Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:16][CH2:17][CH:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:34][CH:35]=4)[CH2:19][CH2:20]3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CCOC(=O)c1ccc(OCCCC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(OCCCC2CCN(c3ccc(-c4ccc(F)cc4)nn3)CC2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A mixture of 2.1 parts of 3-chloro-6-(4-fluorophenyl)pyridazine, 2.9 parts of ethyl 4-[3-(4-piperidinyl)propoxy]benzoate, 1.1 parts of sodium carbonate and 2 parts of N,N-dimethylacetamide was stirred for 2 hours in an oil bath at 140° C. The reaction mixture was diluted with water while cooling. The precipitated product was filtered off, washed with water and dissolved in trichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 3.4 parts (73.3%) of ethyl 4-[3-[1-[6-(4-fluorophenyl)-3-pyridazinyl]-4-piperidinyl]propoxy]benzoate; mp. 160.4° C. (comp. 81).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>C(Cl)Cl>[Br:31][CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(CO)ccn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CBr)ccn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a 100-mL round-bottomed flask was added (2-methoxy-4-pyridinyl)methanol (1.52 g, 10.92 mmol), triphenylphosphine (3.15 g, 12.02 mmol, Aldrich, St. Louis, Mo.), and carbon tetrabromide (1.165 mL, 12.02 mmol, Aldrich, St. Louis, Mo.) in DCM (20 mL). The reaction mixture was stirred at 0° C. for 2 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 20% EtOAc/hexanes to give 4-(bromomethyl)-2-methoxypyridine (1.98 g) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12]C)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.CO.O.O.[OH-].[Li+]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc[nH]c2c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 94.9 %

Procedure:
A solution of methyl indole-6-carboxylate (11.0 g) in a mixture of tetrahydrofuran (150 ml), methanol (150 ml), and water (63 ml) was treated with lithium hydroxide monohydrate (15.8 g). The mixture was stirred at 60° C. for 6 hours and then concentrated to remove the organic solvents. The residue was dissolved in water, and the solution was acidified with 50% (v/v) hydrochloric acid. The precipitate which formed was collected by filtration and dried to give indole-6-carboxylic acid (9.6 g, 95%) as a tan powder; mp 253°-254°: NMR (80 MHz; CDCl3) 6.51(m, 1H, H3 -indole), 8.04(m, 1H, H7 -indole), 11.43(broad s, 1H, NH), 12.42(broad s, 1H, OH).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[C:34]([NH2:45])(=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:45][C:34](=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCCCC(N)=O
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Product: CCCCCCCCCC(=O)NC(=O)c1ccc(C(C)(C)C)c(NC(=O)CC(CCCCC)c2ccc(OC)cc2OC)c1

Procedure:
Following a similar procedure to that described in Example 139, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 7) and decanamide, the title compound was obtained as crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[SH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[S:17][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2
Reactant: Sc1ccccn1
Reactant: O=C1CCc2cc(OCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCSc3ccccn3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(3-bromopropoxy)-3,4-dihydro-carbostyril and 2-mercapto-pyridine.
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12]O>ClCCl>[CH3:1][C@H:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:12][CH2:11][NH:9]1
Reactant: C[C@H](N)c1ccccc1
Reactant: OCCBr
Solvent: ClCCl
Product: C[C@@H]1NCCc2ccccc21
Temperature: 51 °C
Reaction time: 52 h
Yield: 88312.6 %

Procedure:
108.23 g(0.903 mmole) of (S)-(-)-α-methylbenzylamine was dissolved in 140 ml of dichloromethane and 144.0 g(1.071 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 52 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and the residue was subjected to fractional distillation to obtain 117.4 g of the title compound, which had a pale yellow color.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Cl)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2].[CH2:24](B(CC)CC)[CH3:25].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10]([CH2:24][CH3:25])=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2]
Reactant: CCB(CC)CC
Reactant: CCOC(=O)c1c(Cl)cc(-c2c(CC)cccc2CC)nc1C
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: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(CC)cc(-c2c(CC)cccc2CC)nc1C
Temperature: 95 °C
Yield: 64.3 %

