Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=3)[S:13][C:6]=12.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:15][CH2:16][N:17]([C:36](=[O:38])[CH3:37])[CH2:18][CH:19]=3)[S:13][C:6]=12
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(C4=CCNCC4)sc23)c(F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC=C(c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a suspension of 4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-1,2,3,6-tetrahydropyridine 268 (400 mg, 1.08 mmol) and DIPEA (0.207 mL, 1.19 mmol) in DCM was added acetyl chloride (0.15 mL, 2.16 mmol) at room temperature and the mixture (that turned homogeneous soon after) was stirred for 1 h. The crude mixture was concentrated under reduced pressure and the residue purified by flash chromatography (5% MeOH to 10% MeOH in DCM) affording 269 (358.2 mg, 0.87 mmol, 80% yield) as a white solid. MS (m/z): (M+1) 414.4 (100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[CH:8]=1)[CH3:2]>O1CCCC1.C(O)C.[H][H].[C].[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:16](=[O:20])[N:17]([CH3:18])[CH3:19])[CH:8]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CCc1ccc([N+](=O)[O-])c(C(=O)N(C)C)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1ccc(N)c(C(=O)N(C)C)c1
Yield: 69.6 %

Procedure:
3-(3-Dimethylcarbamoyl-4-nitrophenyl)propionic acid ethyl ester (1.52 g) was dissolved in a mixed solution of THF (tetrahydrofuran) (15 mL) and ethanol (15 mL). 7.5% (w/w) palladium-carbon (300 mg) was added thereto, followed by stirring overnight at normal pressure in hydrogen atmosphere. The reaction solution was filtered through a Celite pad and concentrated to give the title compound (0.950 g) as a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.C([SiH](CC)CC)C.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1)[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1ccc(C(=O)Cc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CCc2ccc(OC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.5 %

Procedure:
To a solution of R)-2-(4-phenylacetyl-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (40 mg, 0.16 mmol) in TFA (1.0 mL) was added triethylsilane (0.2 mL, 0.9 mmol) at 0° C. The resulting mixture was allowed to warm to rt and stir at rt for 16 h. The mixture was poured onto 20 mL ice-water solution, neutralized with aq NaOH (2N) to pH=6-7, and then extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL) and brine (20 mL) and dried over anhy. Na2SO4. The solvent was removed in vacuo to obtain the crude product which was purified by silica gel flash chromatography to afford the title product (25 mg, 82%); LCMS; 99%, ESI+, Calcd: 281.4; Found m/z: 282.6 M+1); 1HNMR (400 MHz, CDCl3); δ 1.54-1.61 (m, 1H), 1.74-1.84 (m, 2H), 1.90-1.99 (m, 1H), 2.84-3.07 (m, 6H), 3.49-3.52 (m, 1H), 3.83-3.92 (m, 2H), 6.82 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 7.16-7.20 (m, 3H)-7.34 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](SC)[N:3]=1.[CH3:17][NH:18][CH3:19]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:18]([CH3:19])[CH3:17])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CNC
Reactant: CSc1nc(N)nc(-c2ccco2)c1C#N
Solvent: CCO
Product: CN(C)c1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-(2-furyl)-6-(methylthio)-5-pyrimidinecarbonitrile and dimethylamine in ethanol. EI-MS m/e (%): 229 (M+, 49), 228 ([M—H]+, 100), 214 (3)8), 200 (48), 44 (44).
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH3:12][CH:13]1[CH2:17][CH2:16][CH2:15][NH:14]1.O>ClCCl>[CH3:12][CH:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4]
Reactant: CC1CCCN1
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Solvent: O
Solvent: ClCCl
Product: CC1CCCN1c1ccc([N+](=O)[O-])cc1N
Temperature: 100 °C

Procedure:
5 g (32.03 mmol) of 2-fluoro-5-nitroaniline and 4.9 ml (48.04 mmol) of 2-methylpyrrolidine (racemic) are placed in a screw reactor. The reactor is closed and the mixture is heated at 100° C. for 5 h. After cooling, the mixture is taken up with 100 ml of water and 100 ml of dichloromethane. The organic phase is separated, washed with 50 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. The resulting product is used as it is in the subsequent reaction.
Reaction SMILES: [C:1]1([B:7]([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:10]([O-])(O)=O>C(OC(=O)C)(=O)C>[NH2:10][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[B:7]([OH:9])[OH:8]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: Nc1ccccc1B(O)O
Temperature: 25 °C

