Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH3:41])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:37](=[O:38])[C:36]2[N:35]([CH3:39])[CH:34]=[N:33][C:32]=2[N:31]([CH3:40])[C:29]1=[O:30].C(N(CC)CC)C.Cl>ClCCl>[O:11]=[C:12]([CH3:41])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:37](=[O:38])[C:36]2[N:35]([CH3:39])[CH:34]=[N:33][C:32]=2[N:31]([CH3:40])[C:29]1=[O:30]
Reactant: CC(O)CCCCCCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)CCCCCCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 46.2 %

Procedure:
To a solution of oxalyl chloride (0.036 ml, 0.41 mmol) in dichloromethane (3 ml) at -78° C. was added dimethylsulfoxide (0.063 ml, 0.82 mmol), and over 5 minutes, 1-(16-hydroxyheptadecyl)-3,7-dimethylxanthine (0.15 g, 0.35 mmol) in dichlorornethane (2 ml). The resulting reaction mixture was stirred at -78° C. for 30 minutes, and after the addition of triethylamine (0.23 ml, 1.64 mmol), was allowed to warm to 25° C. olier 30 minutes. Hydrochloric acid (1.0M, 10 ml) and dichloromethane (5 ml) were added to the warmed reaction mixture. The organic phase was separated and the aqueous phase was washed with dichlorornethane (10 ml). The organic portions were combined, dried over magnesium sulfate and evaporated to obtain a slightly yellow solid. The yellow solid, purified by chromatography (silica, ethyl acetate/hexane) resulted in 0.070 g of 1-(16-oxoheptadecyl)-3,7-dimethylxanthine as a white solid (47% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>C1COCC1>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([N:12]([CH3:11])[CH2:13][CH2:14][OH:15])=[N:6][CH:7]=1
Reactant: CNCCO
Reactant: COc1nc(Cl)ncc1Br
Solvent: C1CCOC1
Product: COc1nc(N(C)CCO)ncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
A mixture of 5-bromo-2-chloro-4-methoxypyrimidine (5 g, 22.4 mmol) and 2-(methylamino)ethanol (2.19 g, 29.1 mmol) in THF (40 mL) was stirred for 18 h at rt and concentrated. The residue was purified by flash chromatography (hexane/EtOAc, 3:2) to afford 5.38 g of the title compound. tR: 0.84 min (LC-MS 2); ESI-MS: 262.1/264.1 [M+H]+ (LC-MS 2); Rf: 0.15 (hexane/EtOAc 3:2).
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH:3]([CH3:19])[CH:4]=[CH:5][CH:6]([CH:8]1[C:16]2([CH3:17])[CH:11]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15]2)[CH2:10][CH2:9]1)[CH3:7].[CH3:22][Si:23]([CH3:30])([CH3:29])N1C=CN=C1.O>C(Cl)Cl>[CH3:7][CH:6]([CH:8]1[C:16]2([CH3:17])[CH:11]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15]2)[CH2:10][CH2:9]1)[CH:5]=[CH:4][CH:3]([CH3:19])[C:2]([CH3:20])([O:1][Si:23]([CH3:30])([CH3:29])[CH3:22])[CH3:21]
Reactant: C[Si](C)(C)n1ccnc1
Reactant: CC(C=CC(C)C(C)(C)O)C1CCC2C(=O)CCCC21C
Solvent: O
Solvent: ClCCl
Product: CC(C=CC(C)C(C)(C)O[Si](C)(C)C)C1CCC2C(=O)CCCC21C
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
A solution of 200.0 mg (0.679 mmol) of [1R-[1α-(1R*,2E,4S*),3aβ,7aα]]-octahydro-1-(5-hydroxy-1,4,5-trimethyl-2-hexenyl)-7a-methyl-4H-inden-4-one in 10 mL of dry methylene chloride was treated with 0.4 mL (2.726 mmol) of N-(trimethylsilyl)imidazole and the resulting mixture stirred at room temperature, under argon, for 18 hours. It was then treated with 1 mL of water, stirred for an additional 30 minutes then diluted with methylene chloride. The organic phase was separated, washed with water and brine, dried and evaporated to dryness. The residue obtained was purified by rapid filtration through a short silica gel column, eluted with hexane-ethyl acetate (5:1) to give 214.0 mg (84% yield) of pure [1R-[1α-(1R*,2E,4S*),3aβ,7aα]]-octahydro-1-(1,4,5-trimethyl-5-trimethylsilyloxy-2-hexenyl)-7a-methyl-4H-inden-4-one, as a thick, colorless oil.
