Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=O)[CH:5]=[C:6](Br)[N:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23]1.C([N:37](CC)[CH:38]([CH3:40])[CH3:39])(C)C.C1CC=CCC=1.C1(N)CC1.C([Mg]Cl)(C)C>[Pd].O1CCCC1>[CH:38]1([NH:37][C:12](=[O:14])[C:11]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:9]([N:4]3[CH:5]=[CH:6][N:7]=[C:2]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH:24]4[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:3]3=[O:20])[CH:10]=2)[CH2:40][CH2:39]1
Reactant: CN1CCNC(c2ccccc2)C1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(Br)c2=O)c1
Agent: [Pd]
Agent: CC(C)[Mg]Cl
Agent: NC1CC1
Solvent: C1CCOC1
Solvent: C1=CCC=CC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(N2CCN(C)CC2c2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 115 mg), 1-methyl-3-phenyl-piperazine (77 mg), N,N-diisopropylethylamine (0.1 mL) and tetrahydrofuran (1 mL) was heated within a microwave for 30 minutes at 100° C. before being cooled to room temperature. The mixture was transferred to a mixture of palladium on carbon (10%, 50 mg) and tetrahydrofuran (1 mL) and 1,4-cyclohexadiene (1 mL) was added. The mixture was heated under atmosphere of nitrogen within a microwave for 2.5 h at 120° C. An additional portion of palladium on carbon (50 mg) in tetrahydrofuran (1 mL) was added and the mixture was heated for 1 h at 120° C. After cooling, cyclopropylamine (0.3 mL) was added followed by dropwise addition of a solution of iso-propylmagnesium chloride (2M in tetrahydrofuran, 2.5 mL). The mixture was stirred for 10 min. and quenched with sat. aqueous NH4Cl and extracted into ethyl acetate. The organic phase was dried (Na2SO4), filtered and concentrated. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded N-cyclopropyl-4-methyl-3-(4-methyl-3′-oxo-2-phenyl-3,4,5,6-tetrahydro-2H,3′H-[1,2′]bipyrazinyl-4′-yl)-benzamide (49 mg) and 3-(6′-Bromo-4-methyl-3′-oxo-2-phenyl-3,4,5,6-tetrahydro-2H,3′H-1-[1,2′]bipyrazinyl-4′-yl)-N-cyclopropyl-4-methyl-benzamide (8 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:20])=[CH:9][C:10]2[O:14][C:13]([CH3:16])([CH3:15])[CH:12](O)[C:11]=2[C:18]=1[CH3:19])=[O:5].C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:20])=[CH:9][C:10]2[O:14][C:13]([CH3:15])([CH3:16])[CH2:12][C:11]=2[C:18]=1[CH3:19])=[O:5]
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)C(O)C(C)(C)O2
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a mixed solution of 3,3-dimethyl-N-(3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)butanamide (2.0 g, 6.55 mmol) obtained in Example 338 in trifluoroacetic acid (3 mL) was added dropwise with ice-cooling triethylsilane (2.09 g, 13.10 mmol). The reaction solution was warmed to room temperature and stirred for 30 minutes. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined organic layers were washed with an aqueous 1 N sodium hydroxide solution and an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain 1.75 g (yield: 92%) of the title compound. Melting point: 181-182° C. (THF-hexane).
Reaction SMILES: C(C1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1)#N.[OH-:19].[K+].[CH2:21]([OH:24])[CH2:22]O.Cl>O>[C:21]([C:22]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1)([OH:24])=[O:19]
Reactant: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1C#N
Reactant: [OH-]
Reactant: OCCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1C(=O)O

