Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[N:33][CH:32]=[CH:31][N:30]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cnccn3)c2)=Nc2cc(C(F)(F)F)c(Cl)cc2N1

Procedure:
The title compound was prepared from {4-chloro-2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M101) (0.28 g, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (50 mg, 23%).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([C:13]#N)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[Cl-].[NH4+]>O1CCCC1.C([Mg]Cl)CC1C=CC=CC=1>[CH3:1][N:2]([CH3:15])[C:3]1([CH2:13][CH2:13][C:3]2[CH:12]=[CH:11][CH:6]=[CH:5][CH:4]=2)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Agent: Cl[Mg]CCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(CCc2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
45 g 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile were dissolved in 250 ml analytical grade tetrahydrofuran, 238 ml 1.0 molar phenethylmagnesium chloride solution in THF were added under a nitrogen atmosphere and the mixture was stirred overnight at room temperature. For working up, 100 ml ammonium chloride solution (20 per cent by weight) were added, while cooling with ice, the phases were separated, the aqueous phase was extracted twice with 200 ml diethyl ether each time, the combined organic phases were washed successively with 100 ml water and 100 saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. The crude dimethyl-(8-phenethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine obtained as a yellow oil (54.1 g) was stirred, without further purification, with a mixture of 120 ml conc. hydrochloric acid (32 per cent by weight) and 70 ml water for 24 hours at room temperature. The reaction mixture was then first washed three times with 50 ml diethyl ether each time, then rendered alkaline by addition of sodium hydroxide solution (32 per cent by weight), while cooling with ice, and extracted three times with 100 ml methylene chloride each time, the combined methylene chloride extracts were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. 35.7 g of crude 4-dimethylamino-4-phenethyl-cyclohexanone were obtained as a slowly crystallizing brown oil.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C@H:5]([N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:18][C:19]2[C:23]3[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[S:21][N:20]=2)[C:8]1=[O:30])[CH3:6].[Li+].[OH-].Cl>C1COCC1.O>[CH3:29][C:24]1[C:23]2[C:19]([CH2:18][N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16](=[O:17])[N:7]([C@H:5]([CH3:6])[CH2:4][C:3]([OH:31])=[O:2])[C:8]3=[O:30])=[N:20][S:21][C:22]=2[CH:27]=[C:26]([CH3:28])[CH:25]=1
Reactant: COC(=O)C[C@@H](C)n1c(=O)c2ccccc2n(Cc2nsc3cc(C)cc(C)c23)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c2c(Cn3c(=O)n([C@H](C)CC(=O)O)c(=O)c4ccccc43)nsc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-3-[1-(4,6-dimethyl-1,2-benzisothiazol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-butyric acid methyl ester (60 mg, 0.14 mmol) in THF (1 mL) is added a solution of LiOH (8.5 mg, 0.20 mmol) in water (0.5 mL) and the resulting mixture is agitated at ambient temperature for 24 hours, heated at 50° C. for 6 hours, then agitated an additional 48 hours at ambient temperature. The reaction mixture is neutralized with 1N HCl (0.2 mL) then extracted with ethyl acetate (2×10 mL). The combined extracts are washed with water (1×10 mL) and brine (1×10 mL), dried with sodium sulfate and concentrated to provide the title compound. LCMS (ESMS): m/z 410 (M+H+).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][OH:9])[C@H:4]([CH2:5][CH2:6][CH3:7])[O:3]1.CC(OC([C@H](O)[C@@H](O)C(OC(C)C)=O)=O)C>>[CH3:1][C@@:2]1([CH2:8][OH:9])[C@@H:4]([CH2:5][CH2:6][CH3:7])[O:3]1
Reactant: CCC[C@@H]1O[C@]1(C)CO
Agent: CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C
Product: CCC[C@H]1O[C@]1(C)CO
Yield: 79 %

