Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:18])=[N:13][N:14]([CH3:17])[C:15]=1[OH:16])=[O:10].N12CCN(CC1)CC2.[C:27]1([S:37](Cl)(=[O:39])=[O:38])[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1.[Cl:41][C:42]1[N:47]=[N:46][C:45]([O:48][C:49]2[C:54]([CH3:55])=[CH:53][CH:52]=[CH:51][C:50]=2[CH:56]2[CH2:58][CH2:57]2)=[C:44]([OH:59])[CH:43]=1>C(#N)C.O>[C:27]1([S:37]([O:59][C:44]2[CH:43]=[C:42]([Cl:41])[N:47]=[N:46][C:45]=2[O:48][C:49]2[C:54]([CH3:55])=[CH:53][CH:52]=[CH:51][C:50]=2[CH:56]2[CH2:58][CH2:57]2)(=[O:39])=[O:38])[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([O:16][C:15]2[N:14]([CH3:17])[N:13]=[C:12]([CH3:18])[C:11]=2[C:9](=[O:10])[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])(=[O:34])=[O:35])[CH:28]=1
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Agent: C1CN2CCN1CC2
Solvent: CC#N
Solvent: O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1OS(=O)(=O)c1cccc(S(=O)(=O)Oc2c(C(=O)c3ccc(Cl)cc3Cl)c(C)nn2C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
In acetonitrile (4 mL) was suspended 122 mg (0.428 mmol) of (2,4-dichlorophenyl)(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)methanone, 72.0 mg (0.643 mmol) of 1,4-diazabicyclo[2.2.2]octane, then 117 mg (0.425 mmol) of 1,3-benzenedisulfonyl dichloride were added to the suspension in an ice bath, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled, and further 100 mg (0.361 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was added to the mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane:ethyl acetate, gradient) to obtain 135 mg (0.177 mmol, Yield: 49.0%) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-1H-pyrazol-5-yl 1,3-benzenedisulfonate (Compound No. 2333) and 38.0 mg (0.0503 mmol, Yield: 13.9%) of bis[6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl] 1,3-benzenedisulfonate (Compound No. 3755).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:17])[CH2:13][C:14]([CH3:16])=O)[CH3:10].[C:18]([CH:23]=[C:24]1[NH:28][CH2:27][CH2:26][NH:25]1)([O:20][CH2:21][CH3:22])=[O:19]>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:23]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:24]2[NH:25][CH2:26][CH2:27][N:28]2[C:14]=1[CH3:16])=[O:17])[CH3:10]
Reactant: CCOC(=O)C=C1NCCN1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C1=C(C)N2CCNC2=C(C(=O)OCC)C1c1ccccc1
Yield: 81 %

Procedure:
Upon heating a solution of 5.3 g of benzaldehyde, 6.5 g of acetoacetic acid ethyl ester and 7.8 g of 2-carbethoxymethylideneimidazolidine in 50 ml of ethanol for 6 hours, 5-methyl-7-phenyl-1,2,3,7-tetrahydroimidazolo[1,2-a]pyridine-6,8-dicarboxylic acid diethyl ester of melting point 165° (alcohol) is obtained. Yield: 81% of theory.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]([C:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=3)[CH2:20][CH:21]=2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[Pd]>[CH2:1]([C:8]1[N:9]=[N:10][C:11]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][N:23]=3)[CH2:20][CH2:21]2)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Cc2ccccc2)nnc(C2=CCN(c3ccc(C(F)(F)F)cn3)CC2)c1C
Agent: [Pd]
Solvent: CCO
Product: Cc1c(Cc2ccccc2)nnc(C2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1C
Reaction time: 16 h
Yield: 39.9 %

