Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:45]I>C(Cl)Cl.CO>[I:45][CH2:2][CH2:3][CH2:4][C@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: II
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCO)C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCI)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of t-butyl (S)-5-hydroxy-2-(t-butoxycarbonylamino)-pentanoate (5.79 g, 20.0 mmol), triphenylphosphine (8.13 g, 31.0 mmol) and imidazole (2.04 g, 30.0 mmol) in CH2Cl2 (200 mL) at room temperature is added iodine (6.35 g, 25.0 mmol), portionwise, over 30 minutes. The mixture is then stirred 16 hours at room temperature. Methanol (20 mL) is added to the solution, which is then stirred an additional 1 hour. Solvent is evaporated, and the residue is purified by chromatography (silica, 33% EtOAc/hexane) to yield t-butyl (S)-5-iodo-2-(t-butoxycarbonylamino)-pentanoate as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][CH2:14]Cl)[CH:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[CH:25][CH:24]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][CH2:14][N:34]1[CH2:35][CH2:36][CH:31]([C:29](=[O:30])[C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)[CH2:32][CH2:33]1)[CH:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)N1CCCl
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Solvent: CCO
Product: O=C(c1ccc(F)cc1)C1CCN(CCN2C(=O)Nc3ccc(Cl)cc3C2c2ccccc2)CC1
Yield: 57 %

Procedure:
A mixture of 5.8 parts of 6-chloro-3-(2-chloroethyl)-3,4-dihydro-4-phenyl-2(1H)-quinazolinone, 7.4 parts of (4-fluorophenyl) (4-piperidinyl)methanone and 56 parts of ethanol is stirred and refluxed overnight. The reaction mixture is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue solidifies on triturating in 2,2'-oxybispropane. The product is filtered off and dried, yielding 5 parts (57%) of 6-chloro-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-3,4-dihydro-4-phenyl-2(1H)-quinazolinone; mp. 196° C.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.[CH:49]1([C:52]([OH:54])=O)[CH2:51][CH2:50]1>>[CH:49]1([C:52]([N:46]2[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][NH:40][C@:5]34[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]3[C@@H:7]3[C@@:2]([CH3:1])([CH2:3][CH2:4]4)[C@@:19]4([CH3:20])[C@@H:10]([C@:11]5([CH3:33])[C@@H:16]([CH2:17][CH2:18]4)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]4[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=4)=[CH:13][CH2:12]5)[CH2:9][CH2:8]3)[CH2:44][CH2:45]2)=[O:54])[CH2:51][CH2:50]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)C1CC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C4CC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound (0.9 mg) was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure as described above using cyclopropanecarboxylic acid as the acylating agent. LCMS: m/e 710.8 (M+H)+, 4.41 min (method 15). 1H NMR (500 MHz, METHANOL-d4) δ 7.88 (d, J=7.9 Hz, 2H), 7.16 (d, J=7.9 Hz, 2H), 5.30 (d, J=4.9 Hz, 1H), 4.78 (s, 1H), 4.67 (s, 1H), 3.84 (br. s., 2H), 3.77-3.50 (m, 2H), 3.09-2.97 (m, 1H), 2.94-2.81 (m, 2H), 2.77 (td, J=10.5, 5.3 Hz, 1H), 2.73-2.57 (m, 4H), 2.48 (br. s., 1H), 2.21-1.82 (m, 8H), 1.75 (s, 3H), 1.73-1.07 (m, 15H), 1.24 (s, 3H), 1.10 (s, 3H), 1.06 (s, 3H), 0.97 (s, 3H), 0.97 (s, 3H), 0.93-0.87 (m, 2H), 0.87-0.79 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[O:23][CH2:24][CH:25]2[O:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[O:27][CH2:26]2)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].Cl>C1COCC1.[OH-].[Na+].CO>[O:30]1[C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[O:27][CH2:26][CH:25]1[CH2:24][O:23][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[C:11]([NH:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:12]
Reactant: COC(=O)C1(NC(=O)c2ccc3ccccc3c2OCC2COc3ccccc3O2)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NC1(C(=O)O)CCCC1)c1ccc2ccccc2c1OCC1COc2ccccc2O1
Yield: 50.5 %

Procedure:
96 mg 1-{[1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-naphthalene-2-carbonyl]-amino}-cyclopentanecarboxylic acid methyl ester in 0.5 ml THF, 0.62 ml of 2 M sodium hydroxide and 1.4 ml methanol were reacted in a microwave at 120° C. for 6 min. The reaction was then acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate, and concentrated to yield 47 mg of 1-{[1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-naphthalene-2-carbonyl]-amino}-cyclopentanecarboxylic acid.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][O:30][C:31](=[O:48])[CH:32](OS(C(F)(F)F)(=O)=O)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[C:8]2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([O:30][CH3:29])=[O:48])[CH:22]=[CH:21]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(Cc1ccccc1)OS(=O)(=O)C(F)(F)F
