacuo to give an oil that was flash chromatographed (10% MeOH:90% EtOAc) on silica gel. There yielded 650 mg of the desired acid along with some of the methyl ester of the desired acid. The methyl ester was resubjected to reaction conditions to give more of the desired acid for a total yield of 690 mg, 76.6%. 1H NMR (CDCl3) δ 2.63 (s, 3H); 4.19 (s, 2H); 7.65 (t, J=7.36 Hz, 2H); 7.87-7.95 (m, 4H); 8.06-8.26 (m, 4H); 10.10 (s, 2H).
Reaction SMILES: [C:1]1([C:7]2N=N[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25](N1CCCC1)=[CH2:26]>C(Cl)(Cl)Cl>[C:1]1([C:7]2[CH:25]=[CH:26][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)c(-c2ccc(C)cc2)n1
Reactant: C=CN1CCCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccccc2)c(-c2ccc(C)cc2)n1

Procedure:
Following General Procedure D, ethyl 6-phenyl-5-p-tolyl-1,2,4-triazine-3-carboxylate (Compound 17, 361 mg, 1.13 mmol) and crude 1-vinylpyrrolidine (Compound 38, 806 mg) in CHCl3 (10 ml) were reacted to produce the title compound as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH2:26][CH2:27][O:28][CH3:29].[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([CH2:26][CH2:27][O:28][CH3:29])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:36]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:37])[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)N1CCOCC1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
Under a nitrogen atmosphere, triethylamine (1.04 mL, 7.51 mmol) was added to a chilled (0°) solution of 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.01 mmol) in chloroform (75 mL). 4-Morpholinecarbonyl chloride (830 mg, 5.51 mmol) was added dropwise. The reaction was allowed to warm to ambient temperature and was maintained over the weekend. An equal volume of aqueous 1% sodium carbonate was added with vigorous stirring. A precipitate was isolated by filtration to provide 1.73 g of crude product as a white powder. This material was purified by column chromatography (silica gel eluting with a 0–5% methanol in chloroform gradient) and then triturated with diethyl ether to provide 1.6 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide as a white powder, m.p. 194.0–196.0° C. Analysis: Calculated for C21H28N6O3: % C, 61.15; % H, 6.84; % N, 20.37; Found: % C, 60.82; % H, 6.94; % N, 20.34.
Reaction SMILES: N(OCCC(C)C)=O.[N:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:20]3[C:24]4[N:25]=[C:26](N)[N:27]=[CH:28][C:23]=4[N:22]=[N:21]3)=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(I)[I:31]>>[I:31][C:26]1[N:27]=[CH:28][C:23]2[N:22]=[N:21][N:20]([CH2:19][C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[N:9]=[CH:10][CH:11]=[CH:12]4)[C:24]=2[N:25]=1
Reactant: ICI
Reactant: Nc1ncc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: CC(C)CCON=O
Product: Ic1ncc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 85 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Isoamyl nitrite (0.78 mL) was added to a suspension of 3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine (102 mg, 0.370 mmol) in CH2I2 (2.4 mL) under a nitrogen atmosphere. The mixture was stirred at 85° C. for 1 h. The solvent was removed under reduced pressure. Flash chromatography of the resulting residue over silica gel to afford the desired product (57 mg, 40%). 1H NMR (300 MHz, CDCl3) δ 6.03 (s, 2H), 7.44 (m, 1H), 7.79-8.18 (m, 4H), 8.94 (m, 1H), 9.27 (s, 1H); LCMS (APCI) m/z 389.0 (M+H+).
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]([O:9][C:10](=[O:11])[CH:5]2[CH2:4][CH:3]=[CH:2]1)=O.[CH2:12]([O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[Cl:23])[NH2:19])[CH:13]=[CH2:14]>C(O)(=O)C>[CH2:12]([O:15][C:16]1[CH:17]=[C:18]([N:19]2[C:10](=[O:11])[C:5]3[CH2:4][CH2:3][CH2:2][CH2:1][C:6]=3[C:7]2=[O:9])[CH:20]=[CH:21][C:22]=1[Cl:23])[CH:13]=[CH2:14]
Reactant: C=CCOc1cc(N)ccc1Cl
Reactant: O=C1OC(=O)C2CC=CCC12
Solvent: CC(=O)O
Product: C=CCOc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4.4 g of THPA, 5.3 g of 3B and 60 mL of glacial acetic acid was refluxed for 1 hour, then poured into 300 mL of ice water. The resulting mixture was allowed to stand for 10 minutes, then filtered. The collected solid was washed with cold water, dried under reduced pressure and recrystallized from ethyl acetate/hexane, to give N-(3-(allyloxy)-4-chlorophenyl)-3,4,5,6-tetrahydrophthalimide (3C), as yellow crystals, m.p.: 118.5°-120° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:12][NH:11][C:10](=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:12][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc(-c2cc(=O)[nH]cc2-c2ccncc2)c1
Product: Cc1cccc(-c2cc(Cl)ncc2-c2ccncc2)c1