Procedure:
Using the same procedure as for the preparation of 13, (+)-DIPT and allylic alcohol 12 gave 15 in 79% yield. 1HNMR, 13C NMR IR and high resolution MS are identical to 13. [α]D=+13.9° (c=1.35, CH2,Cl2). -P NMR (10% C6D6 in benzene, 145.786 MHz) δ:132.4 (93.2%) and 133.5 (6.8%), 86.5% ee.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]2[O:20][C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[NH:13][C:12](=[O:21])[C:11]=2[CH:22]=1.[OH-].[Na+].[C:26]1([CH2:32][CH:33]=O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH3:2][O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]2[O:20][C:14]3([CH2:19][CH2:18][N:17]([CH2:33][CH2:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:16][CH2:15]3)[NH:13][C:12](=[O:21])[C:11]=2[CH:22]=1
Reactant: O=CCc1ccccc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCNCC1)O2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCN(CCc3ccccc3)CC1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
(E)-3-{3,4-Dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester hydrochloride (obtained as described in Example 25, Step B, 300 mg, 0.886 mmol) was dissolved in MeOH (30 ml). The pH was adjusted to 5 with AcOH and 1 M NaOH in MeOH, and then phenyl-acetaldehyde (128 mg, 1.06 mmol) and NaCNBH3 (67 mg, 1.06 mmol) were added. The mixture was stirred overnight at RT, then the solvent was removed and the residue partitioned between 5% aqueous NaHCO3 and DCM. The organic phase was dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (eluent:DCM/MeOH 95:5) to give (E)-3-{1′-(2-phenyl-ethyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (322 mg).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[O:20][CH3:21])[CH2:5][CH2:4]1)=O.B.CO.ClCCl>O1CCCC1>[CH3:1][N:3]1[CH2:4][CH2:5][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=2[O:20][CH3:21])[CH2:7][CH2:8]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCC1CCN(C=O)CC1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])ccc1OCC1CCN(C)CC1
Temperature: 60 °C

Procedure:
A suspension of N-formyl-4-(2-methoxy-4-nitrophenoxymethyl)piperidine (1.24 g, 4.2 mmol) in tetrahydrofuran (5 mL) under nitrogen was stirred while adding the borane solution (8.4 mL of a 1M soln in THF) then heated to 60° C. for 2 h. Further borane solution (to a total of 5 equivalents) and 20 mL tetrahydrofuran (20 mL) were added and the mixture was heated overnight. The mixture was cooled, methanol (25 mL) was added carefully followed by dichloromethane. The mixture was then washed with brine, 2M NaOH, dried over Na2SO4 and solvent evaporated. The residue was dissolved in methanol, a few drops of acetic acid added and the mixture was heated under reflux for 3 days. Evaporation of the solvent and chromatography in 9:1 dichloromethane:methanol containing 1% triethylamine afforded the product as a brown solid. 1H NMR (400 MHz, dmso-d6): 1.4-1.5 (2H, m); 1.85-2 (3H, m); 2-2.1 (2H, m); 2.8-3 (2H, m); 4.05 (3H, s); 4.15 (2H, d, J 7 Hz); 7.35 (1H, d, J 8 Hz); 7.9 (1H, d, J 2 Hz); 8.05 (1H, dd, J 2 and 8 Hz).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[CH3:7][C:8](=[CH:10][CH2:11][CH2:12]/[C:13](=[CH:15]/[CH2:16][OH:17])/[CH3:14])[CH3:9].C([N+](CCCC)(CCCC)CCCC)CCC>CCCCCC.O>[CH2:16]([O:17][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])/[CH:15]=[C:13](/[CH2:12][CH2:11][CH:10]=[C:8]([CH3:9])[CH3:7])\[CH3:14]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: BrCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCCCCC
Solvent: O
Product: CC(C)=CCC/C(C)=C/COCCCCBr
Temperature: 25 °C
Reaction time: 20 h
Yield: 352.4 %