Procedure:
A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester (251 mg, 0.76 mmol), triethylborane (4.6 mL of 1 M solution in hexane, 4.6 mmol), Pd(PPh3)4 (26 mg, 0.023 mmol), and Na2CO3 (1.27 g, 6 mL of 2M solution in H2O) in toluene (20 mL) is heated for 48 hours at 95° C. After cooling to room temperature the mixture is diluted with water (10 mL) and extracted with EtOAc. The combined extracts are washed with saturated brine, dried (Na2SO4), concentrated, and purified by flash chromatography (elution with hexane/EtOAc 10:1) to yield 159 mg 6-(2,6-diethyl-phenyl)-4-ethyl-2-methyl-nicotinic acid ethyl ester as a colorless oil: 1H NMR (CDCl3) 7.29 (dd, 1H), 7.13 (d, 2H), 7.00 (s, 1H), 4.47 (q, 2H), 2.68 (q, 2H), 2.59 (s, 3H), 2.36-2.27 (m, 4H), 1.45 (t, 3H), 1.24 (t, 3H), 1.05 (t, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C)C=O.C(OCC)(=O)C.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>[CH2:8]([C:5]1[CH:4]=[N:3][C:2]([C:24]#[C:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:7][CH:6]=1)[CH3:9]
Reactant: CCc1cnc(Cl)nc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cnc(C#Cc2ccccc2)nc1
Temperature: 47.5 °C
Yield: 105.6 %

Procedure:
2-Chloro-5-ethylpyrimidine (500 mg, 3.5 mmol), PdCl2(PPh3)2 (250 mg, 0.35 mmol), CuI (203 mg, 1.06 mmol), triethylamine (6.0 mL, 43 mmol), and n-Bu4NI (3.85 g, 10.4 mmol) were combined in dimethylformamide (DMF) (30 mL). The mixture was cooled in an ice bath and then phenylacetylene (1.5 mL, 14 mmol) was added. The reaction mixture was then heated to 45-50° C. and after 1.5 h, additional phenylacetylene (1.5 mL, 14 mmol) was added. After an additional 17 h the reaction was diluted with ethyl acetate, washed with brine (4×15 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting black oil was purified by column chromatography eluting with hexane then 90:10 hexane:ethyl acetate to afford 5-ethyl-2-(phenylethynyl)pyrimidine (770 mg, >100%) as a black oil. MS (EI ionization) 208 (M+). This material was carried on to the salt formation without further purification
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:22])[C:5](=[O:8])[NH:6][N:7]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI.CN(C)C=O.Cl>C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>[OH:1][CH2:2][C:3]1[N:4]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:22])[C:5](=[O:8])[N:6]([CH3:23])[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(-c2ccccc2)cc1Cn1c(CO)n[nH]c1=O
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2)cc1Cn1c(CO)nn(C)c1=O
Yield: 99.5 %

Procedure:
6.29 g (21.3 mmol) of 5-hydroxymethyl-4-(2-methyl-5-phenylbenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one, 3.53 g (25.6 mmol) of potassium carbonate and 3.63 g (25.6 mmol) of methyl iodide were stirred for 4 hours at 60° C. in 38 mol of anhydrous N,N-dimethylformamide. To the reaction solution was added 200 ml of a 5 wt % hydrochloric acid aqueous solution, and this was extracted with ethyl acetate. The organic layer was washed with water, 5 wt % sodium bicarbonate solution, then, saturated saline, dried over anhydrous magnesium sulfate, then, concentrated. The residuie was subjected to silica gel column chromatography (eluant: hexane/ethyl acetate=1/1 (v/v), then, ethyl acetate), to obtain 6.52 g (21.2 mmol) of 5-hydroxymethyl-2-methyl-4-(2-methyl-5-phenylbenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(N)cc1
Agent: O=S(=O)(O)O
Product: CCc1ccc(N)cc1[N+](=O)[O-]
Temperature: 8 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
4-Ethylaniline (10.3 mL, 82.5 mmol) was added drop wise to sulfuric acid (96%, 63 mL), cooled to 8° C., maintaining the temperature below 10° C. After the addition, the reaction mixture was cooled to −5° C., before the addition of a mixture of nitric acid (100%, 4 mL) and sulfuric acid (96%, 10 mL), keeping the temperature below 0° C. The reaction mixture was then stirred at the same temperature for 1 h. The reaction mixture was poured into ice (200 mL) and the precipitate filtered and washed with water. The solid was suspended with water (100 mL) and neutralized with ammonium hydroxide (35%). The precipitate was filtered and dried in the oven to obtain a light-brown solid (10 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([N:40]2[CH2:39][CH2:38][N:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=3)[CH2:42][CH2:41]2)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)O
Reactant: COc1cccc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4ccccc4Cl)noc3C)CC2)c1
Yield: 76.1 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(2-chlorophenyl)-5-methylisoxazol-4-carboxylic acid (437 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (576 mg, 1.40 mmol, 76%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[Cl:20])[N:7]([CH2:21][CH2:22]O)[C:6]=2[C:5]([C:24]([O:26][CH3:27])=[O:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]([O:26][CH3:27])=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[Cl:20])[CH2:22][CH2:21][N:7]21
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3Cl)n(CCO)c12
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCN3c1c(C)cc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 14 h
Yield: 65.9 %

