Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:11]=[C:12]([C:27](O)([CH3:29])[CH3:28])[C:13]2[O:17][C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)=[N:15][C:14]=2[CH:26]=1>O>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[O:17][C:13]3[C:12]([C:27]([CH3:29])=[CH2:28])=[CH:11][C:10]([OH:9])=[CH:26][C:14]=3[N:15]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(-c2nc3cc(OC)cc(C(C)(C)O)c3o2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C=C(C)c1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
Pyridine hydrochloride (400 mg) was heated to 190° C. To the melt was added 2-[5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole-7-yl]propan-2-ol (114 mg, 0.36 mmol) and the reaction was stirred for 2 h. The mixture was cooled to room temperature, dissolved in water and extracted with EtOAc. The organic layers were combined and washed with HCl (1N), water then brine and dried over MgSO4. Evaporation and purification by flash chromatography (50%-60% EtOAc/petroleum ether) gave (40 mg, 41% yield) of the product as a light red-brown solid, m.p. 225-228° C.; MS m/e 268 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]1C=CN[N:12]=1.[C:17]1([C:23]2[N:24]=CN[CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]1[NH:12][CH:27]=[C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]=1
Reactant: O=C(Cc1cc[nH]n1)c1ccc(Cl)cc1Cl
Reactant: c1ccc(-c2c[nH]cn2)cc1
Product: O=C(Cc1nc(-c2ccccc2)c[nH]1)c1ccc(Cl)cc1Cl

Procedure:
Made using the same procedure as for 1-(2,4-dichlorophenyl)-2-pyrazolylethan-1-one except that 4-phenylimidazole (6.5 g, 44.8 mmol) was used in place of pyrazole. The crude residue was purified on silica gel (50% EtOAc/hexanes) to yield a light yellow solid.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17]C)=[O:16])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>O.CO>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([OH:17])=[O:16])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(-c2cc(-c3ccccc3)on2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(-c2cc(-c3ccccc3)on2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A mixture of methyl 3-(5-phenyl-3-isoxazolyl)benzoate (1.30 g), 1 M aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (20 ml) and methanol (10 ml) was stirred at 60° C. for 1 hr. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid (10 ml) was added. The crystals were collected by filtration and recrystallized from tetrahydrofuran-hexane to give 3-(5-phenyl-3-isoxazolyl)benzoic acid (1.05 g, yield 85%) as colorless crystals. melting point: 250–251° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(=O)([O-])O.[Na+]>C(OCC)C>[CH3:20][S:21]([O:1][CH2:2][C@H:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1)(=[O:23])=[O:22]
Reactant: OC[C@@H]1COc2ccccc2O1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)OC[C@@H]1COc2ccccc2O1
Reaction time: 0.5 h

