Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:31])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C.[CH2:39]([S:42](Cl)(=[O:44])=[O:43])[CH2:40][CH3:41]>C(Cl)Cl>[F:31][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:26][CH2:27][N:28]([S:42]([CH2:39][CH2:40][CH3:41])(=[O:44])=[O:43])[CH2:29][CH2:30]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1
Reactant: CCCS(=O)(=O)Cl
Reactant: FC1(F)Oc2ccc(-c3c[nH]c4ncc(-c5cnn(C6CCNCC6)c5)cc34)cc2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N1CCC(n2cc(-c3cnc4[nH]cc(-c5ccc6c(c5)OC(F)(F)O6)c4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 324 (50 mg, 0.1182 mmol) in DCM was added triethylamine (17.9 mg, 0.1773 mmol) and propane sulfonyl chloride 339 (16.7 mg, 0.1182 mmol) and stirred for 2 h at rt. The RM was diluted with dichloromethane and washed with water twice. The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified by flash column using 100-200 mesh silica gel. The compound was eluted at 2% Methanol in chloroform as off white coloured solid 345. 1HNMR (400 MHz, DMSO) δ: 11.95 (s, 1H), 8.55 (d, 1H), 8.39 (m, 2H), 8.03 (s, 1H), 7.88 (d, 1H), 7.78 (d, 1H), 7.58 (m, 1H), 7.44 (d, 1H), 4.35 (m, 1H), 3.69 (m, 2H), 3.03 (m, 4H), 2.14 (m, 2H), 1.97 (m, 2H), 1.70 (m, 2H), 1.00 (m, 3H) and MS ES+530.1.
Reaction SMILES: [NH2:1][NH2:2].[H-].[Na+].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]=1[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[C:12]#[N:13])([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH3:8][C:6]([C:9]1[CH:10]=[C:11]([C:12]([NH:1][NH2:2])=[NH:13])[CH:14]=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]=1[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])([CH3:5])[CH3:7]
Reactant: COCCOCOc1c(C(C)(C)C)cc(C#N)cc1C(C)(C)C
Reactant: NN
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOc1c(C(C)(C)C)cc(C(=N)NN)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
97% anhydrous hydrazine (4.8 g, 0.151 mole) is added dropwise to a stirred 0° C. suspension of sodium hydride (2.8 g of a 60% dispersion in mineral oil, 0.071 mol) in tetrahydrofuran (70 m) under nitrogen. After 90 minutes, a solution of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzonitrile (6.7 g, 0.021 mole) in tetrahydrofuran (15 ml) is added dropwise. After stirring two hours at 0° C., water 2.4 ml) is added dropwise. The mixture is poured into cold, saturated aqueous sodium bicarbonate 20 ml). The product is extracted with a 1:1 ethyl acetate/ether mixture (60 ml). The organic layer is washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration provided a solid which was recrystallized from ethyl acetate/hexane to give 4.9 g (7.3 g theor., 67%) of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzene carboximidic acid hydrazide, mp 133° C.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]1[O:23][C:7]2([C:12]3[CH:13]=[CH:14][C:15]4[C:20]([C:11]=3[S:10](=[O:22])(=[O:21])[NH:9][CH2:8]2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:6][CH2:5]1.[OH-].[Na+].O>C(O)(C)C>[CH2:4]1[O:23][C:7]2([C:12]3[CH:13]=[CH:14][C:15]4[C:20]([C:11]=3[S:10](=[O:22])(=[O:21])[N:9]([CH2:1][CH3:2])[CH2:8]2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:6][CH2:5]1
Reactant: CCI
Reactant: O=S1(=O)NCC2(OCCO2)c2ccc3ccccc3c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCN1CC2(OCCO2)c2ccc3ccccc3c2S1(=O)=O
Reaction time: 84 h
Yield: 100.4 %