Procedure:
To a solution of methyl 4-chloro-2-[(2,4-dichloro-6-methylphenyl)amino]-1-(2-hydroxyethyl)-1H-benzimidazole-7-carboxylate (156 mg, 0.364 mmol) and triethylamine (0.203 mL, 1.46 mmol) in tetrahydrofuran (7.2 mL) was added methanesulfonyl chloride (0.056 mL, 0.72 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hr and at room temperature for 14 hr. Then the mixture was warmed to 45° C. and stirred at 45° C. for 10 hr. Water was added to the mixture and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-70% ethyl acetate/n-hexane gradient mixture to give the title compound (99 mg, 0.24 mmol, 66%) as colorless crystals.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[BH4-].[Na+]>C1COCC1>[Cl:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(CCCl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1ccc(CCCl)cc1
Temperature: 60 °C

Procedure:
To 100 g (525 mmol) 4-(2-chloro-ethyl)-benzoic acid in 1.0 L of THF is added 170 g (1050 mmol) CDI in small portions. The mixture is stirred at 60° C. until the gas evolution ceased. After cooling to RT, the mixture is slowly added into a solution of 39.7 g (1050 mmol) sodium borohydride in ice water and is stirred for 3 h at RT. The solution is acidified with diluted HCL and extracted twice with EtOAc. The organic phase is separated and dried over MgSO4. After evaporation of the solvent, the residue is dissolved in water/EtOAc. The aqueous phase is separated, washed once with EtOAc and the combined organic phase is dried over MgSO4. After evaporation of the solvent the residue is purified by silica gel column chromatography with PE/EtOAc (7:3) as eluent.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])[CH2:18][CH2:17]1.S(=O)(=O)(O)O.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[O:8][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])[CH2:20][CH2:21]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Reactant: OC(c1ccccc1)c1ccccn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccccn2)CC1
Temperature: 120 °C
Reaction time: 4 h
Yield: 29.3 %