Procedure:
To a solution of 0.410 g (2.467 mM) of (R)-2-hydroxymethyl-1,4-benzodioxane and 0.52 ml (3.70 mM) of triethylamine in 30 ml of diethyl ether was added 0.21 ml (2.71 mM) of methanesulfonyl chloride dropwise with ice-cooling and the mixture was stirred for 0.5 hour. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 2 portions of ethyl acetate. The organic layers were combined and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was passed through a short silica gel column (hexane-ethyl acetate=3/1 to 2/1) to provide crude (S)-2-methanesulfonyloxymethyl-1,4-benzodioxane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1.Cl[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CC(C)([O-])C.[K+]>C1COCC1>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][C:8]=1[CH3:9]
Reactant: COc1ncc([N+](=O)[O-])cc1C
Reactant: CC(C)(C)OC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1nc(CC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A yellow solution of 2-methoxy-3-methyl-5-nitropyridine (68.8 g, 409 mmol) from Example 1 Part I and tert-butyl 2-chloroacetate (77.0 g, 511 mmol) in THF (1 L) was stirred and cooled to −20° C. in a dry ice/isopropanol bath. Potassium tert-butoxide (115 g, 1.02 mol) was added at a rate so that the reaction temperature was less than −10° C. The reaction mixture turned dark purple. When the addition was complete, the cooling bath was removed and the reaction was stirred for 30 min. The stirred reaction mixture was quenched with HCl (500 mL, 2.4 N). The purple solution turned pale yellow and the mixture separated into two layers. The organic layer was separated, washed three times with brine, and concentrated in vacuo. Hexane was added to the amber residue. The mixture was concentrated in vacuo and then dried under high vacuum for 1 hr to give tert-butyl 2-(6-methoxy-5-methyl-3-nitropyridin-2-yl)acetate (83.4 g, 72% yield) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 4.09 (s, 2H), 4.02 (s, 2H), 2.21 (s, 3H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.81, 163.63, 147.88, 139.41, 135.19, 120.82, 81.66, 54.69, 44.48, 28.03, 15.27. An analytical sample was recrystallized from hexane to give white needles, mp 71-72.5° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:15](OC1C=CC([N+]([O-])=O)=CC=1)=[O:16]>C(OCC)(=O)C.ClCCl>[CH:15]([N:8]1[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10][CH:9]1[C:11]([O:13][CH3:14])=[O:12])=[O:16]
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C1CC2(CCN1)OCCO2
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C1CC2(CCN1C=O)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24 g of methyl 1,4-dioxa-8-azaspiro[4.5]decane-9-carboxylate (111 mmol) are dissolved in 80 mL of ethyl acetate and 80 mL of dichloromethane. There are added 26 g of (4-nitrophenyl) formate (155 mmol), and the whole is stirred at ambient temperature for one hour. The reaction mixture is evaporated to dryness and taken up in ethyl acetate. The organic phase is subsequently washed in succession with a 1 N NaOH solution, water, and then with a saturated NH4Cl solution until a neutral pH is reached. It is subsequently dried over magnesium sulphate, filtered and concentrated to dryness. The oil so obtained is purified by flash chromatography (heptane/ethyl acetate gradient). The title product is obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O1CCCC1.[F:29][C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>C(N(CC)CC)C>[C:14]([O:13][C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([F:29])[CH:31]=3)(=[O:38])=[O:37])=[CH:10][CH:9]=2)[C:5]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:6]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccccc2)c2cc(N)ccc21
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1nc(-c2ccccc2)c2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Yield: 74.4 %

Procedure:
N-(N-tert-Butoxycarbonyl-3-phenyl-1H-indazol-5-yl)-3-fluorobenzenesulfonamide can be obtained as described in Example 1 from 0.4 g of 5-amino-N-tert-butoxycarbonyl-3-phenyl-1H-indazole, 15 ml of tetrahydrofuran, 0.36 ml of triethylamine and 0.27 g of 3-fluorobenzenesulfonyl chloride. 0.45 g of N-(N-tert-butoxycarbonyl-3-phenyl-1H-indazol-5-yl)-3-fluorobenzenesulfonamide is thus obtained in the form of an ochre solid melting at 100° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](O)=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([N:42]=C=NCCCN(C)C)C.CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([NH2:42])=[O:14])[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(COc2nn(Cc3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(Cc3ccccc3)cc2C(N)=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.2 %

Procedure:
A mixture of 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylic acid (0.25 g), 1-hydroxybenzotriazole ammonia complex (0.11 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.14 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carboxamide as colorless crystals (0.23 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 160-161° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:36]>C(Cl)Cl.CO.O1CCOCC1>[ClH:36].[CH:31]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[N:22]([CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[N:35]=[CH:34][C:17]=43)[CH:21]=2)=[N:30][CH:29]=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(C3CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(C3CCNCC3)cc1OCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A solution of 4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (58 mg, 0.12 mmol) in DCM (0.5 mL) and methanol (0.3 mL) was treated with 4M HCl in dioxane (0.8 mL) and the reaction mixture stirred at RT for 1.5 h before being concentrated in vacuo. The resultant residue was triturated with diethyl ether to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene hydrochloride (66 mg, 100%). LCMS RT=1.68 min, [M+H]+=380
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11](=O)[CH:12]=[CH2:13].[N:15]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:30]([C:27]3[CH:28]=[CH:29][C:24]([S:21]([N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)(=[O:23])=[O:22])=[CH:25][CH:26]=3)[C:11]([CH3:10])=[CH:12][CH:13]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1ccc(S(=O)(=O)N2CCCCC2)cc1
Reactant: C=CC(C)=O
Reactant: O=Cc1cccc(Cl)c1
Product: Cc1ccc(-c2cccc(Cl)c2)n1-c1ccc(S(=O)(=O)N2CCCCC2)cc1

