Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[O:19][CH2:18][CH:17]([OH:20])[CH2:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[O:19][CH2:18][C:17](=[O:20])[CH2:16]2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(C2CC(O)CO2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCCCCc1ccc(C2CC(=O)CO2)cc1
Reaction time: 16 h
Yield: 84.5 %

Procedure:
5-(4-octylphenyl)tetrahydrofuran-3-ol (1 g, 3.62 mmol) was dissolved in dichloromethane (36.2 ml) in a sealed vial. PCC (3.12 g, 14.47 mmol) (Aldrich) was added and the reaction stirred for about 16 h. The methylene chloride was evaporated and the residue stirred with ethyl acetate. The ethyl acetate was filtered through a pad of silica gel (approx. 50 mL silica) and product eluted with ethyl acetate. This removed most of the brown color. Concentrate and then chromatograph on a 40 g redi-sep column with 20-50% ethyl acetate in heptane. Remove solvent under reduced pressure to provide 5-(4-octylphenyl)dihydrofuran-3(2H)-one (0.839 g, 3.06 mmol, 85% yield) as a colorless oil: LC/MS (method A) Rt=4.14 min.; MS m/z: 275.25 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([N:8]=[C:9]=[O:10])([CH3:7])([CH3:6])[CH3:5].[Cl-].[Na+]>C(O)C>[C:4]([NH:8][C:9](=[O:10])[NH:2][NH2:3])([CH3:7])([CH3:6])[CH3:5]
Reactant: NN
Reactant: CC(C)(C)N=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NC(=O)NN
Reaction time: 1 h

Procedure:
To a solution of 30 g of hydrazine hydrate (80%) in 100 ml of ethanol was added dropwise 34 ml of t-butyl isocyanate under ice-cooling, followed by stirring for 1 hour. After stirring at room temperature for an additional 3 hours, a saturated aqueous solution of sodium chloride was added to the reaction solution. The mixture was extracted three ,times with ethyl acetate, and the organic layer was distilled under reduced pressure. To the residue was added 65 ml of a 10% hydrochloric acid aqueous solution. After washing with chloroform, 16 ml of a 50% aqueous solution of sodium hydroxide was added thereto, and sodium chloride was further added thereto The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. Recrystallization of the residue from n-hexane/ethyl acetate (9:1 by volume) to obtain 36 g of 4-t-butylsemicarbazide (melting point:109 -110 ° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:4]2([NH:8][C:7](=[O:9])[NH:6][C:5]2=[O:10])[CH2:3]1.O1CC1C[O:21][CH:22]1[CH2:27][CH2:26][CH:25]([C:28]([CH:31]2[CH2:36][CH2:35][CH:34]([O:37][CH2:38][CH:39]3[O:41][CH2:40]3)[CH2:33][CH2:32]2)([CH3:30])[CH3:29])[CH2:24][CH2:23]1>>[OH:21][CH:22]([CH2:27][N:6]1[C:5](=[O:10])[C:4]2([CH2:3][C:2]([CH3:17])([CH3:1])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9])[CH2:23][O:21][CH:22]1[CH2:27][CH2:26][CH:25]([C:28]([CH:31]2[CH2:32][CH2:33][CH:34]([O:37][CH2:38][CH:39]([OH:41])[CH2:40][N:6]3[C:5](=[O:10])[C:4]4([CH2:3][C:2]([CH3:17])([CH3:1])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]4)[NH:8][C:7]3=[O:9])[CH2:35][CH2:36]2)([CH3:30])[CH3:29])[CH2:24][CH2:23]1
Reactant: CN1C(C)(C)CC2(CC1(C)C)NC(=O)NC2=O
Reactant: CC(C)(C1CCC(OCC2CO2)CC1)C1CCC(OCC2CO2)CC1
Product: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC(O)COC1CCC(C(C)(C)C3CCC(OCC(O)CN4C(=O)NC5(CC(C)(C)N(C)C(C)(C)C5)C4=O)CC3)CC1)C2=O