Procedure:
To a solution of 3-benzyl-4,5-dimethyl-6-(1-(5-(trifluoromethyl)pyridin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyridazine (20 mg, 0.047 mmol) in 8 mL EtOH is added 10% Pd—C (25 mg, 19 mmol). The reaction mixture is stirred under hydrogen atmosphere for 16 h. The mixture is filtered through Celite and the filtrate is concentrated to afford a off-white solid. The mixture is purified by prep HPLC, eluting with 10%-100% acetonitrile:water (both mobile phases modified by 3% n-PrOH). Fractions containing the desired product are combined and freeze-dried to afford a white solid (8 mg, 40%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[NH:10][C:9]1=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[C:21]([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CC#N>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[N:10]([CH3:21])[C:9]1=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(Br)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (4.0 g, 12.8 mmol), iodomethane (2.74 g, 9.2 mmol), and K2CO3 in CH3CN (60 mL) was stirred at room temperature under a blanket of nitrogen overnight. Upon completion of the reaction, ethyl acetate (200 mL) was added and the organic layer was washed with H2O (200 mL), dried over Na2SO4, and concentrated. The residue was purified via chromatography (silica gel, 25% ethyl acetate/hexane) to give 5-bromo-3-methyl-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester as a white solid: mp 98-99° C.; 1H-NMR (CDCl3) δ 7.7 (d, 1H, J=8.5 Hz), 7.27 (bs, 2H), 7.09 (d, 1H, J=2 Hz), 3.4 (s, 3H), 1.7 (s, 9H); MS (ES) m/z 349([M+Na]+, 20%), 351([M+Na]+, 20%); Anal. Calc. For C13H15BrN2O3: C, 47.73, H, 4.62, N, 8.56. Found: C, 47.46, H, 4.5, N, 8.29.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]2[C:11]([CH2:12][C:13](=[O:35])[N:14]([CH2:22][C:23]([N:25]([CH:32]([CH3:34])[CH3:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=32)=[N:10][N:9]=1.[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH:45]=O)=[CH:37]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]2[C:11]([CH:12]([CH2:45][C:38]3[C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[NH:36][CH:37]=3)[C:13](=[O:35])[N:14]([CH2:22][C:23]([N:25]([CH:32]([CH3:33])[CH3:34])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:24])[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=32)=[N:10][N:9]=1
Reactant: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3ccccc3F)n2-c2ccccc21)c1ccccc1
Reactant: O=Cc1c[nH]c2ccccc12
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3F)n2-c2ccccc21)c1ccccc1

Procedure:
Following the procedure described for Example 6(A), Step A; 2-(1-(2-fluorophenyl)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-N-phenyl-acetamide (Preparation 7(B)) was condensed with 1H-indole-3-carbaldehyde. This intermediate was carried forward according to Example 6(A) Step B to afford 2-[1-(2-fluoro-phenyl)-4-(1H-indol-3-ylmethyl)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide. 1H NMR (CD2Cl2) δ 8.26 (s, 1H), 7.71-7.74 (m, 1H), 7.60-7.67 (m, 2H), 7.40-7.59 (m, 6H), 7.34-7.38 (m, 2H), 7.23-7.32 (br. m, 2H), 7.14-7.20 (m, 1H), 7.05-7.12 (m, 3H), 6.81-6.83 (m, 1H), 4.98-5.03 (m, 1H), 4.28 (d, 1H), 3.93 (d, 1H), 3.83-3.84 (m, 3H), 1.12 (d, 6H); MS 599 (M+1).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=CC=2)=O)[CH2:3][CH2:2]1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.[CH2:30](N(CC)CC)[CH3:31].[CH:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46][CH:47]([C:51]([OH:53])=O)[C:48]([OH:50])=[O:49])([CH3:39])[CH3:38]>C(Cl)Cl>[CH:4]1([CH2:7][O:8][C:9]2[CH:10]=[CH:12][C:17]([C:16]3[O:50][C:48](=[O:49])[C:47]([S:46][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[CH:37]([CH3:38])[CH3:39])=[C:51]([OH:53])[CH:15]=3)=[CH:31][CH:30]=2)[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1
Reactant: CCN(CC)CC
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: O=C(COCC1CCCCC1)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(OCC3CCCCC3)cc2)oc1=O