Procedure:
4-(3-methylphenyl)-5-(4-pyridyl)-1H-pyrid-2-one (33 mg, 0.13 mmole) in POCl3 (2 mL) was heated to 105° C. for 12 hr. POCl3 was removed under reduced pressure. The residue was diluted with methylene chloride and was carefully quenched with aqueous sodium carbonate. Standard work up, followed by purification (silica gel, hexane/ethyl acetate) gave the title compound. MS (m/z): Calcd. C17H13N2Cl (M+): 280.5, found (M+H)+: 281 and 283.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:3]=1
Reactant: Oc1cc(-c2cccc(C(F)(F)F)c2)nc2ncnn12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc(-c2cc(Cl)n3ncnc3n2)c1

Procedure:
A mixture of 3.50 g. of 7-hydroxy-5-(m-trifluoromethylphenyl)-1,2,4-triazolo[1,5-a]pyrimidine and 25 ml. of phosphorus oxychloride is refluxed for 6 hours. The excess reagent is removed by evaporation; ice is added and 1 N sodium hydroxide is added until the aqueous phase is basic to indicator paper. The compound is extracted with methylene chloride and the solution passed through a short column of a hydrous magnesium silicate. Evaporation of eluent gives the desired compound as a light yellow solid.
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.[H-].[Na+].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:36](Cl)=[O:37]>C1(C)C(C)=CC=CC=1>[CH3:45][O:44][C:40]1[CH:39]=[C:35]([CH:34]=[C:33]([O:32][CH3:31])[C:41]=1[O:42][CH3:43])[C:36]([O:1][CH:2]([CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:22]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2)=[O:37]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: O=C1CCc2c(cccc2OCC(O)CN2CCN(c3ccccc3)CC2)N1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1cc(C(=O)OC(COc2cccc3c2CCC(=O)N3)CN2CCN(c3ccccc3)CC2)cc(OC)c1OC

Procedure:
1.9 Grams of 5-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril and 0.24 g of sodium hydride are dispersed in 40 ml of xylene and heated for 1 hour under refluxing conditions. Then the temperature of the bath is lowered to 130° C. and 1.40 g of 3,4,5-trimethoxybenzoyl chloride are added gradually and heated for 8 hours under refluxing condition. Xylene is removed from the reaction mixture by distillation, then the residue is poured into 80 ml of water and extracted with chloroform. The chloroform layer is washed with water, dried and chloroform is removed by distillation. The residue is recrystallized from ethanol to obtain 1.5 g of 5-[2-(3,4,5-trimethoxybenzoyloxy)-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless crystals with a melting point of 125°-127° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([N:14]3[C:19](=[O:20])[C:18]([CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[N:17][C:16]4[CH:28]=[CH:29][CH:30]=[N:31][C:15]3=4)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:32]1(=[O:42])[O:37][C:35](=[O:36])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12>O1CCOCC1.O>[C:35]([C:34]1[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=1[C:32]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([N:14]3[C:19](=[O:20])[C:18]([CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[N:17][C:16]4[CH:28]=[CH:29][CH:30]=[N:31][C:15]3=4)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:42])([OH:37])=[O:36]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cccc(-c2cccc(-n3c(=O)c(Cc4cccnc4)nc4cccnc43)c2)c1
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccccc1C(=O)Nc1cccc(-c2cccc(-n3c(=O)c(Cc4cccnc4)nc4cccnc43)c2)c1
Yield: 80.6 %