Procedure:
To a three necked round bottom flask equipped with an addition funnel (and argon inlet), thermometer and septum is added phenylboronic acid (40.13 g, 0.33 moles). Acetic anhydride (400 ml) is charged through the septum via syringe. Using a stir bar the mixture is then stirred under argon until the temperature reaches 0° C. with external cooling (ice bath). Fuming nitric acid (25.01 g, 0.397 moles) is added slowly over the course of thirty minutes. The reaction is then allowed to stir an additional two hours at 0° C., before removing the ice bath and allowing the reaction to warm to room temperature. The reaction is poured into ice water (1 L) at which point it appears cloudy. After stirring overnight, however, it becomes homogeneous. The solution is paced on a rotary evaporator at 40° C. under a 5 mm vacuum. When the volume is reduced by about 50%, enough water is added to bring the volume back to 100%. This process is repeated twice more, before bringing the volume to about 300 ml on the rotary evaporator when a precipitate is noticed. Twenty hours are allowed for complete crystallization, and the solids (p-nitrobenzeneboronic acid, 3.66 g) are removed by filtration. Enough water is then added to the filtrate to bring the total volume to 800 mi. The volume is reduced once more under reduced pressure to about 150 ml when a precipitate begins to form. The solids (o-nitrophenylboronic acid, 48.04 g) are collected by filtration and dried in a vacuum oven. To a pressure vessel is added o-nitrophenylboronic acid (31.64 g), 10% palladium on carbon (6.3 g) and ethanol (100 ml). The vessel is shook at room temperature under 50 psi hydrogen on a PARR shaker. After four hours the catalyst is removed by filtration, and the filtrate taken to dryness under reduced pressure. The solids (o-aminophenylboronic acid, 24.4 g) are dried under vacuum for 18 hours.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][CH:15]1[C:20](=[O:21])[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16]1>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:20]2([OH:21])[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:16][CH:15]2[CH3:14])=[CH:3][CH:4]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)CCC1(O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 83.5 %

Procedure:
A solution of 1-bromo-4-chlorobenzene (9.24 g, 48.2 mmol) in anhydrous THF (100 mL) was cooled to −78° C. and treated dropwise with 1.6 M n-butyllithium in hexanes (28.7 mL, 46.0 mmol). The mixture was stirred at −78° C. for 45 minutes, during which time a precipitate was observed, then the slurry was treated dropwise with a solution of tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (4.9 g, 22.98 mmol) in anhydrous THF (50 mL). The reaction was stirred at −78° C. for 2 hours, then allowed to slowly warm to −20° C. and quenched with saturated ammonium chloride. The layers were separated, and the organic phase was concentrated in vacuo. The aqueous phase was extracted once with ethyl acetate (300 mL), and the organic phase was combined with the residue from the original organic phase. The mixture was washed 3× with water, and once with brine, then dried over sodium sulfate and concentrated in vacuo. The residue was digested in boiling hexanes (100 mL) for 1 hour, then the mixture was cooled to room temperature. The solids were collected by filtration, rinsed with a small amount of hot hexanes, and dried under vacuum to yield the title compound (6.25 g, 19.18 mmol, 83% yield) as a white powder. MS (ESI+)=252.2 (M−tert-BuO)+.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:42]([F:45])([F:44])[F:43])=[C:10]([CH2:12][O:13][C:14](=[O:41])[C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([S:31][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=4)[C:23]([O:25]CC(Cl)(Cl)Cl)=[O:24])=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>C(Cl)Cl.[Zn]>[C:1]1([C:7]2[O:8][C:9]([C:42]([F:43])([F:45])[F:44])=[C:10]([CH2:12][O:13][C:14](=[O:41])[C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH:22]([C:23]([OH:25])=[O:24])[S:31][CH2:32][CH2:33][C:34]4[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=4)=[CH:19][CH:20]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1nc(-c2ccccc2)oc1C(F)(F)F)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(OCc1nc(-c2ccccc2)oc1C(F)(F)F)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 10.2 %

