Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].Cl.[C:4]([NH2:12])(=[NH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH:14]1[CH2:29][CH2:28][C:17]2=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:19][C:20]([S:21][CH3:22])=[C:16]2[C:15]1=O>O.C(Cl)(Cl)Cl>[CH3:22][S:21][C:20]1[S:19][C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:17]2[CH2:28][CH2:29][C:14]3[N:11]=[C:4]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[NH:12][C:15]=3[C:16]=12
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(Br)C2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1sc(SC)c2c1CCc1nc(-c3ccccc3)[nH]c1-2
Yield: 13.2 %

Procedure:
A solution of sodium hydroxide (1.65 g) in water (3 ml) was added to a solution of benzamidine hydrochloride (5.38 g) in water (2 ml) at room temperature; a solution of ethyl 5-bromo-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.00 g) in chloroform (30 ml) was further added. The reaction mixture was refluxed under heating for 3 days, after which it was poured over water and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to yield ethyl 4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzimidazole-6-carboxylate (0.28 g, 13.2%), which was then recrystallized from ethyl acetate-ethanol. Brown prisms. Melting point 218-219° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:36])([F:35])[F:34])[C:25]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Cl-].[CH3:42][O-].[Na+]>C(Cl)Cl.CO>[CH2:29]([N:27]([CH3:28])[C:25]1[C:24]([C:33]([F:35])([F:36])[F:34])=[CH:23][C:18]2[NH:19][C:20](=[O:22])[CH2:21][C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][O:1][CH3:42])[CH:8]=4)[CH:10]=3)=[N:16][C:17]=2[CH:26]=1)[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COCc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-(isobutyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 366) (248 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with sodium methanolate (5.4M, 1 ml) in MeOH (5 ml)/CH2Cl2 (5 ml) according to the general procedure of Example 288. Obtained as a light yellow solid (58 mg, 23%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[CH2:15][CH2:14][O:13][CH:12]1[CH2:16][CH2:17][CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27])[OH:19].CCN(CC)CC>C(Cl)Cl>[O:11]1[CH2:15][CH2:14][O:13][CH:12]1[CH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:27])([F:28])[F:29])=[O:19]
Reactant: OC(CCC1OCCO1)c1ccccc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(CCC1OCCO1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (115.0 mmol, 10.0 ml) in CH2Cl2 (200 ml) was cooled to −78° C. under an argon atmosphere. DMSO (240.0 mmol, 17.0 ml) was then added slowly, keeping the internal temperature below −50° C. After completing the addition, the solution was held 20 minutes at −78° C. 3-[1,3]Dioxolan-2-yl-1-(2-trifluoromethylphenyl)-propan-1-ol (32.8 g of crude material prepared above) in CH2Cl2 (30 ml) was added slowly, keeping the internal temperature below −50° C. The mixture was held at −78° C. for 30 minutes, then treated with Et3N (480 mmol, 70.0 ml). The mixture was allowed to warm to room temperature, then washed with water (2×75 ml), then concentrated under reduced pressure to give crude 3-[1,3]dioxolan-2-yl-1-(2-trifluoromethyl-phenyl)-propan-1-one, which may be used without further purification. 1H NMR (CDCl3) δ7.00 (1H, d, J=7.7), 7.63-7.50 (2H, m), 7.44 (1H, d, J=7.4), 4.99 (1H, t, J=4.3), 3.97-3.82 (4H, m), 2.98 (2H, t, J=7.3) 2.12 (2H, dt, J=7.4, 4.3).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7](=[N:10][O:11][CH2:12][CH2:13][OH:14])[CH2:8][CH3:9])=[CH:3][CH:2]=1.O[C:22]1[CH:54]=[CH:53][C:25]([CH2:26][CH:27]2[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]2=[O:52])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([C:7](=[N:10][O:11][CH2:12][CH2:13][O:14][C:22]2[CH:54]=[CH:53][C:25]([CH2:26][CH:27]3[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]3=[O:52])=[CH:24][CH:23]=2)[CH2:8][CH3:9])=[CH:5][CH:6]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(=NOCCO)c1ccc(-c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccccc2)cc1
Yield: 76 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 539 mg of 2-[1-(4-biphenylyl)-propylideneaminooxy]ethanol (prepared as described in Preparation 38), 1.02 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 577 mg of triphenylphosphine and 383 mg of diethyl azodicarboxylate, 1.09 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[NH:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[N:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[H-].[Na+].CI.[N+](CCCC)(CCCC)(CCCC)[CH2:38]CCC.[F-]>CC#N.C1COCC1.CCOC(C)=O>[CH3:38][N:25]1[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[N:23][C:22]([CH:9]([OH:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:26]1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1nnc(-c2ccccn2)[nH]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cn1nc(C(O)CCCCCCc2ccccc2)nc1-c1ccccn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