Procedure:
3-Chlorobenzaldehyde and but-3-en-2-one were treated according to the procedure outlined in General Procedure C followed by subjecting the resulting product to conditions outlined in General Procedure D along with p-piperidinylsulfonyl phenylamine to obtain the titled compound. 1H NMR (CDCl3) δ ppm 1.42-1.65 (6H), 2.18 (3H), 3.00 (4H), 6.18 (1H), 6.40 (1H), 6.85-7.90 (8H); MS (ESI) m/z 415 (M+H).
Reaction SMILES: [F-:1].[K+].[F-].[Cs+].Cl[C:6]1[C:11]([F:12])=[CH:10][C:9]([Cl:13])=[CH:8][N:7]=1.CCOCC>S1(CCCC1)(=O)=O.C1OCCOCCOCCOCCOCCOC1>[Cl:13][C:9]1[CH:10]=[C:11]([F:12])[C:6]([F:1])=[N:7][CH:8]=1
Reactant: Fc1cc(Cl)cnc1Cl
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Agent: [K+]
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Product: Fc1cc(Cl)cnc1F
Temperature: 140 °C
Reaction time: 35 h
Yield: 88 %

Procedure:
64.6 g (1.11 mol) of potassium fluoride and 11.25 g (0.074 mol) of caesium fluoride are suspended in 240 ml of sulfolane and the suspension is heated to 140° C. 50 mol of sulfolane are distilled off by decreasing the pressure and then 61.4 g (0.37 mol) of 2,5-dichloro-3-fluoropyridine and 1.45 g (0.0055 mol) of 18-crown-6 in 20 ml of sulfolane are added to the suspension. This reaction mixture is stirred for 35 hours at 140° C. and then taken up in ice water. The product is isolated from the aqueous mixture either by extraction with ether or by steam distillation, affording 48.7 g (88% of theory) of 5-chloro-2,3-difluoropyridine, b.p. 65°-66° C. at 133 mbar.
Reaction SMILES: [C:1]1([OH:9])[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]([CH3:8])[CH:2]=1.[N+:10]([O-])([OH:12])=[O:11].C(OCC)(=O)C>C(O)(=O)C>[CH3:8][C:3]1[C:2]([N+:10]([O-:12])=[O:11])=[C:1]([OH:9])[CH:6]=[CH:5][C:4]=1[CH3:7]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)cc1C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(O)c([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 12.2 g of 3,4-xylenol in 100 ml of acetic acid was added a solution of 7.48 ml of 61% nitric acid in 50 ml of acetic acid while keeping the reaction temperature at 20° C. Then the mixture was reacted with stirring at room temperature for two hours. To the reaction mixture was added 200 ml of ethyl acetate and the mixture was washed successively with water, an aqueous solution of sodium hydrogencarbonate, water and a brine, and then, ethyl acetate was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent:chloroform] to give 0.69 g of 3,4-dimethyl-2-nitrophenol.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([C:33](Cl)=[O:34])[CH:29]=1>>[CH3:27][C:28]1[O:32][N:31]=[C:30]([C:33]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=2)=[O:34])[CH:29]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: Cc1cc(C(=O)Cl)no1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)c5cc(C)on5)c4)CC3)cccc2n1
Yield: 40 %

