Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([NH2:9])[CH2:7][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1)=[N+:2]=[N-:3].[Br:17][CH2:18][C:19]([F:26])([F:25])[CH2:20][CH2:21][C:22](O)=[O:23].C(N(CC)CC)C>C(OCC)(=O)C>[N:1]([C@H:4]1[CH2:5][N:6]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:7][C@@H:8]1[NH:9][C:22](=[O:23])[CH2:21][CH2:20][C:19]([F:26])([F:25])[CH2:18][Br:17])=[N+:2]=[N-:3]
Reactant: O=C(O)CCC(F)(F)CBr
Reactant: [N-]=[N+]=N[C@H]1CN(Cc2ccccc2)C[C@@H]1N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=N[C@H]1CN(Cc2ccccc2)C[C@@H]1NC(=O)CCC(F)(F)CBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
To a solution of the product from Step 5 (17.5 g, 80.6 mmol), 5-bromo-4,4-difluoropentanoic acid (17.5 g, 80.6 mmol) from Preparation 3 and triethylamine (32.6 g, 323 mmol) in ethyl acetate (250 mL) was added a 50% solution of propanephosphonic acid cyclic anhydride in ethyl acetate (48.0 mL, 80.6 mmol). The reaction was warmed to reflux and stirred for 16 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate and H2O. The organic phase washed with saturated sodium carbonate solution and saturated sodium chloride solution and then dried over sodium sulfate and concentrated to provide 22.0 g (65%) of the product as an oil. MS m/z 416. (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.[F:23][C:24]1[CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[C:27]([CH3:34])=[C:28]2[C:33]=1[O:32][CH2:31][CH2:30][CH2:29]2>>[F:23][C:24]1[CH:25]=[C:26]([C:2]2[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:3]=2)[C:27]([CH3:34])=[C:28]2[C:33]=1[O:32][CH2:31][CH2:30][CH2:29]2
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(F)c2c1CCCO2
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1cc(F)c2c(c1C)CCCO2

Procedure:
This compound is prepared according to general method E starting from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate and 2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:27])[C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][S:22][CH2:21][C:20]4=[O:25])=[C:15]([CH3:26])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:27])[C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][S:22](=[O:38])[CH2:21][C:20]4=[O:25])=[C:15]([CH3:26])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCSCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCS(=O)CC1=O
Temperature: -12.5 °C
Reaction time: 1 h

Procedure:
204 mg (0.48 mmol) N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethyl]-3-methyl-4-(thiomorpholin-3-on-4-yl)-benzamide are dissolved in a mixture of 12 ml dichloromethane and 1.2 ml acetic acid at −15° C. and combined with 110 mg (0.48 mmol) 3-chloroperbenzoic acid. The mixture is then stirred for one hour at −15 to −10° C., heated to ambient temperature and stirred for a further 3 hours. Then the reaction mixture is combined with semi-concentrated sodium hydrogen carbonate solution and extracted with a solvent mixture dichloromethane/methanol 19:1. The combined organic phases are washed with water, dried over magnesium sulphate, evaporated down i. vac. and purified by chromatography on silica gel (eluting gradient: ethyl acetate/(ethanol/conc. ammonia solution 19:1)=1:0->4:1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=O)=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16])[CH:2]([CH3:4])[CH3:3].S(O)(O)(=O)=O.[NH2:23][C:24]1[C:29]([NH2:30])=[C:28]([NH2:31])[N:27]=[CH:26][N:25]=1.O>O1CCOCC1.[OH-].[Na+]>[NH2:31][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[C:29]=1[NH:30][C:10]([C:9]1[CH:13]=[CH:14][C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=1)=[N:23]2
Reactant: Nc1ncnc(N)c1N
Reactant: CC(C)COc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)COc1ccc(-c2nc3ncnc(N)c3[nH]2)cc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 21 %

Procedure:
A solution of 4-isobutoxy-3-nitrobenzoyl chloride (538 mg, 2.09 mmol) in 1,4-dioxane (2 mL) was dropwise added to a suspension of 4,5,6-triaminopyrimidine sulfate (466 mg, 2.09 mmol) in aqueous 1M sodium hydroxide (4.18 30 mL) under cooling with ice. The resulting mixture was stirred for 4 hours at the same temperature. Water (12 mL) was added to the reaction mixture. The precipitated solid product was collected by filtration, dried in air, and subjected to silica gel column chromatography. The elute using chloroform/methanol (10/1) gave 144 mg (yield 20%) of the desired compound in the form of a yellow powdery product.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH:18]([C:20]1[CH:29]=[CH:28][C:27]2[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=2[CH:21]=1)=O>>[CH3:30][C:26]1([CH3:31])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]2[CH:21]=[C:20]([C:18]#[C:2][C:3]3[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=3)[CH:29]=[CH:28][C:27]1=2
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc(C)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Product: Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 55.8 %

