Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][S:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:38])=[O:37])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NS(=O)(=O)c2ccccc2)c1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and benzenesulfonyl chloride following the procedure of Example 61 as an off-white solid: MS (EI) m/z 533.2 (M+H)+; 1H NMR (DMSO-d6): δ 6.95 (d, J=7.7 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 7.05 (s, 1H), 7.20 (t, J=7.9 Hz, 1H), 7.35 (t, J=7.5 Hz, 2H), 7.50-7.70 (m, 9H), 7.76 (t, J=8.2 Hz, 1H), 8.33 (d, J=7.1 Hz, 1H), 9.11 (s, 1H), 10.38 (s, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].[CH3:8][S:9](Cl)(=[O:11])=[O:10]>C(Cl)Cl>[CH3:8][S:9]([O:7][CH2:6][C@H:2]1[CH2:3][CH2:4][CH2:5][O:1]1)(=[O:11])=[O:10]
Reactant: OC[C@H]1CCCO1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.6 %

Procedure:
A mixture of (R)-(tetrahydrofuran-2-yl)methanol (600 mg, 5.87 mmol), DCM (35 ml), TEA (0.983 ml, 7.05 mmol) was diluted with methanesulfonyl chloride (0.467 ml, 5.99 mmol), via a dropwise addition. The reaction mixture was stirred at ambient temperature for 5 hours and the reaction progress was followed by LCMS. The crude reaction mixture was washed with saturated sodium bicarbonate (1×), water (2×), filtered and concentrated to a constant mass, giving 980 mg of the title compound, which was used without further purification. LCMS (m/z): 181.0 (MH+), retention time=0.40 min
Reaction SMILES: Cl.Cl.[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[NH2:22].C([O:25]CC)C>>[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[S:12]([CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[NH2:22])=[O:25]
Reactant: COc1ccc(N)c(CSc2nc3ccccc3[nH]2)c1
Reactant: CCOCC
Agent: Cl
Product: COc1ccc(N)c(CS(=O)c2nc3ccccc3[nH]2)c1

Procedure:
The title compound was prepared by the method of Example 3 using 2.20 g of the free base of the title product of Example 19 instead of the title product of Example 2. Trituration with diethyl ether gave 900 mg of the title compound: m.p. 152-153° C. Anal. Calc'd. for C15H5N3O2S: C, 59.78; H, 5.02; N, 13.94; S, 10.64. Found: C, 59.01; H, 4.97; N, 13.65; S, 10.65.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:16]3[CH2:25][CH2:24][CH2:23][C:17]3([F:26])[C:18](=O)[NH:19][C:20]=2[CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:16]3[CH2:25][CH2:24][CH2:23][C:17]3([F:26])[C:18](=[S:44])[NH:19][C:20]=2[CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc2c(c1)NC(=O)C1(F)CCCC21)Cc1cccc(Cl)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCCc1ccc2c(c1)NC(=S)C1(F)CCCC21)Cc1cccc(Cl)c1

Procedure:
A solution of 100 mg (0.21 mmol) of 7-[3-(N-tert-butoxycarbonyl-3-chlorobenzylamino)propyl]-3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one and 223 mg (0.55 mmol) of Lawesson's reagent in 15 ml of THF is refluxed for 1.5 hours. After concentration by evaporation in a vacuum, the residue is purified by column chromatography with hexane-ethyl acetate: 80 mg of product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Brc1cccc2cccnc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(Br)c2ncccc12
Temperature: 0 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
8-Bromoquinoline (25.00 g, 120.2 mmol) was dissolved in sulfuric acid (82.5 mL) at rt and then cooled to 0° C. HNO3 (fuming, 32.5 mL) was then slowly added over a 10 minute period. The reaction was then warmed to rt and then to 65° C. After 48 h at 65° C., the reaction was cooled to rt and poured onto 500 g of ice. This solution was extracted with methylene chloride (5×200 mL). The organic layers were washed once with brine and dried over anhydrous sodium sulfate. Concentration gave the crude compound 464A as a light yellow solid (28.6 g, 94%). HPLC: 98% at 2.717 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:7]([NH2:10])=[N:8][CH:9]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22]Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Br:3][C:4]1[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:7]([N:10]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:8][CH:9]=1
Reactant: ClCCCCBr
Reactant: Nc1ncc(Br)nc1-c1ccccc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccccc1-c1nc(Br)cnc1N1CCCC1
Reaction time: 3 h
Yield: 98.6 %