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3-c3ccccc3)ccc2c1
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
In a similar manner as described in step 1 of Example 7, the title compound was prepared from 6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthol (0.300 g, 0.676 mmol), prepared in step 2 of Example 11, 3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester (0.317 g, 1.02 mmol) and cesium carbonate (0.441 g, 1.35 mmol) with the exception that this reaction was complete after 30 minutes at ambient temperature. Purification on a Biotage Horizon™ system with a KP-Sil Flash 25+M column (40 g Silica Gel, 60 Å) using 25% to 65% methylene chloride in hexane as the eluent gave methyl 2-{[6-(1,5-diphenyl-1H-pyrrol-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate as a white solid (0.257 g, 89%), mp 178–179° C. Elemental Analysis for C36H29NO3 Calc'd: C, 82.58; H, 5.58; N, 2.67. Found: C; 81.87; H, 5.10; N, 2.50.
Reaction SMILES: C([O:3][C:4](=O)[CH:5](O)[CH:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[C:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11])C.O.[NH2:29][NH2:30]>C(O)(=O)C>[CH2:8]([C:7]1[C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=2)=[CH:5][C:4](=[O:3])[NH:29][N:30]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCC(=O)C(c1ccc(OC2CCCCC2)cc1)C(O)C(=O)OCC
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1n[nH]c(=O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of the octanoic acid ethyl ester (105 mmol, 39.5 g) in glacial acetic acid (25.5 mL) was added hydrazine hydrate (525 mmol, 25.5 mL), and the reaction was heated at 100° C. for 12 h. After cooling, the volatiles were removed in vacuo, the residue was dissolved in ethyl acetate (300 mL). The organic layer was washed with water (100 mL), saturated NaHCO3 (3×100 mL), brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate (200 mL) and hexanes (300 mL) to afford 6-butyl-5-(4-cyclohexyloxy-phenyl)-2H-pyridazin-3-one.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:17])[CH2:11][C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13].ClO[N:20]=[CH:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29]>CCO.CCOC(C)=O>[CH3:8][O:9][C:10]([C:11]1[C:21]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:29])=[N:20][O:13][C:12]=1[CH:14]1[CH2:16][CH2:15]1)=[O:17]
Reactant: ClON=Cc1c(Cl)cccc1Cl
Reactant: COC(=O)CC(=O)C1CC1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Triethylamine (1.82 L, 12.84 mol) is added to 3-cyclopropyl-3-oxo-propionic acid methyl ester (913 g, 6.42 mol) and the mixture is stirred at room temperature for 30 minutes. Then, the mixture is cooled to about 10° C. and a suspension of 2,6-dichloro-benzaldehyde chloro-oxime (1440.9 g, 6.42 mol) in EtOH (3.2 L) is added slowly (the internal temperature does not exceed 24° C.). After the addition, the reaction is stirred overnight at room temperature. The reaction is diluted with EtOAc (5.3 L) and washed with water (1.7 L). The layers are separated and the aqueous layer is extracted with EtOAc (3 L). The combined organics are washed with brine, dried over Na2SO4 (anhyd), filtered and concentrated to about 10% of its total volume. The precipitate formed is filtered, triturated with ether (2 L) and dried under vacuum to obtain title compound as a (1275.36 g, 64% yield) as a white solid. MS (m/e): 312 (M+1).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[NH:7]1)=[O:5])C.O.[OH-].[Li+].O>O1CCCC1>[O:11]=[S:8]1(=[O:12])[CH2:9][CH2:10][CH:6]([C:4]([OH:5])=[O:3])[NH:7]1
Reactant: CCOC(=O)C1CCS(=O)(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCS(=O)(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude 2-{3-[((S)-4-chloro-phenyl)-1-dimethylaminomethyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid ethyl ester (310 mg, approx. 0.61 mmol) in tetrahydrofuran (3.6 mL) was added lithium hydroxide hydrate (51 mg, 1.2 mmol) followed by water (910 μL). The reaction mixture was stirred at room temperature for 2 h, and then the mixture was concentrated under reduced pressure to remove tetrahydrofuran. The remaining solution was stirred and approximately 25 drops of 1 M hydrochloric acid were added to bring the pH to 4.5. The sample was stirred for 10 min and the aqueous solution was decanted away from the yellow gum. The gum was washed with water (2 mL). The combined aqueous layers were evaporated to dryness, and dried overnight to give 2-{3-[((S)-4-chloro-phenyl)-1-dimethylaminomethyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid as a pale yellow residue (292 mg).
