Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].C[N:33]1[CH2:38][CH2:37][O:36]CC1.CN([C:42]([O:46]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:36][CH2:37][CH:38]([NH:33][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH2:42][OH:46]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CN1CCOCC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NC(CO)CO)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 32.6 %

Procedure:
Single enantiomer 2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 30 mg, 0.070 mmol), (R/S)-2-aminopropane-1,3-diol (9.51 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were dissolved in DMF (1 mL). After stirring 1 h, the reaction mixture was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.33 min) to provide the product N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide as a mixture of diastereomers (13 mg, 0.023 mmol, 32.6% yield): LCMS=505.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.27 (2 H, m), 7.92-8.01 (1 H, m), 7.50-7.81 (7 H, m), 5.16 (1 H, s), 3.95 (1 H, dt, J=8.53, 5.42 Hz), 3.55-3.79 (4 H, m); HPLC peak RT=8.3 min (Method A).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]([F:39])([F:38])[C:7]1[CH:8]=[C:9]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]#[N:20])[CH2:14][C@H:13]1[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:11].[Cl-:40].[NH4+]>CN(C)C=O>[ClH:40].[F:38][C:6]([F:5])([F:39])[C:7]1[CH:8]=[C:9]([CH:31]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:33]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[NH:20][N:3]=[N:2][N:1]=2)[CH2:14][C@H:13]1[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: [Cl-]
Reactant: N#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2nnn[nH]2)C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 115 °C
Reaction time: 16 h
Yield: 51.2 %

Procedure:
Sodium azide (0.21 g) was added to a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(cyanomethyl)-2-(1H-indol-3-yl-methyl)piperazine (0.32 g) and ammonium chloride (0.17 g) in dimethylformamide (5 ml). The mixture was stirred at 115° C. for 16 hours. Additional sodium azide and ammonium chloride were added to the reaction mixture until the starting material was consumed. After cooling, the mixture was poured into ice-cold water. The resulting precipitate was collected by filtration, washed with water and dried. The precipitate was treated with 4N hydrogen chloride in dioxane solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)-4-(1H-tetrazol-5-yl-methyl)piperazine hydrochloride (0.19 g).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[F:7][C:8]([F:19])([F:18])[C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[CH:30][C:31]3[CH2:38][C@H:37]4[C@:39]5([CH2:43][N:42]([CH2:44][C:45]([F:48])([F:47])[F:46])[S:41](=[O:50])(=[O:49])[NH:40]5)[C@H:34]([CH2:35][CH2:36]4)[CH2:33][C:32]=3[CH:51]=2)O1>CS(C)=O>[F:7][C:8]([F:19])([F:18])[C:9]1[CH:14]=[CH:13][C:12]([N:5]2[CH:6]=[C:2]([C:28]3[CH:29]=[CH:30][C:31]4[CH2:38][C@H:37]5[C@:39]6([CH2:43][N:42]([CH2:44][C:45]([F:48])([F:47])[F:46])[S:41](=[O:49])(=[O:50])[NH:40]6)[C@H:34]([CH2:35][CH2:36]5)[CH2:33][C:32]=4[CH:51]=3)[N:3]=[CH:4]2)=[CH:11][CH:10]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC1(C)OB(c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)OC1(C)C
Reactant: Brc1c[nH]cn1
Solvent: CS(C)=O
Product: O=S1(=O)N[C@@]2(CN1CC(F)(F)F)[C@@H]1CC[C@H]2Cc2ccc(-c3cn(-c4ccc(C(F)(F)F)cc4)cn3)cc2C1

