Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[CH2:13][CH2:12][N:11]([C:14]3[CH:26]=[CH:25][C:17]([CH2:18][NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[C:16]([C:27]([F:30])([F:29])[F:28])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N+]([O-])([O-])=[O:37].[NH4+].[Ce].COC(C)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:35])=[C:4]([C:9]2([C:31]([F:34])([F:32])[F:33])[CH2:13][CH2:12][N:11]([C:14]3[CH:26]=[CH:25][C:17]([CH2:18][NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[C:16]([C:27]([F:28])([F:29])[F:30])[CH:15]=3)[CH:10]2[OH:37])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3F)(C(F)(F)F)C2)cc1C(F)(F)F)C1CC1
Reactant: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3F)(C(F)(F)F)C2O)cc1C(F)(F)F)C1CC1

Procedure:
N-{4-[3-(3,5-dichloro-2-fluorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-(trifluoro-methyl)benzyl}cyclopropanecarboxamide (0.18 g) was dissolved in N,N-dimethylformamide (5 ml), cooled by using an ice bath, and then stirred. To the solution, a 1 M aqueous solution of cerium ammonium nitrate (IV) (0.72 ml) was added dropwise and stirred in an ice bath for 2 minutes. After that, t-butyl methyl ether was added for dilution and the organic layer was washed with water, an aqueous solution of sodium thiosulfate and saturated brine in that order. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure, and the residue obtained was purified by column chromatography to obtain N-{4-[3-(3,5-dichloro-2-fluorophenyl)-2-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]-2-(trifluoromethyl)benzyl}cyclopropanecarboxamide (0.08 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Br:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[F:16])[NH2:12].C(N(CC)CC)C>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]([NH:12][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1ccc(F)c(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCl)Nc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
A solution of 4-chlorobutanoyl chloride (4.12 mL, 36.84 mmol) in DCM (50 mL) was added over 15 mins to an ice-cooled solution of 3-bromo-4-fluoro-aniline (7 g, 36.84 mmol) and triethylamine (5.12 mL, 36.84 mmol) in DCM (100 mL) under N2. After addition was complete the cooling bath was removed and the solution stirred at ambient temp for 4 h. The reaction solution was washed with water (2×150 ml) dried (MgSO4) and concentrated to a white solid, which was dried at RT under vacuum overnight to give N-(3-bromo-4-fluoro-phenyl)-4-chloro-butanamide (D57) (9.04 g);
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]=O>C(O)=O>[CH2:1]([O:8][N:9]=[C:10]([CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CON=C(c2ccccc2)C2CCCN2)cc1
Reactant: C=O
Solvent: O=CO
Product: CN1CCCC1C(=NOCc1ccccc1)c1ccccc1

Procedure:
1.2 g (4.28 mmol) of phenyl(2-pyrrolidinyl)methanone O-benzyloxime in 4 ml of a mixture (1/1) of formic acid and aqueous 37% formaldehyde are introduced into a 50 ml round-bottomed flask equipped with a magnetic stirrer, and the mixture is refluxed for 16 hours.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:24])=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]2[CH:23]=[CH:22][N:21]=[N:20]2)[N:14]=1)=O)C.[NH3:25]>CO>[Cl:24][C:9]1[N:8]=[N:7][C:6]([C:4]([NH2:25])=[O:3])=[C:11]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)[N:14]=2)[CH:10]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(-n2ccnn2)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1nnc(Cl)cc1Nc1cccc(-n2ccnn2)n1
Reaction time: 4 h
Yield: 100 %

Procedure:
6-Chloro-4-(6-[1,2,3]triazol-1-yl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid ethyl ester (48 mg, 0.139 mmol) was suspended in 7M ammonia in methanol (23 mL). After 4 h, the reaction mixture was concentrated in vacuo to give 6-chloro-4-(6-[1,2,3]triazol-1-yl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (44 mg, 100%) as an off-white solid which was used directly in the next step without purification. MS (EI/CI) m/z: 317 [M+H].
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: NCc1ccccc1
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1NCc1ccccc1

