Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[CH:26]([Cl:29])(Cl)[Cl:27].[CH3:30][C:31]1([CH3:44])[O:43][C:35]2[C:36]([CH3:42])=[N:37][CH:38]=[C:39]([CH:40]=O)[C:34]=2[CH2:33][O:32]1>CCCCCCC>[Cl:27][C:26]([Cl:29])=[CH:40][C:39]1[CH:38]=[N:37][C:36]([CH3:42])=[C:35]2[O:43][C:31]([CH3:44])([CH3:30])[O:32][CH2:33][C:34]=12
Reactant: Cc1ncc(C=O)c2c1OC(C)(C)OC2
Reactant: ClC(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Product: Cc1ncc(C=C(Cl)Cl)c2c1OC(C)(C)OC2

Procedure:
To a well stirred ice-cooled mixture of 0.1 mole of triphenylphosphine and 0.1 mole of potassium t-butoxide in 250 ml. of heptane is added over thirty minutes a mixture of 0.1 mole of chloroform in 200 ml. of haptane. The resulting mixture is concentrated in vacuo at 15°-20° to a volume of about 100 ml. and a solution of 0.1 mole of 2,2,8-trimethyl-4H-1,3-dioxino[4,5-c]pyridine-5-carboxaldehyde in 250 ml. of heptane is added. The reaction mixture was heated at 40°-50° for 5 hours, then cooled, filtered, and concentrated in vacuo to give crude product. Chromatography on silica gel and elution with ether-petroleum ether (10-50%) gives pure 5-(2,2-dichlorovinyl)-2,2,8-trimethyl-4H-1,3-dioxino-[4,5-c]pyridine.
Reaction SMILES: [C:1]12([OH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14]>>[C:12]([O:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)(=[O:15])[CH:13]=[CH2:14]
Reactant: C=CC(=O)Cl
Reactant: OC12CC3CC(CC(C3)C1)C2
Product: C=CC(=O)OC12CC3CC(CC(C3)C1)C2

Procedure:
1-Adamantanol and acrylic acid chloride were subjected to desalting reaction by using a basic catalyst to obtain adamantyl acrylate (Compound (III-h)).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Br:42][C:43]1[CH:44]=[C:45]([NH:50]C)[C:46]([NH2:49])=[CH:47][CH:48]=1>CN(C=O)C>[NH2:50][C:45]1[CH:44]=[C:43]([Br:42])[CH:48]=[CH:47][C:46]=1[NH:49][C:6]([CH:4]1[CH2:3][C:2](=[O:1])[CH2:5]1)=[O:8]
Reactant: O=C1CC(C(=O)O)C1
Reactant: CNc1cc(Br)ccc1N
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: CN(C)C=O
Product: Nc1cc(Br)ccc1NC(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.9 %

Procedure:
To a stirred solution of 3-oxocyclobutanecarboxylic acid (1.1 g) in DMF (50 ml) were added HATU (5.7 g) and N,N-diisopropylethylamine (4.2 ml) at 0° C., and the mixture was allowed to warm to room temperature for 30 min. A solution of 4-bromo-N2-methylbenzene-1,2-diamine (2.0 g) in DMF (2 ml) was added, and the resulting mixture was stirred at room temperature for 18 h. The mixture was concentrated in vacuo and diluted with DCM. The mixture was washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine successively, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (hexane/EtOAc) to afford the title compound (2.7 g) as an off-white solid.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15](CC)[CH2:14][CH2:13]2)[C:7]=1[F:20])(=[O:4])=[O:3].ClC(OC(Cl)=O)C>ClCCCl>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[C:7]=1[F:20])(=[O:3])=[O:4]
Reactant: CCN1CCC(c2cccc(OS(C)(=O)=O)c2F)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CS(=O)(=O)Oc1cccc(C2CCNCC2)c1F

Procedure:
3-(1-ethylpiperidin-4-yl)-2-fluorophenyl methanesulfonate (0.020 g, 0.033 mmol) was dissolved in dry 1,2-dichloroethane (5 ml) and α-chloroethylchloroformat (0.014 ml, 0.033 mmol) was added. The resulting mixture was refluxed for 1 h, and the solvent was evaporated. MS m/z (rel. intensity, 70 eV) 273 (M+, 2), 195 (11), 194 (bp), 178 (5), 56 (60).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[CH:4][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[N:6][CH:7]=1.[ClH:39].CO>>[ClH:1].[ClH:39].[Cl:1][C:2]1[C:3]([CH:20]([S:29]([C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)(=[O:30])=[O:31])[C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[CH:4][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Agent: Cl
Solvent: CO
Product: NCCCNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reaction time: 2 h
Yield: 83 %