A sample of 2-(5-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-4H-1,2,4-triazol-3-yl)-pyridine (S64, 6 mg, 0.01 mmol) was dissolved in MeCN (142 μL) and cooled to 0° C. NaH (60%, 0.4 mg, 0.01 mmol) was added as a solid. After 5 min, MeI (1 μL) was added. Upon completion of the reaction (1.5 h), the solvent was removed in vacuo. The residue was purified by preparative thin layer chromatography (SiO2, 50% EtOAc-hexanes) to afford two separate compounds, the N1 and N2 alkylated triazoles (4.5 mg, 68%) as colorless oils. The individual N1 alkylated TBS ether (6.6 mg, 0.014 mmol) was dissolved in THF (178 μl), treated with Bu4NF (1 M in THF, 18 μL) and stirred at room temperature for 16 h under Ar. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude alcohol that was purified by preparative thin layer chromatography (SiO2, 50% EtOAc-hexanes) to afford the title compound (2.0 mg, 41%) as a colorless oil (N1 isomer determined by HMBC): 1H NMR (CDCl3, 600 MHz) δ 8.68 (d, 1H, J=4.7 Hz), 8.19 (d, 1H, J=7.9 Hz). 7.82 (dt, 1H, J=1.8, 7.8 Hz), 7.35 (ddd, 1H, J=1.0, 4.8, 7.5 Hz), 7.26 (m, 2H), 7.15 (m, 3H), 4.82 (br s, 1H), 4.33 (s, 3H), 2.59 (t, 2H, J=7.7 Hz), 1.97 (m, 1H), 1.88 (m, 1H), 1.61 (m, 2H), 1.50 (m, 2H), 1.40 (m, 4H); 13C NMR (CDCl3, 150 MHz) δ 164.9, 152.3, 149.0, 148.1, 143.0, 137.1, 128.5, 128.4, 125.7, 124.2, 124.1, 68.7, 38.9, 37.1, 36.1, 31.6, 29.5, 29.4, 25.3; HRMS-ESI-TOF m/z 351.2179 ([M+H]+, C21H26N4O requires 351.2179).
Reaction SMILES: [CH2:1]([C:13]1([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])[CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][C:20]([CH3:28])([CH3:27])[CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].F[P-](F)(F)(F)(F)F.[CH3:44][S:45]([C:48]1[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=1[N+:57]#[N:58])(=[O:47])=[O:46]>C(O)(=O)C.O.O1CCCC1>[CH2:1]([C:13]1([CH2:29][C:30]2[CH:35]=[C:34]([N:58]=[N:57][C:49]3[CH:50]=[CH:51][C:52]([N+:54]([O-:56])=[O:55])=[CH:53][C:48]=3[S:45]([CH3:44])(=[O:47])=[O:46])[CH:33]=[CH:32][C:31]=2[OH:36])[CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([CH3:27])([CH3:28])[CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCC1(Cc2ccccc2O)COCCOCC(C)(C)COCCOC1
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])ccc1[N+]#N
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCC1(Cc2cc(N=Nc3ccc([N+](=O)[O-])cc3S(C)(=O)=O)ccc2O)COCCOCC(C)(C)COCCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.9 %

Procedure:
To a solution of 3.1 g (6.1 mmol) of Compound 15 in 50 cc acetic acid at 5° C. was added a solution of 3.0 g (8.0 mmol) of 2-methylsulfonyl-4-nitrophenyldiazonium hexafluorophosphate in 25 cc water and 75 cc tetrahydrofuran. The suspension was stirred at room temperature for 16 hours. The product was extracted into ethyl acetate and isolated by silica gel chromatography yielding 0.22 g (4.7%) of Compound 16. The 1H NMR spectrum is consistent with the assigned structure.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[N:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[N+:8]([C:7]1[C:2]([C:20]2[CH:21]=[N:22][C:17]([C:16]([F:27])([F:26])[F:15])=[CH:18][CH:19]=2)=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1-c1ccc(C(F)(F)F)nc1
Yield: 77.3 %

Procedure:
Under an argon atmosphere, to a solution of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1 g) in 1,4-dioxane (15 mL) were added (6-(trifluoromethyl)pyridin-3-yl)boronic acid (925 mg), a solution of tricyclohexylphosphine in 15% toluene (2.0 mL), tris(dibenzylideneacetone)dipalladium (2.02 g) and a tripotassium phosphate aqueous solution (2 mol/L, 5.9 mL) and stirred overnight at 90° C. The reaction mixture was added with water and filtered through Celite® and the filtrate was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified on silica gel column chromatography (hexane:ethyl acetate=85:15) to give the titled compound (1.15 g) having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:31])([C@H:16]([S:18][C@@H:19]1[CH2:24][O:23][C@@H](C2C=CC=CC=2)[O:21][CH2:20]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.Cl.O1CCOCC1>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:31])([C@H:16]([S:18][CH:19]([CH2:20][OH:21])[CH2:24][OH:23])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](S[C@H]1CO[C@H](c2ccccc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
In 3.5 ml of methanol were dissolved 253 mg of (2R,3R)-2-(2,4-difluorophenyl)-3-[[trans-2-phenyl-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Example 40, and 0.35 ml of a 4N HCl-dioxane solution were added to the solution, followed by stirring of the resulting mixture at room temperature for 30 minutes. To the reaction mixture were added 250 mg of a NAHCO3 powder, and the mixture was stirred for 10 minutes, followed by filtration of the reaction mixture and concentration of the filtrate under reduced pressure. The thus obtained oil was subjected to column chromatography using 5 g of silica gel and eluted with 10% methanol-ethyl acetate to obtain 179 mg (yield: 88%) of the title compound as a viscous oil.