Procedure:
Sodium hydride (0.55 g) is added at room temperature to a solution of 5-bromo-3-(2-chloro-phenyl)-pyrazin-2-ylamine (0.23 g) in DMF (10 mL). Subsequently 1-bromo-4-chlorobutane (0.21 g) is added and the mixture is stirred for 3 h. Citric acid (10%, 20 mL) is added and the mixture is extracted with ethyl acetate (3×50 mL). Organic phases were pooled, washed with sodium bicarbonate and brine, dried with Na2SO4 and the solvent was evaporated. The residue was purified by chromatography on silica gel with heptane/ethyl acetate 2:1 to yield 0.27 g of the title compound as a yellow oil, MS (ISP) 338.1, 340.0 (M+H)+.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([C:7](O)=[O:8])[CH2:4][O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.Cl.[N:47]1([C:53]2[CH:58]=[CH:57][C:56]([N:59]3[CH2:63][C@H:62]([CH2:64][O:65][C:66]4[CH:70]=[CH:69][O:68][N:67]=4)[O:61][C:60]3=[O:71])=[CH:55][C:54]=2[F:72])[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>ClCCl>[OH:6][C@H:5]([CH2:7][OH:8])[C:4]([N:50]1[CH2:49][CH2:48][N:47]([C:53]2[CH:58]=[CH:57][C:56]([N:59]3[CH2:63][C@H:62]([CH2:64][O:65][C:66]4[CH:70]=[CH:69][O:68][N:67]=4)[O:61][C:60]3=[O:71])=[CH:55][C:54]=2[F:72])[CH2:52][CH2:51]1)=[O:3]
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Reactant: CC1(C)OC[C@H](C(=O)O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C([C@H](O)CO)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Yield: 19.8 %

Procedure:
A solution of 2,2-dimethyl-1,3-dioxolane-4(R)-carboxylic acid (162 mg, 1.1 mmol) in dichloromethane (20 ml) under nitrogen was cooled with stirring to 4°, and treated successively with dicyclohexylcarbodiimide (227 mg, 1.1 mmol) and 1-hydroxybenzotriazole (147 mg, 1.1 mmol), then stirred at the same temperature for 1 hour. N,N-Diisopropylethylamine (129 mg, 1 mmol) was added, followed by 3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (399 mg, 0.92 mmol). The mixture was stirred for 2 hours, allowing the temperature to rise to ambient. Solid was filtered off, and the organic solution washed with water (2×20 ml), dried over magnesium sulfate and evaporated to dryness. The residue was purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (82 mg).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:16])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:18]1[N:19]([CH3:32])[C:20](=[O:31])[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[F:30])[N:23]=1.C(N(CC)CC)C>O1CCCC1>[CH3:2][N:3]([CH3:16])[C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([C:18]3[N:19]([CH3:32])[C:20](=[O:31])[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][C:25]=4[F:30])[N:23]=3)[CH2:11]2)=[CH:8][CH:9]=1
Reactant: CN(C)c1ccc([C@H]2CNCCO2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)c1ccc([C@H]2CN(c3nc(-c4ccncc4F)cc(=O)n3C)CCO2)cc1
Yield: 46.1 %