Reaction SMILES: I[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=1[CH3:11].[F-].[K+].CC1(C)C(C)(C)OB([C:22]2[CH:26]=[CH:25][S:24][CH:23]=2)O1>C1(C)C=CC=CC=1.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:11][C:3]1[N:4]=[C:5]([NH:7][C:8](=[O:10])[CH3:9])[S:6][C:2]=1[C:22]1[CH:26]=[CH:25][S:24][CH:23]=1
Reactant: CC1(C)OB(c2ccsc2)OC1(C)C
Reactant: CC(=O)Nc1nc(C)c(I)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [F-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc(C)c(-c2ccsc2)s1
Temperature: 120 °C
Yield: 66 %

Procedure:
In a microwave tube, N-(5-iodo-4-methyl-1,3-thiazol-2-yl)acetamide, Intermediate 1 (564.2 mg; 2 mmol; 1 eq) and Pd(dppf)Cl2 (73.2 mg; 0.10 mmol; 0.05 eq) are suspended in Toluene (7 ml). A solution of potassium fluoride (464.8 mg; 8 mmol; 4 eq) in MeOH (7 ml) is added. 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene (630.3 mg; 3 mmol; 1.50 eq) is finally added as a solid. The resulting solution is flushed with argon, the tube is closed and heated under microwave action at 120° C. for 15 minutes. The reaction mixture is filtered over Celite and the solvents are evaporated. The resulting crude product is dissolved in EtOAc, washed with water and brine and dried over MgSO4. It is then purified by preparative HPLC, affording the title compound as white-off solid (316.7 mg; 66% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24](=[O:25])[N:13]2[CH2:14][CH2:15][O:16][CH2:17][C:18]3([CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:12]2=[N:11][C:10]=1[C:26](O)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[N:38]1[C:42](=[O:43])[N:41]([CH3:44])[CH:40]=[N:39]1.C(N(C(C)C)CC)(C)C.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl>CC#N>[CH2:1]([O:8][C:9]1[C:24](=[O:25])[N:13]2[CH2:14][CH2:15][O:16][CH2:17][C:18]3([CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:12]2=[N:11][C:10]=1[C:26]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[N:38]1[C:42](=[O:43])[N:41]([CH3:44])[CH:40]=[N:39]1)=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cnn(-c2cc(F)ccc2CN)c1=O
Reactant: O=C(O)c1nc2n(c(=O)c1OCc1ccccc1)CCOCC21CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1cnn(-c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCOCC32CCOCC2)c1=O
Temperature: 23 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
To a solution of 3′-(benzyloxy)-4′-oxo-2,3,4′,5,6,6′,7′,9′-octahydrospiro[pyran-4,10′-pyrimido[1,2-d][1,4]oxazepine]-2′-carboxylic acid (0.095 g, 0.246 mmol) in CH3CN (15 mL) was added 1-(2-(aminomethyl)-5-fluorophenyl)-4-methyl-1H-1,2,4-triazol-5(4H)-one (0.070 g, 0.271 mmol), diisopropylethylamine (0.171 mL, 0.984 mmol) and O-(7-azabenzotriazole-1yl)-N,N,N′,N′-tetramethyluronium (0.103 g, 0.271 mmol). The reaction mixture was stirred at 23° C. for 18 hours. HCl (1N, 50 mL) was added and the organic material was extracted with EtOAc (3×50 mL). The combined organic phases were washed with H2O (50 mL), brine (50 mL), dried over MgSO4 and concentrated in vacuo. The crude material was purified on Silica gel column (Biotage™), eluted with EtOAc:Hex (1:1) to EtOAc 100% to afford the title compound as a white solid (0.130 g, 77%): 1H NMR (400 MHz, CDCl3) δ 8.54 (1 H, brs), 7.67 (1H, dd, J=8.7, 6.2 Hz), 7.52 (2H, m), 7.45 (1H, s), 7.27-7.36 (3H, m), 7.22 (1H, dd, J=9.3, 2.5 Hz), 7.08 (1H, td, J=8.2, 2.5 Hz), 5.31 (2H, s), 4.54 (2 H, d, J=6.3 Hz), 4.1-3.6 (10H, m), 3.36 (3H, s), 2.4-2.2 (1H, brm), 2.1-1.6 (2H, brs). LCMS (+ESI, M+H+) m/z 591.