Reaction SMILES: CS(O[C@@H:6]1[C@@H:11]([CH3:12])[CH2:10][C@@H:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH:19]C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=O)=O.[C-:35]#[N:36].[Na+].C(O)(C(F)(F)F)=O.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>CN(C=O)C.C(Cl)Cl.O1CCOCC1>[NH2:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[C@H:9]1[CH2:8][C@@H:7]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[C@@H:6]([C:35]#[N:36])[C@@H:11]([CH3:12])[CH2:10]1
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Reactant: [C-]#N
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
To a solution of (+/−)-(1R,2R,4R,6S)-2-(tert-butoxycarbonylamino)-4-(3-(tert-butoxycarbonylamino)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate (1.0 equiv.) in DMF (0.20 M) was added NaCN (5.0 equiv.). The solution was submerged in an 85° C. oil bath and left stirring under Ar for 16 hrs. The solution was cooled to rt and left stirring under Ar overnight. The solution was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat), NaCl(sat), dried over MgSO4, filtered, concentrated. To a solution of the bis-Boc product (10 equiv.) in DCM (0.20 M) was added TFA (62.0 equiv.). The mixture was stirred at ambient temperature for 40 min and concentrated and neutralized with saturated aqueous sodium bicarbonate. Dioxane (0.15 M) and Boc2O (4.0 equiv.) were added. The reaction mixture was stirred vigorously at ambient temperature for 16 hrs. Volatiles were removed in vacuo. The aqueous phase was extracted with 10:1 DCM: MeOH. The combined extracts were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by ISCO chromatography over silica gel to give (+/−)-tert-butyl (1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-2-cyano-3-methylcyclohexylcarbamate in 20% yield. LC/MS (m/z)=331.2 (MH+), Rt=0.62 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][NH:10][CH:11]([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:26].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(#N)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][N:10]([C:16]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:26])[CH:11]([CH3:12])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Reactant: CC(C)NCCNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)N(CCNC(=O)OC(C)(C)C)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
A mixture of (2-Isopropylamino-ethyl)-carbamic acid tert-butyl ester (100 mg, 0.5 mmol), rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (185 mg, 0.5 mmol) and K2CO3 (138 mg, 1 mmol) in DCM (1 mL) and acetonitrile (2 mL) was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography to give 180 mg rac-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-carbamic acid tert-butyl ester. MS: [M+H]+=492
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]([O-])=[CH:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].Cl.[Cl:27][C:28]1[CH:29]=[C:30]([NH:34][NH2:35])[CH:31]=[CH:32][CH:33]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(OCC)=O)=N2)C=CC=1F>>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[CH:29]=3)[N:35]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:24])[F:23])[CH:8]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Cl
Agent: [Li+]
Product: CCOC(=O)c1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 19A and 3-chlorophenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 2.42 g (62% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1(=[O:14])C2C(C3C(C=2)=CC=CC=3)=CN=N1.[CH:15]1[C:28]2[C:19](=[CH:20][CH:21]=[C:22]3[C:27]=2[CH:26]=[CH:25][CH:24]=[N:23]3)[N:18]=[CH:17][CH:16]=1>>[CH3:1][O:14][C:20]1[CH:21]=[C:22]2[C:27]([CH:26]=[CH:25][CH:24]=[N:23]2)=[C:28]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2
Reactant: O=C1N=NC=C2C1=Cc1ccccc12
Reactant: c1cnc2ccc3ncccc3c2c1
Product: COc1cc2ncccc2c2cccnc12

Procedure:
Some phenanthrolines are very reluctant to undergo the usual basic oxidative rearrangement to the corresponding diazafluorenone. This is true of 4,7-phenanthroline, for instance. In this case, one uses 2-methoxyparaphenylenediamine in a double Skraup synthesis to produce the enolether, 5-methoxy-4,7-phenanthroline (150). Reaction of it with concentrated sulfuric acid and fuming nitric acid yields 4,7-phenanthrolin-5,6-quinone (151). The quinone undergoes oxidative rearrangement to produce 1,8-diazafluoren-9-one (152). Hydrazine reduction produces 1,8-diazafluorene (153) which is alkylated to the target compound, 9,9-bis(4-pyridinylmethyl)-1,8-diazafluorene (154). Other diazafluorenes produced by this method include 1,5-diazafluorene, (Scheme 67, 157), 1,6-diazafluorene, 2,5-diazafluorene, 3,5-diazafluorene, and 4,5-diazafluorene. See references for Scheme 64 and: French patent 1,382,542; French patent 1,369,626, U.S. Pat. No. 2,640,830, Swiss patent 275,433. ##STR87##