Procedure:
A solution of (2S)-2-(4-(dimethylamino)phenyl)morpholine hydrochloride (0.20 g, 0.64 mmol), 2-chloro-1-methyl-6-oxo-4-(3-fluoropyridin-4-yl)-1,6-dihydropyrimidine (0.12 g, 0.53 mmol), and triethylamine (0.19 g, 1.92 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for 3 hours. The solvent was evaporated off in vacuo and the residue treated with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (chloroform-methanol, 10:1) to afford 2-((2S)-2-(4-(dimethylamino)phenyl)morpholin-4-yl)-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.10 g, 50%) as yellow crystals
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]#[N:15])=[C:7]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)([O-])=O.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCO>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]#[N:15])=[C:7]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(C(F)(F)F)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A mixture of 6.0 g (16.8 mmol) of 6-nitro-4-(3-trifluoromethylphenylamino)quinoline-3-carbonitrile and 18.9 g (83.8 mmol) of SnCl2.2H2O in 240 mL of EtOH was refluxed under N2 for 1 hr. Ice water was added followed by NaHCO3 to pH 8. The mixture was stirred for 2 hr and then extracted with CHCl3. Darco was added and the extracts were filtered through anhyd MgSO4 and evaporated. The residue was filtered through silica gel with 10% MeOH in CHCl3. Solvent evaporation and drying in vacuo (40° C.) gave 4.87 g of 6-amino-4-(3-trifluoromethylphenylamino)quinoline-3-carbonitrile as a brown solid: mass spectrum (electrospray, m/e): M+H 329.1.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:31])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=C(Cl)C=C(C(OO)=[O:44])C=1.[OH-].[Na+]>C(Cl)Cl>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:22][C:21]([Cl:31])=[N+:20]([O-:44])[CH:19]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(Cl)[n+]([O-])cc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To the solution of 2-(3,5-bis(trifluoromethyl)phenyl)-N-(6-chloro-4-(o-tolyl)pyridin-3-yl)-N,2-dimethylpropanamide (5.14 g, 10 mmol) in 60 mL of DCM was added m-CPBA (6.92 g, 40 mmol) at 0° C. under N2 atmosphere. Then the solution was stirred overnight at room temperature. 1 N aq. NaOH solution was added to wash twice for removing the excess m-CPBA and a side product. The organic phase was washed by brine, dried over Na2SO4, filtered and concentrated to afford 5.11 g of crude 5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-2-chloro-4-(o-tolyl)pyridine 1-oxide as a white solid (Yield: 96.4%).
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:11])([CH2:9][CH3:10])[S:4]1)[OH:2].[C:12]([N:15]([CH3:19])[C:16](Cl)=[O:17])(=[O:14])[CH3:13]>>[CH3:19][N:15]([C:12](=[O:14])[CH3:13])[C:16]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:11])([CH2:9][CH3:10])[S:4]1)=[O:17]
Reactant: CCC1(C)SC(=NO)N=C1C
Reactant: CC(=O)N(C)C(=O)Cl
Product: CCC1(C)SC(=NOC(=O)N(C)C(C)=O)N=C1C

Procedure:
2-oxo-4,5-dimethyl-5-ethyl-3-thiazoline-oxime was reacted with N-acetyl-N-methyl-carbamoyl chloride as described above to yield 2-oxo-4,5-dimethyl-5-ethyl-3-thiazoline-O-[methyl(acetyl)carbamoyl]oxime, m.p. 98°-101° C.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.[ClH:36]>O1CCCC1.ClCCl>[ClH:36].[OH:1][C@@H:2]([CH2:3][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@@H]2CO2)c1
Reactant: C1CCNC1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@@H](O)CN2CCCC2)c1
Temperature: 45 °C
Yield: 87.3 %

Procedure:
To (R)-1-(1-(oxiran-2-ylmethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)-pyridin-2(1H)-one (250 mg, 0.61 mmol) in tetrahydrofuran (5 mL) was added LiClO4 (969 mg, 9.11 mmol) followed by pyrrolidine (0.51 mL, 6.1 mmol). The reaction mixture was heated in a 45° C. oil bath for 3.75 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml) and washed with water (25 mL), brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The material was purified by column chromatography (silica gel, 9:1 CH2Cl2/MeOH to 90:9:1 CH2Cl2/MeOH/conc. NH4OH). The dried residue (233 mg, 0.48 mmol) was dissolved in dichloromethane (2 mL), and HCl (1.25 M solution in methanol, 0.42 mL, 0.53 mmol) was added. The mixture was concentrated under reduced pressure and dried to afford the title compound (240 mg, 76%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 9.60 (br s, 1H), 8.20 (s, 1H), 8.02-8.00 (m, 2H), 7.89-7.80 (m, 5H), 7.46 (dd, J=8.5, 1.5 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.74 (dd, J=7.5, 2.0 Hz, 1H), 4.57-4.53 (m, 1H), 4.49-4.46 (m, 1H), 4.27 (br s, 1H), 3.25-2.75 (br m, 6H), 1.85 (br s, 4H); ESI MS m/z 483 [M+H]+; HPLC (Method B)>99% (AUC), tR=15.1 min; [α]23D −11.3° (c 0.11, Methanol).
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1([CH3:14])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH2:5]1>C(O)=O>[CH3:3][C:4]1([CH3:14])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6](=[O:1])[CH2:5]1
Reactant: CC1(C)CC=Cc2ccccc21
Reactant: OO
Solvent: O=CO
Product: CC1(C)CC(=O)Cc2ccccc21
Temperature: 25 °C
Yield: 40 %