Procedure:
1,4-Dibromobutane (42.7 g, 198 mmol), geraniol (8.78 g, 56.9 mmol) and tetrabutylammonium w/v, 70 mL) was added with stirring. The reaction mixture was heated at reflux for 3 h under N2. then left stirring under N2 for a further two days. Heating at reflux was resumed for a further 20 h and then the reaction mixture was cooled to room temperature and diluted with hexane (80 mL) and water (80 ml). The product was partitioned into the hexane layer and then the water layer was extracted with ether (2×20 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure to give a pale yellow oil. The oil was distilled under high vacuum (Kugelrohr) to remove the remaining dibromobutane thereby leaving the product as a yellow/orange oil (58 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](OC3CCOCC3)[C:10]=2[N:11]=1.[CH:19]1([NH2:23])[CH2:22][CH2:21][CH2:20]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:23][CH:19]3[CH2:22][CH2:21][CH2:20]3)[C:10]=2[N:11]=1
Reactant: NC1CCC1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc2ncnc(NC3CCC3)c2n1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.100 g, 0.500 mmol), cyclobutanamine (0.047 ml, 0.550 mmol), PdCl2(dppf)-CH2Cl2Adduct (4.08 mg, 5.00 μmol) and sodium tert-butoxide (0.096 g, 1.00 mmol) in dioxane (2.50 ml) was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give 6-chloro-N-cyclobutylpyrido[3,2-d]pyrimidin-4-amine (0.098 g, 84%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.79-1.89 (2H, m), 2.06-2.17 (2H, m), 2.48-2.56 (2H, m), 4.71-4.82 (1H, m), 7.11 (1H, brs), 7.61 (1H, d, J=8.8 Hz), 8.03 (1H, d, J=8.8 Hz), 8.61 (1H, s).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][S:29][CH2:30][CH2:31][CH2:32][C:33]([CH2:44][CH3:45])([O:36][Si](CC)(CC)CC)[CH2:34][CH3:35])[CH2:12][C@@H:11]([O:46][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:34]([C:33]([OH:36])([CH2:44][CH3:45])[CH2:32][CH2:31][CH2:30][S:29][CH2:28][C:20]1[C@:21]2([CH2:23][CH2:24][C@H:25]3[C:16](=[CH:15][CH:14]=[C:13]4[C@:26]3([CH3:27])[C@@H:9]([OH:8])[CH2:10][C@H:11]([OH:46])[CH2:12]4)[C@@H:17]2[CH2:18][CH:19]=1)[CH3:22])[CH3:35]
Reactant: CCC(CC)(CCCSCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(CC)CCCSCC1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 76.5 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-{4-ethyl-4-(triethylsilyloxy)hexylthiomethyl}androsta-5,7,16-triene (310 mg, 0.386 mmol) and a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (5 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (3 hours), worked up and purified by column chromatography (ethyl acetate) to give the titled compound (136 mg, 77%) as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>C1COCC1>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:35])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Reactant: O=C=Nc1ccccc1Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Temperature: 25 °C
Reaction time: 9 h

Procedure:
The compound of example 392 (100 mg, 0.295 mmol) was dissolved in 3 mL THF and to this reaction mixture, 2-chlorophenyl isocyanate (49.83 mg, 0.324 mmol) was added and stirred at room temperature for 8-10 h. The reaction mixture was concentrated and purified by column chromatography (silica gel, 30-40% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: [Li]C(C)(C)C.[CH3:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1.Br[C:13]1[S:17][C:16]([S:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)(=[O:20])=[O:19])=[CH:15][CH:14]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:6][C:7]1[O:8][C:9]([C:13]2[S:17][C:16]([S:18]([N:21]3[CH:25]=[CH:24][CH:23]=[CH:22]3)(=[O:19])=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:11]=1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: Cc1ccco1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)o1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 19.3 %

Procedure:
t-BuLi (1.7 m solution in hexane, 7.9 ml, 14.6 mmol) was added dropwise under constant stirring under a nitrogen atmosphere to a solution of 2-methylfuran (1.0 g, 12 mmol) in THF (20 ml) at −78° C. The solution was then warmed to −10° C. and stirring continued for 45 min. The solution was then added to a solution of zinc chloride (27 ml of a 0.5 M solution in THF) at −30° C. and then warmed to room temperature where stirring continued for 1 hr. resulting in a pale yellow clear solution. The solution was then transferred via a steel canula under nitrogen to a solution of N-(5-bromothiophene-2-sulfonyl)pyrrole (Example 33A, 3.5 g, 12 mmol) and tetrakis(triphenylphosphine)-palladium (0) (693 mg, 0.6 mmol) in THF (15 ml) at −78° C. The solution was then wanned to room temperature and stirred for a period of 2 hours. Purification by column chromatography using 2% ethyl acetate gave 680 mg of N-[5-(2-methyl-5-furyl)thiophene-2-sulfonyl]pyrrole as a pale yellow powder (19% yield).
Reaction SMILES: C(O)(=O)C.[S:5]([O-:9])(=[O:8])(=[O:7])[CH3:6].C([O:17][CH:18]([CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:19][S:20]([CH2:23][CH2:24][CH2:25][N+:26]([CH3:29])([CH3:28])[CH3:27])(=[O:22])=[O:21])C1C=CC=CC=1>[C].[Pd].O>[S:5]([O-:9])(=[O:8])(=[O:7])[CH3:6].[OH:17][CH:18]([CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:19][S:20]([CH2:23][CH2:24][CH2:25][N+:26]([CH3:27])([CH3:29])[CH3:28])(=[O:22])=[O:21]
Reactant: CCCCCCCCCCCCCCCCCCOCC(CS(=O)(=O)CCC[N+](C)(C)C)OCc1ccccc1
Agent: [Pd]
Agent: CS(=O)(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCC(O)CS(=O)(=O)CCC[N+](C)(C)C
Yield: 88.1 %