Reaction SMILES: [CH2:1]1[CH:5]2[C@@H:6]3C=C[C@H]([CH:4]2C=[CH:2]1)C3.[CH3:11][O:12][C:13](=[O:16])[CH:14]=[CH2:15].C1(C=CC(O)=CC=1)O>>[CH3:11][O:12][C:13]([CH:14]1[CH2:4][CH:5]2[CH2:6][CH:15]1[CH:2]=[CH:1]2)=[O:16]
Reactant: C=CC(=O)OC
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Agent: Oc1ccc(O)cc1
Product: COC(=O)C1CC2C=CC1C2
Temperature: 220 °C
Yield: 57.6 %

Procedure:
DCPD (dicyclopentadiene, Aldrich, 256.5 mL, 1.9 mol), methylacrylate (Aldrich, 405 mL, 4.5 mol) and hydroquinone (3.2 g, 0.03 mol) were charged into a 2 L high-pressure autoclave, and the temperature was raised to 220° C. The resulting mixture was reacted for 5 hours with stirring at 300 rpm. After the reaction was completed, the reaction mixture was cooled and transferred to a distilling apparatus. The reaction mixture was distilled under a reduced pressure (1 torr) using a vacuum pump to yield the title compound at 50° C. (yield: 57.6%, exo/endo=58/42).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].CO>O1CCOCC1>[C:13]([C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH2:5][NH:4]2)=[CH:8][CH:9]=1)#[N:14]
Reactant: CC(=O)N1CCc2ccc(C#N)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: N#Cc1ccc2c(c1)NCC2
Temperature: 25 °C
Yield: 51.1 %

Procedure:
1-Acetyl-6-cyanoindoline (2.4 g, 12.9 mmol, Tetrahedron, 1967, 23, 3823) was stirred in a solution containing 5 N NaOH (20 mL), MeOH (60 mL) and dioxane (60 mL). The mixture was stirred at RT over the weekend. Solvent was removed under reduced pressure and the residue was partitioned between water (100 mL) and DCM (100 mL). Aqueous layer was extracted with DCM (2×75 mL). Combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. Chromatography (10-30% EtOAc/hexanes) provided 6-cyanoindoline (0.95 g, 51%) which was then converted to 12A in a manner similar to that found in Example 4, Step 1.
Reaction SMILES: [CH2:1]([CH2:8][NH:9][CH2:10][C:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=2)[C:12]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]1(O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([CH2:8][NH:9][CH2:10][C:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:17]=2)[C:12]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCCC1
Reactant: Oc1ccc2c(c1)CCC(CNCCc1ccccc1)=C2c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(CCNCC2=C(c3ccccc3)c3ccc(OC4CCCCC4)cc3CC2)cc1
Reaction time: 5 h

Procedure:
To a mixture of 2-(N-benzylmethylamino)methyl-6-hydroxy-1-phenyl-3,4-dihydronaphthalene (0.53 g), cyclohexanol (0.26 cm3), triphenylphosphine (0.579 g) and tetrahydrofuran (20 cm3), was added diethyl azodicarboxylate (0.35 cm3) at room temperature. After stirring for 5 h the solvent was removed under reduced pressure. The crude product was purified by column chromatography [silica, eluting with ethyl acetate-heptane (1:4)] to yield the title compound (0.442 g) as a yellow oil.