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:19]([OH:21])=[O:20])=O)(C)(C)C.[CH3:22][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO.C(O)(=O)C>[CH3:22][O:21][C:19]([C:10]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=2[CH:17]=[CH:18][C:9]=1[NH2:8])=[O:20]
Reactant: CC(C)(C)OC(=O)Nc1ccc2ccccc2c1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1c(N)ccc2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The white solid from Example 128B (7.17 g, 24.61 mmol) was dissolved in benzene (250 ml) and methanol (62 ml). To the stirring solution was added 2 M trimethylsilyldiazomethane (12.3 ml) until the yellow color persisted for ten minutes. The reaction was then stirred at room temperature or 1 hour. To the solution was added acetic acid until the yellow color disappeared. The solvent was then removed. The crude material (7.52 g, 24.61 mmol) was dissolved in acetic acid (100 mL) and Pt2O (3.50 g, 15.4 mmol) was added shaken in a reactor pressurized with 60 psi of H2 at 25° C. for 80 hours, filtered, and concentrated. The concentrate was treated with dichloromethane (70 mL) and TFA (12 mL) and stirred for 3 hours. The organic layer was washed with NaOH (2×250 mL) and brine (200 mL), dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 206+H)+; 1H NMR (300 MHz, DMSO-d6) δ 6.83 (d, 1H), 6.53 (d, 1H), 5.26 (bs, 2H), 3.78 (s, 3H), 2.62 (m, 2H), 2.57 (m, 2H), 1.64 (m, 4H).
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[Cl:19])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:20](Br)[C:21]#[CH:22]>>[CH2:22]([O:15][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:10]([O:9][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])=[C:11]([Cl:19])[CH:12]=1)[C:21]#[CH:20]
Reactant: CC(C)CCCC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: C#CCBr
Product: C#CCOC(=O)c1ccc(OC(C)CCCC(C)C)c(Cl)c1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(1,5-dimethylhexyl)oxy]-3-chlorobenzoic acid with propargyl bromide, there is obtained 4-[(1,5-dimethylhexyl)oxy]-3-chlorobenzoic acid propargyl ester; nD26 = 1.5155.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].CC(C)([O-])C.[Na+]>>[CH2:12]([N:16]([CH2:17][CH2:18][CH2:19][CH3:20])[C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNCCCC
Reactant: CC(C)(C)c1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCCCN(CCCC)c1ccc(C(C)(C)C)cc1
Yield: 89.1 %

Procedure:
According to the general procedure B, 2-tert-butylbromobenzene (213 mg, 1.00 mmol) reacted with N,N-di-n-butylamine (130 mg, 1.00 mmol) using 1 mol % of catalyst and sodium tert-butoxide (115 mg, 1.20 mmol) at 60° C. to give the title compound (233 mg, 89%) as an oil: 1H-NMR (300 MHz, CDCl3): δ 7.25 (d, 2H, J=8.7 Hz), 6.62 (d, 2H, J=8.7 Hz), 3.25 (t, 4H, J=7.2 and 8.1 Hz), 1.58 (m, 4H), 1.35 (M, 4H), 1.30 (s, 9H), 0.97 (t, 6H, J=7.2 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 146.01, 137.59, 125.92, 111.29, 50.84, 33.61, 31.56, 29.53, 20.39, 14.02. GC/MS(EI): m/z 261 (M+).