Procedure:
Prepared from 4-bromo-1H-imidazole, 4-(trifluoromethyl)phenylboronic acid and homochiral boronate from Example 24 Step 1 following the procedures in Example 76 Steps 1 and 2. δ (1H, 360 MHz, DMSO) 1.08-1.11 (2H, m), 1.67-1.75 (2H, m), 2.35-2.38 (2H, m), 2.56-2.70 (2H, m), 3.15-3.20 (2H, m), 3.46 (2H, s), 4.00-4.05 (2H, m), 7.15 (1H, d, J=7.2 Hz), 7.56-7.62 (2H, m), 7.90-8.05 (4H, m), 8.36 (1H, s), 8.49 (1H, s). MS (ES+) 571 ([MH]+).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])=[C:12]([C:14]2[C:15]([F:22])=[CH:16][C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)[CH:13]=1.N1C=CC=CC=1.Cl>ClCCl>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[O:23][C:11]1[CH:10]=[CH:9][C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:13][C:12]=1[C:14]1[C:15]([F:22])=[CH:16][C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2F)c(F)cc1=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)cc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
Ethylsulfonyl chloride (177 mg, 1.4 mmol) was added dropwise to a stirred solution of 5-[5-amino-2-(2,4-difluorophenoxyl)phenyl]-4-fluoro-1-methylpyridin-2-one (72 mg, 0.21 mmol) and pyridine (50 μL, 0.63 mmol) in dichloromethane (500 μL) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir for 2 h, it was treated with 1N HCl (3 mL) and extracted with dichloromethane (3×10 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (4 g ISCO, gradient 0-10% MeOH in dichloromethane) to afford the desired product, N-[4-(2,4-difluorophenoxy)-3-(4-fluoro-1-methyl-6-oxopyridin-3-yl)phenyl]ethanesulfonamide (66 mg, 72%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.18-1.26 (m, 3H), 3.07-3.16 (m, 2H), 3.45 (s, 3H), 6.22-6.33 (m, 1H), 6.82-6.93 (m, 1H), 7.01-7.16 (m, 2H), 7.18-7.28 (m, 2H), 7.38-7.49 (m, 1H), 7.95-8.05 (m, 1H), 9.77-9.87 (s, 1H). LCMS (M+H)+ =439.
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.[O:17]=[C:18]1[O:22][C@H:21]2[CH2:23][C@@H:24]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:25]([CH:26]=O)[C@H:20]2[CH2:19]1>CC(OC)(C)C.O.ClCCl.[Zn](O)O>[F:15][C:9]([F:14])([CH2:10][CH2:11][CH2:12][CH3:13])[C:8](=[O:16])/[CH:7]=[CH:26]/[C@@H:25]1[C@@H:20]2[C@@H:21]([O:22][C:18](=[O:17])[CH2:19]2)[CH2:23][C@H:24]1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OCc1ccccc1
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: O[Zn]O
Solvent: O
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 76 %

Procedure:
To a mixture of dimethyl(3,3-difluoro-2-oxoheptyl)phosphonate (210 mg, 0.81 mmoL) in MTBE/H2O (3/0.1 mL) was added Zn(OH)2 (100 mg, 0.81 mmoL) and the mixture was stirred under nitrogen for 1 h. A solution of (3aR,4R,5R,6aS)-hexahydro-2-oxo-5-(phenylmethoxy)-2H-cyclopenta[b]furan-4-carboxaldehyde (200 mg, 0.77 mmoL) in dichloromethane (3 mL) was added and the mixture was stirred for 24 h. After completion of the reaction, the reaction was then quenched with cold 1N HCl (12 mL). The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to dryness under vacuum. The crude material was further purified by column chromatography [25% ethyl acetate in heptanes] to yield (3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-2-oxo-5-(phenylmethoxy)hexahydro-2H-cyclopenta[b]furan (7, R1 is phenyl, and R2 and R3 are H) in 76% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[S].CC1C=CC2C(OC(=O)C2C1)=O>>[CH2:11]=[CH:12][C:2](=[CH2:1])[CH3:3].[C:6]1(=[O:7])[O:8][C:9](=[O:10])[CH:4]=[CH:5]1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Agent: CC1C=CC2C(=O)OC(=O)C2C1
Agent: [S]
Product: C=CC(=C)C
Product: O=C1C=CC(=O)O1

Procedure:
4-Methylphthalic anhydride is also able to be prepared by dehydrogenation, with sulfur, of tetrahydro-4-methylphthalic anhydride obtained from the reaction between isoprene and maleic anhydride: ##STR4##
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9](=[O:22])[N:8]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(O)(OO)(=O)=[O:30]>>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][S:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:30])[C:9](=[O:22])[N:8]2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C(CCSc2ccccc2)C(=O)N(c2ccccc2)N1c1ccccc1
Reactant: O=S(=O)(O)OO
Product: O=C1C(CCS(=O)c2ccccc2)C(=O)N(c2ccccc2)N1c1ccccc1