Procedure:
5-Benzylamino-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and benzylamine. Mass spectrum (ES) MH+=427.
Reaction SMILES: C12[N:8]([C:9]3C=N[C:16]4[C:11](=CC=[CH:14][CH:15]=4)[N:10]=3)CC1CCNC2.[C@@H:19]12[NH:26][CH2:25][C@@H:24]1[CH2:23][CH2:22][N:21]([C:27]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:28])[CH2:20]2.ClC1C=C(C)N=CN=1>>[F:35][C:33]1[CH:32]=[CH:31][C:30]([N:36]2[N:40]=[CH:39][CH:38]=[N:37]2)=[C:29]([C:27]([N:21]2[CH2:22][CH2:23][C@@H:24]3[C@@H:19]([N:26]([C:11]4[CH:16]=[C:15]([CH3:14])[N:8]=[CH:9][N:10]=4)[CH2:25]3)[CH2:20]2)=[O:28])[CH:34]=1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN[C@H]2C1
Agent: Cc1cc(Cl)ncn1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)ncn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using (1R,6S)-3,8-diazabicyclo[4.2.0]octan-3-yl(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 4-chloro-6-methylpyrimidine. MS (ESI) mass calcd. for C20H20FN7O, 393.4; m/z found, 394.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:17](O)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:22]=1[NH2:23].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:17](=[O:18])[NH:23][C:22]1[C:21]([F:20])=[CH:27][CH:26]=[CH:25][C:24]=1[F:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2[C@H]1C(=O)O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1Cc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
To the solution of (S)-2-(tert-butoxycarbonyl)isoindoline-1-carboxylic acid (300 mg, 1.14 mmol, Eq: 1.00) and 2,6-difluoroaniline (177 mg, 1.37 mmol, Eq: 1.2) in pyridine (3.00 mL) at 0° C. was added POCl3 (262 mg, 159 μL, 1.71 mmol, Eq: 1.5). The mixture was warmed to RT and stirred for 2 h. The mixture was evaporated, water was added and the mixture extracted with EtOAc. The combined organics were washed with water, brine, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography to give (S)-1-(2,6-difluoro-phenylcarbamoyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (298 mg) as a light yellow foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:13]3[NH:12][CH2:11][C@@H:10]4[CH2:16][C@H:17]([N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH2:18][C:8]=2[C:9]=34)[CH:2]=1.N1C2C(=CC=CC=2)C=C1.C1([Se](O[Se](C2C=CC=CC=2)=O)=O)C=CC=CC=1>C1COCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[CH2:16][C@H:17]([N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH2:18][C:8]=2[C:9]=34)[CH:2]=1
Reactant: CCCN(CCC)[C@@H]1Cc2c(-c3cccnc3)ccc3c2[C@H](CN3)C1
Agent: O=[Se](O[Se](=O)c1ccccc1)c1ccccc1
Agent: c1ccc2[nH]ccc2c1
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(-c4cccnc4)c(c23)C1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
A solution of 1.0 g (2.99 mmol) of (2aR,4S)-6-(3-pyridyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole and 1.0 g (9 mmol) of indole in 50 ml of THF was treated at 0° C. with 0.61 g (1.70 mmol) of benzeneseleninic anhydride. The resulting solution was allowed to warm to room temperature. After 2 hours the reaction solution was diluted with water and the product was extracted into methylene chloride. The methylene chloride was evaporated and the resulting residue was taken up in aqueous tartaric acid. This acidic solution was washed with methylene chloride, then basified with 5M sodium hydroxide solution. The product was extracted into methylene chloride. After evaporating the methylene chloride the product was chromatographed over 25 g of silica gel using 10% ethyl acetate in toluene followed by 1:1 ethyl acetate/toluene as eluent. The material from the column was crystallized from toluene/hexane to afford 0.53 g of title compound. m.p. 185°-186° C. MS (FD) 334 [α]D -52.0° (MeOH)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.Cl[C:27](Cl)([O:29][C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.[CH:38]1(O)[CH2:43][CH2:42]C[CH2:40][CH2:39]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30](=[O:36])[O:29][CH:27]2[CH2:42][CH2:43][CH2:38][CH2:39][CH2:40]2)=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCCC4)c([N+](=O)[O-])c3)c2cc1OC
Yield: 87.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cyclohexanol (44 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (120 mg, yield 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[C:11]1([C:17]2[O:21][N:20]=[CH:19][C:18]=2[CH2:22][CH2:23][C:24](O)=[O:25])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:24](=[O:25])[CH2:23][CH2:22][C:18]2[CH:19]=[N:20][O:21][C:17]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:3][CH:4]=1)(=[O:7])[NH2:8]
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: NC(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(NC(=O)CCc2cnoc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
A mixture of 4-aminobenzamide (0.55 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.87 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.68 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.88 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-carbamoylphenyl)-3-(5-phenyl-4-isoxazolyl)propionamide (0.95 g, yield 71%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 250–251° C.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[S-2:12].[Na+].[Na+]>C(O)C.O>[NH2:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[SH:12]
Reactant: [S-2]
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc([N+](=O)[O-])ccc1S

