Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[C:11]1([CH:17](O)[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:20](O)(=O)C(O)=O>C(O)(=O)C.O>[CH3:18][CH:17]([C:8]1[C:7]([O:10][CH3:20])=[CH:6][C:4]2[O:5][CH2:1][O:2][C:3]=2[CH:9]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:18][CH:17]([C:8]1[C:7]([OH:10])=[CH:6][C:4]2[O:5][CH2:1][O:2][C:3]=2[CH:9]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=C(O)C(=O)O
Reactant: CC(O)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(c1ccccc1)c1cc2c(cc1O)OCO2
Product: COc1cc2c(cc1C(C)c1ccccc1)OCO2

Procedure:
(α-Methylbenzyl)-3,4-methylenedioxy-6-methoxybenzene was prepared as follows: A solution of sesamol (41.4 g), 1-phenylethyl alcohol (36.6 g) and oxalic acid (2 g) in acetic acid (100 ml) and water (10 ml) was refluxed for 24 hours and diluted with water. Distillation of the oily product gave a pale yellow oil, b.p. 204°-205° at 4.0 mm Hg (56 g) which crystallized. Recrystallization from benzene-skelly solve F gave (α-methylbenzyl)-3,4-methylenedioxy-6-hydroxybenzene as colorless needles, m.p. 101°-102° (Found: C, 74.2, H, 5.75. Calc. for C15H14O3 : C, 74.4; H, 5.83%); pmr spectrum: δ1.57, 3H, D (J=7 Hz); δ4.29, 1H, Q (J=7 Hz); δ4.50, 1H, S; δ5.86, 2H, S; δ6.35, 1H, S; δ6.72, 1H, S; δ7.25, 5H, S.
Reaction SMILES: Cl.C(C1(NC(C(N[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])CC(C)(C)C)=O)CCNCC1)#N.N1(C(Cl)=O)CC[O:31]CC1.CN1CCOCC1>C(Cl)Cl>[N:22]1([C:20]([OH:21])=[O:31])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)CC(NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCNCC1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(O)N1CCOCC1

Procedure:
The title compound is prepared from morpholine-4-carboxylic acid [1-(4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amide hydrochloride and 4-morpholine carbonyl chloride in the presence of a tertiary amine base such as N-methylmorpholine in a solvent such as methylene chloride.
Reaction SMILES: [F:1][C:2]([F:26])([CH:15]([F:25])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)[CH2:3][N:4]1C(=O)C2C(=CC=CC=2)C1=O>C(O)C.O1CCCC1.O.NN>[F:1][C:2]([F:26])([CH:15]([F:25])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)[CH2:3][NH2:4]
Reactant: O=C1c2ccccc2C(=O)N1CC(F)(F)C(F)c1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: NCC(F)(F)C(F)c1cccc([N+](=O)[O-])c1
Reaction time: 18 h
Yield: 65.6 %

Procedure:
To a solution of 2-(2,2,3-trifluoro-3-(3-nitrophenyl)propyl)isoindoline-1,3-dione (C33, 531 mg) in ethanol (4 mL) and tetrahydrofuran (4 mL), hydrazine monohydrate (349 μL) was added at room temperature, and the mixture was stirred at the same temperature for 18 hours. The insoluble matter was removed by filtration, and then the solvent was evaporated under reduced pressure to obtain 2,2,3-trifluoro-3-(3-nitrophenyl)propan-1-amine (C34, 224 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:12][C:9]=2[C:10]=1Br)=[O:5])[CH3:2].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:12][C:9]=2[C:10]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc2ccc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc2c1Br
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)c1sc2ccc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc2c1-c1ccccc1
Yield: 61 %