Procedure:
Using a process similar to that described in Example 13, 61.4 g (0.22 mole) of diethyl 1-chloro-1-(4-tolyl)-methylphosphonate, 51.1 g (0.22 mole) of 2-formyl5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene and 50 g (0.44 mole) of potassium tert.-butylate were reacted for 1 hour to give 37.1 g (56%) of the title compound of melting point 99° C., the reaction mixture being poured onto water and acidified, and the precipitated solid being filtered off under suction and recrystallized twice from methanol.
Reaction SMILES: CC1S[C:4]([C:10]2[CH:15]=CC=C[CH:11]=2)=[C:5]([C:7]([OH:9])=O)[N:6]=1.C(N(C(C)C)CC)(C)C.[C:25](Cl)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[OH:9][CH2:7][C@H:5]1[N:6]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:11][C@@H:10]2[C@H:4]1[CH2:15]2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1C[C@H]2C[C@H]2[C@H]1CO
Temperature: 25 °C

Procedure:
To a solution of racemic 7-1 (7.2 g, 63.6 mmol, synthesized as in Example 1) in dichloromethane (320 mL) at 0° C. was added diisopropylethylamine (10.7 g, 83.0 mmol) followed by CbzCl (11.9 g, 70.0 mmol) and the reaction mixture was slowly warmed to ambient temperature over 48 h. The mixture was then quenched with water and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to an oil. The oil was purified by normal phase silica gel chromatography (0 to 100% EtOAc in hexanes) to afford the product as an oil. ESI+ MS: [M+H]+ 248.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[C:7]1[S:11][C:10](/[CH:12]=[CH:22]/[CH:23]=[O:24])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2ncccn2)s1
Product: O=C/C=C/c1ccc(-c2ncccn2)s1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 5-(2-pyrimidinyl)-2-thiophenecarboxaldehyde (prepared as described in Reference Example 86) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 217 (M+H)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[CH:12]3)O1.I[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[N:29]([CH:37]([CH3:39])[CH3:38])[N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:29]([CH:37]([CH3:39])[CH3:38])[N:28]=[C:27]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH:13]=[CH:12]4)[C:35]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CC(C)(C)OC(=O)n1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 9.5 %

Procedure:
A solution of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (212 mg, 0.61 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (75 mg, 0.25 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O) to yield BA86 (9.3 mg, 9% yield). ESI-MS (M+H)+ m/z calcd 362.1, found 362.0.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-:18].O.[CH2:20]([O:27][C:28]1[CH:51]=[C:50]([Cl:52])[C:31]([CH2:32][C@@H:33]2[CH2:37][CH2:36][N:35]([C@H:38]3[CH2:43][CH2:42][C@H:41](OS(C)(=O)=O)[CH2:40][CH2:39]3)[C:34]2=[O:49])=[C:30]([Cl:53])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH2:20]([O:27][C:28]1[CH:51]=[C:50]([Cl:52])[C:31]([CH2:32][C@@H:33]2[CH2:37][CH2:36][N:35]([C@H:38]3[CH2:43][CH2:42][C@@H:41]([F:18])[CH2:40][CH2:39]3)[C:34]2=[O:49])=[C:30]([Cl:53])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CC#N
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1[C@H]1CC[C@@H](F)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Dissolve TBAF.3H2O (1.595 g, 1.30 mmol) in 10 ml of acetonitrile. Add water (0.18 ml, 9.91 mmol) and stir for 10 minutes. Add (R)-trans-Methanesulfonic acid 4-[3-(4-benzyloxy-2,6-dichloro-benzyl)-2-oxo-pyrrolidin-1-yl]-cyclohexyl ester (Preparation 14) (1.30 g, 2.48 mmol). Stir at 80° C. for 12 hours. Quench with saturated NaHCO3 and extract with ethyl acetate. Wash the extract with brine. Dry over magnesium sulfate, filter, and concentrate. After flash column chromatography receive 0.230 g (21%) of the title compound: Mass spectrum (apci) m/z=450 (M+H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=3[C:5]=2[N:6]=1.CS(O[CH2:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=O)=O>>[C:28]1([CH:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:26][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=4[C:5]=3[N:6]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)COc1cccc2c1Cc1sc(S)nc1-2
Reactant: CS(=O)(=O)OCC(c1ccccc1)c1ccccc1
Product: O=C(O)COc1cccc2c1Cc1sc(SCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 37 %