Procedure:
To t-butyl 3-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]propylcarbamate (70 mg, 0.13 mmol) was added a 20% hydrochloric acid-methanol solution (2 ml). The resulting mixture was stirred for 2 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was crystallized from ethanol to give the title compound as a white solid (42 mg, 83%).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[C:16]([O:20]C)=[CH:17][CH:18]=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[CH2:1]([NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[C:16]([OH:20])=[CH:17][CH:18]=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc2c1CCCC(NCc1ccccc1)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc2c1CCCC(NCc1ccccc1)C2
Reaction time: 2 h
Yield: 87 %

Procedure:
Under nitrogen, N-benzyl-(1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (4.5 g) in dichloromethane (45 ml) was added boron tribromide (1M in dichloromethane, 32 ml) dropwise at 0° C., and the mixture was stirred at the same temperature for 2 hours. The resulting mixture was poured into ice-cold water and the precipitate was collected by filtration. The filter cake was added to the mixture of water and ethyl acetate, and then adjusted to pH 9 with 1N sodium hydroxide. After separation, the organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to afford N-benzyl-(1-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (3.72 g).
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH:16]=O.C([O-])(=O)C.[Na+].Cl.[NH2:24][OH:25]>O>[CH3:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH:16]=[N:24][OH:25]
Reactant: NO
Reactant: COc1ccc2ccccc2c1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2ccccc2c1C=NO
Yield: 97.7 %

Procedure:
To 400 ml of ethanol and 180 ml of water were added 80 g (0.43 mole) of 2-methoxy-1-naphthaldehyde, 66 g (0.81 mole) of sodium acetate and 35.5 g (0.51 mole) of hydroxylamine hydrochloride, and the mixture was heated at reflux for 2 hours. After the reaction, the reaction mixture was added to 1 liter of water. The precipitated crystals were collected by filtration to give 85 g (0.42 mole) of 2-methoxy-1-naphthaldoxime.
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:36]([NH:38][C:39]([NH:41][C:42](=[O:51])[CH2:43][C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)=[S:40])[CH:35]=[CH:34][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12.Cl>C(O)(=O)C>[F:1][C:2]1[CH:37]=[C:36]([NH:38][C:39]([NH:41][C:42](=[O:51])[CH2:43][C:44]2[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=2)=[S:40])[CH:35]=[CH:34][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][CH2:30][CH2:31][O:32][CH3:33])=[CH:18][N:19]=3)[S:13][C:6]=12
Reactant: COCCN(CCc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(=O)O
Product: COCCNCCc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.6 %

Procedure:
To a solution of 186 (0.19 g, 0.26 mmol) in acetic acid (10 mL) was added aqueous HCl (3M, 1.0 mL, 3.0 mmol). The mixture was stirred at room temperature for 3 h then partially concentrated. The residue was partitioned between ethyl acetate and water, the organic phase was collected, washed with saturated aqueous sodium bicarbonate and brine. It was then dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent 15% methanol/chloroform) to give title compound 187 (80 mg, 49% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.53 (d, J=5.5, 1H), 8.50 (d, J=1.6, 1H), 8.30 (s, 1H), 8.18 (d, J=7.8, 1H), 8.04 (dd, J=11.2, 1.6, 1H), 7.89 (dd, J=8.2, 2.2, 1H), 7.54-7.50 (m, 2H), 7.40-7.35 (m, 2H), 7.22-7.15 (m, 2H), 6.67 (d, J=5.5, 1H), 3.83 (s, 2H), 3.40 (s, 2H), 3.37 (t, J=5.7, 2H), 3.22 (s, 3H), 2.82-2.75 (m, 4H), 2.69 (t, J=5.7, 2H). LRMS (M+H): 634.4
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:22])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:29](O)=[O:30])=[N:10][CH:9]=1.[Cl-].[NH4+].C1C=[N:38]C2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C.CO.O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([C:21]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[O:22])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:29]([NH2:38])=[O:30])=[N:10][CH:9]=1
Reactant: O=C(O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Reactant: On1nnc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: NC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Reaction time: 8 h
Yield: 33 %