Procedure:
A solution of 4-[3-(3-aminophenyl)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (100 mg) and phthalic anhydride (48 mg) in dioxane (3 ml) was stirred overnight at room temperature. The reaction mixture was diluted with water, and precipitated crystals were collected to give 4-[3-[3-(2-carboxybenzoylamino)phenyl]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (110 mg).
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].OC1C2N=NNC=2C=CC=1.[NH2:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([NH2:43])=[O:42])=[O:38].Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:12]([NH:35][CH2:36][C:37]([NH:39][CH2:40][C:41]([NH2:43])=[O:42])=[O:38])=[O:14])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: NCC(=O)NCC(N)=O
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)NCC(N)=O
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
40 mL of Dimethyl formamide was added to 2.52 g (7.47 mmol) of Z-Glu(OtBu)-OH, 1.3 g (8.49 mmol) of hydroxybenzotriazole, 1.3 g (7.76 mmol) of H-Gly-GlyNH2, and 1.52 g (7.93 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride. 2.5 mL (14.3 mmol) of diisopropyl ethyl amine was added and the reaction was stirred over night. The reaction mixture was purified in three equal portions by direct injection on a preparative 5 cm×25 cm C18 HPLC column. The column was run at 100 mL/min with deionized water containing 0.3% formic acid with 5% acetonitrile for 10 min followed by a 15 min linear gradient from 5% acetonitrile to 90% acetonitrile. Product fractions (retention time 18-20 min) were combined and solvent was removed by rotary evaporation under vacuum to give 2.9 g (83%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.79-7.68 (m, 1H), 7.64 (s, 1H), 7.27 (q, J=4.9, 5H), 6.90 (s, 1H), 6.42 (s, 1H), 6.35 (d, J=6.8, 1H), 5.08 (d, J=12.0, 1H), 4.98 (d, J=12.2, 1H), 4.20 (dd, J=12.9, 7.6, 1H), 3.84-3.95 (m, 2H), 3.83 (d, J=5.0, 2H), 2.42-2.19 (m, 2H), 2.07 (d, J=6.9, 1H), 1.96-1.83 (m, 1H), 1.39 (s, 9H). 13C NMR (101 MHz, DMSO) δ 171.79, 171.65, 170.82, 168.87, 163.04, 156.08, 136.86, 128.31, 127.74, 79.64, 65.58, 53.96, 42.17, 41.81, 31.25, 27.73, 27.01.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][C:7]=3[N:8]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:9]=2[CH:10]=1.[OH-].[K+]>O=S(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][C:7]=3[N:8](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)\[CH3:13])[C:9]=2[CH:10]=1
Reactant: CN1CCc2c(c3ccc(Cl)cc3n2CC(C)(O)c2ccncc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: C/C(=C\n1c2c(c3ccc(Cl)cc31)CN(C)CC2)c1ccncc1
Temperature: 100 °C