Procedure:
The title compound was prepared in 40% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 5-methyl-3-isoxazolecarbonyl chloride.
Reaction SMILES: C[C@@H:2]1[CH2:6][CH2:5][C:4](=[C:7]([CH3:9])C)[CH:3]1[C:10]([O:12][CH2:13]C)=[O:11].[CH2:15]=[O:16].[ClH:17]>CS(C)=O.C[O-].[Na+]>[Cl:17][C:2]1[CH:6]=[CH:5][C:4]([CH:3]([CH2:15][OH:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:9]=1
Reactant: C=O
Reactant: CCOC(=O)C1C(=C(C)C)CC[C@H]1C
Reactant: Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A stirring solution of methyl 2-(4-chlorophenyl)acetate (36.7 g, 199 mmol) (From Example 1, Step 1) and paraformaldehyde (6.27 g, 209 mmol) in DMSO (400 mL) was treated with sodium methoxide (537 mg, 9.94 mmol) at room temperature. The mixture was allowed to stir for two hours to completion and then poured into ice-cold water (700 mL) forming a white emulsion. The quench was neutralized with the addition of 1M HCl solution, and the aqueous was extracted with ethyl acetate (3×). The combined organic portions were washed with water (2×), then brine, dried over MgSO4, and concentrated in vacuo. The residue was filtered through a plug of silica gel eluted stepwise with 9:1 to 1:1 hexanes:ethyl acetate to afford the pure methyl 2-(4-chlorophenyl)-3-hydroxypropanoate (39.4 g, 92%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.32 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 4.10 (m, 1H), 3.82 (m, 2H), 3.72 (s, 3H), 2.25 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][CH:11]=[C:12]3[CH:16]=[C:15]([CH3:17])[NH:14][C:13]=23)=[CH:4][CH:3]=1.CNC.[C:21]([OH:24])(=O)[CH3:22].[CH2:25]=O>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][CH:11]=[C:12]3[C:16]([CH2:25][O:24][CH2:21][CH3:22])=[C:15]([CH3:17])[NH:14][C:13]=23)=[CH:6][CH:7]=1
Reactant: Cc1cc2ccnc(-c3ccc(Cl)cc3)c2[nH]1
Reactant: C=O
Reactant: CC(=O)O
Agent: CNC
Solvent: CCO
Product: CCOCc1c(C)[nH]c2c(-c3ccc(Cl)cc3)nccc12

Procedure:
A solution of 7-(4-chlorophenyl)-2-methyl-1H-pyrrolo[2,3-c]pyridine (170 mg, 0.07 mmol) prepared in Example 463, dimethylamine (2.0M tetrahydrofuran solution; 375 μl, 0.75 mmol), acetic acid (0.36 ml) and formaldehyde (0.68 ml) in ethanol (10 ml) was refluxed for 60 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with a sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v) to give 85 mg of the titled compound as a white solid.
Reaction SMILES: [C:1]([CH2:6][C:7]1[O:8][C:9]([SH:12])=[N:10][N:11]=1)([O:3]CC)=[O:2].[OH-].[Na+]>O.C(O)C>[C:1]([CH2:6][C:7]1[O:8][C:9]([SH:12])=[N:10][N:11]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)Cc1nnc(S)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1nnc(S)o1

Procedure:
A solution of 3.15 g (0.017 mol) of 2-carbethoxymethyl-1,3,4-oxadiazole-5-thiol in 25 ml of water and 25 ml of ethanol was stirred for 5 hours while maintaining the pH at 10-11 by addition of 10% aqueous sodium hydroxide solution. The mixture was neutralized to pH 7.0 then evaporated to dryness. The residue was dissolved in 15 ml of water, 50 ml of ethyl acetate was added and the solution was acidified to pH 1.5 with 3N hydrochloric acid. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined extracts were dried (Na2SO4) and the solvent was evaporated to give a residue which was recrystallized from ether-cyclohexane to give 2-carboxymethyl-1,3,4-oxadiazole-5-thiol, m.p. 167°-169° (dec.)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][C:17]([CH2:26][C:27](OCC)=[O:28])([CH2:20][C:21](OCC)=[O:22])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][C:17]([CH2:20][CH2:21][OH:22])([CH2:26][CH2:27][OH:28])[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CC1(CC(=O)OCC)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1(CCO)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To an ice-cooled solution of lithium aluminum hydride (0.76 g) in tetrahydrofuran (120 mL) was added a solution of diethyl 1-benzylpiperidine-4,4-diacetate (3.47 g) in tetrahydrofuran (10 mL) dropwise. The ice bath was removed and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was again ice-cooled, to which water (0.76 mL), a 15% aqueous sodium hydroxide solution (0.76 mL) and water (2.28 mL) were added successively. The substance thus separated out was filtered off with Celite. The filtrate was concentrated under reduced pressure to give the title compound (ca. 2.63 g). This product was subjected to the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:4].[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:34].C(S(O)(=O)=O)(F)(F)F>ClCCl>[F:16][C:2]([F:1])([F:15])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[I:34])=[O:4]
Reactant: [IH2+]
Reactant: O=C(NCCc1ccc(Cl)cc1)C(F)(F)F
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCCc1ccc(Cl)cc1I)C(F)(F)F
Reaction time: 8 h
Yield: 38.9 %