Procedure:
Herein is described a process for oxidizing 1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione with peroxymonosulfuric acid to obtain 1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl]-3,5-pyrazolidinedione.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([O:11][C:12]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([N:22]=[C:23]([N:25]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:33])[CH2:27][CH2:26]3)[CH3:24])[C:13]=2[C:14]#[N:15])[CH2:10][CH2:9][CH2:8]1>COCCOC>[NH3:15].[NH2:15][C:14]1[C:13]2[C:16](=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=2[O:11][CH:7]2[CH2:8][CH2:9][CH2:10]2)[N:22]=[C:23]([N:25]2[CH2:31][CH2:30][CH2:29][N:28]([C:32]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[O:33])[CH2:27][CH2:26]2)[CH:24]=1
Reactant: COc1cc(N=C(C)N2CCCN(C(=O)N3CCOCC3)CC2)c(C#N)c(OC2CCC2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1cc(OC2CCC2)c2c(N)cc(N3CCCN(C(=O)N4CCOCC4)CC3)nc2c1
Product: N
Temperature: 90 °C
Reaction time: 1 h
Yield: 112.5 %

Procedure:
Potassium tert-butoxide (810 mg, 0.00725 mol) was added to a solution of 2-cyclobutyloxy-4-methoxy-6-{1-[4-(morpholinecarbonyl)-1,4-diazepan-1-yl]ethylidene-amino}benzonitrile (1.65 g, 0.00363 mol) in 1,2-dimethoxyethane (250 ml) and the reaction stirred at 90° C. under a nitrogen atmosphere for 1 hour. On cooling, the reaction mixture was washed with 1N aqueous citric acid solution (100 ml) and extracted with ethyl acetate (100 ml). The aqueous layer was then basified with 2N aqueous sodium hydroxide solution and extracted with dichloromethane (2×100 ml). These combined organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with a solvent gradient of dichloromethane:methanol:0.880 aqueous ammonia (100:0:0 to 91:9:1 v/v) gave the title compound as a foam (0.93 g, 56%). Rf 0.27 (dichloromethane:methanol:0.880 aqueous ammonia, 97:2:1, v/v). MS m/z 456 (MH)+. 1H-NMR (CDCl3): δ=1.75 (1H, m), 1.92 (1H, m), 2.05 (2H, m), 2.24 (2H, m), 2.54 (2H, m), 3.14 (4H, t), 3.34 (2H, t), 3.57 (2H, t), 3.64 (4H, t), 3.70 (2H, t), 3.88 (3H, s), 3.94 (2H, bm), 4.62 (1H, m), 5.55 (2H, bs), 5.70 (1H, s) 5.96 (1H, s), 6.56 (1H, bs). Found: C, 60.87; H, 7.45; N, 14.79; C24H33N5O4H2O, requires C, 60.67; H, 7.08; N, 14.51%.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)[N:14]=[C:13]([NH:27][CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:12]=1>C1C=CC=CC=1>[Cl:26][C:20]1[CH:19]=[C:18]([NH:17][C:15]2[N:14]=[C:13]([NH:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[N:12]=[C:11]([N:4]3[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]3)[N:16]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: OC1CCCNC1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N3CCCC(O)C3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 3-hydroxypiperidine (0.198 g, 1.96 mmol) and sodium hydroxide (79 mg, 1.96 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.25 g, 0.65 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography (1–2% MeOH—CHCl3) to afford the title compound E23 as an off-white solid (0.06 g, 21%). mp 100–102° C.; HPLC: Hichrom RPB (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 5.5); solvent B═CH3CN], Gradient elution program: T/% B=0/20, 10/20,25/80, 40/80, 55/60, 65/20, 70/20; 270 nm, Rt 41.95 min, 98.43% purity; MS (CI): m/z 447 (M+H, 100).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.CCN(CC)CC.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.F[C:32](F)(F)[CH2:33][O:34]P(CC(OC)=O)(=O)OCC(F)(F)F>C1COCC1.ClCCl>[Cl:10][C:6]1[C:7]2[CH:8]=[CH:32][C:33](=[O:34])[N:26]([C:25]3[CH:27]=[CH:28][C:22]([C:21]([F:29])([F:30])[F:20])=[CH:23][CH:24]=3)[C:2]=2[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1nc(Cl)c2ccc(=O)n(-c3ccc(C(F)(F)F)cc3)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.9 %