Procedure:
1-(7-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol (1 g, 2.8 mmol) in SOCl2 (10 mL) was stirred RT for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N-methyl-2-pyrrolidone (6 mL), KOH (1.5 g, 28 mmol) was added and heated at 100° C. for 2 h. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic layer was washed with water and concentrated and purified by silica gel chromatography, 100-200 mesh (eluent in 5% MeOH-DCM). 1H NMR (CD3OD, HCl salt) δ (ppm): 8.90 (d, 2H), 8.40 (d, 2H), 7.80 (s, 1H), 7.55 (d, 1H), 7.38 (s, 1H), 7.22 (d, 1H), 4.80 (d, 1H), 4.40 (d, 1H), 3.90 (m, 1H), 3.60 (m, 2H), 3.25 (m, 1H), 3.18 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[Cl:14][S:15](O)(=[O:17])=[O:16]>C(Cl)Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)N1CCc2ccccc2C1
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a solution of 140 g. (0.8 mole) 2-acetyl-1,2,3,4-tetrahydroisoquinoline in 150 ml. dry methylene chloride at -15° C. with sufficient stirring was added dropwise 300 ml. (4.5 mole) chlorosulfonic acid. After the addition of the chlorosulfonic acid was complete, the reaction mixture was stirred for one hour at -15° C. and then heated to reflux for 2 hours. The reaction mixture was then cooled to 10° C. and then cautiously poured onto 3 l. of ice. The crude reaction product was then extracted in methylene chloride (2×150 ml.), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to dryness at reduced pressure to afford 2-acetyl-7-chlorosulfonyl-1,2,3,4,-tetrahydroisoquinoline as a viscous yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:35])[CH:14]([CH2:18][S:19]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)(=[O:21])=[O:20])[CH:15]([CH3:17])[CH3:16])(C)(C)C>ClCCl>[Br:34][C:31]1[CH:32]=[CH:33][C:28]([N:25]2[CH2:26][CH2:27][N:22]([S:19]([CH2:18][CH:14]([CH:15]([CH3:17])[CH3:16])[C:13]([OH:35])=[O:12])(=[O:21])=[O:20])[CH2:23][CH2:24]2)=[CH:29][CH:30]=1
Reactant: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 353.2 %

Procedure:
Trifluoroacetic acid (10 ml) was added slowly to a solution of 2-[4-(4-Bromophenyl)piperazine-1-sulfonylmethyl]-3-methylbutyric acid tert-butyl ester (2 26 g) in dichloromethane (50 ml). After stirring at room temperature for 3.5 h, the solvents were removed under vacuum, and the residue azeotroped twice with 1:1 dichloromethane/hexane (30 ml). The residue was then dissolved in 1 M sodium hydroxide (20 ml) and washed with diethyl ether (50 ml). The aqueous phase was then acidified to pH 3-4 with citric acid and extracted with dichloromethane (60 ml, then 2×20 ml). The combined dichloromethane extracts were then washed with water (20 ml), saturated brine (20 ml), dried (MgSO4) and the solvents removed under reduced pressure to provide the title compound as a white solid (3 81 g, 79%).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[C:13]2[S:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:12]=2[C:11]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[CH:9]2.C([O-])(=O)C.[K+].O>C(O)(=O)C>[Br:1][C:23]1[CH:24]=[C:19]([C:11]2[C:12]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:13]=3[C:4]([Br:3])=[C:5]3[C:10]=2[CH:9]=[CH:8][CH:7]=[CH:6]3)[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[C:22]=1[OH:25]
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c([N+](=O)[O-])c3)c2c1C
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c([N+](=O)[O-])c3)c2c1C
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
A solution of bromine (0.040 mL, 0.756 mmol) in acetic acid (0.5 mL) was added dropwise to a stirred suspension of 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol (0.20 g, 0.467 mmol), potassium acetate (0.228 g, 2.335 mmol) in acetic acid (4 mL). After 10 min, water was added and the reaction mixture was extracted with ether. Silica gel was added to the ether phase and the solvent was removed. The adsorbate was flashed (gradient: 95:5 to 85:15) to provide the title compound as a yellow solid (0.141 g, 60%): mp 129-130° C.: NMR (DMSO-d6); δ11.30 (s, 1H), 8.22 (d, J=8 Hz, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 7.67 (quintuplet, J=4 Hz, 1H), 7.51 (d, J=4 Hz, 2H), 2.45 (s, 3H), 1.65 (s, 3H); MS (EI): 2 bromine isotope pattern 505 (40%), 507 (100%), 509 (50%); Anal. Calc. for C20H13Br2NO3S: C, 47.36; H, 2.58; N, 2.76. Found: C, 47.18; H, 2.55; N, 2.63.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:21][CH2:22][O:23][CH2:24][C:25]([NH2:27])=[O:26].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:21][CH2:22][O:23][CH2:24][C:25]([NH2:27])=[O:26])[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: NC(=O)COCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: c1ccccc1
Product: NC(=O)COCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 120 °C
Yield: 73 %