Procedure:
The title compound was prepared by Method A using 4-cyclohexylmethoxy acetophenone (2.0 g, 8.61 mmol), trimethylsilyl triflate (1.91 g, 8.61 mmol), triethylamine (1.74 g, 17.22 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (4.0 g, 12.92 mmol). m.p. 187-188° C.; 1H NMR (400 MHz, DMSO-d6) δ0.96-1.33 (m+1.24 d 11H), 1.61-1.87 (m, 6H), 3.4 (m, 1H), 3.86 (d, 2H), 6.76 (s, 1H), 6.92 (dd, 1H), 7.11 (m, 4H), 7.29 (dd, 1H), 7.81 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[C:10](=[O:31])[CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:34].[C:35](Cl)(=O)[O:36]C1C=CC([N+]([O-])=O)=CC=1.[CH:48]1([CH2:51][NH2:52])[CH2:50][CH2:49]1.C(N(CC)CC)C>O1CCOCC1.ClCCl>[CH:48]1([CH2:51][NH:52][C:35]([NH:1][C:2]2[CH:33]=[CH:32][C:5]([C:6]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][C:15]4[CH:16]=[CH:17][C:18]([C:21]([OH:30])([C:22]([F:23])([F:24])[F:25])[C:26]([F:28])([F:29])[F:27])=[CH:19][CH:20]=4)[C:10](=[O:31])[CH2:9]3)=[O:7])=[CH:4][C:3]=2[F:34])=[O:36])[CH2:50][CH2:49]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)C(=O)C2)cc1F
Reactant: NCC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)C(=O)C2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
A solution of 4-(4-amino-3-fluorobenzoyl)-1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-2-one (0.405 mmol, 200 mg) and 4-nitrophenyl carbonochloridate (0.405 mmol, 82 mg) in 1,4-dioxane (2 mL) was stirred at room temperature for 30 minutes. Cyclopropylmethanamine (0.405 mmol, 28.8 mg) and triethylamine (1.216 mmol, 123 mg) were added and the reaction stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (10 mL). The organic phase was concentrated and the resulting residue was purified by column chromatography on silica gel (eliciting with 3% methanol/97% dichloromethane—10% methanol/90% dichloromethane gradient) to afford the title compound (45 mg).
Reaction SMILES: [Si]([C:5]#[CH:6])(C)(C)C.[CH3:7][C:8]1([CH3:16])[CH2:13][CH2:12][CH2:11][CH:10]([CH3:14])[C:9]1=O.CC[N+](S(/N=C(/OC)\[O-])(=O)=O)(CC)CC.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:10]([C:9]1[C:8]([CH3:16])([CH3:7])[CH2:13][CH2:12][CH2:11][C:5]=1[CH3:6])#[CH:14]
Reactant: C#C[Si](C)(C)C
Reactant: CC1CCCC(C)(C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[N+](CC)(CC)S(=O)(=O)/N=C(\[O-])OC
Agent: [F-]
Product: C#CC1=C(C)CCCC1(C)C

Procedure:
The prerequisite 2-ethynyl-1,3,3-trimethyl-1-cyclohexene was synthesized according to standard procedures by addition of the Li-derivative of TMS-acetylene to 2,2,6-trimethylcyclohexanone, dehydration by treatment with Burgess-reagent (methoxy-carbonylsulfamoyl-triethylammonium hydroxide, inner salt), and finally desilyation with tetrabutylammonium fluoride. It has to be used immediately due to its instability.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=1)(=[O:12])=[O:11])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2ccc(OC)cc2)cc1
Reactant: BrCc1ccccc1
Product: COc1ccc(N(Cc2ccccc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxyphenyl)sulfamoyl)-benzoate (example 5-35a) and benzyl bromide MS (M−H, 396); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.66 (s, 3H), 4.75 (s, 2H), 6.76 (d, J=8 Hz, 2H), 6.90 (d, J=8 Hz, 2H), 7.23 (m, 5H), 7.74 (d, J=8 Hz, 2H), 8.11 (d, J=8 Hz, 2H), 13.51 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:32]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[OH-].[Na+]>CN(C=O)C>[C:41]([O:40][C:38]([N:32]1[CH2:37][CH2:36][N:35]([C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[CH:10][CH:9]=2)[CH2:34][CH2:33]1)=[O:39])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)cc2)CC1
Reaction time: 22 h
Yield: 86.9 %

Procedure:
To a solution of 4-aminobenzoic acid (411 mg, 3.00 mmol) in DMF (3.0 mL) at room temperature was added EDC (862 mg, 4.50 mmol), HOBt (608 mg, 4.50 mmol), triethylamine (606 mg, 0.835 mL, 6.00 mmol) and tert-butyl piperazinecarboxylate (671 mg, 3.60 mmol). The mixture was stirred for 22 h, and then 2 N aq. NaOH was added to adjust the PH>10. The mixture was extracted with ethyl acetate, and the organic layer was dried over MgSO4, concentrated. The residue was purified by silica gel column chromatograghy eluted with EtOAc:hexanes (50 to 90% EtOAc) to give 4-(4-amino-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (796 mg, 87%) as a colorless oil. MS (ES+): m/z=306.2
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:11][CH2:12]Cl)(=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7]>O.CCOC(C)=O>[C:5]([O:11][CH2:12][N:1]=[N+:2]=[N-:3])(=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)C(=O)OCN=[N+]=[N-]
Temperature: 90 °C
Reaction time: 16 h
Yield: 63.9 %