Procedure:
According to Step 6, after reaction of 3-Bromo-5-(4-tert-butylbenzene-sulfonylamino)-1-benzothiophene-2-carboxylic acid ethyl ester (469 mg, 1.0 mmol) from Example 1c) with phenylboronic acid (176 mg, 1.44 mmol) followed by chromatographic purification (silica gel, hexane/ethyl acetate (0-100% ethyl acetate) and ethyl acetate/methanol (0-15%)), the desired compound is obtained at 61% yield (300 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:33]=[CH:34][C:35]=1[N+:36]([O-:38])=[O:37])[C:13]([C:15]1[N:23]2[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]2)=[C:17]([NH:24]C(=O)OC(C)(C)C)[C:16]=1[CH3:32])=[O:14].C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OC(C)C)(C)C>[NH2:24][C:17]1[C:16]([CH3:32])=[C:15]([C:13]([C:12]2[CH:33]=[CH:34][C:35]([N+:36]([O-:38])=[O:37])=[C:10]([O:9][CH3:8])[CH:11]=2)=[O:14])[N:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[CH:22]2
Reactant: COc1cc(C(=O)c2c(C)c(NC(=O)OC(C)(C)C)c3ccccn23)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: COc1cc(C(=O)c2c(C)c(N)c3ccccn23)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 86.5 %

Procedure:
2.32 ml of trifluoroacetic acid are added dropwise to a solution of 643 mg (1.51 mmol) of tert-butyl 3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-ylcarbamate in 20 ml of dichloromethane, cooled to 0° C. Once the introduction is complete, the medium is allowed to return to room temperature and it is stirred for 4 hours. The reaction medium is poured over a saturated aqueous potassium carbonate solution and extracted with ethyl acetate. The organic phase is separated after settling out, washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crystals obtained are taken up in isopropyl ether, filtered off, washed with isopropyl ether and then dried. 425 mg of a brown solid are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[Br-:28].[NH2:29][CH2:30][CH2:31][CH2:32][CH2:33][P+:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O.C(Cl)Cl>[Br-:28].[CH3:15][N:8]([C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:9][CH2:10][CH2:11][C:12](=[O:14])[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][P+:34]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(CCCC(=O)O)C(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CCCC(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.9 %