Procedure:
15.6 gm (0.1 mol) of ethyl iodide were added dropwise in several portions to a solution of 10.0 gm (0.034 mol) of 2H-naphtho[2,1-e]-1,2-thiazine-4(3H)-one-1,1-dioxide-ethylene ketal in a mixture of 150 ml of isopropanol, 36 ml of 1 N sodium hydroxide and 36 ml of water, while stirring. Stirring was continued for 84 hours, whereupon the mixture was evaporated in vacuo, the residue was taken up in methylenechloride, and the solution was washed with water, dried and evaporated. 10.9 gm (99% of theory) of 2-ethyl-2H-naphtho[2,1-e]-1,2-thiazine-4(3H)-one-1,1-dioxide-ethylene ketal were obtained, which were used as such in the next reaction step.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[CH2:10]1[CH:15]2[C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:14]2[CH2:13][CH2:12][N:11]1[CH2:29][CH2:30][CH2:31][OH:32].C(OCC)(=O)C>C(Cl)Cl>[C:3](=[O:4])([O:32][CH2:31][CH2:30][CH2:29][N:11]1[CH2:12][CH2:13][N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][C:17]3[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=3[CH:15]2[CH2:10]1)[NH2:5]
Reactant: OCCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)OCCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
0.2 ml of trichloroacetyl isocyanate were added to a solution of 400 mg of 3-(1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepin-2-yl)propanol (prepared as described in Example 16) in 20 ml of methylene chloride, whilst ice-cooling, and the mixture was stirred at room temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure. The resulting residue was dissolved in 22 ml of methanol, 9.0 g of silica gel were added to the solution and the mixture was stirred at room temperature for 15 hours. At the end of this time, the mixture was filtered using a Celite (trade mark) filter aid, and the filtrate was concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel eluted with ethyl acetate, to give, after recrystallization from ethyl acetate, 260 mg (yield 59%) of the title compound as crystals, melting at 160°-161° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=2[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12](O)=[O:13])[C:10]=1[C:18]([OH:20])=O.Cl.[NH2:26][CH:27]1[CH2:33][CH2:32][C:31](=[O:34])[NH:30][C:28]1=[O:29]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=2[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]2[C:10]=1[C:18](=[O:20])[N:26]([CH:27]1[CH2:33][CH2:32][C:31](=[O:34])[NH:30][C:28]1=[O:29])[C:12]2=[O:13]
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(OCc2sc3ccccc3c2Cl)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4sc5ccccc5c4Cl)c3C2=O)C(=O)N1
Yield: 38 %

Procedure:
A mixture of 3-(3-chloro-benzo[b]thiophen-2-ylmethoxy)-phthalic acid (1.6 g, 4.4 mmol), alpha-amino-glutarimide hydrochloride (0.76 g, 4.6 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(3-chloro-benzo[b]thiophen-2-ylmethoxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (0.76 g, 38% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 5.26 min (98.7%); mp, 240-242° C.; 1H NMR (DMSO-d6) δ 2.02-2.06 (m, 1H, CHH), 2.54-2.62 (m, 2H, CH2), 2.83-2.95 (m, 1H, CHH), 5.10 (dd, J=6, 12 Hz, 1H, CH), 5.74 (s, 2H, CH2), 7.49-8.10 (m, 7H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.94, 30.90, 48.79, 63.99, 116.26, 116.98, 118.36, 120.46, 121.39, 123.36, 125.57, 126.19, 132.93, 133.34, 135.42, 136.91, 137.04, 154.62, 165.05, 166.64, 169.85, 172.73. Anal Calcd For C22H15N7O5SCl+0.1H2O: C, 58.09; H, 3.32; N, 6.16; S, 7.05; Cl, 7.79. Found: C, 57.77; H, 3.06; N, 6.08; S, 6.87; Cl, 8.05.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:16]3[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=3)=[N:9][N:10]3[CH2:15][CH2:14][CH2:13][S:12][C:11]=23)=[CH:3][CH:2]=1.[F:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.CN1CCOCC1>C(Cl)Cl>[F:23][C:24]1[CH:25]=[C:26]([S:30]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:8]3[C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[C:11]4[S:12][CH2:13][CH2:14][CH2:15][N:10]4[N:9]=3)[CH:17]=2)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(-c2nn3c(c2-c2ccncc2)SCCC3)c1)c1cccc(F)c1
Reaction time: 2 h
Yield: 92.8 %

Procedure:
3-(3-Pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenylamine (prepared as described in Example 3) (30 mg, 0.097 mmol) was dissolved in dry DCM (1 mL). At room temperature 3-fluorobenzensulfonylchloride (0.013 mL, 0.097 mmol, 1 eq) was added followed by NMM (0.011 mL, 0.097 mmol, 1 eq) and the mixture was stirred for 2 hours. It was then diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (eluant DCM/MeOH/NH3 7 N in MeOH 95:5:0.5) to give 42 mg (93%) of 3-fluoro-N-[3-(3-pyridin-4-yl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazin-2-yl)-phenyl]-benzenesulfonamide.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([N+:21]([O-])=O)=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[CH:8]=[C:9]([F:11])[CH:10]=1)[CH:2]=[CH2:3].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[C:6]=1[NH2:21])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(F)cc(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCOc1cc(F)cc(Nc2ccc(I)cc2F)c1N
Temperature: 70 °C
Yield: 40 %

