Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:5]2.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:16]([N:7]1[CH:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[CH2:8]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)C1Cc2cc(F)ccc2CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C1Cc2cc(F)ccc2CN1Cc1ccccc1
Yield: 45.8 %

Procedure:
702 mg of methyl 6-fluoro-1,2,3,4-tetrahydroisoquinoline-3-carboxylate, 425 mg of benzyl chloride, and 425 mg of potassium carbonate were dissolved in 5 mL of acetonitrile, followed by stirring under reflux for 3 hours. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (acetone:n-hexane=1:20) to obtain 460 mg (yield 46%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:24])=[O:23])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Product: Cn1c(C#N)ccc1-c1ccc(NS(=O)(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to general procedure for sulfonylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using benzenesulfonyl chloride (70 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]benzene sulfonamide (0.046 g).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:20][CH2:21][S:22][CH3:23])[C:10]([O:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:11])=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[CH3:19][N:16]1[CH2:15][CH2:14][CH:13]([O:12][C:10](=[O:11])[C@H:9]([CH2:20][CH2:21][S:22][CH3:23])[NH2:8])[CH2:18][CH2:17]1
Reactant: CSCCC(NC(=O)OC(C)(C)C)C(=O)OC1CCN(C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCC[C@H](N)C(=O)OC1CCN(C)CC1

Procedure:
A solution of the 1-methylpiperidin-4-yl 2-tert-butoxycarbonylamino-4-methylsulfanylbutyrate (3.8 g; 11 mmol) in dichloromethane (5 ml) and TFA (10 ml) was stirred at ambient temperature for 2 hours. After evaporation to dryness, the residue was redissolved in dichloromethane and treated with a solution of 3.8 M HCl in ether (6 ml) at 0° C. The resulting precipitate was triturated with ether and filtrated to give L-methionine (N-methylpiperidin-4-yl) ester.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.Br[CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:27]1([CH2:26][CH2:25][N:2]2[CH2:7][CH2:6][CH2:5][CH:4]([C:8]3[CH:9]=[CH:10][C:11]([O:12][C:13]4[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=4)=[CH:22][CH:23]=3)[CH2:3]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: BrCCC1CCCCC1
Reactant: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(C3CCCN(CCC4CCCCC4)C3)cc2)nc1
Yield: 41.8 %

Procedure:
Combine 6-(4-Piperidin-3-yl-phenoxy)-nicotinamide (free base compound of example 322) (0.0255 g, 0.0858 mmol), 1-bromo-2-cyclohexylethane (0.0150 mL, 0.0958 mmol), and potassium carbonate (0.0245 g, 0.177 mmol) in dimethylformamide (1.0 mL) and stir for 10 min. Purify the reaction mixture by ion exchange chromatography (SCX resin, methanol→2 M ammonia/methanol) and silica gel chromatography (15:1→10:1 ethyl acetate:methanol) to provide 0.0146 g (42%) of the title compound as an off-white foam: high resolution mass spectrum (electrospray): m/z calc for C25H34N3O2 408.2651, found 408.2661; 1H NMR (methanol-d4): 8.61 (s br, 1H), 8.28 (d, 1H, J=7.8 Hz), 7.36 (d, 2H, J=7.8 Hz), 7.12 (d, 2H, J=7.8 Hz), 7.01 (d, 1H, J=8.3 Hz), 3.07 (d, 2H, J=10.2 Hz), 2.89 (t, 1H, J=11.2 Hz), 2.55-2.42 (m, 2H), 2.15-1.93 (m, 4H), 1.93-1.64 (m, 8H), 1.63-1.43 (m, 4H), 1.40-1.15 (m, 8H), 1.07-0.86 (m, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl.[N:30]1([CH2:36][CH2:37][O:38][C:39]2[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=2)[C:42](O)=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([N:3]([CH2:42][C:41]1[CH:45]=[CH:46][CH:47]=[C:39]([O:38][CH2:37][CH2:36][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:40]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: O=C(O)c1cccc(OCCN2CCCCC2)c1
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: Cl
Product: CCN(Cc1cccc(OCCN2CCCCC2)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 86.5 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (60 mg) and 3-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (85 mg) according to an analogous synthetic method to Example 152, the title compound (70 mg) was obtained.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:36]2=[N:37][CH:38]=[N:39][C:40]([O:41][C@@H:42]([CH2:46][O:47][CH:48]([CH3:50])[CH3:49])[C:43]([OH:45])=O)=[C:35]2[CH:34]=[N:33]1.[CH3:51][C:52]1[CH:53]=[CH:54][C:55]([NH2:58])=[N:56][CH:57]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:36]2=[N:37][CH:38]=[N:39][C:40]([O:41][C@@H:42]([CH2:46][O:47][CH:48]([CH3:50])[CH3:49])[C:43]([NH:58][C:55]3[CH:54]=[CH:53][C:52]([CH3:51])=[CH:57][N:56]=3)=[O:45])=[C:35]2[CH:34]=[N:33]1
Reactant: Cc1ccc(N)nc1
Reactant: CC(C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2ccccc2Cl)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.8 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (333 mg, 0.88 mmol) was added to (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoic acid D2 (300 mg, 0.80 mmol), 5-methylpyridin-2-amine (95 mg, 0.88 mmol) and N-ethyldiisopropylamine (0.153 mL, 0.88 mmol) in DCM (15 mL) at room temperature under nitrogen. The resulting solution was stirred at room temperature for 24 hours. The reaction mixture was diluted with DCM (25 mL) and washed with saturated brine (20 mL). The aqueous layer was re-extracted with DCM (30 mL). The combined organics were evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (175 mg, 47.1%), 10% ee. 143 mg of this material was further purified by chiral preparative HPLC on Chiralcel OJ (50 mm×20 μm), eluent isohexane/EtOH/MeOH 70/15/15 to afford (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (56 mg, >99% ee which eluted after the R enantiomer).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH2:5](N)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N>>[CH2:5]([NH:1][C:2]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCc1ccccc1
Reactant: NC(N)=O
Agent: N
Product: O=C(NCc1ccccc1)NCc1ccccc1
Yield: 599.4 %