Procedure:
A mixture of 37.8 g (0.15 mole) of 1-(diphenylmethyl)-piperazine, 27.5 g (0.2 mole) of 2-(2-chloroethoxy)-acetamide and 26.5 g of anhydrous sodium carbonate in 120 ml of xylene is heated for 4 hours to 90° to 120° C. Thereafter, 120 ml of benzene are added to the reaction mixture, the precipitate formed is filtered off and the organic phase is extracted with dilute hydrochloric acid (30 ml of concentrated hydrochloric acid and 100 ml of water). 40 ml of a concentrated aqueous solution of sodium hydroxide are added, followed by extraction with benzene. The benzene solution is washed with water, dried over anhydrous sodium carbonate and the benzene is evaporated off to dryness. The evaporation residue is triturated with diethyl ether and left to crystallize. 2-[2-[4-(Diphenylmethyl)-1-piperazinyl]ethoxy]-acetamide is obtained in a yield of 73% of theory; M.P. 119°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10]([Cl:12])=[N:11][C:7]=2[CH:6]=1)=[O:4].CCN(C(C)C)C(C)C.Cl[CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]([CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[C:10]([Cl:12])=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2[nH]c(Cl)nc2c1
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOCn1c(Cl)nc2cc(C(=O)OC)ccc21
Reaction time: 18 h

Procedure:
To a mixture of 2-chloro-1H-benzoimidazole-5-carboxylic acid methyl ester (2.00 g, 9.50 mmol) and THF (17 mL) was added DIPEA (2.46 mL, 14.3 mmol) followed by 1-chloromethoxy-2-methoxy-ethane (1.30 mL, 11.4 mmol) at 23° C. After stirring for 18 h the reaction mixture was concentrated under reduced pressure. The residue was purified (FCC) (5-50% EtOAc/hexanes) to yield the titled compound as a mixture of regioisomers (1.71 g, 60%). MS (ESI/CI): mass calcd. for C13H15ClN2O4, 298.1; m/z found, 299.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.34-8.31 (m, 1H), 8.21-8.20 (m, 1H), 7.98 (dd, J=8.6, 1.6 Hz, 1H), 7.91 (dd, J=8.5, 1.6 Hz, 1H), 7.83 (dd, J=8.6, 0.5 Hz, 1H), 7.74 (dd, J=8.5, 0.5 Hz, 1H), 5.78 (s, 1H), 5.73 (s, 1H), 3.89 (d, J=6.3 Hz, 6H), 3.64-3.60 (m, 5H), 3.43-3.39 (m, 5H), 3.17 (d, J=2.6 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2(O)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1.COCCN(S(F)(F)[F:32])CCOC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([F:32])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(Cl)ccn2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2cc(Cl)ccn2)CC1
Temperature: -40 °C

Procedure:
To a solution of tert-butyl 4-(4-chloropyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (C3) (0.600 g, 1.92 mmol) in CH2Cl2 (10 mL) cooled to −78° C. was added bis(2-methyoxyethyl)aminosulfur trifluoride (Deoxofluor, 0.71 mL, 3.8 mmol). The reaction was slowly warmed to −40° C. over 3 h, then quenched with water (5 mL) and warmed to RT. The mixture was extracted with CH2Cl2 (2×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified via silica gel chromatography eluting with 10-40% ethyl acetate in hexanes to provide tert-butyl 4-(4-chloropyridin-2-yl)-4-fluoropiperidine-1-carboxylate (C4).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O.CCOCC>[CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=2[CH2:2]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1CCCc2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOCC
Product: O=C1CCCc2c1cccc2[N+](=O)[O-]

Procedure:
10 ml (75 mmol) of α-tetralone was added dropwise to 7.6 g (75 mmol) of potassium nitrate dissolved in 75 ml of concentrated sulfuric acid (at -10° C). The resulting mixture was poured onto ice and the precipitate was suspended in ether. The precipitate (the 7 nitro isomer) was filtered off and the ether solution was evaporated. The residue was purified by column chromatography on silica gel. Yield: 4.7 g of the title compound, M.p. 94°-96° C.