Procedure:
There was stirred at 120° C. for 4 hours a mixture of 6.74 g of phenyl-2-pyridylmethanol, 7.85 g of 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine, 11.0 g of concentrated sulfuric acid and 15 ml of toluene. After cooling, the reaction solution was poured into ice water, made alkaline with an aqueous sodium hydroxide, and extracted with toluene. The extract was washed with water, and toluene was removed under reduced pressure. The residue was eluted with ethyl acetate-ethanol-dichloromethane (1:1:1) by silica gel column chromatography to give 3.67 g of oily 4-(phenyl-2-pyridylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:5]([C:25]([F:28])([F:27])[F:26])=[N:6][N:7]([CH2:9][C:10]([NH:12][C:13]2[S:17][C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[C:14]=2[C:22]([NH2:24])=[O:23])=[O:11])[CH:8]=1)[CH3:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.C(OCC)C>[C:2]([C:4]1[C:5]([C:25]([F:26])([F:28])[F:27])=[N:6][N:7]([CH2:9][C:10]([NH:12][C:13]2[S:17][C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[C:14]=2[C:22]([NH2:24])=[O:23])=[O:11])[CH:8]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 2-(2-(4-(1-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (1.4 g, 3.36 mmol) in DCM (17 mL) was added a 15 wt % Dess-Martin periodinane in DCM solution (9.51 g, 6.99 mL, 3.36 mmol). The reaction was blanketed with argon and allowed to stir at RT for 6 h. Sodium thiosulfate pentahydrate (5.84 g, 23.53 mmol) was dissolved in water (20 mL) and mixed with saturated aqueous sodium bicarbonate (40 mL) before addition to the reaction mixture. The reaction mixture was allowed to stir for 40 min before the addition of diethyl ether. The aqueous was separated and extracted with diethyl ether (×3). The organics were combined and washed with water (×2) and brine (×1) before drying over MgSO4. The solvent was removed in vacuo to give the title compound as an off white solid (1.2 g, 2.90 mmol, 86%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:18]=[C:19]1[CH2:23][CH2:22][CH2:21][NH:20]1.[C@@H]1(N)CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.C(OCC)(=O)C.C1(C)C=CC=CC=1>[O:18]=[C:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCCN1
Reactant: CC(C)(C)OC(=O)C1(c2ccc(Br)cc2)CC1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1(c2ccc(N3CCCC3=O)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 1-(4-bromophenyl)cyclopropanecarboxylate (297.2 mg, 1.0 mmol), 2-oxo-pyrrolidine (1.2 mmol), copper(I) iodide (20.0 mg, 0.1 mmol), (trans)-cyclohexane-1,2-diamine (22.8 mg, 0.2 mmol) and potassium carbonate (300.0 mg, 2.17 mmol) was dearated under vacuum and then charged with nitrogen. To the mixture was added toluene (2.0 mL). The resulting mixture was heated at 100° C. for overnight. Then ethyl acetate (10 mL) was added to the mixture. The resulting mixture was filtered through a pad of celite, and the solid was washed with additional ethyl acetate. The filtrate was concentrated. The residue was purified by flash chromatography with ethyl acetate/hexane to afford tert-butyl 1-[4-(2-oxo-pyrrolidin-1-yl)phenyl]cyclopropanecarboxylate.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2.[CH3:16]C1C=CC(S(O)(=O)=O)=CC=1.C(OC)(OC)OC.C([O-])(O)=O.[Na+]>CO.OS(O)(=O)=O>[OH:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)c1cc2cccc(O)c2cc1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: COC(=O)c1cc2cccc(O)c2cc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 4404.1 %

Procedure:
To a solution of 3,5-dihydroxy-2-naphthoic acid (5.05 g) in MeOH (100 mL) was added TsOH (93 mg). Tho reaction mixture was stirred at reflux for 18 hours and then CH(OMe)3 (1 mL) was added. The reaction mixture was stirred at reflux for an additional 5 hours, at which point H2SO4 (10 drops) was added. After an additional 18 h, the reaction mixture was cooled to rt, poured into saturated aqueous NaHCO3 and extracted with EtOAc. The extract was dried over MgSO4 and concentrated in vacuo to give the title compound as a yellow-white solid (5.19 g, 96%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:33]1([CH2:39][CH2:40]O)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Br:1][C:2]1[C:3]([O:13][CH2:40][CH2:39][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c(C)c(Br)c1OCCN1CCOCC1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 30.6 %

Procedure:
A solution of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (34 mg, 0.13 mmol), triphenylphosphine (47 mg, 0.18 mmol), and 4-morpholineethanol (23 μL, 0.19 mmol) in tetrahydrofuran (0.38 mL, 4.6 mmol) at −10° C. was treated with diisopropyl azodicarboxylate (35 μL, 0.18 mmol) dropwise and stirred at −10° C. for 15 min and warmed to 20° C. for 30 minutes. The reaction mixture was concentrated, diluted with ethyl acetate (5 mL), and washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to a crude oil. Purification by flash column chromatography using ethyl acetate in hexanes (0%-60%) gave the desired product (15 mg, 31%). LCMS for C15H20BrClNO3 (M+H)+: m/z=376.0, 378.0. Found: 375.9, 378.0.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:13][CH:14]1OC(C)OC(C)O1>>[CH3:12][C:4]1[NH:3][C:2]([CH3:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]=1[CH2:13][CH3:14]
Reactant: CC1OC(C)OC(C)O1
Reactant: CCOC(=O)c1cc(C)[nH]c1C
Product: CCOC(=O)c1c(C)[nH]c(C)c1CC

Procedure:
As in Example 32 but using 2,5-dimethyl-3-carbethoxy-pyrrole and paraldehyde. Colourless crystals (75%), m.p. 105°-107° (lit18) 106°-107°). Anal. Calc. for C11H17NO2 : C, 67.66; H, 8.78; N, 7.17. Found: C, 67.54; H, 8.69; N, 7.28.