Procedure:
Into a mixed solvent consisting of 50 ml of acetic acid and 5 ml of water is dissolved 1.4 g of 3-[(2-benzyloxy-3-octadecyloxypropyl)sulfonyl]propyltrimethylammonium mesylate and the solution is shaked in the presence of palladiumcarbon under hydrogen streams. The catalyst is then removed by filtration and the filtrate is concentrated. The resulting residue is treated with acetone to give 1.07 g of the captioned compound as powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[CH2:7][CH2:6]2.[H][H].[ClH:25]>C(O)C.O.[Pd]>[ClH:25].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)N(c1ccc([N+](=O)[O-])cc1)CC2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1OC)N(c1ccc(N)cc1)CC2
Yield: 84.9 %

Procedure:
5,6-Dimethoxy-1-(4-nitrophenyl)-indoline was hyrogenated overnight with Pd (5%) on carbon in ethanol/water (8:2) in a shaking “duck”. When the uptake of hydrogen had come to an end, 10% hydrochloric acid was added, the catalyst was filtered off and the remainder was concentrated to dryness. The residue was dried in vacuo at 45° C. The product 4-(5,6-dimethoxyindolinyl)-phenylamine hydrochloride was obtained in a yield of 84.9% (melting point: 143-145° C.).
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].O1CCOCC1.S(Cl)([Cl:21])=O>CN(C=O)C>[Cl:21][C:5]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[S:1](=[O:3])(=[O:2])[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1NS(=O)(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=S1(=O)N=C(Cl)c2ccccc21

Procedure:
Saccharin (10 g) was treated sequentially with dioxane (40 mL), thionyl chloride (15 mL) and DMF (0.4 mL). The resulting suspension was heated to reflux for 24 hours. The reaction mixture was concentrated to dryness and recrystalized from 60 mL toluene to give 5.7 g of the sub-title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:22]=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].O.CO>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:24]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:22]=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(N2CCOCC2)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCOCC3)ccc2C(=O)O)CC1
Yield: 93.1 %

Procedure:
Using methods substantially equivalent to those described in Example 21-D, methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(morpholin-4-yl)benzoate (2.40 g, 5.71 mmol), lithium hydroxide monohydrate (605 mg, 15.1 mmol), and 2:1 (10% water in tetrahydrofuran):methanol (75 mL) afforded 2.16 g (93%) of the title compound; which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([O:8][C:9]2[CH:23]=[CH:22][C:12]3[CH2:13][CH2:14][N:15]([CH:18]4[CH2:21][CH2:20][CH2:19]4)[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29].C(=O)([O-])[O-].[K+].[K+].CNCCNC>O1CCOCC1.CO.[Cu]I>[CH:18]1([N:15]2[CH2:14][CH2:13][C:12]3[CH:22]=[CH:23][C:9]([O:8][C:5]4[N:6]=[CH:7][C:2]([N:24]5[CH2:28][CH2:27][CH2:26][C:25]5=[O:29])=[N:3][CH:4]=4)=[CH:10][C:11]=3[CH2:17][CH2:16]2)[CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCCN1
Reactant: Clc1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C1CCCN1c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Temperature: 175 °C
Yield: 42.3 %