Procedure:
Heated was a mixture of urea 5.84 g (9.72 mmol) and benzylamine 25.0 g (23.3 mmol, 2.4 equivalents) at 150° C.-155° C. for 5 hours attaching with an air cooler. During the heating, observed was the ammonia gas evolution from colorless liquid reaction mixture. By cooling, it turned solidified at around room temperature. Purified was the reaction product by recrystallization from ethanol-benzene (1:1 mixture) to give N,N′-dibenzylurea 14.0 g as white fine needles (59.9% yield).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]/[CH:10]=[CH:11]/[CH2:12][N+:13]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:5][CH:4]=1.[H][H]>C(O)(=O)C>[Cl-:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][N+:13]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CCCCCCC[N+](CC)(CC)C/C=C/Cc1ccc(Cl)cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCCCCCC[N+](CC)(CC)CCCCc1ccc(Cl)cc1

Procedure:
Add 2.1 g (5.6 mmole) of (E)-4-(4-chlorophenyl)-N,N-diethyl-N-heptyl-2-buten-1-aminium chloride to a suspension of 0.11 g catalyst (rhodium (5%) on carbon) in 100 ml glacial acetic acid and stir under 1 atmosphere hydrogen for 19 hours at room temperature. Filter through celite and then wash celite with 100 ml H2O. Combine filtrates and extract into 4×100 ml methylene chloride. Wash methylene chloride extracts with 1×100 ml 1N HCl, 2×250 ml saturated aqueous sodium bicarbonate and 200 ml saturated aqueous sodium chloride. Dry methylene chloride over sodium sulfate, filter and evaporate solvent to provide 4-chloro-N,N-diethyl-N-heptylbenzenebutanaminium chloride. Dissolve product in 75 ml H2O/MeOH (50:50) and pour onto column containing 6 g anion exchange resin (hydroxide form BIO-RAD AG-1-X8). Elute sample through column with distilled water and collect eluate having pH≥9. Wash this aqueous solution with 2×150 ml methylene chloride. Titrate sample to pH= 5.0 with 10% phosphoric acid and to pH=4.5 with 0.1N phosphoric acid. Evaporate to provide 1.25 (51%) of title compound.
Reaction SMILES: C[C@@H:2]1[CH2:7][C:6]([CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:27])[N:3]1[C@H:28]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([OH:40])([CH3:39])[CH3:38])=[CH:32][CH:31]=1)[CH3:29].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(Cl)Cl.O>[OH:40][C:37]([CH3:38])([CH3:39])[CH2:36][C:33]1[CH:34]=[CH:35][C:30]([C@@H:28]([N:3]2[CH2:2][CH2:7][C@:6]([CH2:14][CH2:15][CH2:16][O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[O:5][C:4]2=[O:27])[CH3:29])=[CH:31][CH:32]=1
Reactant: COc1ccc(COCCCC2(c3ccccc3)C[C@@H](C)N([C@@H](C)c3ccc(CC(C)(C)O)cc3)C(=O)O2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COCCC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(CC(C)(C)O)cc3)C(=O)O2)cc1
Reaction time: 3 h
Yield: 0.8 %