Reaction SMILES: [P:1]([O-:19])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:26]1[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]3[CH:43]=[CH:44][C:45]([NH:47][C:39]=3[CH:38]=2)=O)[CH2:30][CH2:29][N:28]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=2[Cl:55])[CH2:27]1.CC(C)([O-])C.[K+]>ClCCl.CN(C)C=O.CC1CCCO1>[P:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:19][C:45]1[CH:44]=[CH:43][C:40]2[C:39](=[CH:38][C:37]([O:36][CH2:35][CH2:34][CH2:33][CH2:32][N:31]3[CH2:30][CH2:29][N:28]([C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=4[Cl:55])[CH2:27][CH2:26]3)=[CH:42][CH:41]=2)[N:47]=1)=[O:2]
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Agent: CC(C)(C)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC1CCCO1
Solvent: ClCCl
Product: O=P(OCc1ccccc1)(OCc1ccccc1)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dibenzyl phosphate (2.48 g, 8.91 mmol) in dichloromethane (25 ml) was added dimethyl formamide (1 drop) followed by oxalyl chloride (0.75 mL, 8.91 mmol). After 2 hours the reaction mixture was concentrated in vacuo. The residue was dissolved in 2-methyltetrahydrofuran (5 mL) and added to a suspension of dehydro-aripiprazole (1.66 g, 3.71 mmol) and potassium t-butoxide (0.92 g, 8.17 mmol) in 2-methyltetrahydrofuran (35 mL) at 0° C. under Ar (g) then allowed to gradually warm to room temperature. After stirring overnight the reaction was quenched with water (25 mL) and 28% aq NH3 (15 mL) and stirred for 10 minutes. The reaction mixture was then extracted with ethyl acetate (2×40 mL). The combined organics were washed with water (50 mL) and brine (50 mL) then dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by column chromatography eluting with 5% methanol (1:1 ethyl acetate/dichloromethane) to give the product. The 1H-NMR showed minor impurities still present (impurities not observed by LCMS). Various further purifications were attempted but failed to remove these impurities.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([OH:35])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]([CH2:44][CH2:45][CH2:46]Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[C:1]1([CH2:7][O:8][C:9](=[O:36])[C:10]2[CH:11]=[C:12]([O:35][CH2:46][CH2:45][CH2:44][O:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:13]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCOc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Yield: 96 %

Procedure:
A mixture of 12 g (0.024 mol) of 3-hydroxy-5-(octadecyloxy)benzoic acid phenylmethyl ester, 6 ml (0.038 ml) of 3-phenoxypropyl bromide, 3.6 g (0.024 mol) of sodium iodide and 10 g (0.072 mol) of potassium carbonate in 40 ml of acetone and 80 ml of DMF was stirred at reflux for 46 hours. The reaction mixture was filtered and the filtrate was concentrated to dryness at reduced pressure. Water was added to the residue and the product was extracted with ethyl acetate. The dried extract was concentrated at reduced pressure to an oil which was purified by HPLC using 5% ethyl acetate-hexane. The pure fractions were combined, triturated with hexane and filtered to give 14.6 g (96% yield, mp 46°-47°) of 3-(octadecyloxy)-5-(3-phenoxypropoxy)benzoic acid phenylmethyl ester. The structure was confirmed by nmr and mass spectra.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:40][C:41]([CH3:43])=[CH2:42]>C1COCC1>[CH3:1][O:2][C:3](=[O:28])[CH:4]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=2)[N:8]=[C:7]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH:6]=1)[CH2:42][C:41]([CH3:43])=[CH2:40]
Reactant: COC(=O)Cc1cc(-c2ccc(F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: C=C(C)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)OC)c1cc(-c2ccc(F)cc2)nc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
To a solution of [2-(4-fluoro-phenyl)-6-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-acetic acid methyl ester (130 mg, 0.3 mmol) in THF (5 mL) at −78° C. under argon was added potassium bis(trimethylsilyl)amide (0.5 M solution in toluene, 600 μL, 0.3 mmol). After stirring for 30 minutes, 3-bromo-2-methylpropene (40 mg, 0.3 mmol) was added and stirred for 30 additional minutes. The reaction mixture was allowed to warm up slowly and stirred for another 30 minutes at 0° C. The mixture was then concentrated and purified by column chromatography on silica gel (0-8% ethyl acetate in heptane) to give the product as a colorless oil (80 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J=8.29 Hz, 2H), 8.08-8.18 (m, 2H), 7.75 (d, J=8.29 Hz, 2H), 7.67 (d, J=1.88 Hz, 2H), 7.19 (t, J=8.85 Hz, 2H), 4.78 (d, J=18.08 Hz, 2H), 3.95 (dd, J=6.78, 9.04 Hz, 1H), 3.72 (s, 3H), 2.94 (dd, J=9.04, 14.69 Hz, 1H), 2.55 (dd, J=6.40, 14.69 Hz, 1H), 1.77 (s, 3H). MS m/e 444.3 (M+H).