Procedure:
A mixture of 8 g of 7,7,8,9,9-pentamethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione and 5 g of 2,2-bis[4-(2,3-epoxypropoxy)cyclohexyl]propane was heated at 180°-200° C. for 5 hours. The reaction mixture was then purified by column chromatography through silica gel eluted with a 60:10:1 by volume mixture of ethyl acetate, ethanol and triethylamine and then by recrystallisation from ethyl acetate, giving the desired compound in the form of white crystals melting at 130°-133° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc(-c2ccccc2F)nc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 94.4 %

Procedure:
A mixture of 6-Chloro-nicotinonitrile (7.26 g, 52.4 mmol) and 2-fluorophenyl boronic acid (11 g, 78.6 mmol) and Na2CO3 (11 g, 103 mmol) in toluene (200 mL) and water (10 mL) is degassed and filled with nitrogen for three times, then Pd(PPh3)4 (0.73 g) is added under nitrogen. The reaction mixture is heated at 90° C. After 12 hrs, the reaction mixture is cooled to room temperature, diluted with ethyl acetate, washed with water, dried, concentrated. Column chromatography on silica gel (Hexane/ethyl acetate as eluent) gave 9.8 g of 6-(2-Fluoro-phenyl)-nicotinonitrile.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH2:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[CH:23]1([CH2:26][O:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[CH2:25][CH2:24]1>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH:21][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH:23]2[CH2:24][CH2:25]2)=[CH:36][CH:35]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:18]([F:19])[F:20])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(OC(F)F)cc1
Reactant: O=C(O)c1ccc(OCC2CC2)cc1
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(OC(F)F)cc1)NC(=O)c1ccc(OCC2CC2)cc1

Procedure:
A reaction similar to that described in Example 50 was conducted using 2-({(2S)-2-amino-3-[4-(difluoromethoxy)phenyl]propanoyl}amino)ethyl acetate and 4-(cyclopropylmethoxy)benzoic acid prepared in Example 18 (18a) to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1.[N-:13]=[N+:14]=[N-:15].[Na+].ClCCl>CN(C)C=O>[N:13]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1)=[N+:14]=[N-:15]
Reactant: CC(C)(O)c1cccc(CBr)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(O)c1cccc(CN=[N+]=[N-])n1

Procedure:
2-Bromomethyl-6-(1-hydroxy-1-methylethyl)pyridine (7.61 g, 33 mmol) was dissolved in dimethylformamide (100 mL) and sodium azide (2.6 g, 39.7 mmol) added. After stirring the resultant mixture overnight at ambient temperature, the reaction was poured into dichloromethane and washed well with water. The organic layer was dried (magnesium sulphate), filtered and concentrated to dryness. The resulting yellow oil (5.88 g, 93%) was used without further purification; NMR δH (400 MHz, CDCl3) 7.70 (1H, t, J 7.8 Hz), 7.30 (1H, d, J 8.0 Hz), 7.19 (1H, d, J 7.8 Hz), 4.82 (1H, br s), 4.42 (2H, s), 1.51 (6H, s); LC-MS Retention time 2.06 min, (M+H)+ 193.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([F:17])[C:11](S(=S)(O)=O)=[N:12][C:5]=2[N:4]([CH:18]2[CH2:20][CH2:19]2)[C:3]1=[O:21].[C:22]([O:26][C:27](=[O:36])[NH:28][C@@H:29]([C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)[CH3:30])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(#N)C>[C:22]([O:26][C:27](=[O:36])[NH:28][C@H:29]([C@@H:31]1[CH2:35][CH2:34][N:33]([C:11]2[C:10]([F:17])=[CH:9][C:6]3[C:7](=[O:8])[N:2]([NH2:1])[C:3](=[O:21])[N:4]([CH:18]4[CH2:20][CH2:19]4)[C:5]=3[N:12]=2)[CH2:32]1)[CH3:30])([CH3:23])([CH3:24])[CH3:25]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@H]1CCNC1
Reactant: Nn1c(=O)c2cc(F)c(S(=O)(O)=S)nc2n(C2CC2)c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CCN(c2nc3c(cc2F)c(=O)n(N)c(=O)n3C2CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.7 %