Procedure:
To a stirred solution of 172.6 g (1 mole) of 2-chloro-5-nitroaniline in boiling ethanol/water (5:2) is added a solution of sodium sulfide (generated from sodium sulfide nonahydrate and sodium bicarbonate), and the reaction is heated at reflux for one hour. The mixture then is cooled in ice, and the resulting crystalline product is collected by filtration and recrystallized from water.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)=[N:7][C:8]=2[NH:9][C:10](=[O:12])[CH:11]=1.Cl.[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:6]2[N:7]=[C:8]3[C:3]([C:2]([CH3:1])=[CH:11][C:10](=[O:12])[NH:9]3)=[CH:4][CH:5]=2)[CH2:30][CH2:29]1
Reactant: Cc1cc(=O)[nH]c2nc(OCCCC=O)ccc12
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cc(=O)[nH]c2nc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
The crude 4-(5-methyl-7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde from the previous reaction in 1,2-dichloroethane (30 mL) is treated with 1-(2,3-dichlorophenyl)piperazine monohydrochloride (1.144 g, 4.20 mmol), followed by triethylamine (0.90 mL, 6.46 mmol) and sodium triacetoxyborohydride (0.955 g, 4.50 mmol). The cloudy yellow solution is stirred at room temperature for 1 hour. The mixture is quenched with H2O and saturated NaHCO3 solution and extracted with CH2Cl2. The organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to a yellow oil. The oil is purified by column chromatography (5:95 methano/vethyl acetate) to afford the title compound (0.97 g, 63% over 2 steps) as a white solid. mp 181–182° C. 1H NMR (CDCl3, 400 MHz): δ 7.57 (br s, 1H), 7.40 (d, 1H), 7.18–7.12 (m, 2H), 7.00–6.94 (m, 1H), 6.38 (d, 1H), 4.23 (t, 2H), 3.16–3.00 (m, 5H), 2.77–2.68 (m, 4H), 2.75–2.56 (m, 1H), 2.52–2.36 (m, 3H), 1.86–1.75 (m, 2H), 1.75–1.64 (m, 2H), 1.28 (d, 3H). MS ES: m/z=460.70, 462.58.
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:26](Cl)(=[O:29])[CH:27]=[CH2:28].Cl>C(N(CC)CC)C.C1(C)C=CC=CC=1>[C:26]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:29])[CH:27]=[CH2:28]
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)Oc1c(Cc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a 500-ml four-necked flask equipped with a thermometer, stirring apparatus, condenser and dropping funnel were added 82.0 g (0.241 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 200 g of toluene and 23.9 g (0.290 mole) of triethylamine. After replacing the air in the container with nitrogen, 25 g (0.276 mole) of acryloyl chloride was added dropwise with stirring. After completion of the dropwise addition, stirring was continued for 1 hour, excess triethylamine was neutralized with a dilute hydrochloric acid and the formed triethylamine hydrochloride was then removed by washing with water. Toluene was then removed by evaporation from the toluene layer after completion of the washing, and the residue obtained was recrystallized from 20 g of n-hexane to obtain 90.0 g of 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monoacrylate as a white crystal. Melting point, 132°-134° C. Yield, 95%.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:24])=[C:9]([CH2:19][C:20]([O:22]C)=[O:21])[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[S:5][C:4]=1[CH3:25])[CH3:2].[O-2].[Li+].[Li+].Cl>O1CCOCC1.O>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:24])=[C:9]([CH2:19][C:20]([OH:22])=[O:21])[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[S:5][C:4]=1[CH3:25])[CH3:2]
Reactant: CCc1c(C)sc2nc(C)c(CC(=O)OC)c(-c3ccc(C)cc3)c12
Agent: Cl
Agent: [Li+]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O
Product: CCc1c(C)sc2nc(C)c(CC(=O)O)c(-c3ccc(C)cc3)c12
Temperature: 60 °C
Yield: 64.9 %

Procedure:
To a solution of methyl 2-(3-ethyl-2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.045 g; 0.127 mmol) in dioxane (3 mL) and water (0.8 mL) was added a 1N lithium oxide solution (0.8 mL; 0.80 mmol). The reaction mixture was heated at 60° C. for 2 h. After cooling to room temperature, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.028 g (65%) of the title compound as a beige solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28](C)([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:32])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(C1C=CC(N2C=CC(OC3CCN(C(OC(C)(C)C)=O)CC3)=CC2=O)=CC=1)(=O)=O>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][CH:28]([CH3:29])[CH3:30])=[O:26])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:32])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Product: CC(C)OC(=O)N1CCCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1

