Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([C:56](=[NH:71])[NH:57][C:58]([O:60][CH2:61][C:62]3[CH:67]=[CH:66][C:65]([N+:68]([O-:70])=[O:69])=[CH:64][CH:63]=3)=[O:59])[CH2:52][CH2:51]2)=[O:49])[CH2:43]1>C(#N)C.C(N(C(C)C)CC)(C)C>[OH:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:19]2[C:20]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])=[C:16]([S:41][C@@H:42]3[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]4[CH2:55][CH2:54][N:53]([C:56](=[NH:71])[NH:57][C:58]([O:60][CH2:61][C:62]5[CH:67]=[CH:66][C:65]([N+:68]([O-:70])=[O:69])=[CH:64][CH:63]=5)=[O:59])[CH2:52][CH2:51]4)=[O:49])[CH2:43]3)[C@H:17]([CH3:40])[C@H:18]12)[CH3:37]
Reactant: CN1C[C@@H](S)C[C@H]1C(=O)N1CCN(C(=N)NC(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=N)NC(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C)C3)[C@H](C)[C@H]12
Reaction time: 8 h
Yield: 76.9 %

Procedure:
1600 mg of 4-nitrobenzyl (1R, 5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R) -1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) were dissolved in 16 ml of dry acetonitrile, and a solution of 1120 mg of (2S,4S)-4-mercapto-1-methyl-2-[4-(4-nitrobenzyloxycarbonylamidino) piperazin-1-ylcarbonyl]pyrrolidine (prepared as described in Preparation 93) in 11 ml of dry acetonitrile and 430 μl of diisopropylethylamine were added dropwise to the resulting solution, whilst ice-cooling. The resulting mixture was stirred at the same temperature overnight, after which it was concentrated by evaporation under reduced pressure. The resulting residue was diluted with ethyl acetate, and the mixture was washed with an aqueous solution of sodium hydrogencarbonate, with water and with an aqueous solution of sodium chloride, in that order. The ethyl acetate layer was dehydrated over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was subjected to reverse phase silica gel column chromatography (Cosmosil 75C18 -prep, manufactured by Nacalai Tesque, 300 ml), eluted with a 1 by volume mixture of acetonitrile and water. The fractions containing the desired compound were collected and concentrated by evaporation under reduced pressure, to obtain 1520 mg of the title compound, as a powder.
Reaction SMILES: O[CH:2]([CH3:13])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N1C(C)=CC=CC=1C.C(N(C(C)C)CC)(C)C.Cl.Cl.[F:48][C:49]1[CH:50]=[C:51]([C:55]2([CH2:61][CH2:62][N:63]3[C@H:68]4[CH2:69][CH2:70][C@@H:64]3[CH2:65][CH:66]([N:71]3[C:75]5[CH:76]=[CH:77][CH:78]=[CH:79][C:74]=5[N:73]=[C:72]3[CH3:80])[CH2:67]4)[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH:52]=[CH:53][CH:54]=1>C(Cl)Cl>[F:48][C:49]1[CH:50]=[C:51]([C:55]2([CH2:61][CH2:62][N:63]3[C@H:68]4[CH2:69][CH2:70][C@@H:64]3[CH2:65][CH:66]([N:71]3[C:75]5[CH:76]=[CH:77][CH:78]=[CH:79][C:74]=5[N:73]=[C:72]3[CH3:80])[CH2:67]4)[CH2:56][CH2:57][N:58]([CH:2]([CH3:13])[C:3]([O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:4])[CH2:59][CH2:60]2)[CH:52]=[CH:53][CH:54]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCNCC1
Reactant: CC(O)C(=O)OCc1ccccc1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(C)C(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 36.3 %