Reaction SMILES: [Li]CCCC.[CH2:6]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[I:17]I.O>O1CCCC1>[CH2:6]([C:12]1[O:13][C:14]([I:17])=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCc1ccco1
Reactant: II
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCc1ccc(I)o1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
A solution of n-BuLi (24.7 mL, 1.6 M in hexanes, 39.5 mmol, 1.4 equivalents) was added dropwise to a solution of 2-hexylfuran (4.3 g, 28.3 mmol) in dry tetrahydrofuran (THF, 50 mL) at −78° C. under N2. The reaction mixture was warmed to 0° C., stirred for 10 min and cooled again to −78° C. To this solution was added slowly iodine (9.3 g, 36.7 mmol) in 25 mL of THF, and the solution was warmed slowly to 0° C. and stirred for 2 h at 0° C. After addition of 100 mL of water, the solution was extracted with hexane. The organic layer was washed with aqueous Na2S2O3 solution (30 mL) and water, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (elution with hexane) to afford 6 g of 2-hexyl-5-iodofuran (76%) as a pale brownish oil. 1H NMR (300 MHz, CDCl3): δ6.37 (d, J=3.14 Hz, 1H), 5.88 (d, J=3.16 Hz, 1H), 2.60 (t, J=7.56, 7.56 Hz, 2H), 1.58 (td, J=15.11, 7.66, 7.66 Hz, 2H), 1.24-1.39 (m, 6H), 0.86 (t, J=6.77, 6.77 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 162.3, 120.6, 108.0, 84.3, 31.6, 28.8, 28.3, 27.8, 22.6, 14.1 ppm. HRMS (FD): m/z calcd for C10H15IO: 278.0168. found 278.0172.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1.[H-].[Li+].[CH3:23]I>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([N:7]=[C:8]2[N:13]([CH3:23])[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[N:18][C:10]=3[S:9]2)=[CH:5][CH:4]=1
Reactant: CI
Reactant: COc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(N=c2sc3ncccc3c(=O)n2C)cc1

Procedure:
The reaction procedure of Example 11 was followed except that 428 mg of 2-(4-methoxyanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 14 mg of lithium hydride and 0.094 ml of methyl iodide were used. As a result, 200 mg of 2-[(4-methoxyphenyl)imino]-3-methyl-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a low polarity substance, and 35 mg of 2-[N-(4-methoxyphenyl)-N-methylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained as a high polarity substance.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[NH:25]1[C:33]2[C:28](=[CH:29][C:30]([NH2:34])=[CH:31][CH:32]=2)[CH:27]=[N:26]1>>[NH:25]1[C:33]2[C:28](=[CH:29][C:30]([N:34]3[C:2]4[N:3]=[C:4]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)[N:5]=[C:6]([C:11]5[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=5)[C:7]=4[CH2:8][CH2:9]3)=[CH:31][CH:32]=2)[CH:27]=[N:26]1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Reactant: Nc1ccc2[nH]ncc2c1
Product: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc3[nH]ncc3c2)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 1H-indazol-5-ylamine, the desired compound was obtained.