Procedure:
A solution of 0.12 g (0.38 mmol) of 3-amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidine-7-thiosulfonic acid (Compound 24c) in 10 mL of acetonitrile is treated with 0.24 g (1.14 mmol) of ((R)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J. Het. Chem., 1992; 29:1481), 0.25 g (2.5 mmol) of triethylamine and stirred at room temperature for 18 hours then 50° C. for 1 hour. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate (50 mL) and water (25 mL). The organic layer is washed with water, dried (MgSO4), filtered and evaporated in vacuo to give 0.28 g. Chromatography on flash grade silica gel (230–400 mesh) column (2×12 cm) eluting with dichloromethane/ethanol (95:5) provided 0.1 g of the title compound, mp 175–177° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.[Br:19]N1C(=O)CCC1=O.Br>C(Cl)(Cl)(Cl)Cl>[Br:19][CH:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)[C:3]([O:2][CH3:1])=[O:18]
Reactant: COC(=O)Cc1ccc(Oc2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(Oc2ccccc2)cc1

Procedure:
A mixture of 22.68 g of methyl[p-(phenoxy)phenyl]acetate, 17.195 g of N-bromosuccinimide and 20 drops of carbon tetrachloride saturated with HBr in 300 ml of carbon tetrachloride is heated at reflux for 28 hours. After cooling, the mixture is filtered through aluminum oxide, concentrated and distilled at 0.15 mm to give the product as a colorless oil (bp 162.5°-165° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br.Br[CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Reactant: CCN(CC)CCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 90 °C

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.616 g) is dissolved in DMF (4 mL), and K2CO3 (0.93 g, 6.72 mmol) and 2-bromo-N,N-diethylethylamine hydrobromide (0.88 g, 3.35 mmol) are added. The reaction mixture is heated to 90° C. for 16. The mixture is partitioned between CHCl3 and water. The organic layer is concentrated in vacuo to give an oil. Column chromatography (elution with 1-5% MeOH/CHCl3) gave 0.10 g of a brown oil. Crystallization from ethyl acetate/hexane gave 0.013 g of the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@H:9]1[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:23][CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](Br)=[CH:27][CH:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][C@H:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[CH2:12][C@H:9]1[CH:10]([OH:11])[C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]([CH2:24][OH:23])=[CH:26][CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1ccc(Br)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1ccc(CO)c2ccccc12
Yield: 43.8 %

Procedure:
(2S,4R)-N-t-Butoxycarbonyl-4-t-butyldimethylsiloxy-2-[hydroxy(4-hydroxymethyl-1-naphthyl)methyl]pyrrolidine (2.71 g, yield: 44.0%) was prepared as a colorless oily substance from (2S,4R)-N-t-butoxycarbonyl-4-(t-butyldimethylsiloxy)prolinal (4.17 g, 12.7 mmol), 4-hydroxymethyl-1-bromonaphthalene (3 g, 12.7 mmol) and 1.6M n-butyl lithium-hexane solution (20.6 ml, 39.9 mmol), in the same manner as in Reference Example 111-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]#[CH:18].C1(C)C=CC=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH2:18][C:17]#[CH:16]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: C#CCOc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,5-Dichlorophenol (8 g, 49 mmol) was mixed with potassium carbonate (13.6 g, 98 mmol) and 80% solution of propargyl bromide in toluene (11 ml, 98 mmol) in acetone (100 ml) and stirred overnight at room temperature. The precipitate was removed by filtration and washed with acetone. The acetone solution obtaind was concentrated by rotary evaporation and kept under vacuum for 5 h. The product was obtained as yellow oil with quantitative yield. It was used for futher transformations without additional purification.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:20][CH2:19][CH2:18][CH2:17][N:8]2[CH:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: O=C(NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1)Nc1cccc(Cl)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 3-chlorophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[OH:17])[N:13]=[CH:12][CH:11]=[C:10]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH2:2][CH2:3][OH:4])[N:13]=[CH:12][CH:11]=[C:10]2[O:18][C:19]1[C:20]([CH3:29])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
A solution of 2-bromo-ethanol (226 mg) in N,N-dimethylformamide (6 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (100 mg) and potassium carbonate (250 mg), and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (51.3 mg, yield 45%).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17].O>N1C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:4][O:2][CH3:3])(=[O:14])=[O:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CONS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 76 %