Procedure:
Sodium azide (1.942 g, 29.9 mmol) was added to a suspension of chloromethyl pivalate (3.00 g, 19.92 mmol) in water (5 mL) and stirred vigorously at 90° C. for 16 h. The reaction mixture was diluted with water (20 mL) and EtOAc (20 ml). The organic layer was washed with brine, dried (Na2SO4) and concentrated to afford azidomethyl pivalate as a liquid (2 g, 64% yield). 1H NMR (400 MHz, Acetone-d6): δ 5.23 (s, 2H), 1.22 (s, 9H).
Reaction SMILES: ClC(C1C=C(CC(C)C)C=CC=1C(C1C=CC(CC(C)C)=CC=1C(Cl)C)=O)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[CH:37]=[CH:36][CH:35]=[CH:34]2.C(C1C=CC=CC=1)C(C)C.[Cl:51][CH:52]([CH3:56])[C:53](Cl)=[O:54]>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[CH:37]=[C:36]([C:53]([CH:52]([Cl:51])[CH3:56])=[O:54])[CH:35]=[CH:34]2
Reactant: COc1ccc2ccccc2c1
Reactant: CC(Cl)C(=O)Cl
Agent: CC(C)Cc1ccc(C(=O)c2ccc(CC(C)C)cc2C(C)Cl)c(C(C)Cl)c1
Solvent: CC(C)Cc1ccccc1
Product: COc1ccc2cc(C(=O)C(C)Cl)ccc2c1

Procedure:
Following the procedure of Example 1, but substituting in part (a) thereof 6-methoxynaphthalene for isobutylbenzene in the reaction with the alpha-chloropropionyl chloride, there is formed 1-chloroethyl 6-methoxy-2-naphthyl ketone. Then, as in part (b) of Example 1, the 1-chloroethyl 6-methoxy-2-naphthyl ketone, in heptane, is reacted with neopentyl glycol to form the neopentyl ketal of the ketone (also named 2-(1-chloroethyl)-2-(6'-methoxynaphthyl)-5,5-dimethyl-1,3-dioxane). In step (c) this alpha-chloroketal is mixed with a solution of zinc 2-ethylhexanoate in heptane, at a temperature of from about 135° to 150° C. to distill the heptane away and to cause the rearrangement of the α-chloroketal to the 3-chloro-2,2-dimethylpropyl ester of 2-(6-methoxy-2-naphthyl)propionic acid. The resulting oil can be cooled, treated with filter aid to adsorb zinc compounds, and diluted with heptane, stirred and filtered. The filtrate can be treated with carbon and filter aid material to remove colored impurities. The chloro-ester solution, so clarified, can be mixed with aqueous base as in part (d) of Example 1 to hydrolyze the ester and to form the sodium 2-(6'-methoxy-2-naphthyl)propionate salt. Then the sodium salt intermediate product can be precipitated from the mixture by dilution with water, cooling, seeding with sodium naproxen [sodium 2-(6'-methoxy-2-naphthyl)propionate] crystals and cooled to 0° to crystallize the sodium naproxen salt from the mixture, which solid salt is filtered and washed with heptane and dried, if desired. Then, as in step (c) of Example 1, the sodium naproxen crystals can be converted to the free naproxen acid [2-(6'-methoxy-2-naphthyl)propionic acid] by dilution with water and heptane, acidified as in part (e) of Example 1, separate the aqueous and organic liquid phases and washing the organic liquid phase with an aqueous buffer solution, and the organic solvent can be distilled to leave as residue the substantially pure naproxen acid, which can be further washed and dried with nitrogen to obtain drug-quality naproxen acid for use in preparing pharmaceutical formulations thereof.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8].N1C2C(=CC=CC=2)C=CC=1.[H][H]>C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Ba+2].[Pd+2].S([O-])([O-])(=O)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:13][CH:14]=1)/[CH:6]=[CH:7]\[CH3:8]
Reactant: [H][H]
Reactant: CC#CC(CC(=O)OC)c1ccc(OC2CCCCO2)cc1
Agent: [Pd+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: C/C=C\C(CC(=O)OC)c1ccc(OC2CCCCO2)cc1
Yield: 93.5 %