Procedure:
A suspension of N-(3-(allyloxy)-5-fluoro-2-nitrophenyl)-2-fluoro-4-iodobenzenamine (Intermediate 11, 1.56 g, 3.73 mmol) in ethanol (20 mL) was stirred at 70° C. to obtain a clear solution. To this hot solution was added dropwise a freshly prepared solution of Na2S2O4 (1.94 g, 11.19 mmol) in water (3.5 mL) and stirred the reaction mixture at 90° C. for 1 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and concentrated to yield 3-(allyloxy)-5-fluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (600 mg). 1H-NMR (400 MHz, CDCl3): δ 3.65 (2H, bs), 4.57 (2H, d, J=5.6), 5.32 (1H, d), 5.40 (1H, s), 5.46 (1H, d), 6.03-6.10 (1H, m), 6.45 (1H, dd, J=10.4, 2.8), 6.52 (1H, dd), 6.59 (1H, t) 7.27 (1H, d, J=9.2), 7.38 (1H, dd, J=10.4, 2).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:7])=[CH:5][CH:6]=1.C(=O)=O.CC(C)=O.[Cl:15][S:16](O)(=[O:18])=[O:17]>>[Cl:1][C:2]1[S:3][C:4]([Cl:7])=[CH:5][C:6]=1[S:16]([Cl:15])(=[O:18])=[O:17]
Reactant: O=S(=O)(O)Cl
Reactant: Clc1ccc(Cl)s1
Agent: O=C=O
Solvent: CC(C)=O
Product: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A 96.8-g (0.632 mol) sample of 2,5-dichlorothiophene was added dropwise to a cooled (dry ice/acetone bath, about -10° to -15° C) and stirred solution of 163 g (1.39 mol) of chlorosulfonic acid. After the addition was completed, the reaction mixture was stirred at 50° C for 2 hours, cooled, and then poured into 200 g of ice. The aqueous reaction mixture was extracted with methylene chloride. The methylene chloride extract was washed with saturated aqueous sodium bicarbonate solution, washed with water, dried over magnesium sulfate, and evaporated to give 87 g of 2,5-dichloro-3-thienylsulfonyl chloride.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[CH:7][C:8]([C:27]([OH:29])=[O:28])=[C:9]([OH:26])[C:10]=2[CH2:11][C:12]2[C:21]([OH:22])=[C:20]([C:23]([OH:25])=[O:24])[CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[CH:17]3)[CH:6]=1.[OH-].[Na+:31]>O1CCOCC1.O1CCOCC1.O>[CH:16]1[CH:17]=[C:18]2[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[C:21]([O-:22])=[C:12]([CH2:11][C:10]3[C:4]4[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=4)[CH:7]=[C:8]([C:27]([OH:29])=[O:28])[C:9]=3[O-:26])[C:13]2=[CH:14][CH:15]=1.[Na+:31].[Na+:31]
Reactant: O=C(O)c1cc2ccccc2c(Cc2c(O)c(C(=O)O)cc3ccccc23)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc2ccccc2c(Cc2c([O-])c(C(=O)O)cc3ccccc23)c1[O-]