Reaction SMILES: [OH:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])=[O:11].Cl.O.[N+]([O-])([O-])=O.[Na+].[N-:27]=[N+:28]=[N-].[Na+]>>[OH:1][C:2]1[C:7]([N:8]=[N+:27]=[N-:28])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Br:19])=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cccc(NC(=O)Nc2ccccc2Br)c1O
Agent: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cccc(NC(=O)Nc2ccccc2Br)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
The N-(2-hydroxy-3-aminophenyl)-N'-(2-bromophenyl)urea(274 mg, 0.85 mmol) was added to HCl/H2O (0.85 mL/1.7 mL), cooled to 0° C. Sodium nitrate (58.6 mg, 0.85 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0° C. for 30 minutes. Sodium azide (55 mg, 0.85 mmol) was added to reaction mixture and it was warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours then it was extracted with three times with ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane:ethyl acetate; 5:1) gave product (210 mg, 71%). EI-MS m/z 349 (M+H)+.
Reaction SMILES: [P:1]([O:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[CH2:23][OH:24])[CH:16]=[CH:15][CH:14]=1)([O:7][CH2:8][CH:9]=[CH2:10])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].CC(C)=[O:27].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.CC(O)C>CC(C)=O.O>[CH2:4]([O:3][P:1]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[C:21]([C:23]([OH:27])=[O:24])=[CH:20][CH:19]=[CH:18]2)([O:7][CH2:8][CH:9]=[CH2:10])=[O:2])[CH:5]=[CH2:6]
Reactant: CC(C)=O
Reactant: C=CCOP(=O)(OCC=C)OCc1cccc2cccc(CO)c12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: C=CCOP(=O)(OCC=C)OCc1cccc2cccc(C(=O)O)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of diallyl [8-(hydroxymethyl)-1-naphthyl]methyl phosphate (1.1492 g, 3.30 mmol) in acetone (20 ml) obtained from Example 25-(2) was added Jones reagent (a mixture of chromic anhydride (5.34 g) and concentrated sulfuric acid (4.6 ml) diluted with water to 20 ml total volume; 5 ml, ca. 13.2 mmol). The reaction mixture was stirred at room temperature for 90 minutes, then cooled to 0° C., and then 2-propanol (0.5 ml) was added thereto to stop the reaction. The insoluble material was filtered off, and the solvent was distilled off under reduced pressure to give an oily residue. The residue was dried using a vaccum pump, and then subjected to chromatography on a silica gel (30 g) column (eluent; ethyl acetate:dichloromethane=1:10˜3:10) to afford crude 8-[[bis(allyloxy)phosphoryl]oxymethyl]-1-naphthoic acid as an oil. The product was dissolved in dichloromethane (10 ml), and then oxalyl chloride (1 g, 7.88 mmol) and N,N-dimethylformamide (15 μl) were added thereto. After the mixture was stirred at room temperature for 30 minutes, crude 8-[[bis(allyloxy)phosphoryl]oxymethyl]-1-naphthoyl chloride was obtained according to a similar procedure to that described in Example 1-(12). According to a similar procedure to that described in Example 1-(12), 4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (542.7 mg, 1.0 mmol) described in Reference example 1, sodium hydride (55% dispersion in mineral oil; 43 mg, 1.0 mmol), and the crude 8-[[bis(allyloxy)phosphoryl]oxymethyl]-1-naphthoyl chloride obtained above were reacted in tetrahydrofuran (5 ml) and the reaction mixture was worked up to afford, after extraction, the title compound as a crude oil. The crude oil was subjected to chromatography on a silica gel (50 g) column (eluent; ethyl acetate:hexane=1:1˜5:1) to afford the title compound (459.2 mg, 52% yield) as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][C@H:2]1[N:7](CC2C=CC=CC=2)[C@@H:6]([CH3:15])[CH2:5][N:4]([C:16]2[CH:17]=[C:18]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[C:19](OC)=[N:20][CH:21]=2)[CH2:3]1.C[C@H]1N[C@@H](C)CN(C2C=C(NC(=O)OC(C)(C)C)C=NC=2)C1>>[CH3:15][C@H:6]1[NH:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:16]2[CH:17]=[C:18]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:27])[F:28])[CH:19]=[N:20][CH:21]=2)[CH2:5]1