Procedure:
To a yellow, heterogeneous solution of 4-(2-fluorophenyl)-7-(morpholine-4-carbonyl)-9H-pyrido[3,4-b]indole-1-carboxylic acid (0.0381 g, 0.091 mmol), ammonium chloride (9.72 mg, 0.182 mmol), HOAt (0.025 g, 0.182 mmol) and EDC (0.035 g, 0.182 mmol) in DMF (1.0 mL) was added DIPEA (0.063 mL, 0.364 mmol). The reaction was stirred overnight. EtOAc and water were added, and the layers were separated. The organic layer was washed with brine and 10% aq. LiCl successively, dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was diluted with MeOH (1 mL) and subjected to autoprep reverse phase HPLC purification. The appropriate fractions were combined, basified with NaHCO3 (solid), and concentrated in vacuo. It was extracted with CH2Cl2 (3×). The organic layers were combined, dried over Na2SO4, and concentrated in vacuo to give the desired product (0.0124 g, 0.030 mmol, 32.6% yield) as a white solid. LC/MS (M+H)=419.08; 1H NMR (500 MHz, DMSO-d6) δ ppm 12.03 (s, 1H), 8.38 (br. S, 1H), 8.32 (s, 1H), 7.89 (s, 1H), 7.86 (br. S, 1H), 7.63-7.75 (m, 2H), 7.44-7.58 (m, 2H), 7.34 (d, J=8.2 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 3.42-3.83 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16]C(=O)OCC2C=CC=CC=2)[CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1.C(O)C>[Pd].C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1)[NH2:16]
Reactant: COc1cc(NC(=O)OCc2ccccc2)ccc1C1CCN(C)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(N)ccc1C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
To a mixture of benzyl [3-methoxy-4-(1-methylpiperidin-4-yl)phenyl]carbamate (Preparation Example 464) (1.26 g), ethanol (20 mL) and THF (10 mL), 5% palladium on carbon (0.38 g) was added and stirred overnight at room temperature under a hydrogen atmosphere at normal pressure. After filtration through celite, the filtrate was distilled off under reduced pressure to give 3-methoxy-4-(1-methylpiperidin-4-yl)aniline (0.80 g) as a light pink solid.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:10]=1[CH2:11][O:12][C:13]1[C:14]2[N:15]([C:19]([CH:23]=[O:24])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C:9]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:10]=1[CH2:11][O:12][C:13]1[C:14]2[N:15]([C:19]([CH:23]=[O:24])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1COc1cccn2c(C=O)c(C)nc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(N)c1COc1cccn2c(C=O)c(C)nc12
Yield: 95.6 %

Procedure:
Starting from 8-(2-tert-butoxycarbonylamino-6-methylbenzyloxy)-3-formyl-2-methylimidazo[1,2-a]pyridine (5.0 g) and trifluoroacetic acid (40 ml) analogously using the process of Example C1 (Method B) gives 3.57 g (96%) of the title compound of m.p. 144-150° C. (dec.).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH:28]([CH3:32])[C:29]([OH:31])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:33])[C:17]=3[CH:34]=2)[C:3]1=[O:35].C(Cl)(=O)C(Cl)=O.[CH2:42](O)[C:43]#[CH:44].C(OCC)C>C(Cl)Cl>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH:28]([CH3:32])[C:29]([O:31][CH2:44][C:43]#[CH:42])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:33])[C:17]=3[CH:34]=2)[C:3]1=[O:35]
Reactant: Cc1ccc(OC(C)C(=O)O)cc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: C#CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C#CCOC(=O)C(C)Oc1ccc(C)c(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
A mixture of 2-{{2-{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl}-p-tolyl}oxy}propionic acid (0.510 g, 1.00 mmol) and oxalyl chloride (0.380 g, 3.00 mmol) in methylene chloride is stirred at room temperature for 30 minutes and concentrated in vacuo to obtain a yellow foam. The foam is diluted with methylene chloride and the resultant solution is treated with a solution of propargyl alcohol (0.110 g, 2.00 mmol) in methylene chloride, stirred at room temperature for 24 hours, and concentrated in vacuo to obtain an oil. Flash column chromatography of the oil using silica gel, a hexanes/methylene chloride solution (1:1) and a 5% diethyl ether in methylene chloride solution gives the title product (0.400 g) which is identified by NMR spectral analyses.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15].Cl[C:19]1[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][N:20]=2)=[CH:9][C:8]=1[C:14]([F:15])([F:16])[F:17]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cnc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 79.1 %