Procedure:
4-[(tert-butoxycarbonyl)(methyl)amino]butanoic acid (J. Organic Chemistry, 1985, 50, 1302-1304, 349 mg, 1.61 mol) was dissolved in N,N-dimethylformamide (3.5 mL) and treated with N,N-carbonyldiimidazole (273 mg, 1.69 mmol). The mixture was stirred at room temperature for 30 minutes. (4-Aminobutyl)(triphenyl)phosphonium bromide (929 mg, 1.40 mmol) was added, and the reaction was stirred overnight at room temperature. The reaction mixture was diluted with methylene chloride and washed with 5% aqueous lithium chloride (3 times), 1N aqueous hydrogen chloride, and saturated sodium bicarbonate. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (0.91 g, 92%, 83% pure) as a white foam. Sample was used crude in next step.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#N)=[C:6]([Cl:13])[CH:5]=1.[CH3:14]I.C[N:17]([CH:19]=O)C>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:14])([CH3:11])[C:19]#[N:17])=[C:6]([Cl:13])[CH:5]=1
Reactant: CN(C)C=O
Reactant: CI
Reactant: N#CCc1ccc(Br)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
NaH (95%, 1.18 g, 49.35 mmol) was suspended in DMF (25 mL) and cooled to 0° C. 4-bromo-2-chloro-phenyl)-acetonitrile (2.27 g, 9.87 mmol) from step 3 above, was dissolved in THF (10 mL) and slowly added via cannula and the reaction mixture stirred 20 min. MeI (6.10 mL, 98 mmol) was added and the resulting mixture was stirred overnight at room temperature. Reaction was quenched with H2O (50 mL). Solvents were removed in vacuo and residue partitioned between EtOAc and 1N HCl (50 mL). The organic phase was dried over Na2SO4 and evaporated. The crude organic product was purified by flash column chromatography (5% EtOAc in hexanes) to give the product (2.23 g, 87%) as a clear oil. 1H NMR (400 MHz, CDCl3): δ 7.34 (d, J=8.4 Hz, 1H), 7.43 (dd, J=8.4, 2.0 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H).
Reaction SMILES: ClS([N:5]=C=O)(=O)=O.[CH3:8][O:9][C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](O)=O)[CH2:14][CH2:13]1)=[O:11].CN(C=O)C>C(Cl)Cl>[C:18]([C@H:15]1[CH2:16][CH2:17][C@H:12]([C:10]([O:9][CH3:8])=[O:11])[CH2:13][CH2:14]1)#[N:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](C#N)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Chlorosulfonyl isocyanate (1.0 mL, 0.012 mol) was added to a solution of trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (2.00 g, 0.0107 mol) in DCM cooled to 0° C. The resulting solution was heated at reflux for 15 minutes and then cooled 0° C. and treated dropwise with DMF. The mixture was stirred at room temperature overnight then poured onto ice water and the organic phase separated and washed with a saturated solution of sodium bicarbonate. The solvent was removed in vacuo and the crude material was taken up in ethyl acetate, washed with 1N aq. NaOH (10 mL) and the ethyl acetate removed in vacuo. The resulting crude product was used in subsequent steps without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36-1.70 (4 H, m), 2.01-2.18 (4 H, m), 2.24-2.54 (2 H, m) and 3.68 (3 H, s).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[CH3:10].[CH2:11]([CH:13]1[O:15][CH2:14]1)[Cl:12]>C1COCC1.CN(C=O)C.[Cu]I.BrCCBr>[Cl:12][CH2:11][CH:13]([OH:15])[CH2:14][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[CH3:10]
Reactant: Cc1c(F)cccc1Br
Reactant: ClCC1CO1
Agent: [Cu]I
Agent: [Mg]
Solvent: BrCCBr
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(F)cccc1CC(O)CCl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 104.9 %

Procedure:
0.867 g (35.67 mmol) of magnesium turnings were dried and suspended in 17 ml of anhydrous THF under argon. A solution of 1,2-dibromoethane (0.14 ml, 1.62 mmol) and 2-bromo-6-fluoro-toluene (6.74 g, 35.67 mmol) in 17 ml of anhydrous THF was then added dropwise so as to maintain a gentle reflux. Once the magnesium had been consumed, copper(I) iodide (0.432 g, 2.27 mmol) was then added, followed by a solution of epichlorohydrine (3.00 g, 32.42 mmol) in DMF (8 ml). The mixture was stirred for 3.5 h at room temperature and then quenched with a saturated solution of ammonium chloride (120 ml). The organic layer was separated, and the aqueous phase was extracted twice with EA. The combined organic phases were washed twice with a saturated solution of ammonium chloride, dried over sodium sulfate, filtered and evaporated to dryness. The product was purified by chromatography on silica gel (cyclohexane/EA, from 100:0 to 90:10) to give 6.89 g of 1-chloro-3-(3-fluoro-2-methyl-phenyl)-propan-2-ol. 3.92 g (16.23 mmol) of this alcohol were dissolved in DCM under argon, and 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane reagent; 7.57 g, 16.23 mmol) was added. The mixture was stirred at room temperature overnight and then diethyl ether (150 ml) was added. The mixture was washed three times with 1 N hydrochloric acid (70 ml) and twice with a saturated solution of sodium chloride, and extracted with ether. The extracts were dried over sodium sulfate, filtered and evaporated to dryness. 2.69 g of the title compound were obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]([F:18])([F:17])[F:16])=[CH:4][C:5]([C:9]#[C:10][Si](C)(C)C)=[C:6]([CH:8]=1)[NH2:7].CN(C)C=O>[Cu]I.C(OCC)C>[Cl:1][C:2]1[CH:8]=[C:6]2[C:5]([CH:9]=[CH:10][NH:7]2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16]
Reactant: C[Si](C)(C)C#Cc1cc(C(F)(F)F)c(Cl)cc1N
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOCC
Product: FC(F)(F)c1cc2cc[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.3 %