Procedure:
To a solution of methyl (R)-3-((S)-1-(4-(2-hydroxy-2-methylpropyl)phenyl)ethyl)-6-(3-(4-methoxybenzyloxy)propyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 0.188 mmol) in DCM/H2O (10:1, 2 mL) was added CAN (100 mg). The formed mixture was stirred for 3 h. The reaction was washed with water and extracted with CH2Cl2. The combined organic phase was concentrated to provide the crude product, which was purified by preparative HPLC to give (R)-3-((S)-1-(4-(2-hydroxy-2-methylpropyl)phenyl)ethyl)-6-(3-(4-methoxybenzyloxy)propyl)-6-phenyl-1,3-oxazinan-2-one (0.8 mg, 10%). LC-MS Method 2 tR=1.191 min, m/z=411.24; 1H NMR (CDCl3): δ=0.81 (m, 4H), 1.09 (d, 6H), 1.43 (d, 3H), 1.64 (m, 3H), 1.92 (m, 3H), 2.16-2.26 (m, 4H), 2.59 (s, 2H), 2.83 (m, 1H), 3.52 (t, 2H), 5.62 (q, 1H), 6.78 (m, 2H), 6.86 (m, 2H), 6.94 (m, 1H), 7.26 (m, 4H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1>[CH2:24]([O:23][C:21]([O:12][C:11]1[C:5]2[O:4][CH2:3][CH:2]([OH:1])[CH2:7][C:6]=2[CH:8]=[CH:9][CH:10]=1)=[O:22])[CH3:25]
Reactant: Oc1cccc2c1OCC(O)C2
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1cccc2c1OCC(O)C2
Yield: 100.2 %

Procedure:
23.05 g of 3,4-dihydro-3,8-dihydroxy-2H-1-benzopyran was dissolved in 320 ml of tetrahydrofuran, and 16.7 g of triethylamine was added. With stirring under cooling, a solution of 17.9 g of ethyl chloroformate in 100 ml of tetrahydrofuran was added dropwise. The mixture was worked up in the same way as in Example 1 to give 33.1 g (yield 100%) of 3,4-dihydro-8-ethoxycarbonyloxy-3-hydroxy-2H-1-benzopyran.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18]>O1CCCC1>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1])=[O:18]
Reactant: Cc1ncc[nH]1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nccn1C(=O)c1c(Cl)cccc1Cl

Procedure:
20.5 g of 2-methylimidazole and 25.3 g of triethylamine are dissolved in 200 ml of tetrahydrofuran. To this solution are added dropwise, within 15 minutes at reflux temperature, 52.4 g of 2,6-dichlorobenzoyl chloride (dissolved in 100 ml of tetrahydrofuran). The mixture is refluxed for 30 minutes, and subsequently freed from triethylamine hydrochloride by filtration in vacuo. The filtrate is concentrated to dryness in a rotary evaporator and the residue is recrystallised from 130 ml of acetonitrile. The crystals are filtered off with suction, washed with acetonitrile, and dried at 60° C. in vacuo to thus obtain 46.0 g (72.2% of theory) of the product, m.p. 116°-119° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[F:9].[Li+].CC([N-]C(C)C)C.CN([CH:21]=[O:22])C>C1COCC1>[Br:1][C:2]1[C:3]([F:9])=[C:4]([C:5]([Cl:8])=[CH:6][CH:7]=1)[CH:21]=[O:22]
Reactant: Fc1cc(Cl)ccc1Br
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(Cl)ccc(Br)c1F
Temperature: -20 °C
Yield: 169 %

Procedure:
A solution of 1-bromo-4-chloro-2-fluorobenzene (20.4 g, 0.100 mol) in THF (50 mL) was slowly added to LDA (0.125 mol) in THF (600 mL) at −50° C. The resulting solution was then warmed to −20° C. and cooled again to −50° C. A solution of DMF (14.6 g, 0.20 mol) in THF (50 mL) was slowly added and the reaction mixture was allowed to warm to room temperature. The reaction was quenched with water (250 mL) and extracted with ethyl acetate (2×150 mL). The combined organic phases were dried and concentrated. The product was recrystallized from hexane to give 3-bromo-6-chloro-2-fluorobenzaldehyde (40.0 g, 0.169 mol): mp 92-93° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6](=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[CH3:2].CC(C)([O-])C.[K+].[F:22][C:23]([F:32])([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:25][CH2:26]I.O>C1COCC1>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:26][CH2:25][CH2:24][C:23]([F:32])([F:22])[C:28]([F:31])([F:30])[F:29])[C:6](=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[CH3:2]
Reactant: FC(F)(F)C(F)(F)CCCI
Reactant: C=CCCCCCC(=O)CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCCC(=O)C(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
On the other hand, to a solution of 3-oxo-dec-9-enoic acid ethyl ester (4.32 g, 20.3 mmol) in THF (15 ml) at 0° C. was added potassium tert-butoxide (2.73 g, 24.3 mmol) This resulting mixture was stirred at room temperature under nitrogen for 30 min. The mixture of 4,4,5,5,5-pentafluoro-iodopentane was added and mixture was refluxed under nitrogen for 2 days, and then poured into H2O. The mixture was extracted with hexane. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (silica gel, 60% CHCl3/hexane) to afford 3-oxo-2-(4,4,5,5,5-pentafluoropentyl)-dec-9-enoic acid ethyl ester (4.46 g, 59%).
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[CH2:6]([O:8][C:9]([C:11]1[C:12]2[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][C:13]=2[N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:15]=1)=[O:10])[CH3:7].[Na+].[I-]>CC#N>[CH2:6]([O:8][C:9]([C:11]1[C:12]2[C:27]([O:28][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:26][CH2:25][CH2:24][CH2:23][C:13]=2[N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH:15]=1)=[O:10])[CH3:7]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CCCC2
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(O[Si](C)(C)C)=CCCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
TMSCl (4.03 ml, 31.74 mmol) is added slowly to a solution of 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (6.0 g, 18.67 mmol), NaI (4.76g, 31.74 mmol) and TEA (7.8 ml, 56 mmol ) in CH3CN (100 ml) at room temperature. The reaction mixture is stirred at room temperature for 18 h. It is then quenched with saturated NaHCO3 (aq., 70 ml). The layers are separated and the aqueous phase extracted with 1:1 EtOAC/hexanes. The organic layers are combined, dried (Na2SO4), and evaporated to afford the title compound as a brown oil . The title compound is used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[F:10][C:11]([F:23])([F:22])[C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([NH:8][S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:10])([F:22])[F:23])[CH:13]=2)(=[O:20])=[O:19])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cc(Cl)cnc1Br
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)cnc1Br)c1cccc(C(F)(F)F)c1
Reaction time: 18 h