Procedure:
A solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (1.0 g, 4.5 mmol) and Et3N (1.26 mL, 9.0 mmol) in THF (25 mL) was mixed with 4-trifluoromethylaniline (0.62 mL, 4.9 mmol). The resultant mixture was stirred at room temperature for 2 hours before bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)-phosphonate (0.95 mL, 4.5 mmol) was added. After stirring at room temperature for additional 12 hours, the mixture was diluted with dichloromethane (50 mL) and washed with H2O (2×25 mL). The organic layer was dried over Na2SO4, filtered and concentrated. This crude product was further purified by washing with a mixture of THF/Hexane (1: 3, 2>10 mL) to provide the title compound (1.17 g, 70%): MS (ES) m/z 372 (M+H)+; 1H-NMR(CDCl3) δ 2.18 (s, 3H), 6.79 (d, J=9.8 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H), 8.03 (d, J=9.8 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][C:3]1=[O:8].CC(C)([O-])C.[K+].[N:15](OCC(C)C)=[O:16].Cl>O1CCCC1.C(O)C>[N:15](=[C:4]1[C:3](=[O:8])[N:2]([CH3:1])[CH2:7][CH2:6][O:5]1)[OH:16]
Reactant: CN1CCOCC1=O
Reactant: CC(C)CON=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCOC(=NO)C1=O

Procedure:
While maintaining the temperature near -55°, a solution of 11.5 grams of 4-methyltetrahydro-1,4-oxazin-3-one dissolved in 100 ml of anhydrous tetrahydrofuran was added over a period of twenty minutes to a slurry of 14.6 grams of potassium t-butoxide in 100 ml of tetrahydrofuran vigorously stirring under a nitrogen atmosphere. After equilibrating the resultant mixture for 30 minutes at -60°, a solution of 11.4 grams of isobutyl nitrite in 50 ml of tetrahydrofuran was added over 15 minutes while maintaining the temperature at -60° with external cooling. After a 15-minute equilibration at -60°, the reaction mixture was brought to 25° and stirred for 3 hours. The solution was then cooled to 0° and neutralized to pH 5 with 65 ml of a solution of 18 ml of conc. hydrochloric acid diluted to 100 mls. with absolute ethanol. After a 15-minute equilibration, potassium chloride was filtered off and the solvent removed in vacuuo. The resulting oil was triturated with 50 ml of ethyl acetate and the resulting solid was collected and then recrystallized from 150 ml. of acetonitrile yielding 5.07 g of the oxime product, mp. 199°-201°.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].C([CH:8]([C:22]([O-:24])=O)[C:9]([C:19]([O-:21])=O)([OH:18])[C:10](CC)(CC)[C:11]([O-:13])=O)C>CO>[CH2:1]([NH:5][C:11](=[O:13])[CH2:10][C:9]([CH2:8][C:22]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:24])([C:19]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:21])[OH:18])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: CCC(C(=O)[O-])C(O)(C(=O)[O-])C(CC)(CC)C(=O)[O-]
Solvent: CO
Product: CC(C)CNC(=O)CC(O)(CC(=O)NCC(C)C)C(=O)NCC(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.3 %