Procedure:
A mixture of 5-chloro-4-(trifluoromethyl)-2-[(trimethylsilyl)ethynyl]aniline (16.5 g), copper(I) iodide (20.4 g) and dimethylformamide (100 ml) was stirred at room temperature for 10 min and then stirred with heating at 100° C. for 2.5 hr. The reaction mixture was allowed to cool, diethyl ether was added and the mixture was stirred at room temperature. The reaction mixture was filtered through a celite (trademark) filter, and the filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a brown oil. The oil was purified by silica gel column chromatography (elution solvent:ethyl acetate-hexane (1:5-1:3)) to give 6-chloro-5-(trifluoromethyl)-1H-indole (5.75 g, yield 46%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([F:25])([F:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:3]=1.[CH3:26][C:27]1[NH:31][N:30]=[C:29]([NH2:32])[CH:28]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:25][C:16]([F:24])([C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C:4]1[N:3]=[C:2]([NH:32][C:29]2[CH:28]=[C:27]([CH3:26])[NH:31][N:30]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: COC(=O)c1ccc2c(Cl)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(Nc3cc(C)[nH]n3)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 101.4 %

Procedure:
A mixture of methyl 4-chloro-2-(difluoro(4-fluorophenyl)methyl)quinazoline-7-carboxylate (1 g, 2.7 mmol), 5-methyl-1H-pyrazol-3-amine (0.32 g, 3.27 mmol), DIEA (0.62 mL, 3.5 mmol), and KI (0.5 g, 3 mmol) in DMF (20 mL) was stirred at rt for 20 h. The mixture was diluted with H2O and stirred for 1 h, and then the precipitated solid was collected by filtration, washed with H2O, and dried to afford methyl 2-(difluoro(4-fluorophenyl)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazoline-7-carboxylate (1.17 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3 H), 3.97 (s, 3 H), 6.31 (s, 1 H), 7.15-7.50 (m, 2 H), 7.62-7.90 (m, 2 H), 7.99-8.13 (m, 1 H), 8.20-8.55 (m, 1 H), 8.69-9.04 (m, 1 H), 10.96 (s, 1 H), 12.28 (s, 1 H); LC-MS (ESI) m/z 428 (M+H)+.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[N:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=2)=[CH:19][CH:18]=1>ClCCl.CN(C)C=O>[N:29]([C:25]1[CH:24]=[C:23]([C:20]2[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=2)[N:28]=[CH:27][N:26]=1)=[C:1]=[S:2]
Reactant: Nc1cc(-c2ccncc2)ncn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: S=C=Nc1cc(-c2ccncc2)ncn1
Temperature: 60 °C