Reactant: COc1ncc(N2C[C@@H](C)N(Cc3ccccc3)[C@@H](C)C2)cc1NC(=O)C(F)(F)F
Agent: C[C@@H]1CN(c2cncc(NC(=O)OC(C)(C)C)c2)C[C@H](C)N1
Product: C[C@@H]1CN(c2cncc(NC(=O)C(F)(F)F)c2)C[C@H](C)N1

Procedure:
The title compound was prepared in a manner similar to N-[5-[cis-3,5-dimethyl-4-(phenylmethyl)-1-piperazinyl]-2-(methyloxy)-3-pyridinyl]-2,2,2-trifluoroacetamide (D28) using 1,1-dimethylethyl {5-[cis-3,5-dimethyl-1-piperazinyl]-3-pyridinyl}carbamate (D34) as the starting material. MS (ES+) m/e 303 [M+H]+.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[CH3:13][NH:14][CH3:15].Cl>>[CH3:13][N:14]([CH3:15])[CH:4]([CH2:3][CH2:2][CH3:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: CNC
Reactant: C=CCCCCCCCCCBr
Agent: Cl
Product: C=CCCCCCC(CCC)N(C)C
Temperature: 20 °C
Reaction time: 48 h

Procedure:
A mixture of 96.49 g of undecylenyl bromide and 314.0 ml of dimethylamine is agitated for 48 hours at 20° C. At the end of the reaction, the pH is brought to 2 by a hydrochloric acid solution (10%). The amine is extracted with methylene chloride.
Reaction SMILES: P(OC)(OC)OC.CN1CCCC1=O.F[C:16]([F:36])(F)/[C:17](=[N:24]\[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][N:34]=1)[C:28]([O:30][CH3:31])=[O:29])/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[F:36][C:16]1[N:34]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]2=[N:24][C:17]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccnc(/N=C(/c2ccccc2)C(F)(F)F)c1
Agent: COP(OC)OC
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccn2c(F)c(-c3ccccc3)nc2c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
Trimethyl phosphite (1.9 ml) was added to an N-methylpyrrolidone (10 ml) solution of the (Z)-methyl 2-((2,2,2-trifluoro-1-phenylethylidene)amino)isonicotinate (2.5 g) obtained in (Example 2.19) <Step 1>, and the obtained mixture was then stirred in microwave at 150° C. for 60 minutes. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. Organic layers were gathered, and the gathered organic layer was then dried over sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (silica gel:eluent; heptane:ethyl acetate=90:10-50:50), so as to obtain the title compound (1.9 g) in the form of a brown solid.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:10]([O:12][CH3:13])=[O:11])[OH:6])[CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH:1]1([CH2:4][C:5]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:10]([O:12][CH3:13])=[O:11])=[O:6])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C)c(C(O)CC2CC2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(C(=O)CC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 3-(2-cyclopropyl-1-hydroxyethyl)-4-methylbenzoate (compound 4.4, 200 mg, 0.85 mmol) in dichloromethane (30 mL). This was followed by the addition of Dess-Martin periodinane (721 mg, 1.70 mmol) in portions at room temperature. The resulting solution was stirred for 1 h at room temperature, then quenched with saturated aqueous Na2S2O3 (30 mL). The resulting mixture was extracted with DCM (3×20 mL) and the combined organics was washed with brine (2×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:5) as the eluent to yield the title compound as a yellow oil (150 mg, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][CH2:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>>[Br:9][CH2:10][CH2:11][CH2:12][O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: BrCCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: BrCCCOc1cccc(Br)c1
Yield: 57.5 %

Procedure:
A mixture of 5.0 g (0.029 mol) of 3-bromophenol, 29 ml (0.29 mol) of 1,3-dibromopropane and 12 g (0.087 mol) of potassium carbonate in 75 ml ofacetone was stirred ar reflux for 22 hours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure. The residue was purified by HPLC using 3% ethyl acetate-hexane to give 4.9 g (58% yield) of 3-(3-bromopropoxy)bromobenzene. The structure was confirmedby the nmr spectrum.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:7]([O:9]N1C(=O)CCC1=O)=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:24][C@H:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[OH:29].CN1CCOCC1>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH:1]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:2]([C:7]([NH:24][C@H:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH2:27][C:28](=[O:29])[OH:30])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
To a solution of Boc-Leu-OSu and Glu-OtBu in DMF was added NMM and DMAP. The solution was stirred at ambient temperatures for 18 hours then the solvent was removed. Crude product was taken up in 100 ml CHCl3, washed 3× with pH 3 water (100 ml), once with water (100 ml) and once with brine (100 ml). Organic layer was dried with MgSO4 and filtered. Solvent was removed and solid was dried over vacuum. Solid was collected as a white powder (8.78 g, quant. yield, ˜80% purity TLC). Product was used directly without further characterization.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[C:7]2[CH:8]=[C:9]([NH:12]S(C)(=O)=O)[CH:10]=[CH:11][C:6]=2[NH:5]C(=O)[NH:3]1.[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].NC1C=CC(NS(C)(=O)=O)=CC=1S(N)(=O)=O>S(=O)(=O)(O)O>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[S:2]([NH2:3])(=[O:1])=[O:18]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)NC(=O)N2
Agent: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Product: Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mechanically stirred suspension of N-(1,1,3-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[1,2,4]thiadiazin-7-yl)-methanesulfonamide (Example 3c′, 115.2 g, 0.40 mol) in 9.0 M aqueous sulfuric acid (500 mL) was heated to 130° C. for 2.5 h (considerable gas evolution was noted during this time). The resulting brown solution was cooled to 0° C. and an aqueous solution of sodium hydroxide (351 g in 750 mL water; ca. 11.7 M) was added via addition funnel over 45 min. The pH of the reaction mixture was then adjusted to approximately 7.0 by the dropwise addition of 3.0 M aqueous sodium carbonate solution. The resulting suspension was allowed to warm to 25° C. and stirred for 1 h, then was filtered through medium paper using a Büchner funnel. The collected solid was washed with water (1×300 mL) and was dried in a vacuum oven at 50° C. to afford a mixture of 2-amino-5-methanesulfonylamino-benzenesulfonamide and 2,5-diamino-benzenesulfonamide (1.5:1.0 ratio, 70.0 g, 75% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ: 2.86 (3H, s), 4.54 (2H, bs), 4.98 (2H, bs), 5.77 (2H, s), 6.55-6.60 (2H, m), 6.76 (1H, d, J=8.6 Hz), 6.87 (1H, d, J=2.2 Hz), 6.99 (2H, bs), 7.11 (1H, dd, J1=8.6 Hz, J2=2.4 Hz), 7.25 (2H, bs), 7.43 (1H, d, J=3.1 Hz), 9.16 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:19][CH2:18][C:13]3(OCC[O:14]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O.C1COCC1.O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:19][CH2:18][C:13](=[O:14])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
A solution of methyl-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoate (4.87 g, 17.56 mmol) in 10% aqueous sulfuric acid (50 mL) and THF (50 mL) was stirred at ambient temperature for 72 hours. The reaction mixture was neutralized by cautious addition of NaHCO3 and simultaneously diluting with water. The aqueous mixture was extracted with EtOAc (2×75 mL) and the combined organic extracts were dried (MgSO4), filtered, and concentrated to give the title compound as an off-white, amorphous solid (4.06 g, 99%) which was used without further purification.