Procedure:
A second octreotide-pamoate complex was prepared by dissolving pamoic acid (19.4 mg, 0.05 mmol) in 0.4 N NaOH (250 μL) and dioxane (250 μL) to provide a solution of sodium pamoate in dioxane/water (1:1). Octreotide acetate (50 mg, 0.05 mmol) was dissolved in dioxane/water (1:1, 200 μL). The octreotide acetate solution was added drop wise to the sodium pamoate with mixing to provide a light yellow, homogenous solution. This material was lyophilized to dryness providing a light yellow powder (65 mg). The octreotide/pamoate ratio of this preparation was 1.02 as measured by RP-HPLC. These two preparations were used to prepare new PLGA microparticle formulations.
Reaction SMILES: FC1C=C(C=CC=1OC)C(O[C:8]1[C:13]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=2)=[CH:12][C:11]([O:26][CH3:27])=[CH:10][C:9]=1[Br:28])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC1C=CC(C)=CC=1>O>[Br:28][C:9]1[C:8]2[O:25][C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=3)=[N:14][C:13]=2[CH:12]=[C:11]([O:26][CH3:27])[CH:10]=1
Reactant: COc1cc(Br)c(OC(=O)c2ccc(OC)c(F)c2)c(NC(=O)c2ccc(OC)c(F)c2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccc(C)cc1
Product: COc1cc(Br)c2oc(-c3ccc(OC)c(F)c3)nc2c1
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
A suspension of 2-bromo-6-[(3-fluoro-4-methoxybenzoyl)amino]-4-methoxyphenyl 3-fluoro-4-methoxybenzoate (46.0 g, 88.1 mmol), p-toluenesulfonic acid monohydrate (33.5 g, 177.2 mmol) and anhydrous p-xylene (1 l) was refluxed for 3 h with continuous water removal (Dean Stark Trap). The initial suspension turned into a brown solution at refluxing temperature. The solids were filtered off and washed with ethyl ether. The solids were suspended in ethyl ether (200 mL), stirred for 10 min, filtered off and dried to give a tan solid (25.1 g, m.p. 175–177° C.). The ethyl ether layer was concentrated to 20 mL and 2.5 g of additional product was obtained (90% overall yield). MS m/e 352 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4](Br)[CH:3]=1.[CH2:10]([OH:15])[CH2:11][CH2:12][C:13]#[CH:14]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:15][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:2]1[CH:7]=[C:6]([C:14]#[C:13][CH2:12][CH2:11][CH2:10][OH:15])[CH:5]=[C:4]([C:14]#[C:13][CH2:12][CH2:11][CH2:10][OH:15])[CH:3]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: OCCCC#Cc1cc(C#CCCCO)cc(C#CCCCO)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 73.9 %

Procedure:
1,3,5-Tribromobenzene (10 g, 31.76 mmol), 4-pentyn-1-ol (10.69 g, 127.06 mmol) and bis(triphenylphosphine)palladium(II) dichloride were stirred in triethylamine under nitrogen for 5 minutes. Copper(I) iodide (92 mg, 0.48 mmol) was added and the mixture was stirred for 6 hours at 80° C. The mixture was cooled to room temperature, filtered through a celite pad and rinsed with ethyl acetate. The combined filtrate was evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (CHCl3:MeOH 10:1) to afford 7.61 g of 1,3,5-tris-(5-hydroxy-1-pentynyl)-benzene. Yield: 74%. 1H NMR (300 MHz, CDCl3) δ 7.31 (3, 3h), 3.81 (t, J=6.0 Hz, 6H), 2.52 (t, J=6.9 Hz, 6H), 1.85 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 133.8, 124.2, 90.5, 80.0, 61.9, 31.5, 16.2 ppm.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Br:26][C:27]1[C:28](=[O:40])[N:29]([CH2:37][CH:38]=O)[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:38][CH2:37][N:29]4[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:36]=[C:27]([Br:26])[C:28]4=[O:40])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)c(Br)cc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)c(Br)cc3ccccc32)CC1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To 3 mL of a chloroform solution containing 0.47 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.36 g of (3-bromo-2-oxoquinolin-1(2H)-yl)acetaldehyde, 30 μL of acetic acid and 0.43 g of sodium triacetoxyborohydride were added and stirred at room temperature for 2 nights. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate], to give 0.54 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-bromo-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=2[CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH3:22][C:15]1[CH:16]=[C:17]([CH2:20][OH:21])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1cc(CO)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(CO)ccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.9 %