Procedure:
To a −78° C. solution of benzyl 2-hydroxypropanoate (250 mg, 1.39 mmol) and 4A molecular sieves in 2 mL CH2Cl2 was added trifluoromethanesulfonic anhydride (0.33 mL, 1.97 mmol). After stirring for 10 min at this temperature, 2,6-lutidine (0.31 mL, 2.62 mmol) was added. After 15 min, diisopropylethylamine (0.46 mL, 2.62 mmol) was added and after another 15 min, a solution of 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (400 mg, 0.66 mmol) in 3 mL CH2Cl2 was added. The reaction mixture was stirred at −78° C., then allowed to warm to room temperature overnight, washed with saturated aqueous NaHCO3, and purified by chromatography (3% (2M NH3/MeOH) in CHCl3) to provide benzyl 2-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)propanoate (146 mg, 37%) as a solid. 1H NMR (400 MHz, CDCl3), δ 7.68 (m, 1H), 7.37-7.26 (m, 7H), 7.22-7.13 (m, 2H), 7.08 (m, 1H), 6.98 (m, 1H), 6.92 (m, 1H), 5.09 (s, 2H), 4.62 (m, 1H), 3.39-3.17 (m, 2H), 2.89-1.26 (m, 27H); ESI-MS 609 (M+H).
Reaction SMILES: C(S[N:4]=[CH:5][C:6]1[C:7]([CH:17]([CH3:19])[CH3:18])=[CH:8][C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])C.[CH3:20][O:21][CH2:22][CH2:23][C:24]([NH:26][NH2:27])=O>C(O)(=O)C>[CH:17]([C:7]1[C:6]([C:5]2[NH:4][C:24]([CH2:23][CH2:22][O:21][CH3:20])=[N:26][N:27]=2)=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:16])[CH:8]=1)([CH3:18])[CH3:19]
Reactant: COCCC(=O)NN
Reactant: CCSN=Cc1cc(C(=O)OC)c(C)cc1C(C)C
Solvent: CC(=O)O
Product: COCCc1nnc(-c2cc(C(=O)OC)c(C)cc2C(C)C)[nH]1
Temperature: 80 °C

Procedure:
Methyl 5-((ethylthio)(imino)methyl)-4-isopropyl-2-methylbenzoate (compound 198.4, 33 mg, 0.12 mmol, 1.0 equiv), 3-methoxypropanehydrazide (compound 143.1, 21 mg, 0.18 mmol, 1.5 equiv) and acetic acid (1.2 mL) were added to a 4-mL vial and heated at 80° C. with a loose cap for 4 hours. The solvent was removed in vacuo and the residue was dissolved in DCM (10 mL) and washed with saturated NaHCO3 (5 mL) then brine (5 mL), dried (Na2SO4), filtered and evaporated to a colorless oil (theoretical yield). m/z (ES+) 318 (M+H)+.
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(CC(=O)C)(=O)C.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:30]([NH2:32])[CH3:31]>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:32][CH2:30][CH3:31])=[O:4]
Reactant: COC(=O)CC[C@H](N)C(=O)O
Reactant: CCN
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)CC(C)=O
Solvent: CO
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Yield: 29.6 %

Procedure:
First, 5.0 g (31 mmol) of L-glutamic acid-γ-methyl ester was suspended in 15 mL of methanol. To this, 3.4 g (34 mmol) of acetylacetone, 1.9 g (31 mmol) of acetic acid, and 5.0 g of anhydrous sodium sulfate were added. The mixture was heated at 60° C. for 2 hours. Subsequently, sodium sulfate was filtrated off. To the filtrate, 20 g (310 mmol) of 70% ethylamine was added and the same procedure as in Example 1 was performed to obtain 1.6 g of theanine (yield: 29.6%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:8]3([CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]3)[C:7](=[N:17]S(C(C)(C)C)=O)[C:6]=2[CH:24]=1.CCOCC>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][C:8]3([CH2:9][CH2:10][CH:11]([O:14][CH3:15])[CH2:12][CH2:13]3)[C:7](=[NH:17])[C:6]=2[CH:24]=1
Reactant: COC1CCC2(CC1)Oc1ccc(Br)cc1C2=NS(=O)C(C)(C)C
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC1CCC2(CC1)Oc1ccc(Br)cc1C2=N
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of N-(5-bromo-4′-methoxy-3H-spiro[benzofuran-2,1′-cyclohexane]-3-ylidene)-2-methylpropane-2-sulfinamide (Example 29 Step 1, 2 g, 4.83 mmol) in anhydrous 1,4-dioxane (40 mL) was added 4M HCl in1,4-dioxane (12.07 mL, 48.27 mmol) and the resulting mixture was stirred under a nitrogen atmosphere at rt overnight. Et2O (30 mL) was added and the precipitate was filtered off and washed with Et2O, then partitioned between DCM (40 mL) and sat. aq. NaHCO3 (40 mL). The phases were separated and the organic layer concentrated, yielding 1.37 g of the crude title compound which was used immediately in the next step: MS (EI) m/z 309 M+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]CC)=[O:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1>[NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1nc(Cl)ncc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cnc(Cl)nc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.5 %