Procedure:
7-[(5-Chloro-2-pyrazinyl)oxy]-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine (E257) (132 mg, 0.40 mmol), pyrrolidinone (0.06 ml, 0.80 mmol), potassium carbonate (200 mg, 1.45 mmol), copper (I) iodide (23 mg, 0.12 mmol) and N,N′-dimethylethylenediamine (0.01 ml, 0.12 mmol) were added together in dry dioxane (3 ml) and heated in a microwave reactor at 175° C. for 30 minutes. The mixture was diluted with methanol and applied to a SCX column and washed with methanol then a mixture of 0.880 ammonia/methanol (1:9). The basic fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.2:1.8:98) to afford the title compound (64 mg); MS (ES+) m/e 379 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]([C:26]3[C:27](=[O:56])[N:28]([CH2:42][O:43][P:44]([O:51]C(C)(C)C)([O:46]C(C)(C)C)=[O:45])[C:29](=[O:41])[C:30]=3[C:31]3[C:39]4[C:34](=[C:35]([CH3:40])[CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:9]21[CH2:11][CH2:10]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCCl.CO>[CH2:10]1[C:9]2([CH2:12][N:13]([C:16]3[N:17]=[C:18]([C:26]4[C:27](=[O:56])[N:28]([CH2:42][O:43][P:44](=[O:45])([OH:51])[OH:46])[C:29](=[O:41])[C:30]=4[C:31]4[C:39]5[C:34](=[C:35]([CH3:40])[CH:36]=[CH:37][CH:38]=5)[NH:33][CH:32]=4)[C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:14][CH2:15][NH:8]2)[CH2:11]1
Reactant: Cc1cccc2c(C3=C(c4nc(N5CCN(C(=O)OC(C)(C)C)C6(CC6)C5)cc5ccccc45)C(=O)N(COP(=O)(OC(C)(C)C)OC(C)(C)C)C3=O)c[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CO
Product: Cc1cccc2c(C3=C(c4nc(N5CCNC6(CC6)C5)cc5ccccc45)C(=O)N(COP(=O)(O)O)C3=O)c[nH]c12
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a solution of 7-{1-[1-(di-tert-butoxy-phosphoryloxymethyl)-4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-isoquinolin-3-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester (1.90 g, 2.42 mmol) in 1,2-dichloroethane (50 mL) was added TFA (8.27 g, 72.5 mmol) under argon at 0° C. The reaction mixture was stirred for 3.5 h under argon at 0° C. until UPLC-MS indicated that full conversion of the starting material had occurred. The reaction mixture was diluted with 1,2-dichloroethane (50 mL) and concentrated at reduced pressure to afford the crude product as a red solid. The crude reaction product was dissolved in MeOH and slowly concentrated at reduced pressure until crystallization started to occur. Pentane was added and the solids were filtered off and washed with Et2O. Further purification was achieved by suspending the crude product in DMSO, followed by sonication for 30 min. The solids were filtered off, washed with Et2O and dried at high vacuum (<1 mm Hg) to afford the title compound as a dark red solid. 1H-NMR (400 MHz, DMSO-d6): 12.10 (s, 1H), 8.08 (d, 1H), 7.65-7.61 (m, 2H), 7.44 (t, 1H), 7.20 (s, 1H), 7.06 (t, 1H), 6.74 (d, 1H), 6.43 (t, 1H), 6.00 (d, 1H), 5.29 (d, 2H), 3.87-3.01 (m, 6H), 2.37 (s, 3H), 0.97-0.62 (m, 4H). 31P-NMR (162 MHz, DMSO-d6): −6.0. LCMS: [M+1]+=574.0, Rt(1)=1.77 min., Rt(2)=0.71 min.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=[O:14].O1CCCC1.[Na].[CH3:21][SH:22]>O>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:14])[CH:2]([S:22][CH3:21])[CH2:11][CH2:10]2
Reactant: COc1ccc2c(c1)CCC(Br)C2=O
Reactant: CS
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CCC(SC)C2=O
Reaction time: 3 h
Yield: 64 %

Procedure:
After 20 g of 2-bromo-6-methoxy-1-tetralone [synthesized in accordance with procedures described in W. S. Johnson, et al., J. Am. Chem. Soc., vol.66, p.218 to 220 (1944)] was dissolved into 100 ml of tetrahydrofuran, 36.5 g of a 15% aqueous solution of a sodium salt of methylmercaptan was added dropwise thereto. After the stirring for 3 hours at room temperature, the reaction mixture was poured into 300 ml of cold water. An organic layer was extracted with 200 ml of ether, and the ether layer was sequentially washed with a sodium chloride aqueous solution and water. After the ether layer was dried with magnesium sulfate, the solvent was removed by evaporated under vacuum. The residue was dissolved into 320 ml of a mixed solvent of hexane/ethyl acetate (7/1), and silica gel was added thereto for adsorbing impurities. After the silica gel was removed by filtration, the filtrate was concentrate under vacuum to provide 11.06 g of 6-methoxy-2-(methylthio)-1-tetralone (yield: 64%).