Procedure:
The intermediate 4-(4-methoxycarbonyl-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.42 g) described in Preparation Example 97 was dissolved in diethyl ether (18 mL), 0.99M diisobutylaluminum hydride (9 mL) was added under cooling to −78° C., and the mixture was stirred while rising the temperature to room temperature. The mixture was further stirred at room temperature for 2 hr, methanol (0.7 mL) was added, and aqueous solution (5 mL) of Rochelle salt was added. The precipitate was collected by filtration from the reaction mixture, and the filtrate was concentrated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give 4-(4-hydroxymethyl-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (720 mg). The obtained 4-(4-hydroxymethyl-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (720 mg) was dissolved in chloroform (6 mL), 4N hydrogen chloride/ethyl acetate solution (2.3 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (654 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:28]=2[NH2:29])[CH2:23][CH2:22]1.Cl.O1CCOCC1>CO>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[C:3]([CH3:20])=[C:2]2[NH:29][C:28]1[CH:30]=[C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:32]=[CH:33][C:27]=1[N:24]1[CH2:23][CH2:22][O:21][CH2:26][CH2:25]1
Reactant: Cc1c(-c2ccccc2F)nc2ccc(Cl)cc2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2ccccc2F)nc2ccc(Cl)cc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4,6-dichloro-2-(2-fluorophenyl)-3-methylquinoline (116 mg, 0.38 mmol), 2,5-dimorpholinoaniline (100 mg, 0.38 mmol) and a 4.0M solution of HCl in dioxane (0.095 mL, 0.38 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification 6-chloro-N-(2,5-di-4-morpholinylphenyl)-2-(2-fluorophenyl)-3-methyl-4-quinolinamine was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.10 (1H, d, J=9.0 Hz), 7.90 (1H, d, J=2.3 Hz), 7.58-7.67 (2H, m), 7.47 (1H, d, J=8.2 Hz), 7.31-7.37 (1H, m), 7.16-7.22 (1H, m), 7.13 (1H, d, J=8.6 Hz), 6.45 (1H, dd, J=8.6, 2.7 Hz), 6.00-6.08 (1H, m), 3.93 (4H, t, J=4.5 Hz), 3.76 (4H, dd, J=5.9, 3.9 Hz), 3.06 (4H, d, J=1.2 Hz), 2.91-3.02 (4H, m), 2.20 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=533.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:7][C:8]2([OH:17])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH3:25]I.[I-]>C(O)C.O=[Pt]=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:7][C:8]2([OH:17])[CH:11]2[CH2:12][CH2:13][N:14]([CH3:25])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: OC1(c2ccncc2)CC(c2ccc(F)cc2)c2ccc(F)cc21
Agent: O=[Pt]=O
Agent: [I-]
Solvent: CCO
Product: CN1CCC(C2(O)CC(c3ccc(F)cc3)c3ccc(F)cc32)CC1

Procedure:
6-Fluoro-3-(4'-fluorophenyl)-1-hydroxy-1-pyrid-4-ylindane (5.0 g) was reacted with methyliodide as described in Example 2, and the resulting pyridylium iodide (viscous oil) was dissolved in ethanol (150 ml) and 0.5 g PtO2 added. The estimated amount of hydrogen was consumed in 3 hrs. (3.0-3.5 atm.). The catalyst was filtered off and the ethanol evaporated. Ice-cold NaOH solution (100 ml 0.2M) was added to the residue and the resulting base extracted with ethyl acetate (2×50 ml). The combined organic phases were dried (MgSO4) and the solvent evaporated. The remaining oil was dissolved in isopropylether, and by cooling the product precipitated and was filtered off. Yield: 4.7 g (88.8%) of the title compound. MP: 146°-147° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][CH:30]=O)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][CH2:30][N:13]2[CH2:14][CH2:15][CH:10]([C:8]([C:4]3[S:5][CH:6]=[CH:7][C:3]=3[Cl:2])=[O:9])[CH2:11][CH2:12]2)[CH2:27][CH2:28]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: O=C(c1sccc1Cl)C1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3sccc3Cl)CC2)CC1

Procedure:
From (3-chloro-thiophen-2-yl)-piperidin-4-yl-methanone hydrochloride (100 mg) and [trans-4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (intermediate C, 91 mg) by procedure A.1. Yield: 85 mg (50%). White foam. MS (m/z): 455.3 ([M+H]+).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[C:10](O)([CH3:13])([CH3:12])[CH3:11].C(OCC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:10]([O:8][C:7]([CH:4]1[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]1)=[O:9])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C1CCC(C(=O)O)C1
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1CCC(=O)C1
Temperature: 2 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To a cold (ice bath) solution of 3-oxo-1-cyclopentanecarboxylic acid (1.50 g), tert-butylalcohol (1.05 g) and 4-dimethylaminopyridine (140 mg) in dichloromethane (9 mL) was added a solution of dicyclocarbodiimide in dichloromethane (9 mL). The mixture was stirred 3 hours at ca. 2° C. then diethylether (30 mL) was added and the precipitate was filtered off and discarded. The solution was concentrated in vacuo. The residue was purified by flash chromatography on silica gel with cyclohexane/ethyl acetate (9:1 v/v) as eluant to afford the title compound (1.80 g, 96%) as colorless oil. MS (EI): 111 (M-OtBu.)+.