Procedure:
4-[2-[2-(4-Fluoro-phenyl)-ethylsulfanyl]-2-(2,2,2-trichloro-ethoxycarbonyl)-ethyl]-benzoic acid 2-phenyl-5-trifluoromethyl-oxazol-4-ylmethylester (289 mg, 0.41 mmol) was dissolved in DCM (30 mL) and zinc (530 mg, 8.1 mmol) was added followed by acetic acid (2.5 mL, 41.6 mmol). The resulting suspension was stirred for 6 h at ambient temperature. After filtering off and washing the zinc with MeOH and EtOAc, the combined organic layers were extracted with water, dried (MgSO4) and evaporated under reduced pressure. The remaining crude product was purified by flash chromatography using Et2O/DCM/EtOAc 6:3:1 as the eluent to afford the title compound as a solid (yield: 24 mg, 10%). 1H NMR (400 MHz, CDCl3): δ 8.07 (d, 2H), 7.98 (d, 2H), 7.43-7.55 (m, 3H), 7.24 (d, 2H), 7.07 (m, 2H), 6.92 (t, 2H), 5.39 (s, 2H), 3.43 (t, 1H), 3.22 (dd, 1H), 2.75-2.99 (m, 5H). Mass spectrum: M+H+ 574.14, M−H+ 572.24.
Reaction SMILES: [C:1]1([NH:7][N:8]=[CH:9][CH:10]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20](=[O:22])[CH3:21]>O1CCOCC1>[C:1]1([N:7]2[C:19]([C:20](=[O:22])[CH3:21])=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)CCl
Reactant: O=CC=NNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(=O)c1ccnn1-c1ccccc1
Yield: 34.7 %

Procedure:
To a mixture of 2-(phenylhydrazono)ethanal (3.10 g) (Journal of Chemical Society, Perkin Trans. 1, 1981, 503-513.), potassium carbonate (4.40 g) and dioxane (20.0 mL) was added 1-chloropropan-2-one (2.10 g) at room temperature, and the mixture was heated under reflux for 5 hr. The reaction mixture was concentrated under reduced pressure and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (1.35 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:18][CH3:19])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C:10]#[N:11].CS(C)=[O:22].O.[OH-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)([CH2:18][CH3:19])[C:10]([NH2:11])=[O:22]
Reactant: CCC(C#N)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CS(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(Cn1cncn1)(C(N)=O)c1ccc(Cl)cc1Cl
Temperature: 91 °C
Yield: 79 %

Procedure:
To a 1 liter flask was charged 206.5 g (0.7 mole) of alpha-(2,4-dichlorophenyl)-alpha-ethyl-1H-1,2,4-triazole-1-propanenitrile and 500 mL of dimethylsulfoxide and 200 mL of water. To the stirring solution was added 67.2 g (0.84 mole) of 50% sodium hydroxide. The reaction mixture was heated at 91° C. (steam bath) for 3 hours after which GLC indicated the starting material was consumed. The reaction was cooled to 30° C. then poured into water and extracted with ethyl acetate. After drying, the ethyl acetate was treated with charcoal and filtered through Celite®. Removal of the solvent gave a foamy oil which was stirred and diluted with ethyl acetate then triturated with hexane until cloudy. This mixture was cooled at 0° C. for about 1 hour after which a solid formed. The product was filtered and washed with ether and hexane then dried and provided 172 g (79% yield) of a white solid, Example 154 of Table 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([CH2:24][OH:25])([CH2:22][OH:23])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:33]1([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]Br)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([CH2:22][OH:23])([CH2:24][OH:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:13]([C:18]([F:20])([F:19])[F:21])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(O)c(C(F)(F)F)c1
Reactant: BrCCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(OCCCCCc2ccccc2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 106.4 %

Procedure:
Compound 3-6 (380 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (277 mg) and 5-phenylpentylbromide (281 mg) were added, and the mixture was stirred at 80° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (560 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11](Cl)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]([C:22]1([CH3:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])[CH3:18].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH2:17]([O:19][C:20]([C:22]1([CH3:28])[CH2:27][CH2:26][N:25]([C:11]2[N:10]=[N:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:13]([CH3:14])[C:12]=2[CH3:15])[CH2:24][CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1(C)CCNCC1
Reactant: Cc1c(Cl)nnc(Cc2ccccc2)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1(C)CCN(c2nnc(Cc3ccccc3)c(C)c2C)CC1
Temperature: 210 °C
Yield: 40.5 %