Procedure:
Ethyl 5-amino-2-chloropyrimidine-4-carboxylate (0.90 g, 4.0 mmol) was dissolved in THF (22 mL). To it water (8 mL) and 1M lithium hydroxide (11 mL, 11 mmol) were added and the mixture was stirred at room temperature for 6 h. The reaction was then acidified to pH6 with 6N HCl (1.15 mL) and concentrated in vacuo to remove organic solvent. The solid was collected by filtration and washed with water to give 5-amino-2-chloropyrimidine-4-carboxylic acid as a yellow solid (434 mg, 60%).
Reaction SMILES: C(O[C:4](=[O:38])[CH:5]=[C:6]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[Cl:37])[CH2:7][NH:8][C@H:9]([C:16](=[O:28])[NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[N:19]=1)[CH2:10][C@H:11]([O:13][CH2:14][CH3:15])[CH3:12])C>O1CCCC1>[OH:27][C:24]([CH3:25])([CH3:26])[CH2:23][N:20]1[CH:21]=[CH:22][C:18]([NH:17][C:16](=[O:28])[C@@H:9]([N:8]2[CH2:7][C:6]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=3[Cl:37])=[CH:5][C:4]2=[O:38])[CH2:10][C@H:11]([O:13][CH2:14][CH3:15])[CH3:12])=[N:19]1
Reactant: CCOC(=O)C=C(CN[C@@H](C[C@@H](C)OCC)C(=O)Nc1ccn(CC(C)(C)O)n1)Oc1cccc(Cl)c1Cl
Solvent: C1CCOC1
Product: CCO[C@H](C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Temperature: 160 °C
Yield: 32.6 %

Procedure:
3-(2,3-Dichloro-phenoxy)-4-{(1S,3R)-3-ethoxy-1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-butylamino}-but-2-enoic acid ethyl ester (60 mg) was dissolved in tetrahydrofuran (2 mL). The sealed tube was heated in a microwave at 160° C. for 4 h. The resulting solution was concentrated and the residue was purified by reverse phase column chromatography (acetonitrile in water 25% to 100%) to afford (2S,4R)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-ethoxy-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (18 mg, 32%): HR-ES-MS m/z calculated for C24H30Cl2N4O5 [M+H]+ 525.1666, observed 525.1669; 1H NMR (300 MHz, CDCl3) δ ppm 1.16 (s, 6H), 1.17-1.27 (m, 6H), 1.84-2.01 (m, 1H), 2.20-2.33 (m, 1H), 3.24-3.40 (m, 1H), 3.49-3.70 (m, 2H), 3.80 (br. s., 1H), 3.95 (s, 2H), 4.27 (d, J=17.8 Hz, 1H), 4.41 (d, J=17.8 Hz, 1H), 4.92 (s, 1H), 5.05 (t, J=7.2 Hz, 1H), 6.69 (d, J=1.9 Hz, 1H), 7.19 (dd, J=8.2, 1.2 Hz, 1H), 7.23-7.27 (m, 1H), 7.31 (d, J=1.9 Hz, 1H), 7.42 (dd, J=8.2, 1.2 Hz, 1H), 8.91 (br. s., 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(O)=[O:2].C[CH2:21][N:22]=C=NCCCN(C)C.Cl.CN1CCOCC1.CN>C(Cl)Cl>[CH3:21][NH:22][C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:2]
Reactant: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CNC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 72 h
Yield: 48.2 %