Procedure:
To a solution of 3-[4-(tetrahydropyran-2-yloxy)-phenyl]-hex-4-ynoic acid methyl ester (4.07 g) obtained in Step 1 in ethyl acetate (70 mL) were added successively quinoline (1.52 mL) and 5% palladium-barium sulfate (0.4 g), followed by stirring the reaction mixture under normal pressure in an atmosphere of hydrogen at room temperature for 15.5 hours. Then, after the reaction mixture was filtered through Celite, water and 1N aqueous hydrochloric acid solution were added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed successively with 1N aqueous hydrochloric acid solution and saturated brine, dried and concentrated to give (Z)-3-[4-(tetrahydropyran-2-yloxy)-phenyl]-hex-4-enoic acid methyl ester (3.83 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1)#[CH:2].I[C:12]1[CH:13]=[C:14]([O:18][CH3:19])[CH:15]=[CH:16][CH:17]=1.C(NC(C)C)(C)C.O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: C#Cc1cccc(OC)c1
Reactant: COc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C#Cc2cccc(OC)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a mixed solution of 3-ethynylanisole (347.0 mg, 2.63 mmol), 3-iodoanisole (670.0 mg, 2.86 mmol, 1.1 eq), (PPh3)2PdCl2 (37.2 mg, 0.0530 mmol, 0.02 eq), CuI (5.1 mg, 0.0268 mmol, 0.01 eq) in THF (5 ml), diisopropylamine (0.57 g, 5.63 mmol, 2.1 eq) was added at 0° C., and stirred at room temperature for 1 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/15) to give bis(3-methoxyphenyl)ethyne (594.4 mg, 95.0%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1>CC1C=CC=CC=1>[N:1]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1ccc(OCCCCl)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(OCCCN2CCNCC2)cc1
Reaction time: 8 h
Yield: 98.5 %

Procedure:
A mixture of 224 parts of piperazine, 97 parts of ethyl 4-(3-chloropropoxy)benzoate and 1044 parts of methylbenzene was stirred overnight at reflux temperature. After cooling, the reaction mixture was washed with water (3×), dried, filtered and evaporated, yielding 115.2 parts (98.5%) of ethyl 4-[3-(1-piperazinyl)propoxy]benzoate (interm. 1). In a similar manner there was also prepared ethyl 4-[2-(1-piperazinyl)ethoxy]benzoate (interm. 2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](Cl)=[O:14])[CH3:11].O.CCOC(C)=O>N1C=CC=CC=1>[CH2:10]([N:12]([CH2:16][CH3:17])[C:13]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:14])[CH3:11]
Reactant: CCN(CC)C(=O)Cl
Reactant: c1ccc2c(c1)CCN2
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6 g of indoline in 10 ml of pyridine is cooled to 0° C. 6.4 ml of diethylcarbamoyl chloride are added dropwise and the mixture is stirred for 18 hours at RT. Water is added to the reaction mixture, extraction is carried out with AcOEt, the organic phase is washed with water and with a 5% solution of potassium hydrogensulfate and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using DCM as the eluent to give 8 g of the expected product, which is used as such.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[CH2:9]([O:11][C:12]1[CH:22]=[CH:21][C:15](C(OCC)=O)=[CH:14][CH:13]=1)[CH3:10].Cl.[O:24]1CCC[CH2:25]1>CCCCCC>[CH2:9]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:7]([CH:25]=[O:24])[C:6]#[N:8])=[CH:21][CH:22]=1)[CH3:10]
Reactant: CC#N
Reactant: CCOC(=O)c1ccc(OCC)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCOc1ccc(C(C#N)C=O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
27.1 ml (67.8 mmol) of a 2.5 M solution of n-butyllithium in hexane is added drop by drop at −78° C. under argon to a solution of 4.4 g (108.6 mmol) of acetonitrile in 50 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred for 30 min at −78° C., then a solution of 5.2 g (27.15 mmol) of ethyl 4-ethoxybenzoate diluted in 30 ml of tetrahydrofuran is added at −78° C. drop by drop to the reaction mixture. The reaction mixture is stirred for 2 h at −78° C., then 1 M hydrochloric acid solution is added, and the product is extracted several times with ethyl acetate. The organic phases are combined, dried on magnesium sulfate and concentrated. The solid is triturated in 15 ml of methanol to yield 4.4 g (80%) of 4-ethoxyphenyl-3-oxopropanenitrile in the form of a white solid.