Procedure:
To a solution of 3-benzyl-6-chloro-4,5-dimethyl-pyridazine (1.0 g, 4.3 mmol) in NMP (10 mL) is added 4-methyl-piperidine-4-carboxylic acid ethyl ester (2.0 g, 8.6 mmol) and DIPEA (3.7 mL, 21.6 mmol). The mixture is heated in microwave at 210° C. for 1.5 h. The mixture is concentrated at 80° C. by rotovaporation. The crude product is purified by HPLC (CH3CN/H2O: 22% 45% with 0.1% TFA) to give 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-4-methyl-piperidine-4-carboxylic acid ethyl ester (0.64 g, 41%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:10]([NH2:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH2:35][S:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)(=[O:38])=[O:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH2:35][S:36]([C:39]1[CH:40]=[CH:41][C:42]([C:43]([NH:25][C@H:10]2[C@@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)=[O:44])=[CH:46][CH:47]=1)(=[O:37])=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)C(N)C1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)c2ccc(S(N)(=O)=O)cc2)C1
Reaction time: 8 h
Yield: 45.9 %

Procedure:
1-tert-butoxycarbonyl-3-amino-4-(benzyloxycarbonyl)amino-piperidine (151b) (300 mg) was dissolved in DMF (5 mL) prior to addition of Hunig's base (0.45 mL). 4-(aminosulfonyl)benzoic acid (210 mg) was added followed by BOP (420 mg). The solution was stirred for 8 h then quenched with aqueous NH4Cl. The mixture was partitioned between EtOAc and water. The organic layer was washed with NaHCO3, 5% LiCl (3×), and brine. The organic layer was dried, filtered, and concentrated. Flash chromatography of the residue provided tert-butyl (cis)-3-{[4-(aminosulfonyl)benzoyl]amino}-4-{[(benzyloxy)carbonyl]amino}-1-piperidinecarboxylate (210 mg). MS found: (M−H)−=531.3.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:16]([OH:18])=[O:17])=[CH:8][N:9]2[CH:13]2[CH2:15][CH2:14]2)=[CH:4][N:3]=1.[C@@H:20]12[CH2:28][NH:27][CH2:26][C@@H:25]1[CH2:24][CH2:23][CH2:22][NH:21]2>CN(C)C=O.C(#N)C>[Cl:12][C:11]1[C:2]([N:27]2[CH2:28][C@@H:20]3[C@@H:25]([CH2:24][CH2:23][CH2:22][NH:21]3)[CH2:26]2)=[N:3][CH:4]=[C:5]2[C:10]=1[N:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6]2=[O:19]
Reactant: C1CN[C@@H]2CNC[C@@H]2C1
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(Cl)ncc2c1=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3C[C@@H]4CCCN[C@@H]4C3)ncc2c1=O

Procedure:
200 mg (0.67 mmol) of 7,8-dichloro-1-cyclopropyl-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylic acid are stirred with 190 mg (1.5 mmol) of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane in a mixture of 1.7 ml of dimethylformamide and 1.7 ml of acetonitrile under argon overnight. The precipitate is isolated and washed with acetonitrile. The crude product is purified on silica gel (eluent: dichloromethane/methanol/aqueous ammonia solution 75:20:25).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17].C(N(CC)C(C)C)(C)C>ClCCl>[Br:1][C:2]1[S:6][C:5]([CH2:7][NH:8][S:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Br)s1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCc1ccc(Br)s1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.5 %