Procedure:
N,N′,N″-tri-iso-butylcitramide was prepared by the reaction of iso-butylamine with triethylcitrate. To a round-bottomed flask were added triethylcitrate (30.001 g; 1 eq), iso-butylamine (24.034 g; 3.03 eq) and methanol (40 mL). The clear light yellow solution stirred for 2 days at room temperature and then additional isobutylamine (3.06 eq) was added. After stirring overnight, a wet white solid was observed. Methanol was removed in vacuo and the solid was triturated using diethylether, collected via filtration and dried in vacuo to give a white powder with no detectable odor (31.09 g; 80.3% yield).
Reaction SMILES: [C:1]12[CH:22]=[CH:21][CH:20]=[C:19]([N:23]=1)[CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[N:24][C:8](=[CH:9][CH:10]=[CH:11]1)[CH2:7][NH:6][CH2:5][CH2:4][NH:3][CH2:2]2.C(N([CH2:30][CH3:31])CC)C.ClCl.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[C:30]1([CH3:31])[CH:39]=[CH:38][C:37]([S:40]([N:17]2[CH2:16][CH2:15][N:14]([S:40]([C:37]3[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=3)(=[O:42])=[O:41])[CH2:13][C:12]3[N:24]=[C:8]([CH:9]=[CH:10][CH:11]=3)[CH2:7][N:6]([S:40]([C:37]3[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=3)(=[O:42])=[O:41])[CH2:5][CH2:4][NH:3][CH2:2][C:1]3[N:23]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:18]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cc2nc(c1)CNCCNCc1cccc(n1)CNCCNC2
Reactant: CCN(CC)CC
Agent: ClCl
Product: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)Cc3cccc(n3)CN(S(=O)(=O)c3ccc(C)cc3)CCNCc3cccc(n3)C2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a stirred solution of 3,6,14,17,23,24-hexaazatricyclo-[17.3.1.18,12 ]tetracosa-1(23),8,10,12(24),19,21-hexaene (460 mg, 1.41 mmol) (G L Rothermel, L Miao, A L Hill, L C Jackels, Inorg Chem, 1992, 31, 4854) and triethylamine (0.60 ml, 4.233 mmol) at 0° C. in 40 ml of CH2 Cl2 under an argon atmosphere was added a solution of p-toluenesulphonyl chloride (804 mg, 4.233 mmol) in 10 ml of CH2 Cl2 dropwise over 15 min. The solution was stirred at 0° C. for 30 minutes and warmed to room temperature and stirred a further 4 hours. The reaction mixture was quenched with saturated NH4Cl (10 ml), the aqueous phase extracted with CH2Cl2, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 5% MeOH in CH2Cl2 as eluent giving 3,6,14-tris(p-toluenesulphonyl)-3,6,14,17,23,24-hexaaza-tricyclo[17.3.1.18,12 ]tetracosa-1(23),8,10,12(24),19,21-hexaene (300 mg, 27%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.[Al](Cl)(C)C.[CH3:12][C:13]1[S:14][C:15]2[C:21]([O:22][C@@H:23]([CH3:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][C:19]([C:32](OCC)=[O:33])=[CH:18][C:16]=2[CH:17]=1>ClCCCl>[CH3:12][C:13]1[S:14][C:15]2[C:21]([O:22][CH:23]([CH3:31])[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:20][C:19]([C:32]([NH:1][C:2]3[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=3)=[O:33])=[CH:18][C:16]=2[CH:17]=1
Reactant: CCOC(=O)c1cc(O[C@@H](C)Cc2ccccc2)c2sc(C)cc2c1
Reactant: Cn1ccc(N)n1
Agent: C[Al](C)Cl
Solvent: ClCCCl
Product: Cc1cc2cc(C(=O)Nc3ccn(C)n3)cc(OC(C)Cc3ccccc3)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
3-Amino-1-methylpyrazole (649 mg, 6.69 mmol) was dissolved in DCE (10 mL) at 0° C., then Al(CH3)2Cl (6.69 mL, 1M in hexanes) was added drop wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 min at room temperature. Ethyl 2-methyl-7-[(1S)-1-methyl-2-phenylethoxy]-1-benzothiophene-5-carboxylate (237 mg, 0.669 mmol) was added and the stirring was continued for 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl3, washed with brine and dried over MgSO4. The product was purified by reverse phase HPLC to give the title compound (155 mg, 57%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (d, J=6.03 Hz, 3 H) 2.59 (s, 3 H) 2.95 (dd, J=13.75, 6.22 Hz, 1 H) 3.16 (dd, J=13.75, 6.03 Hz, 1 H) 3.74 (s, 3 H) 4.78-5.01 (m, 1 H) 6.89 (d, J=2.26 Hz, 1 H) 7.00 (d, J=1.13 Hz, 1 H) 7.12-7.23 (m, 1 H) 7.26-7.42 (m, 6 H) 7.81 (d, J=1.13 Hz, 1 H) 9.60 (s, 1 H). LCMS m/z 406.0 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][S:5][CH:6]2[CH2:11][CH2:10][CH:9]([C:12]#[N:13])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.[CH:14]1([CH2:17]Br)[CH2:16][CH2:15]1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>C1COCC1>[CH:14]1([CH2:17][C:9]2([C:12]#[N:13])[CH2:10][CH2:11][CH:6]([S:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:7][CH2:8]2)[CH2:16][CH2:15]1
Reactant: N#CC1CCC(SCC2CC2)CC1
Reactant: BrCC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(CC2CC2)CCC(SCC2CC2)CC1