Procedure:
A mixture of 4-(3-carboxyphenoxy)-1-nitrobenzene (3.72 g, 14.4 mmol), EDCI.HCl (3.63 g, 18.6 mmol), N-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF; 8 mL, 16 mmol) in CH2Cl2 (45 mL) was stirred at room temp. for 3 d, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with a 1M HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2×50 mL). The combined organic phases were washed with a saturated NaCl solution (50 mL), dried (Na2SO4), and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene as an oil (1.89 g).
Reaction SMILES: Cl.[CH2:2]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[S:4][CH2:3]1.Cl[CH2:19][CH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23]>>[CH2:2]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([C:24]5[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=5)=[O:23])[CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[S:4][CH2:3]1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCS2
Agent: Cl
Product: O=C(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCS3)c1ccc(F)cc1
Yield: 31.5 %

Procedure:
The 4-((6bR,10aS)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indol-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone (349 mg, 25%) was prepared from (6bR,10aS)-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indolehydrochloride (750 mg, 2.79 mmol) with 4-chloro-1-(4-fluorophenyl)-1-butanone (3.0 mL, 15.24 mmol) using the procedure described in Example 456 Step A.
Reaction SMILES: P(Cl)(Cl)Cl.P(Br)(Br)Br.C(OCC)(=O)[CH2:10][C:11]([CH3:13])=[O:12].[CH2:18]=[CH:19][C:20](=[CH2:22])[CH3:21]>>[CH3:22][C:20](=[CH2:21])[CH2:19][CH2:18][CH2:10][C:11](=[O:12])[CH3:13]
Reactant: C=CC(=C)C
Reactant: CCOC(=O)CC(C)=O
Agent: BrP(Br)Br
Solvent: ClP(Cl)Cl
Product: C=C(C)CCCC(C)=O

Procedure:
3,7,11-trimethyldodeca-1-yne-6,11-dien-3-ol can be obtained by halogenating 3-methyl-3-buten-1-ol, which is formed as a by-product in isoprene synthesis with phosphorus trichloride or phosphorus tribromide, reacting the halogenation product with ethyl acetoacetate to form 6-methyl-6-hepten-2-one, subjecting 6-methyl-6-hepten-2-one to ethynylation in the same manner as described above, thereafter subjecting the ethynylation product to partial hydrogenation in the presence of a Lindler catalyst, subjecting the partial hydrogenation product to Caroll rearrangement by using ethyl acetoacetate or diketene, and subjecting the rearrangement product to ethynylation.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:3]=1[Cl:20].[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[Cl:20][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:5][C:6]2[C:11]([C:2]=1[C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1)=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2
Reactant: Oc1ccc(-c2nc3ccc(O)cc3c(Br)c2Cl)cc1
Reactant: OB(O)c1ccc(F)cc1
Product: Oc1ccc(-c2nc3ccc(O)cc3c(-c3ccc(F)cc3)c2Cl)cc1
Yield: 95 %