Procedure:
Methoxylamine hydrochloride(0.90 g (10.8 mmol) was suspended in pyridine (3.0 ml). To this, under cooling with ice and with stirring, 4-chloro-3-nitrobenzenesulfonylchloride (2.56 g (10.8 mmol)) was added and the mixture was stirred under cooling with ice for one hour and at room temperature for 3 hours. Water (50.0 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and water successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2.02 g (76%) of 4-chloro-N-methoxy-3-nitrobenzenesulfonamide as pale yellow-white crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[S:21][C:20]([CH3:22])=[N:19][C:18]=3[CH:23]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>O1CCOCC1>[ClH:24].[CH3:22][C:20]1[S:21][C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:23][C:18]=2[N:19]=1
Reactant: Cc1nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2cc(N3CCNCC3)ccc2s1

Procedure:
Prepared in analogy to example 1.6(d) from 4-(2-methyl-benzothiazol-5-yl)-piperazine-1-carboxylic acid tert.-butyl ester and dioxane saturated with gaseous hydrochloric acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:7][C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][O:10][S:21]([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22])=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
The recovered intermediate (20a) (8.5 g, 33 mmol, 1.0 eq) was dissolved into 70 mL pyridine containing potassium hydroxide (2.1 g, 37 mmol, 1.1 eq) and the mixture was chilled in an ice bath. Tosyl chloride (7.1 g, 37 mmol, 1.1 eq) was added and the mixture was stirred at 0° C. for 2 hours then refrigerated overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The recovered residue was dissolved into 300 mL EtOAc, washed with 2×200 mL 1 M H3PO4, saturated bicarbonate, and saturated aqueous NaCl. The organic was dried over MgSO4 and concentrated under reduced pressure to yield intermediate (20b) (10.3 g) as a pale brown oil.
Reaction SMILES: [I:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10]C)[N:5]=[CH:4][CH:3]=1.I[Si](C)(C)C>>[OH:10][C:6]1[N:5]=[CH:4][CH:3]=[C:2]([I:1])[C:7]=1[CH:8]=[O:9]
Reactant: COc1nccc(I)c1C=O
Agent: C[Si](C)(C)I
Product: O=Cc1c(I)ccnc1O

Procedure:
In another embodiment, general acid 2 can be prepared from an acid of formula 40 as illustrated in Scheme 7. Thus, 4-iodo-2-methoxynicotinaldehyde (37; See: WO95/29917) is de-methylated, for example by treatment with iodotrimethylsilane, to provide 2-hydroxy-4-iodonicotinaldehyde (38). Reaction of 38 with arylboronic acid 34 in the presence of copper(II) acetate and pyridine affords N-aryl pyridone aldehyde 39. Oxidation of 39 using sodium chlorite provides acid 40. Alternately, treatment of methyl 2-hydroxy-4-iodonicotinate (41) with arylboronic acid 34 in the presence of copper(II) acetate and pyridine affords N-aryl pyridone ester 42. Saponification of 42 under standard conditions, for example sodium hydroxide, affords acid 40. Treatment of iodo acid 40 with a compound of formula 20, optionally in the presence of a base, for example potassium carbonate, and/or optionally with heating, provides acid 2. Additionally, acid 40 can be used as a general example of acid 17 (W is Iodo, Scheme 3).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([OH:11])=[O:10])=[O:6].CC(C)([O-])C.[K+].Cl>C1COCC1.O>[O:6]=[C:5]1[CH2:4][CH2:3][CH2:2][N:7]1[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(CCCCl)NC(C(=O)O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(c1ccccc1)N1CCCC1=O
Temperature: 0 °C
Yield: 63.2 %