Procedure:
A solution of N-trifluoroacetyl-4-chlorophenethylamine (1.6 g, 6.4 mmol) in dichloromethane (20 mL) was treated with bis(pyridine)iodonium(I)tetrafluoroborate (2.6 g, 7.0 mmol), CF3SO3H (2.1 g, 14.1 mmol) and stirred overnight at 20 C. The product mixture was concentrated, dissolved in EtOAc (100 mL), washed twice with 5% aqueous sodium bisulfite (50 mL), twice with saturated aqueous NaHCO3, (50 mL) once with brine (50 mL), dried with Na2SO4 and concentrated to give 0.94 g of a clear oil. MS calculated for C10H8ClF3INO+H: 378, observed: 378.
Reaction SMILES: [I:1][CH:2]([O:5][C:6](=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14]C(=O)C)=[CH:10][CH:9]=1)[C:3]#[CH:4].C(N)CCC.C(OCC)C.Cl>O1CCOCC1>[I:1][CH:2]([O:5][C:6](=[O:18])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[C:3]#[CH:4]
Reactant: C#CC(I)OC(=O)Cc1ccc(OC(C)=O)cc1
Agent: Cl
Solvent: CCCCN
Solvent: CCOCC
Solvent: C1COCCO1
Product: C#CC(I)OC(=O)Cc1ccc(O)cc1

Procedure:
At room temperature, 15 g (0.042 mole) of 4-acetoxyphenylacetic acid iodopropargyl ester (prepared according to B) and 3.1 g (0.042 mole) of n-butylamine was stirred in 15 ml dioxan for 18 hours. The reaction mixture was distributed between diethyl ether and 1N aqueous hydrochloric acid, the ether phase was dried over sodium sulfate and the solvent mixture was distilled off. Ray yield: 14.4 g. After chromatography on silica gel with trichloromethane/petroleum ether (4:1 parts by volume) as the eluent, 8.2 g (62% of the theoretical amount) 4-hydroxyphenylacetic acid iodopropargyl ester (m.p. 73°-77° C.) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([Cl:14])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)ccc1Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 5-bromo-2-chloro-benzoic acid 15a (7.24 g, 30.8 mmol) in toluene (100 mL) were added thionyl chloride (3.6 mL, 49.2 mmol) and N,N-dimethylformamide (0.2 mL, 2.6 mmol) in turn at 0° C. The mixture was warmed up to 100° C. and stirred for 4 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give the title compound 21d as yellow oil (7.82 g, 100%). This material was not further purified.
Reaction SMILES: [Mg].BrC.Cl[CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.CN(C)[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1>[O:8]1[CH2:9][CH2:10][CH:5]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C=CN(C)C
Reactant: ClC1CCOCC1
Agent: CBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)C=CC1CCOCC1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
9.6 g (400 mmol) of magnesium turnings are covered with tetrahydrofuran, about 2 ml of bromomethane are added, and the mixture is warmed to reflux. 38.45 g (300 mmol) of 4-chlorotetrahydropyran, dissolved in 100 ml of tetrahydrofuran, are added dropwise. The mixture is subsequently stirred for a further 30 minutes and cooled to 10° C., 42.9 g (300 mmol) of ethyl 1-(dimethylamino)eth-1-ene-2-carboxylate are added dropwise, and the mixture is stirred for a further 12 hours. Customary work-up gives 31.4 g (60%) of ethyl 1-(4-tetrahydropyranyl)eth-1-ene-2-carboxylate of boiling point 120° to 140° C./10 mmHg.