Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([C:32]3[CH:52]=[CH:51][C:35]5[NH:36][C:37]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6C(OC(C)(C)C)=O)=[N:38][C:34]=5[CH:33]=3)[CH:26]=[CH:25]4)[CH:20]=[CH:21][C:15]=2[N:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:28]1[C:29]2[C:24](=[CH:23][C:22]([C:19]3[CH:20]=[CH:21][C:15]4[NH:14][C:13]([CH:9]5[CH2:10][CH2:11][CH2:12][NH:8]5)=[N:17][C:16]=4[CH:18]=3)=[CH:31][CH:30]=2)[CH:25]=[CH:26][C:27]=1[C:32]1[CH:52]=[CH:51][C:35]2[NH:36][C:37]([CH:39]3[CH2:43][CH2:42][CH2:41][NH:40]3)=[N:38][C:34]=2[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2cc(-c3ccc4cc(-c5ccc6nc(C7CCCN7C(=O)OC(C)(C)C)[nH]c6c5)ccc4c3)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2cc(-c3ccc4[nH]c(C5CCCN5)nc4c3)ccc2cc1-c1ccc2[nH]c(C3CCCN3)nc2c1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A mixture of tert-butyl 2-(5-(6-(2-(1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-benzimidazol-6-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinecarboxylate (591 mg. 0.844 mmol) and TFA (2 mL) in CH2Cl2 (10 mL) was stirred at ambient conditions for 2 hours. The volatile component was removed in vacuo and the resulting material was loaded onto a MCX column, flushed with methanol, released with 2.0 M NH3/methanol elution) and concentrated to provide 5,5′-(2,6-naphthalenediyl)bis(2-(2-pyrrolidinyl)-1H-benzimidazole) (419 mg) as tan solid. LC-MS retention time 1.02 min; Calcd. for C33H31N5: 498.25 Found m/z 499.25 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. 1H NMR (500 MHz, MeOD) δ ppm 8.18 (s, 1H), 8.06 (d, J=8.6 Hz, 1H), 8.00 (s, 1H), 7.84-7.92 (m, 1H), 7.73-7.81 (m, 2H), 5.08 (t, J=7.6 Hz, 1H), 3.56-3.66 (m, 1H), 3.48-3.56 (m, 1H), 2.62-2.71 (m, 1H), 2.36-2.47 (m, 1H), 2.19-2.36 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.Cl.[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][NH:30][CH2:29]2)=[O:25].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][N:30]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:29]2)=[O:25]
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: COC(=O)c1ccc2c(c1)CNC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn4c3c1OCC4C)C2
Yield: 20.3 %

Procedure:
142 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 109 mg of 5-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 45 mg of the target compound.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:26][N:27]1[C:31]([C:32]([C:34]2[CH:35]=[N:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=2)=[O:33])=[CH:30][N:29]=[CH:28]1.[Li]CCCC>C(=O)=O.CC(C)=O>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:32]([C:31]3[N:27]([CH3:26])[CH:28]=[N:29][CH:30]=3)([C:34]3[CH:35]=[N:36][C:37]([C:40]([F:42])([F:41])[F:43])=[CH:38][CH:39]=3)[OH:33])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (827 mg, 1.91 mmol, Intermediate 3: step c) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (536 mg, 2.10 mmol, Intermediate 2: step c). The flask was evacuated and back-filled with argon, then THF (27 mL) was added. The resulting yellow suspension was heated until nearly all solid dissolved, and the slightly cloudy yellow suspension was allowed to cool to room temperature, and then was cooled in a dry ice acetone bath for 7 minutes before addition of n-BuLi (1.6 M in hexane, 1.55 mL, 2.48 mmol) dropwise. The mixture was stirred for 5 minutes in dry ice/acetone bath, then was moved to an ice/water bath and stirred for 1 hour. The reaction was quenched by the addition of saturated aqueous NH4Cl, and was diluted with water. The aqueous was then extracted with EtOAc (3×). The organic layers were combined and washed once with water. The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, 0-2% MeOH-DCM) affording impure title compound which was used without further purification in the next step.