Procedure:
Twenty parts 4-cyano-2,5-diisopropylbenzenesulfonamide is refluxed with 50 parts of potassium hydroxide and 400 parts of ethylene glycol under nitrogen for 24 hours. The cooled reaction mixture is diluted with 600 parts of water and acidified with hydrochloride acid. The precipitated product is filtered and washed with water. Drying gives 17 parts of 4-carboxy-2,5-diisopropylbenzenesulfonamide having a.m.p. of 225°-231°.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][P:13]([CH2:25]C(O)=O)([CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:14].C(N(CC)CC)C.OS([O-])(=O)=O.[K+]>O1CCCC1.C(OCC)(=O)C>[OH:14][P:13]([CH2:25][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])([CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)CP(=O)(O)CCCCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CP(=O)(O)CCCCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of benzyl chloroformate (1.8 ml, 12.6 mmol) in 5 ml of dry tetrahydrofuran was added dropwise to a solution of [hydroxy(4-phenylbutyl)phosphinyl]acetic acid (2.55 g, 10 mmol) and triethylamine (2.0 ml, 14.5 mmol) in 30 ml of dry tetrahydrofuran at 0° C. After addition was complete, the mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. The mixture was positioned between ethyl acetate and 5% KHSO4 and the ethyl acetate layer was evaporated to a residue. The residue was taken up in aqueous NaHCO3, washed with ethyl acetate, and the aqueous solution acidified to pH 1 and extracted with ethyl acetate. The extracts were dried (Na2SO4) and evaporated to give the crude product which was triturated with pentane to yield a solid, melting point 64°-67° C. (3.30 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([F:22])[C:15]=2[F:23])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>ClCCl>[F:22][C:16]1[C:15]([F:23])=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:19]=[CH:18][C:17]=1[C:20]#[N:21].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)c(F)c2F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(N2CCNCC2)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-Cyano-2,3-difluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.72 g) in dichloromethane (5 mL) was added trifluoroacetic acid, and the reaction mixture was stirred at room temperature for 30 minutes. After such time the reaction mixture was concentrated in vacuo to yield the title compound (0.63 g). MS (m/e): 224.3 (M+H+, 100%).
Reaction SMILES: [OH:1][CH:2]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>CN(C)C1C=CN=CC=1.CCCCCCC>[C:25]([O:1][CH:2]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C(O)OCCc1ccccc1OC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCCCCCC
Product: CCOC(=O)C(OCCc1ccccc1OC)OC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The solution of ethyl glyoxate (50% toluene sol, 11.66 ml) and 2-methoxybenzeneethano (12.73 ml) were stirred for 1 hr to yield ethyl 2-hydroxy-2-(2-methoxyphenethoxy)acetate. The formation of ethyl 2-hydroxy-2-(2-methoxyphenethoxy)acetate was detected by 1H NMR and the reaction mixture was cooled with ice-bath and treated with pyridine (48.4 ml), 4-dimethylaminopyridine (0.44 g), and acetyl chloride (12.85 ml). After stirring under +7° C. for 1 hr, heptane (50 ml) was added, and the ice-bath cooling was removed to let the reaction mixture reach ambient temperature followed by filtration. The filtare was washed with MTBE (3×50 ml), and the combined solvents were washed with NaHCO3 (sat aq sol), water and NaCl (sat aq sol), dried over Na2SO4, and filtered. Organics were evaporated, toluene added and evaporated. By-products and residual solvents were distilled of (0 mbar-1 mbar/72°-105° C.), and the residual was dissolved in ethyl acetate. Silica gel and active carbon were added, the solution stirred for 10 min, and filtered. Organics were evaporated to yield ethyl 2-acetoxy-2-(2-methoxyphenethoxy)acetate (12.3 g) which was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.FC(F)(F)C(O)=[O:15].C(OO)(=O)C>C(O)(=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N+:3]=1[O-:15]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Agent: CC(=O)OO
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(Cl)[n+]1[O-]
Temperature: 25 °C

Procedure:
2-Chloro-3-nitro-6-picoline (2 g, 11.6 mmol) was added to an ice cooled mixture of trifluoroacetic acid (6 mL) and 30% peracetic acid in acetic acid (6 mL). The mixture was allowed to warm to room temperature over 30 minutes and was heated in a 60° C. oil bath for 5 hours. The mixture was partitioned between methylene chloride (100 mL) and water (50 mL). The pH was adjusted to 8 with 2.5 N sodium hydroxide and the aqueous layer was extracted with more methylene chloride (2×50 mL). The combined methylene chloride layers were dried with magnesium sulfate, filtered and evaporated to give the title compound as a white solid (1.6g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]1[CH2:13][CH2:12][C:7]3(OCC[O:8]3)[CH2:6][C:5]2=1.O>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]1[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][C:5]2=1
Reactant: Fc1ccc2[nH]c3c(c2c1)CC1(CC3)OCCO1
Solvent: O
Solvent: O=CO
Product: O=C1CCc2[nH]c3ccc(F)cc3c2C1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-fluoro-1,2,4,9-tetrahydrospiro[carbazole-3,2′-[1,3]dioxolane] (33.7 g, 0.136 mol) in formic acid (123 ml) was stirred at rt for 4 h30. Then water was added carefully at 0° C., the resulting suspension was stirred for 30 min at 0-5° C. The suspension was filtered off and the yellow solid was washed twice with water (2×14 ml), dried in high vacuum overnight to yield the titled compound as a yellow solid.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[C:16]([O:18][C:19](=[O:24])[C:20]=2[CH:21]([CH3:23])[CH3:22])=[O:17])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.Cl.CCCCCC.C(OCC)(=O)C>C(O)C>[OH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[C:16]([O:18][C:19](=[O:24])[C:20]=2[CH:21]([CH3:22])[CH3:23])=[O:17])[CH2:13][CH2:14]1
Reactant: CC(C)C1=C([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)C(=O)OC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)C1=C([C@H]2CC[C@H](O)CC2)C(=O)OC1=O
Reaction time: 0.5 h