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.601 g, 2.59 mmol) in dichloromethane/N,N-dimethylformamide at room temperature was added 6-(pyridin-4-yl)pyrimidin-4-amine (0.297 g, 1.725 mmol). The orange mixture was heated at 60° C. for 18 hours. LC/MS showed the desired product peak as the major peak. The deep orange mixture was purified by silica gel chromatography (0-40% ethyl acetate-hexanes) to afford 4-isothiocyanato-6-(pyridin-4-yl)pyrimidine (0.055 g, 0.257 mmol, 15% yield) as an orange solid. LCMS R.T.=1.46; [M+H]+=215.09.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:2]([C:14](O)=[O:15])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[CH:5]=1.Cl.[NH2:25][C@@H:26]([C:34]([O:36][CH3:37])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:1]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[C@@H:2]([C:14]([NH:25][C@@H:26]([C:34]([O:36][CH3:37])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:15])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[CH:5]=1
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Reactant: Cn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](Cc1cn(C)c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
To a mixture of Boc-D-Trp(CH3)-OH (1.59 g), HCl.H-D-Phe-OCH3 (1.08 g) and HOBT (0.81 g) in DMF (20 ml) was added WSCD (0.93 g) under ice-bath cooling. After being stirred for 2 hours at room temperature, the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (50 ml). The solution was washed with 0.5N hydrochloric acid (20 ml), water (20 ml), saturated sodium bicarbonate (20 ml) and water (20 ml×2) successively, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with ether to give Boc-D-Trp(CH3)-D-Phe-OCH3 (1.45 g).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.[CH3:39][NH:40][CH2:41][CH2:42][CH3:43]>>[CH3:1][N:2]([C@H:3]1[CH2:4][CH2:5][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][N:40]([CH3:39])[CH2:41][CH2:42][CH3:43])[CH2:7][CH2:8]1)[S:33]([C:30]1[CH:31]=[CH:32][C:27]([C:26]([F:38])([F:37])[F:25])=[CH:28][CH:29]=1)(=[O:35])=[O:34]
Reactant: CCCNC
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN[C@H]1CC[C@H](CCCCOS(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)CCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to examples 31.5 and 31.6, trans-Methanesulfonic acid 4-(4-methylamino-cyclohexyl)-butyl ester.trifluoro-acetic acid and 4-trifluoromethyl-phenyl-sulfonylchloride were reacted, followed by treatment with methyl-propyl-amine to give trans-N-Methyl-N-{4-[4-(methyl-propyl-amino)-butyl]-cyclohexyl}-4-trifluoromethyl-benzenesulfonamide, MS: 449 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][OH:27].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][OH:27])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 63.9 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10.0 g, 45 mmol), K2CO3 (10.0 g), 3-bromo-1-propanol (7.3 g, 46 mmol) and acetonitrile (200 ml) was refluxed for 3 hours. The reaction was poured into H2O and 7.1 g of a beige solid was collected. The filtrate was extracted with dichloromethane, and after concentration an additional 6.7 g of crude solid was harvested. The solids were combined and triturated with refluxing ethyl acetate to afford 8.0 g of 6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole as an off-white solid. A sample (4.0 g) was recrystallized from ethanol-water (with charcoal treatment) to yield 2.4 g (40%) of the alcohol as a white solid, m.p.=140°-142° C.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10](=[O:13])([O-])[O-:11].[K+].[K+].O.[C:17](#N)[CH3:18]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:7]1[C:2]([C:18]2[CH:17]=[CH:7][C:6]([C:10]([OH:11])=[O:13])=[CH:5][CH:4]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC#N
Reactant: O=C([O-])[O-]
Reactant: COc1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: O
Product: COc1cccnc1-c1ccc(C(=O)O)cc1
Temperature: 160 °C
Yield: 77 %