Procedure:
This compound was prepared from 35a and 4-fluorophenylboronic acid according to method P. White solid; Yield: 95%; mp 295-296° C.; 1H-NMR (300 MHz, DMSO-d6) δ 6.55 (d, J=2.6 Hz, 1H), 6.87 (d, J=8.6 Hz, 2H), 7.31 (dd, J=9.1, 2.6 Hz, 1H), 7.45 (m, 4H), 7.57 (d, J=8.6 Hz, 2H), 7.92 (d, J=9.1 Hz, 1H), 9.73 (s, 1H), 10.07 (s, 1H); MS (ESI) m/z 364/366 ([M−H]−), 366/368 ([M+H]+); Anal. Calcd for C21H13ClFNO2: C, 68.96; H, 3.58; N, 3.83. Found: C, 68.19; H, 3.56; N, 3.74.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:26]([O:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:25][C:8]2[CH2:9][C:10]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:11]=3[CH:12]([CH2:14][C:15]([O:17]CC)=[O:16])[CH2:13][C:7]=2[CH:6]=1)[CH3:3].N1C=CC=CC=1NCCCOC1C=CC2C[C@H](CC(OCC)=O)C3C=CC=CC=3CC=2C=1>CC(O)=O>[CH3:1][N:2]([CH2:4][C:5]1[C:26]([O:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:25][C:8]2[CH2:9][C:10]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:11]=3[CH:12]([CH2:14][C:15]([OH:17])=[O:16])[CH2:13][C:7]=2[CH:6]=1)[CH3:3]
Reactant: CCOC(=O)CC1Cc2cc(CN(C)C)c(OCCCNc3ccccn3)cc2Cc2cc(F)ccc21
Agent: CCOC(=O)C[C@H]1Cc2ccc(OCCCNc3ccccn3)cc2Cc2ccccc21
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(cc1OCCCNc1ccccn1)Cc1cc(F)ccc1C(CC(=O)O)C2

Procedure:
Saponification was conducted according to the procedure of Example 6 (c), except substituting ethyl (±)-10,11-dihydro-2-(dimethylamino)methyl-7-fluoro-3-[3-(pyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate for the ethyl (R)-10,11-dihydro-3-[3-(pyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate. The reaction was acidified with glacial HOAc, and the crude product was desalted by chromatography on XAD-2 resin to afford the title compound as a white solid: MS (ES) m/e 478.3 (M+H)+. Anal. Calcd for C30H36FN3O5.1.25 H2O: C, 64.32; H, 6.92; N, 7.50. Found: C, 63.87; H, 6.47: N, 7.96.
Reaction SMILES: [P:1]([O-])([O:11][CH2:12][C:13]1C=CC=CC=1)([O:3][CH2:4][C:5]1C=CC=CC=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:46])[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>[P:1]([O:11][CH2:12][CH3:13])([O:3][CH2:4][CH3:5])([O:46][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: ClCCl
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)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 N,N-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-methyltetrahydrfuran (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-methyltetrahydrfuran (35 mL) at 0° C. under argon gas, 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](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH:7][C@@H:8]1[C:25]2[C:24]3[N:23]([CH3:26])[C:22]4[N:21]=[C:20]5[CH:27]=[CH:28][CH:29]=[CH:30][C:19]5=[CH:18][C:17]=4[C:16](=[O:31])[C:15]=3[C:14]([O:32][CH3:33])=[CH:13][C:12]=2[O:11][C:10]([CH3:35])([CH3:34])[C@@H:9]1[OH:36]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:36][C@@H:9]1[C@H:8]([OH:7])[C:25]2[C:24]3[N:23]([CH3:26])[C:22]4[N:21]=[C:20]5[CH:27]=[CH:28][CH:29]=[CH:30][C:19]5=[CH:18][C:17]=4[C:16](=[O:31])[C:15]=3[C:14]([O:32][CH3:33])=[CH:13][C:12]=2[O:11][C:10]1([CH3:34])[CH3:35])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc2c(c3c1c(=O)c1cc4ccccc4nc1n3C)[C@@H](O)[C@@H](O)C(C)(C)O2
Reactant: CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCC(=O)O[C@@H]1[C@H](O)c2c(cc(OC)c3c(=O)c4cc5ccccc5nc4n(C)c23)OC1(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Add 2 equivalents of butyryl chloride to a solution of 0.74 mmol of the compound of Example 3 in 7 ml of anhydrous pyridine in the presence of 4-dimethylaminopyridine. Stir at ambient temperature for 72 hours and then add 5 equivalents of butyryl chloride and stir again for 72 hours and then evaporate to dryness. Chromatography on silica gel allows the expected product to be isolated.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl.[K+].[Br-]>>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:15]1[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16]1=[O:17]
Reactant: Fc1cccc(CCl)c1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Agent: [Br-]
Agent: [K+]
Product: O=C1C(CCO)Oc2ccccc2N1Cc1cccc(F)c1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 3-flourobenzyl chloride, in 49% overall yield and isolated as a gummy solid; IR (KBr) 3425, 1683, 1501, 1401, 1252, 1061, 751 cm-1 ; 1H NMR (CDCl3) δ 2.16-2.38 (m, 3H), 3.92 (t, J=5.8 Hz, 2H), 4.85 (dd, J=7.6, 5.5 Hz, 1H), 5.14 (s, 2H), 6.82-6.85 (m, 1H), 6.90-7.08 (m, 6H), 7.26-7.33 (m, 1H); MH+ at m/z=302; Anal. Calc'd for C17H16FNO3 : C, 67.76; H, 5.35; N, 4.65. Found: C, 67.48; H, 5.34; N, 4.57.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.CC(C)([O-])C.[K+].C[N:18](C)C=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH2:18]
Reactant: O=[N+]([O-])c1cccc(Cl)c1
Reactant: CN(C)C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Nc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 1 h