Procedure:
2-(4-Chlorobutanamido)-2-phenylacetic acid (650 mg, 2.54 mmol) was dissolved in dry THF (8.5 ml) and the solution was cooled to 0° C. with an ice-bath stirring under nitrogen atmosphere. Potassium tert-butoxide (599 mg, 5.34 mmol) was added in three portions and a white suspension was obtained. The mixture was stirred at the same temperature for 15 minutes. 1N HCl was added dropwise till pH 2-3 and than the mixture was diluted with water (10 ml) and extracted three times with EtOAc (15 ml×3). The organic phase was dried (Na2SO4) and evaporated to obtain the title compound (352 mg, 63.2% yield) as a pale yellow spongy sticky solid.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[Li]CCCC.CCCCCC.[N:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[CH:28][CH:27]=1>C1COCC1>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([C:32]([C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)([OH:34])[CH3:33])=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2cnc(Br)cn2)cc1
Reactant: CC(=O)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(F)cc2)cn1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 27.1 %

Procedure:
2-bromo-5-(4-fluorophenyl)pyrazine (115 mg, 0.4 mmol) in THF (10 mL) was cooled to −78° C., 1.6 M n-BuLi in hexane (0.56 mL, 0.8 mmol) added slowly at −78° C., the reaction mixture was stirred for 10 min at −78° C., and 1-(pyridin-4-yl)ethanone (54 mg, 0.4 mmol) in THF (3 mL) was added. The resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (2×200 mL). The combined extracts were washed with brine solution (20 mL), dried over Na2SO4, filtered and concentrated under vacuum to obtain crude product. The crude product was purified by preparative TLC (mobile phase: 60% ethyl acetate in hexane) to afford 1-(5-(4-fluorophenyl)pyrazin-2-yl)-1-(pyridin-4-yl)ethanol as off-white solid (32 mg, 24% yield) in 98.7% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 9.13 (s, 1H), 8.93 (s, 1H), 8.48 (d, 2H), 8.16-8.13 (m, 2H), 7.49 (d, 2H), 7.34 (t, 2H), 6.43 (s, 1H), 1.90 (s, 3H); LC-MS m/z calculated for [M+H]+ 296.11, found 296.1.
Reaction SMILES: [C:1]([C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]([F:12])[N:4]=1)#[N:2].N.[OH:14]S(O)(=O)=O>>[F:12][C:5]1[N:4]=[C:3]([C:1]([NH2:2])=[O:14])[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1nc(F)ccc1[N+](=O)[O-]
Agent: N
Product: NC(=O)c1nc(F)ccc1[N+](=O)[O-]
Yield: 61 %

Procedure:
A solution of 2-cyano-6-fluoro-3-nitropyridine (1.40 g, 8.39 mmol) in 90% H2SO4 (30 mL) is warmed at 70° C. for 90 min, then cooled, poured onto ice and basified with conc. ammonia. Extraction with EtOAc and workup gives 6-fluoro-3-nitropyridine-2-carboxamide (0.94 g, 61%). 1HNMR (CDCl3) δ 8.70 (1H, dd, J=8.9, 6.5 Hz), 8.30, 8.03 (1H, 1H, brs), 7.62 (1H, dd, J=8.9, 2.9 Hz).