Procedure:
To a solution of 2-(trans-4-t-butyldimethylsilyloxycyclohexyl)-3-isopropylmaleic anhydride (263 mg, 0.745 mmol) in ethanol (7 mL) was added concentrated. hydrochloric acid (83 mg, 0.84 mmol), and the mixture was left standing at 50° C. for 30 min. The reaction mixture was directly concentrated, and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 1:1) to give 179 mg (quantitative) of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C@@H:4]([NH:17][C:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[C:5](=C=O)[C@H:6](OC)[NH:7]2.[OH-:27].[Li+].[O:29]1[CH2:33]CCC1>O>[C:33]([C@H:6]1[CH2:5][C@H:4]([NH:17][C:18]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:19])[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[NH:7]1)([OH:29])=[O:27]
Reactant: C1CCOC1
Reactant: CO[C@@H]1Nc2cc(Cl)cc(Cl)c2[C@@H](NC(=O)Cc2ccccc2)C1=C=O
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Product: O=C(Cc1ccccc1)N[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Reaction time: 3 h

Procedure:
To a suspension of trans-5,7-dichloro-2-methoxy-carbonyl-4-phenylmethylcarbonylamino-1,2,3,4-tetrahydroquinoline (3.11 g, 7.89 mmol) in a mixture of tetrahydrofuran (100 ml) and water (50 ml) was added aqueous lithium hydroxide (17.4 ml of a 0.5M solution, 8.70 mmol) and the resulting mixture was stirred at room temperture for 3 h. The organic solvent was removed in vacuo and the aqueous residue was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (2×100 ml). The combined extracts were washed with saturated brine (1×100 ml), dried (MgSO4) and evaporated to give the crude product which was recrystallised from ethyl acetate/petroleum ether 60-80 to give the title compound as colourless crystals (2 crops, 2.65 g) identical in physical properties to example 34 step b.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[CH3:45][N:46]1[C:50]2([CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[C:49](=[O:56])[NH:48][C:47]1=[O:57].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:53]2[CH2:52][CH2:51][C:50]3([N:46]([CH3:45])[C:47](=[O:57])[NH:48][C:49]3=[O:56])[CH2:55][CH2:54]2)=[O:34])[CH2:18][CH2:17]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reactant: CN1C(=O)NC(=O)C12CCNCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)NC(=O)C12CCN(C(=O)N[C@@H]1CC[C@@H](c3cccc(F)c3F)Cn3c(CC(F)(F)F)cnc31)CC2
Reaction time: 0.25 h
Yield: 35.6 %

Procedure:
Triethylamine (70 μL, 0.50 mmol) was added to a solution of the hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (70 mg, 0.167 mmol) and 4-nitrophenyl chloroformate (34 mg, 0.167 mmol) in tetrahydrofuran (2 mL) at 0° C. After 15 min, a solution of 1-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (31 mg, 0.167 mmol) in dichloromethane (2 mL) and triethylamine (93 μL, 0.67 mmol) were added and the mixture was allowed to warn to ambient temperature. After 4 h, saturated aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) gave the title compound (33 mg). MS 555.2107 (M+1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:25]1([CH2:31][O:32][CH2:33][CH2:34][Br:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC#N>[Br-:35].[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)([OH:10])[C:4]23[CH2:5][CH2:6][N+:1]([CH2:34][CH2:33][O:32][CH2:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([CH2:2][CH2:3]2)[CH2:8][CH2:7]3)=[CH:12][CH:13]=1
Reactant: BrCCOCc1ccccc1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C12CC[N+](CCOCc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 66.3 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl[bis(4-fluorophenyl)]methanol (0.0489 g, 0.148 mmol) and 2-bromoethyl phenylmethyl ether (0.0352 mL, 0.222 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0534 g, 66.1%). EI-MS m/z 464(M+) Rt (1.99 min).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[C:10]1([S:16](N)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.N.OS(O)(=O)=O>C(OCC)(=O)C.O>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][S:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])=[O:17]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)NS(=O)(=O)c1ccccc1
Reaction time: 0.42 h