Procedure:
A 250 ml two-necked round-bottomed flask equipped with a magnetic bar, a thermometer and a reflux condenser is charged with DMF (50 ml), 4-chloro-3-trifluoromethyl-phenol (4.6 g), 2-chloro-3-methyl-5-nitro-pyridine (4.0 g) and potassium carbonate (6.4 g). The reaction mixture is heated at 100° C. for 2.5 hours. After cooling the mixture to room temperature it is then poured into water (200 ml). The mixture is then extracted with ethylacetate (2×40 ml). The combined organic layers are dried over sodium sulfate, filtered and the solvent is removed in vacuo to obtain 6.10 g of the compound as yellow solid (MP: 95-97° C.).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH:59]([CH3:61])[CH3:60].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:59]([CH3:61])[CH3:60])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: CC(C)OC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (69 mg in 3 ml 33% methylene chloride in cyclohexane), isopropyl trichloroacetimidate (22 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 24 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate: hexane (1:1)+1% methanol) gave the title compound (12 mg).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:14]=[C:13]([CH3:15])[C:11]([NH2:12])=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]([CH2:30][C:31](Cl)=[O:32])([CH3:29])([CH3:28])[CH3:27].O>C(Cl)Cl>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:14]=[C:13]([CH3:15])[C:11]([NH:12][C:31](=[O:32])[CH2:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1cc(OCc2ccc(F)cc2)cc(C)c1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2)cc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
To a solution of 4-(4-fluoro-benzyloxy)-2,6-dimethylaniline(0.20 g, 0.82 mmol) from above and triethylamine (125 mg, 1.24 mmol) in anhydrous methylene chloride (20 ml) was added dropwise tert-butylacetyl chloride (135 mg, 1 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ISCO, hexane/EtOAc, 0-40%, 40 min) and recrystallized from hexane/EtOAc (5:1) to give 230 mg (82%) of the white solids. 1H NMR (DMSO-d6, 400 MHz): δ 8.92 (brs, 1H, exchangeable with D2O, NH), 7.46 (dd, J=4.7 and 6.4 Hz, 2H), 7.19 (t, J=7.0 Hz, 2H), 6.70 (s, 2H), 5.02 (s, 2H), 2.16 (s, 2H), 2.08 (s, 6H), 1.03 (s, 9H). MS: 344 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][N:16]1C(=O)C2=CC=CC=C2C1=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.CN>C(O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][NH2:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCCON1C(=O)c2ccccc2C1=O)OCc1ccccc1
Agent: CN
Solvent: CCO
Solvent: C1CCOC1
Product: NOCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of N-[3-(benzyloxycarbonylamino)-1-propoxy]phthalimide (1.42 g, 4.0 mmol), as prepared in the preceding step, in ethanol (20 mL) and tetrahydrofuran (20 mL) was added 40% methylamine (2 mL, 25 mmol). The solution was stirred at room temperature for 1 h. The solvent was evaporated and the residue passed through silica gel (3:1 ethyl acetate:hexane to ethyl acetate) to give the title compound as a white solid (870 mg, 97%). 1H-NMR (300 MHz, CDCl3) δ7.36 (m, 5H), 5.38 (br s, 2H), 5.09 (s, 2H), 5.08 (br s, 1H), 3.73 (t, J=5.9 Hz, 2H), 3.29 (q, J=6.2 Hz, 2H), 1.79 (pentet, J=6.2 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]=2[C:20]([F:23])([F:22])[F:21])[CH2:4][CH2:3]1.[ClH:24]>>[ClH:24].[ClH:24].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[C:20]([F:23])([F:21])[F:22])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1
Agent: Cl
Product: CN1CCN(Cc2ccc(C(=O)O)cc2C(F)(F)F)CC1

Procedure:
This compound was prepared in the same manner as in Reference Example 1 (step 6), except that ethyl 4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoate obtained in the step 3 was used, and that the reaction solution was acidified (pH 3) with concentrated hydrochloric acid in place of 1N hydrochloric acid.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9]O)[CH2:4][CH3:5].P(Br)(Br)[Br:15]>C(Cl)Cl>[CH3:1][CH2:2][CH:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][Br:15])[CH2:4][CH3:5]
Reactant: CCC(CC)c1cccc(CO)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCC(CC)c1cccc(CBr)c1
Yield: 90 %

Procedure:
According to example 17, 1.84 g of 3-(3-pentyl)benzyl alcohol was treated with 0.34 mL of PBr3 in 25 miL of anhydrous CH2Cl2 to afford 2.23 g (90%) of 3-(3-Pentyl)benzyl bromide as a clear liquid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)C1C=CC=CC=1.CS(O)(=O)=O>C(Cl)Cl>[CH2:21]([NH:20][C:18]([NH:17][C:15]1[S:16][C:12]2[C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:10][C:9]([OH:8])=[CH:23][C:13]=2[N:14]=1)=[O:19])[CH3:22]
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(-c3ccccn3)c2s1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(O)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of ix (76 g, 0.187 mol) in DCM (1.7 L) was added methane sulfonic acid (270 mL, 4.17 mol) dropwise over 30 min. The mixture was stirred at RT for 3 h. The reaction was concentrated in vacuo. EtOAc (1 L) was added to the residue and this solution was poured carefully onto the crushed ice. The pH of the solution was modified to 8-9 by addition of saturated NaHCO3 solution followed by extraction with EtOAc (3×5 L). The combined organics were washed with H2O, brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was stirred in Et2O (1.0 L) for 1 h at RT and then filtered to obtain x (57.0 g, 97%). 1H-NMR (DMSO-d6, 400 MHz): δ 1.08 (t, J=7.20 Hz, 3H), 3.20 (m, 2H), 6.86 (br s, 1H), 7.0 (s, 1H), 7.46 (s, 2H), 7.96 (m, 1H), 8.10 (m, 1H), 8.76 (m, 1H), 9.59 (br s, 1H) and 10.41 (br s, 1H). MS: 315.06 [M+H]+.