Procedure:
4-bis(hydroxyl)boron-1-methylbenzoate (2.8 mmol; 582 mg) was dissolved in acetonitrile (2 ml) and added to a 5 ml microwave vessel. To the solution was 3.5 mmol of 2-chloro-3-methoxypyridine (482 mg), 34 mg of tetrakis(triphenylphosphine)palladium(0). After stirring until dissolution, 8.4 mmol of potassium carbonate (1.16 g) was added, followed by 1 ml of water. The mixture was then heated at 160° C. for 300 seconds. After reaction completion, the solvents were evaporated under vacuum. The residue was dissolved in 2N KOH and THF and heated for 10 min. After hydrolysis, the THF was evaporated and the basic layer was washed with EtOAC. The aqueous layer was then acidified and extracted 3 times with EtOAc. The organic layers were combined and washed with water and brine. After drying, filtration and evaporation, the residue was triterated with ether to give the desired product as a yellow solid (423 mg; 77%).
Reaction SMILES: [CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH:6]([N:9]([CH:47]([CH3:49])[CH3:48])[C:10]([C:12]1[CH:44]=[CH:43][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21]C2C=CC3ON=C(NC([C@@H]([NH3+])CC4C=CC=CC=4)=O)C=3C=2)=[C:14]([O:45][CH3:46])[CH:13]=1)=[O:11])([CH3:8])[CH3:7].CS(O)(=O)=O.C(N(C(C)C)C(C1C=CC(OCCCCO[C:71]2[CH:72]=[CH:73][C:74]3[O:78][N:77]=[C:76]([NH:79][C:80]([NH2+:82][CH3:83])=[O:81])[C:75]=3[CH:84]=2)=C(OC)C=1)=O)(C)C.C(O[C:97]([NH:99][CH2:100]C(O)=O)=[O:98])(C)(C)C>>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH:47]([N:9]([CH:6]([CH3:8])[CH3:7])[C:10]([C:12]1[CH:44]=[CH:43][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:72]2[CH:71]=[CH:84][C:75]3[C:76]([NH:79][C:80]([N:82]([CH2:83][CH2:10][C:12]4[CH:44]=[CH:43][CH:15]=[CH:14][CH:13]=4)[C:97]([NH2+:99][CH3:100])=[O:98])=[O:81])=[N:77][O:78][C:74]=3[CH:73]=2)=[C:14]([O:45][CH3:46])[CH:13]=1)=[O:11])([CH3:49])[CH3:48]
Reactant: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCOc1ccc2onc(NC(=O)[C@@H]([NH3+])Cc3ccccc3)c2c1
Reactant: C[NH2+]C(=O)Nc1noc2ccc(OCCCCOc3ccc(C(=O)N(C(C)C)C(C)C)cc3OC)cc12
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CS(=O)(=O)O
Agent: CS(=O)(=O)[O-]
Product: C[NH2+]C(=O)N(CCc1ccccc1)C(=O)Nc1noc2cc(OCCCCOc3ccc(C(=O)N(C(C)C)C(C)C)cc3OC)ccc12
Yield: 80 %

Procedure:
(1S)-1-{5-[4-(4-diisopropylcarbamoyl-2-methoxy-phenoxy)-butoxy]-benzo[d]isoxazole-3-ylcarbamoyl}-2-phenyl-ethyl-ammonium methane sulfonic acid salt, the compound of EXAMPLE 3, was used as a starting material in place of {5-[4-(4-diisopropylcarbamoyl-2-methoxy-phenoxy)-butoxy]-benzo[d]isoxazole-3-ylcarbamoyl}-methyl-ammonium methane sulfonic acid used in the above EXAMPLE 6. According to the same method as in EXAMPLE 6, N-(t-butoxycarbonyl)glycine was used, the above title compound was obtained (yield: 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH3:26])[C:7]3[CH:25]=[CH:24][CH:23]=[CH:22][C:8]=3[C@@H:9]3[C@H:14]([NH:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH3:26])[C:7]3[CH:25]=[CH:24][CH:23]=[CH:22][C:8]=3[C@@H:9]3[C@H:14]([NH:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)CN[C@@H]1CCCN2c3cc(Cl)ccc3N(C)c3ccccc3[C@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN1c2ccccc2[C@@H]2[C@H](NCC(=O)O)CCCN2c2cc(Cl)ccc21
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 12 %

Procedure:
To a solution of ethyl trans-[(7-chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)amino]acetate (35 mg, 0.09 mmol) in dioxane (1 mL) was added 4N (aq) NaOH (250 ul). The reaction mixture was stirred at 65° C. for 1.5 h. It was diluted with water (25 mL) whereafter the pH was adjusted to pH 2 with 2N (aq) HCL. The mixture was extracted with ethyl acetate (2×), washed with water and brine, dried (MgSO4) and evaporated. The crude product was purified with LC-MS to afford the title compound (4 mg, 12%). Data (m/z)=372 (M+H)+.