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH2:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=1>C(Cl)Cl>[NH2:16][C:17]1[C:18]([NH:1][C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: Nc1cccnc1Cl
Solvent: ClCCl
Product: Nc1cccnc1Nc1ccccc1C(=O)c1ccccc1
Temperature: 180 °C
Reaction time: 3 h
Yield: 3.6 %

Procedure:
A stirred mixture of 39.4 g (0.20 mole) of 2-aminobenzophenone and 28.3 g (0.22 mole) of 3-amino-2-chloropyridine was heated at 180° C. under nitrogen atmosphere for 1.5 hr. The mixture was allowed to cool somewhat and 200 ml of methylene chloride was added slowly. After stirring for 3 hr and standing overnight at room temperature, 40.1 g of solid was filtered off and recrystallized twice from methanol-isopropyl ether giving 4.3 g, presumably the hydrochloride salt; m.p. 187°-90° C. This solid was dissolved in a mixture of water-methanol, basified with 3N sodium hydroxide and extracted with methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from isopropyl ether (charcoal) to give 2.1 g of product; m.p. 91°-3° C. Drying prior to analysis was overnight at room temperature/0.02 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([F:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:27][CH2:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([F:25])=[C:22]([Cl:24])[CH:23]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([NH:27][CH2:28][C:29](=[O:30])[NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:5]
Reactant: NCC(=O)NCC(F)(F)F
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)cc1Br
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(CNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)cc1Br)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.1 %

Procedure:
To a stirred solution of (E)-2-bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)benzoic acid (300 mg, 0.638 mmol) in CH2Cl2 (5.0 mL) was added 2-amino-N-(2,2,2-trifluoroethyl)acetamide (172. mg, 0.638 mmol) followed by benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (364.5 mg, 0.701 mmol) and DIPEA (0.32 mL, 1.914 mmol), and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined CH2Cl2 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 40% ethyl acetate/petroleum ether) afforded the title compound as an off-white solid (121 mg, 31%): 1H NMR (400 MHz, CDCl3) δ 8.69 (t, J=6.0 Hz, 1H), 8.58 (t, J=6.0 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J=6.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.0 (m, 1H), 6.76 (d, J=15.6 Hz, 1H), 4.83 (t, J=8.0 Hz, 1H), 3.98 (m, 4H); ESIMS m/z 610.97 ([M+H]+); IR (thin film) 3303, 1658, 1166, 817 cm−1.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Br:7][C:8]1[CH:9]=[N:10][C:11](I)=[N:12][CH:13]=1.[OH:15][CH2:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>O.C1(C)C=CC=CC=1.C(O)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>[Br:7][C:8]1[CH:9]=[N:10][C:11]([C:21]2[CH:22]=[C:17]([CH2:16][OH:15])[CH:18]=[CH:19][CH:20]=2)=[N:12][CH:13]=1
Reactant: Brc1cnc(I)nc1
Reactant: OCc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: OCc1cccc(-c2ncc(Br)cn2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of 70.0 g (660 mmol) of sodium carbonate in 325 ml of water is added to a solution, kept under nitrogen, of 95.0 g (332 mmol) of 5-bromo-2-iodopyrimidine in 325 ml of toluene, and the mixture is heated to 80° C. 2.3 g (3.3 mmol) of bis(triphenylphosphine)palladium(II) chloride are added, and a solution of 50.0 g (329 mmol) of 3-(hydroxymethyl)benzeneboronic acid in 650 ml of ethanol is subsequently added dropwise. The reaction mixture is stirred at 80° C. for 18 hours. The reaction mixture is cooled to room temperature and filtered. 1 l of ethyl acetate and 1 l of water are added to the filtrate. The organic phase is separated off, dried over sodium sulfate and evaporated. The residue is recrystallised from 2-propanol: [3-(5-bromopyrimidin-2-yl)-phenyl]methanol as pale-yellow crystals; m.p. 115-116° C.; LCMS 265, 267.