Procedure:
Using ethyl [(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and 2,2-diphenylethyl methanesulfonate, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 37%.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][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][CH3:30])[CH:11]=1)(=O)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[OH2:36]>>[OH:9][C:10]1[CH:11]=[C:12]([CH2:16][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][CH3:30])[CH:13]=[CH:14][C:15]=1[C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:10][CH:11]=1)=[O:36]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC(=O)c2ccccc2)c1
Reactant: O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCCCCCCCCCc1ccc(C(=O)c2ccccc2)c(O)c1

Procedure:
3-Pentadecylphenyl benzoate (1.366 g) is finely powered, mixed with pulverised anhydrous aluminium chloride (0.616 g) and the intimate miture is heated to 165° during fifteen minutes. After hydrogen chloride evolution has ceased, the cooled mixture is treated with water, concentrated hydrochloric acid added, and the whole thoroughly stirred to decompose the aluminium complex. The product is ethereally extracted and the dried ethereal layer is concentrated to give the crude product (1.348 g) which possesses a greenish ferric chloride reaction. Chromatographic purification and crystallisation from light petroleum (40°-60°) afford 2-hydroxy-4-pentadecylbenzophenone, m.p. 46°-47°.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].N1C=CN=C1.[Si:60](Cl)([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.2 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (3.01 g) in dry methyl ene chloride (70 ml) was added an excess of imidazole (809 mg) followed by tert-butyldimethylsilyl chloride (716 mg). After 3 days of stirring at room temperature, the mixture was diluted with ethyl acetate which in turn was washed with 1N HCl, saturated sodium bicarbonate and brine, dried over magnesium sulfate and purified by flash chromatography (ethyl acetae:hexane (1:3)) to give the title compound (941 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: [C:1]1([Li])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:15][CH2:16][CH2:17]Br>>[CH:1]1[C:13]2[CH:12]([CH2:17][CH2:16][Br:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: BrCCBr
Reactant: [Li]c1cccc2c1Cc1ccccc1-2
Product: BrCCC1c2ccccc2-c2ccccc21

Procedure:
reacting fluorenyllithium with 1,2-dibromoethane to produce 1-(9-fluorenyl)-2-bromoethane,
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:17][O:18][CH3:19])=[C:11]([CH3:20])[CH:10]=2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[C:11]([CH3:20])[C:12]([O:16][CH2:17][O:18][CH3:19])=[C:13]([CH3:15])[CH:14]=4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: COCOc1c(C)cc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)cc1C
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCOc1c(C)cc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)cc1C
Yield: 90.7 %

Procedure:
Using 0.96 g of t-butyl N-[2-amino-5-(4-methoxymethoxy-3,5-dimethylphenoxy)phenyl]-N-methylcarbamate, 0.84 g of 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid, 0.49 g of diethyl cyanophosphonate, 0.30 g of triethylamine and 60 ml of anhydrous tetrahydrofuran, reaction and purification were carried out in a similar manner to that described in Example (2-1), whereby 1.44 g of the desired compound were obtained.
Reaction SMILES: [C:1]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[CH2:8][N:7]1[CH3:20])([O:3][CH2:4][CH3:5])=[O:2].[Li+].CC([N-]C(C)C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([C:39]([CH:46]([CH3:48])[CH3:47])([CH2:42][CH2:43][CH2:44]I)[C:40]#[N:41])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38].Cl>C1COCC1>[C:1]([C:6]1([CH2:44][CH2:43][CH2:42][C:39]([C:33]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([O:30][CH3:29])[CH:32]=2)([CH:46]([CH3:48])[CH3:47])[C:40]#[N:41])[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[CH2:8][N:7]1[CH3:20])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: COc1ccc(C(C#N)(CCCI)C(C)C)cc1OC
Reactant: CCOC(=O)C1Cc2cc(OC)c(OC)cc2CN1C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)Cc2cc(OC)c(OC)cc2CN1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The resulting ester of formula 31 is then treated with an iodoalkane of formula 22 (see Scheme III, step 2) in the presence of a strong base to form an alkylated tetrahydroisoquinoline ester of formula 32. For example, 3-carboethoxy-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (31) is added to a solution of LDA in THF at -70° C. and allowed to stand for 5-60 minutes, preferably about 10 minutes. To this reaction mixture is then added 2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-iodopropyl)acetonitrile (22) in THF, and the resulting mixture allowed to warm to about 0° C. The mixture is then acidified, for example with dilute HCl, and the product extracted and purified to produce 3-carboethoxy-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (32).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]3[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:18]=3[NH:19]2)=[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH:28]=2)[CH:14]=1)=[O:12].CC(O)=O>C(Cl)Cl>[CH3:9][O:10][C:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17]3[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:18]=3[NH:19]2)=[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH:28]=2)[C:14]=1[Cl:1])=[O:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(=O)OC)cc3[nH]c4ncc(C)cc4c23)c1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCS(=O)(=O)c1cccc(-c2c(Cl)c(C(=O)OC)cc3[nH]c4ncc(C)cc4c23)c1
Temperature: 32 °C
Reaction time: 18 h
Yield: 36.8 %