Procedure:
To a stirred mixture of 30% hydrogen peroxide (5 ml) and 97% formic acid (20 ml) in a round bottom flask equipped with an additional funnel, thermometer, and an ice water bath was added 1,2-dihydro-1,1-dimethylnaphthalene (4.5 g, 28 mmoles) dropwise at 5° C. under a nitrogen atmosphere. When the addition was complete, the reaction vessel was raised above the cooling bath to allow the reaction temperature to rise to just below 35° C. at which point the flask was immersed again. In this manner the temperature of the reaction was maintained between 30° and 35° C. for 45 minutes. After this time the exothermic phase of the reaction ended and the mixture was allowed to cool to room temperature. A solution of 10% aqueous ferric sulfate was added in portions of a few milliliters each until cloudiness persisted in the stirred mixture and then all solvent was removed under reduced pressure. The viscous brown residue was refluxed with 20% H2SO4 (20 ml) for 4 hours and then cooled, extracted three times with ether (75 ml each), dried over magnesium sulfate, filtered and evaporated to leave a brown oil. This was purified using silica gel column chromatography eluting with ethyl acetate:hexane (7:93) to give 4,4-dimethyl-2-tetralone. (3.4 g, 74%). Overall yield=40%.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[I-].C[N+]1C=CN([C:15](=[O:24])[N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C=1.C(N(CC)CC)C>C(#N)C>[CH3:7][C:5]1[O:4][N:3]=[C:2]([O:1][C:15](=[O:24])[N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Cc1cc(O)no1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=O)N(C)c2ccccc2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
A mixture of 3-hydroxy-5-methylisoxazole (0.30 g, 3.00 mmol)), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (25:75)) yielding the title compound (0.67 g, 96% yield) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][N:31]3[CH2:32][CH2:33][CH:28]([C:24]4[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=4)[CH2:29][CH2:30]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(Cl)cc4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(4-chlorophenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.34–7.19 (m, 7H), 6.98–6.87 (m, 5H), 3.50 (s, 2H), 2.98 (d, 2H, J=11.8 Hz), 2.58–2.44 (m, 2H), 2.10–1.98 (m, 2H), 1.83–1.76 (m, 4H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 463.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][NH:7][C:6]=2[CH:10]=1.[CH3:11]I>>[CH3:11][N:7]1[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:9]=[N:8]1
Reactant: CI
Reactant: Cc1ccc2nn[nH]c2c1
Product: Cc1ccc2nnn(C)c2c1

Procedure:
6-Methylbenzotriazole is reacted with methyl iodide, yielding the title compound (in addition to the isomeric 2-methyl-2H and 3-methyl-3H compounds). The title compound is obtained in pure form by chromatography.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:10][CH:9]([O:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][NH:7]1)=[O:5].[C:22]([O:26][C:27]([NH:29][CH:30]([CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:2][O:3][C:4]([CH:6]1[CH2:10][CH:9]([O:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][N:7]1[C:31](=[O:32])[CH:30]([NH:29][C:27]([O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:28])[CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:5]
Reactant: COC(=O)C1CC(OS(=O)(=O)c2ccc(Br)cc2)CN1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CC(OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)C(NC(=O)OC(C)(C)C)C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.2 %

Procedure:
To a solution of 4-(4-bromo-benzenesulfonyloxy)-pyrrolidine-2-carboxylic acid methyl ester HCl salt (4 g, 10 mmol) in DCM (50 mL) was added tert-butoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (2.86 g, 11 mmol), HATU (5.7 g, 15 mmol) and DIPEA (7 mL, 40 mmol). The solution was stirred at room temperature for 16 h. The solution was diluted with DCM and washed twice with aq NH4Cl and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The desired product was purified by silica gel column chromotography from hexane/EtOAc to provide 4-(4-bromo-benzenesulfonyloxy)-1-[2-tert-butoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidine-2-carboxylic acid methyl ester (4.25 g 70% yield). LCMS found 606 ([M+H]+.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:17]1[CH2:28][CH2:27][CH2:26][C@H:18]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[CH3:14])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[H][H].C(Cl)(Cl)Cl.CO>CO.[Pd]>[NH2:1][C@H:2]([C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:17]1[CH2:28][CH2:27][CH2:26][C@H:18]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[CH3:14])=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C

Procedure:
533 mg of Z-Val-Gly-Ala-Pro-OtBu are hydrogenated in 10 ml of methanol in the presence of 300 mg of Pd on charcoal (10%) at room temperature. The hydrogen uptake has ended after 20 minutes. The catalyst is filtered off and the filtrate evaporated in a waterpump vacuum at 30°C to give an oil. Rf = 0.52 in the system chloroform-methanol (1:1) on silica gel.