Procedure:
15.6 ml of hexamethyldisilazane (75 mmoles) were added to a refluxing suspension of 15.72 g (0.1 mole) of benzenesulfonamide and 18 mg (0.1 mmole) of saccharin in 45 ml of ethyl acetate under nitrogen and the nitrogen was passed through water to determine the amount of ammonia evolved. By titrating with 1 N H2SO4, it was found that the calculated amount of ammonia was set free in 25 minutes and the residue of N-trimethylsilylbenzensulfonamide obtained after evaporating the volatile materials in vacuo melted at 62°-63° C.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)[C:4]([OH:6])=[O:5].[CH3:23]O>S(Cl)(Cl)=O>[ClH:1].[NH2:2][CH:3]([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:14]=1)[C:4]([O:6][CH3:23])=[O:5]
Reactant: CO
Reactant: CCCCCCCCc1ccc(CCC(N)C(=O)O)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCCCCCCCc1ccc(CCC(N)C(=O)OC)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-Amino-4-(4-octylphenyl)butanoic acid hydrochloride (20 g) in methanol (500 ml), thionyl chloride (7.2 ml) was added under ice-cooling and the mixture was left standing overnight. The reaction mixture was concentrated under reduced pressure to give the subject compound (16 g). MS: 305(M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[C:10]([F:31])=[CH:11][C:12]([F:30])=[C:13]([NH:15][C:16](=[O:29])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4([C:26]#[N:27])[CH2:25][CH2:24]4)[C:18]=3[Cl:28])[CH:14]=2)=[N:6][CH:7]=1.[S-:32][C:33]#[N:34].[K+].BrBr>C(O)(=O)C>[NH2:34][C:33]1[S:32][C:7]2[C:2]([N:1]=1)=[CH:3][CH:4]=[C:5]([O:8][C:9]1[C:10]([F:31])=[CH:11][C:12]([F:30])=[C:13]([NH:15][C:16](=[O:29])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4([C:26]#[N:27])[CH2:24][CH2:25]4)[C:18]=3[Cl:28])[CH:14]=1)[N:6]=2
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc(N)cn4)c(F)cc3F)c2Cl)CC1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(N)sc5n4)c(F)cc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of N-{5-[(5-aminopyridin-2-yl)oxy]-2,4-difluorophenyl}-2-chloro-3-(1-cyanocyclopropyl)benzamide (4.25 g, 9.64 mmol) and potassium thiocyanate (3.75 g, 38.6 mmol) in acetic acid (50 mL) was added dropwise bromine (2.11 g, 13.1 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. The yellow insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and triturated with diethyl ether to give the title compound (4.05 g, 84%) as a pale-yellow amorphous.
Reaction SMILES: [C:1]1([C:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH2:21][OH:22])[CH:16]=[CH:17][CH:18]=3)=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:39]O)(C)(C)C.C(O)(=O)C(C(C(O)=O)O)O>ClCCl.C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:29]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:14]=[C:15]([C@@H:19]4[O:39][C@H:20]4[CH2:21][OH:22])[CH:16]=[CH:17][CH:18]=3)=[N:9]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OO
Reactant: OCC=Cc1cccc(-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: OC[C@@H]1O[C@H]1c1cccc(-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reaction time: 0.17 h

Procedure:
L-(+)-Dimethyl tartrate (1.85 g) was added in dry dichloromethane (10 ml) dropwise to a stirred solution of titanium (IV) isopropoxide (3.1 ml) in dry dichloromethane (30 ml) at -20° to -25° C. under nitrogen. The solution was stirred for 10 minutes and a solution of 3-[3-(2-triphenylmethyl-2H-tetrazol-5-yl)phenyl]-2-propenol (4.5 g) in dry dichloromethane (20 ml) was added, followed by a 3.7M solution of t-butylhydroperoxide in toluene (6.7 ml), both at -20° to -25° C. The pale orange solution was left to stand in a freezer for 3 hours. To the stirred solution was added aqueous tartaric acid (10%; 50 ml) and the mixture stirred for 1 hour, filtered and separated. The dichloromethane layer was dried over magnesium sulphate filtered and evaporated under reduced pressure to give a yellow oil. The oil was dissolved in carbon tetrachloride, washed with water, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a pale yellow oil. The oil was chromatographed on a silica gel column using diethyl ether and hexane (2:1) and the required fractions evaporated under reduced pressure to give a colourless crystalline solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:34]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH2:35][CH2:36][CH2:37][CH3:38]>>[NH:2]=[C:1]([N:42]1[CH2:43][CH2:44][N:39]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:40][CH2:41]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CCCCCN1CCNCC1
Product: CCCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 13 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalents of n-pentylpiperazine as secondary amine. The product was purified by preparative HPLC.