Procedure:
To a stirred suspension of 1-(5-bromo-2-thienyl)methanamine (1.00 g) in dichloromethane (15 mL) were slowly added 2-chlorobenzenesulfonyl chloride (1.18 g) and N,N-diisopropyl ethyl amine (0.76 g) at 0° C. After 15 min the ice bath was removed and the mixture was stirred at r.t. for 1.5 h. The mixture was diluted with dichloromethane and washed with 0.5 M HCl and with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 95:5 to ethyl acetate) to give N-(5-bromo-thiophen-2-ylmethyl)-2-chloro-benzenesulfonamide (0.83 g) as a colorless solid. MS: 363.9 ([M−H]−)
Reaction SMILES: [OH:1]O.[Br:3][C:4]1[C:12]([O:13][CH3:14])=[C:11]2[C:7]([C:8](=[O:16])C(=O)[NH:10]2)=[CH:6][CH:5]=1.[OH-].[Na+]>O>[NH2:10][C:11]1[C:12]([O:13][CH3:14])=[C:4]([Br:3])[CH:5]=[CH:6][C:7]=1[C:8]([OH:16])=[O:1]
Reactant: COc1c(Br)ccc2c1NC(=O)C2=O
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(Br)ccc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
H2O2 (37%, 7.7 mL, 0.075 mol) in H2O (70 mL) is slowly added to the solution of 6-Bromo-7-methoxy-1H-indole-2,3-dione (8.0 g, 0.0312 mol), NaOH (8.8 g, 0.219 mol) in H2O (200 mL) then stirred at room temperature for 1 hour. After reaction, the mixture is filtered and the solid is dried under vacuum to give the desired product.
Reaction SMILES: [Na+].[NH:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([O-:20])(=[O:19])=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>Cl.C(#N)C>[NH:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([OH:20])(=[O:18])=[O:19])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)([O-])CCCCCCCCNc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: O=S(=O)(O)CCCCCCCCNc1ccccc1

Procedure:
8-Anilino-1-octanesulfonic acid sodium salt (10.0 g, 0.5 mol) is dissolved in aqueous 0.5M HCl solution (30 mL) and acetonitrile (400 mL) is added to the solution. The solution is filtered and the filtrate is kept in a refrigerator overnight to obtain 8-anilino-1-octanesulfonic acid as white precipitates. The precipitates are collected by filtration, dissolved in water, neutralized by aniline, and then concentrated under reduced pressure to give a white solid.
Reaction SMILES: Cl[CH2:2][CH:3]([NH:22][C:23](=[O:32])[C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[F:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH:19]([F:21])[F:20])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)(C)C.O>[F:20][CH:19]([F:21])[S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:3]3[CH2:2][O:32][C:23]([C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=4[F:31])=[N:22]3)=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: O=C(NC(CCl)c1ccc(-c2ccc(S(=O)(=O)C(F)F)cc2)cc1)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=S(=O)(c1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cc1)C(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a slurry of 9.18 g (18.9 mmol) of N-[2-chloro-1-[4'-[(difluoromethyl) -sulfonyl][1,1'-biphenyl]-4-yl]ethyl]-2,6-difluorobenzamide in 70 mL of isopropanol was added a solution of 1.8 g (22.5 mmol) of aqueous 50% NaOH at 25-30° C. The mixture was allowed to stir for 30 minutes at ambient temperature, diluted with 40 mL of water, and filtered. The solid product was washed with 20 mL of 50% aqueous isopropanol and suction-dried to afford 7.5 g (88%) of 4-[4'-[(difluoromethyl)sulfonyl][1,1'-biphenyl]-4-yl]-2-(2,6-difluorophenyl)-4,5-dihydrooxazole, m.p. 107-111° C. An analytical sample was prepared by recrystallization from isopropanol, m.p. 109-111° C. IR(KBr): 1669, 1622, 1593, 1485, 1469, 1395, 1345, 1300, 1285, 1240, 1168, 1161, 1114, 1081, 1053, 1041, 1012, 822, 793 cm-1. UV(CH2Cl2): λmax =279 nm (ε=25.9×103). 1H-NMR (benzene-d6): δ3.9 (t, 1H), 4.25 (dd, 1H), 5.15 (dd, 1H), (dq, 2H), 5.68 (m, 1H), 6.22 (t, 1H, J=53 Hz), 6.7 (br d, 1H), 7.0 (t, 2H, J=9 Hz), 7.41 (m, 1H), 7.53 (d, 2H), 7.65 (d, 2H), 7.83 (d, 2H), 8.05 (d, 2H). 13C-NMR (CDCl3): δ69.9, 74.6, 107.1 (dd, JCF =2, 23 Hz), 114.8, 127.6, 127.9, 128.1, 131.2, 132.2. 19F-NMR (CDCl3): δ-112.1 (t, JHF =7.3 Hz), -121.8 (d, JHF =53 Hz).