Procedure:
Example 7 was prepared according to procedures described in Example 3 substituting tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)azepane-1-carboxylate for tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate. 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J=8.80 Hz, 2 H), 7.61 (d, J=8.80 Hz, 2 H), 7.29 (d, J=7.70 Hz, 1 H), 6.22 (s, 1 H), 6.17 (d, J=7.70 Hz, 1 H), 4.90-5.02 (m, 1 H), 4.48-4.56 (m, 1H), 3.36-3.63 (m, 4 H), 3.11 (s, 3 H), 1.91-2.17 (m, 5 H), 1.64-1.77 (m, 1H), 1.27 (d, J=6.05 Hz, 6 H). MS (ESI) 449 (M+H).
Reaction SMILES: [C:1]1([CH3:7])C=CC=CC=1.[Na].[Si:9](Cl)([CH3:12])([CH3:11])[CH3:10].Cl>COCCOCCOC.O>[Si:9]([CH2:7][CH:1]([Si:9]([CH3:12])([CH3:11])[CH3:10])[Si:9]([CH3:12])([CH3:11])[CH3:10])([CH3:12])([CH3:11])[CH3:10]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: COCCOCCOC
Product: C[Si](C)(C)CC([Si](C)(C)C)[Si](C)(C)C
Temperature: 115 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
In a 500 ml three-necked standard taper joint round-bottomed flask were combined 12.2 g (0.53 mol) of Na metal chunks and 201.8 g of anhydrous diglyme. Flask was fitted with an electric heating mantle, mechanical stirrer (stainless steel blade), addition funnel, Dewar condenser (containing toluene cooled by immersion coil through which ice water was circulated), thermometer, and valves to maintain an inert atmosphere (nitrogen). Heat was applied, melting the sodium, and addition of a mixture of 54.8 g (0.5 mol) of Me3SiCl and 24.3 g (0.24 mol) of CH2 =CHSiMe3 begun at 115°, and continued, with continuous heating, at a rate which maintained the reflux temperature above 98°. Heating at reflux (115° C.) continued for 8 hr, and standing at room temperature for 32 hr, followed by termination by slow addition of a solution of 16.0 g H2O in 57.7 g diglyme and neutralization with 5 g conc HCl in 26.8 g diglyme. Salts were removed by filtration, and the organic layer vacuum distilled, yielding 4.65 g (7.9%) of Me3SiCH2CH(SiMe3)2, identified by VPC/NMR, plus 39.6% of Me3SiOSiMe3 and 6.2% of Me3SiSiMe3.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([OH:18])[CH:17]=1>>[Cl:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([O:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:17]=1
Reactant: Oc1cncc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(Oc2cncc(Cl)c2)cc1
Yield: 87.6 %

Procedure:
4-Fluoro-nitrobenzene (5.0 g) and 3-chloro-5-hydroxypyridine (4.59 g) were combined at 60° C. using a method similar to that of Example 21.2 to provide 7.78 g of 4-(3-chloro-5-pyridyloxy)nitrobenzene. mp 80-82° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:17].[C:18]([N:23]=[C:24](OCC)[CH2:25][CH2:26][CH2:27][CH3:28])(OCC)=[O:19]>>[ClH:17].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][NH2:16])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:18](=[O:19])[NH:23][C:24]([CH2:25][CH2:26][CH2:27][CH3:28])=[N:16]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(=NC(=O)OCC)OCC
Agent: Cl
Agent: NNc1ccc(OCc2ccccc2)cc1
Product: CCCCc1nn(-c2ccc(OCc3ccccc3)cc2)c(=O)[nH]1
Yield: 9 %

Procedure:
By the procedure of Example 4, Step C, p-(benzyloxy)phenylhydrazine [generated from the hydrochloride by partitioning between ether and 1N Na2CO3. The p-(benzyloxy)phenylhydrazine hydrochloride was prepared from the corresponding aniline according to H. Stroh and G. Westphal, Chem. Ber., 96, 184 (1963)] was reacted with ethyl N-carbethoxyvalerimidate (from Example 4, Step B). After work-up, the residue was purified by flash chromatography on silica gel to give a 9% yield of the desired compound, homogeneous by TLC in 19.1 CH2Cl2 /CH3OH; mass spectrum (FAB) m/e 324 (M+1)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:10]=[CH:11][C@H:12]([C@@H:14]([C@@H:16]([C@H:18]([CH3:20])[OH:19])[OH:17])[OH:15])[OH:13]>N1C=CC=CC=1>[CH3:20][C@@H:18]1[O:19][CH:11]([O:10][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[C@@H:12]([O:13][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:14]([O:15][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[C@H:16]1[O:17][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Solvent: c1ccncc1
Product: C[C@@H]1OC(OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)C(OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzoyl chloride (21.4 g, 152.3 mmol; 17.7 mL) was added dropwise to a cooled solution of L-fucose (5.0 g, 30.5 mmol) in pyridine (100 mL), at 0-5° C., and the mixture was stirred for three hours at room temperature. The mixture was poured onto ice water and extracted with ethyl acetate (EtOAc). The extracts were successively washed with ice cold dilute HCl aqueous NaHCO3, and brine, dried over anhydrous MgSO4, and concentrated. The product was used for the next step without further purification.