Procedure:
1-chloro-3-nitrobenzene (3.1 g, 0.0197 mol) and o-methoxylamine hydrochloride (2.02 g, 0.0236 mol) were dissolved in N,N-dimethylformamide (15 mL). The solution was added drop wise in 15 min to a suspension of cuprous chloride and potassium tert-butoxide (11.07 g, 0.965 mol) in N,N-dimethylformamide (15 mL) cooled in a 15° C. bath. The cold bath was removed; the mixture was allowed to come to RT and stirred for 1 h. The reaction was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate (4×100 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, concentrated under vacuum and purified by silica gel column chromatography to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ 8.020-7.994 (dd, J=8.8 Hz, 10.4 Hz, 1H), 7.696-7.674 (dd, J=7.2 Hz, 8.8 Hz, 1H), 7.229 (bs, 1H), 6.705-6.664 (t, J=8.4 Hz, 1H).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.C[O:23][B:24](OC)[O:25]C.Cl>CCOCC.C1COCC1.O.CCOC(C)=O>[CH3:6][O:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:11]=1[B:24]([OH:25])[OH:23]
Reactant: COB(OC)OC
Reactant: COCOc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(-c2ccccc2)cc1B(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
Butyllithium (2.5M, 1.44 mL, 3.6 mmol) was added over 5 min to a stirred solution of 4-methoxymethoxy-biphenyl (from the previous step 385 mg, 1.8 mmol) in Et2O (18 mL) at 0° C. The reaction was allowed to warm to rt and stirred for 2 h. The solution was cooled to −78° C. and trimethylborate (1.23 mL, 10.8 mmol) in THF (10 mL) was quickly added. The reaction warmed to rt over 1 h and was stirred 1 h at rt, during which it became cloudy and a gelatin-like residue appeared. EtOAc (70 mL) and water (30 mL) were added along with HCl (1N, 1 mL). The biphasic solution was stirred for 10 min and the layers were separated. The organic layer was further extracted with HCl (0.1N, 3×20 mL), brine (60 mL), and was dried over sodium sulfate. Removal of the solvents in vacuo followed by chromatography of the residue (20–40% EtOAc in hexanes) yielded the title compound (135 mg, 29%) as a light-brown solid. The title compound exists as a mixture of boronic acids and anhydrides in CDCl3, therefore the reported NMR signals represent pairs or groups of related signals. 1H-NMR (CDCl3): δ 8.07 (d, 1H, J=2.6 Hz), 7.60 (m, 3H), 7.42 (m, 2H), 7.31 (m, 1H), 7.19 (d, 1H, J=8.6 Hz), 6.20 (s, 1H), 5.32 (s, 2H), 3.77 (s, 1H), 3.53 (s, 3H).