Procedure:
To a stirred solution of 2-bromo-5-chloro-pyridin-3-ylamine (2.07 g, 10.0 mmol) in anhydrous pyridine (20 mL) was added 3-(trifluoromethyl)benzenesulfonyl chloride (4.90 g, 20.0 mmol) and the progress of the reaction was followed by LCMS. The reaction mixture was stirred overnight (18 h), then concentrated to dryness. The residue was dissolved in THF (20 mL) and stirred 18 h with 1M TBAF (20 mL) in THF to cleave the bis-sulfonamide. The THF was subsequently evaporated and the residue was dissolved in ethyl acetate. The organic phase was then washed with water (2×100 mL), brine, and then dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate-hexane to provide N-(2-Bromo-5-chloro-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide as a white crystalline solid. MS m/z 417.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12]([C:14]([CH3:16])=O)=[CH2:13]>>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)[N:6]=[CH:13][CH:12]=[C:14]2[CH3:16]
Reactant: C=CC(C)=O
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Product: Cc1ccnc2c([N+](=O)[O-])cc(F)cc12
Yield: 39 %

Procedure:
A Skraup reaction was run with 4-fluoro-2-nitroaniline and methyl vinyl ketone. The crude product was recrystallized multiply from benzene to obtain a 39% yield of pure 6-fluoro-4-methyl-8-nitroquinoline; mp 139°-141°.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:19][C:20](O)=[O:21])[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH2:33][NH2:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:19][C:20]([NH:34][CH2:33][C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=4)=[O:21])[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)O)C2=O)cn1
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNC(=O)CC2NC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1
Yield: 50 %

Procedure:
Prepared as in Example 10-48 from 3-(1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,5-dioxoimidazolidin-4-yl)acetic acid (example 10-44) and (3-methoxyphenyl)methanamine. Yield: 50%. LC/MS; expected 453; found 453.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.7 μM.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.[Br:15]Br>C(O)(=O)C>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[NH:6][C:5]3[C:4](=[O:14])[CH:3]=[CH:2][S:1][C:13]=3[C:12]=2[CH:11]=1
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1ccsc2c1[nH]c1ccc(Br)cc12
Reaction time: 0.17 h

Procedure:
A solution of 8.04 g (0.04 mole) of thiopyrano[3,2-b]indol-4(5H)-one in 200 ml of acetic acid is treated dropwise with stirring at room temperature with 8.0 g (0.05 mole) of bromine. An immediate heavy precipitate formed The mixture is concentrated to dryness and the solid residue suspended in 20 ml of pyridine and stirred for 10 minutes at 95°. The reaction mixture is poured onto ice, the solid is filtered and recrystallized from dimethylformamide, mp 334°-337° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].Cl[S:36]([NH2:39])(=[O:38])=[O:37].O>CN(C)C(=O)C>[S:36]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:38])(=[O:37])[NH2:39]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(N)(=O)=O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
4-Hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.145 g, 0.314 mmol) was dissolved in N,N-dimethylacetoamide (1.5 mL), and the solution was added with chlorosulfonamide (0.0440 mL, 0.377 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with water and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (chloroform/methanol=85/15) to obtain 4-sulfamoyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0914 g, yield 54%).