Procedure:
4-[(cyclopropylmethyl)thio]cyclohexanecarbonitrile (either isomer) (1.95 g; 10 mmol) was dissolved in THF (10 mL) and cyclopropyl methyl bromide (2.7 g; 20 mmol) was added followed by the dropwise addition of sodium hexamethyldisilazide (2M, 10 mL, 20 mmol). The reaction was stirred for half an hour and then was quenched with brine and extracted into ethyl acetate. The organic layer was dried and product was purified rigorously from its less polar isomer on silica using a Biotage 65i cartridge eluting with EtOAc/isohexane to yield 1-(cyclopropylmethyl)4-[(cyclopropylmethyl)thio]cyclohexanecarbonitrile as an oil. (2 g, 80%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][CH2:20][OH:21])=[C:11]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH3:35])=[C:29]([O:36][CH3:37])[C:28]=3[O:38][CH3:39])=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[CH3:47][S:48]([O:21][CH2:20][CH2:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][C:11]=1[NH:22][C:23]([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([O:34][CH3:35])=[C:29]([O:36][CH3:37])[C:28]=2[O:38][CH3:39])=[O:24])(=[O:50])=[O:49]
Reactant: COc1cc2cc(C(=O)Nc3cc(OCc4ccccc4)c4ccccc4c3CCO)[nH]c2c(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2cc(C(=O)Nc3cc(OCc4ccccc4)c4ccccc4c3CCOS(C)(=O)=O)[nH]c2c(OC)c1OC
Reaction time: 1 h
Yield: 121.3 %

Procedure:
To a solution of 2-[4-benzyloxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethanol (80 mg, 0.15 mmol) and triethylamine (0.09 mL, 0.61 mmol) in CH2Cl2 (2 mL) was added methanesulfonyl chloride (0.05 mL, 0.61 mmol) with ice bath, and then the mixture was stirred for 1 h. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with H2O (10 mL) and saturated aqueous NaCl (20 mL), and then the organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield as a brown oil 2-[4-benzyloxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl methanesulfonate (0.11 g, quant); 1H NMR (CDC3, 500 MHz) δ 9.24 (s, 1H), 8.47 (s, 1H), 8.41 (d, 8.0, 1H), 7.85 (d, 8.5, 1H), 7.71 (dd, 3.5, 5.5, 1H), 7.60 (t, 7.0, 1H), 7.48-7.56 (m, 3H), 7.44 (t, 8.0, 2H), 7.37 (t, 7.5, 1H), 7.18 (s, 1H), 6.88 (s, 1H), 5.28 (s, 2H), 4.63 (t, 6.5, 2H), 4.09 (s, 3H), 3.95 (s, 3H), 3.93 (s, 3H), 3.56 (t, 6.5, 2H), 2.86 (s, 3H); EIMS m/z 509 (M−CH3SO3H+); IR (neat) νmax 3330, 3099, 2933, 2874, 1725, 1649, 1592, 1537, 1502, 1466, 1411, 1369, 1306, 1238, 1174, 1127, 1076, 1048, 998, 972, 951, 833, 796, 751, 702 cm−1.