Procedure:
N-Chlorosuccinimide (79 mg, 0.59 mmol) was added to a solution of Compound 132 (220 mg, 0.54 mmol) in CH2Cl2 (3 mL) with HOAc (1 mL) at r.t. The reaction was stirred for 18 h at 32° C. and was then concentrated in vacuo. Purification by prep-HPLC gave 88 mg (37%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 14.20 (br s, 1H), 8.23 (s, 1H), 8.11-8.19 (m, 2H), 8.00 (s, 1H), 7.87 (t, 1H, J=7.6 Hz), 7.74 (d, 1H, J=7.6 Hz), 7.28 (s, 1H), 4.01 (s, 3H), 3.23 (q, 2H, J=7.2 Hz), 2.37 (s, 3H), 1.34 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C22H19ClN2O4S, 443, 445; found 443, 445.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[CH:15][C:16]2[C:17]([CH:28]=1)=[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[O:19][N:20]=2.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([C:18]2[O:19][N:20]=[C:16]3[CH:15]=[CH:14][C:13]([CH:34]([C:33]4[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=4)[OH:35])=[CH:28][C:17]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: Clc1cccc(-c2onc3ccc(Br)cc23)c1
Reactant: O=Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 26.8 %

Procedure:
nBuLi 1.6M in hexane (0.112 mol) was added dropwise at −70° C. under N2 flow to a mixture of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.097 mol) in THF (300 ml). The mixture was stirred at −70° C. for 15 min. A mixture of 4-fluorobenzaldehyde (0.112 mol) in THF (100 ml) was added dropwise. The mixture was stirred at −70° C. for 30 min, then hydrolized and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue was taken up in diethyl ether and DIPE. The precipitate was filtered off, washed and dried, yielding 9.2 g (26.8%) of 3-(3-chlorophenyl)-α-(4-fluorophenyl)-2,1-benzisoxazole-5-methanol (intermediate 1), mp. 171° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:39][CH2:40][CH3:41])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:35](OC)=[O:36])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:2].C(OC(OCC)C1C=CC(C2C(C3C=CC(C(OCC)OCC)=CC=3)C(=O)C3C(C(OCC)=O)=CC=CC=3N2)=CC=1)C.O.[NH2:85][NH2:86]>CO>[CH2:40]([O:39][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:85][NH:86][C:35](=[O:36])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:26]=[CH:25][C:24]([CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)[CH3:41]
Reactant: CCOC(OCC)c1ccc(C2Nc3cccc(C(=O)OC)c3C(=O)C2c2ccc(C(OCC)OCC)cc2)cc1
Reactant: NN
Agent: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(OCC)OCC)cc1)C(c1ccc(C(OCC)OCC)cc1)N2
Solvent: CO
Solvent: O
Product: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(OCC)OCC)cc2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A mixture of methyl 2,3-bis(4-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 2,3-bis(4-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (240 mg, 0.43 mmol) in hydrazine monohydrate (5 mL) and methanol (5 mL) was stirred at 40° C. for 2 hr. The mixture was cooled to room temperature and filtered to give the 8,9-bis(4-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (120 mg, yield 52%) as a light yellow solid. LC-MS (ESI) m/z: 544 (M+1)+. MS (ESI) m/e 381 [M+H]+.