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=O)[C:6]1=[O:16])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].P(Cl)(OCC)(OCC)=O.[N+:28]([CH2:30][C:31]1[O:35][N:34]=[C:33]([CH3:36])[CH:32]=1)#[C-:29].CC(C)([O-])C.[K+]>CN(C)C=O.C(O)(=O)C>[C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[CH:29]=[N:28][C:30]([C:31]3[O:35][N:34]=[C:33]([CH3:36])[CH:32]=3)=[C:7]2[C:6]1=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1c(=O)c(=O)[nH]c2ccccc21
Reactant: [C-]#[N+]Cc1cc(C)no1
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cc(-c2ncn3c2c(=O)n(C(C)(C)C)c2ccccc23)on1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-tert-butyl-1,2,3,4-tetrahydro-2,3-dioxoquinoxaline (6.54 g, 30 mmol) in dry dimethylformamide (DMF) (30 ml) under nitrogen was added sodium hydride (80% in oil, 9.6 g, 32 mmol). After stirring for 10 min. the solution was cooled to -20° C. and diethyl chlorophosphate (5.6 ml, 39 mmol) was added. The mixture was allowed to reach room temperature and then cooled to -30° C., whereafter 5-isocyanomethyl-3-methylisoxazole (3.0 g, 25 mmol) and finally a solution of potassium tert-butoxide (3.0 g, 26 mmol) in dry DMF (30 ml) was added keeping the temperature below -20° C. The reaction mixture was warmed to room temperature, acidified with acetic acid (1 ml) and evaporated in vacuo. The residue was triturated with water and ether, and the resulting precipitate was filtered off and partitioned between 0.5 M aqueous sodium hydroxide (50 ml) and dichloromethane (50 ml). The organic layer was filtered through celite, dried, and evaporated to give the title compound, m.p. 395° C. (Compound 17).
Reaction SMILES: CN(C=O)C.[C:6]1([C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][NH:15][C:14](=[O:24])[CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35]>O>[O:24]=[C:14]1[N:15]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[N:16]=[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:13]1
Reactant: COC(=O)CCCCCCCCBr
Reactant: O=c1cc(-c2ccccc2)c(-c2ccccc2)n[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Sodium hydride (840 mg of a 60% dispersion in oil, 20 mmol) was washed twice with hexanes, covered with DMF (25 mL) and 5,6-diphenyl-3(2H)-pyridazinone (4 g, 16 mmol), obtained according to P. Schmidt, et al., Helvetica Chim. Acta., 37, 134-140 (1954), added. After gas evolution had ceased, the mixture was stirred at room temperature for 30 minutes before adding methyl 9-bromononanoate (4.45 g, 18 mmol). The mixture was heated briefly to 110° C. to give a solution and then allowed to cool before being stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with diethyl ether (3×). The combined extracts were washed with water, dried over sodium sulfate and concentrated to leave an oil. Chromatography on a column of silica gel afforded methyl 6-oxo-3,4-diphenyl-1(6H)-pyridazine nonanoate (6.44 g, 95%) as an oil.
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])[CH3:3]>[O-2].[O-2].[Mn+4]>[C:2]([C:4]1[C:12]2[O:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])(=[O:1])[CH3:3]
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1C(C)O)OCC2c1ccc(C(C)C)cc1
Agent: [Mn+4]
Agent: [O-2]
Product: CC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
A mixture of N-(7-(1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (580 mg, 1.37 mmol) obtained in Example 22 and manganese dioxide (1.43 g, 16.4 mmol) were stirred at 100° C. for two hours. Insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 440 mg (yield: 76%) of the title compound. Melting point: 200-201° C. (ethyl acetate-hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[NH:26]1[CH2:29][CH2:28][C:27]1=[O:30]>>[CH3:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:5]3[C:6]([F:8])=[CH:7][C:2]([N:26]4[CH2:29][CH2:28][C:27]4=[O:30])=[CH:3][C:4]=3[F:25])=[O:10])[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=1
Reactant: O=C1CCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4CCC4=O)cc3F)CC2)c(C)c1
Yield: 54.7 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (410 mg) described in Preparation Example 111 and 2-azetidinone (75 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (219 mg) was obtained.
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.CNC.C1COCC1.[I:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25]>O>[I:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([N:3]([CH3:4])[CH3:2])=[O:25]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1cccc(I)c1
Reaction time: 18 h

Procedure:
EDCI (1.3 g, 6.6 mmol) was added to a solution of dimethylamine in THF (2 M, 6 mL, 10 mmol) and 3-iodobenzoic acid (1.5 g, 6 mmol). After 18 h stirring the reaction was transferred into water, and then extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The solvent was evaporated to afford the product as a viscous, clear oil. The product was used in the next reaction step without further purification. MS m/z: 276 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([NH:7][C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6].CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.CN([CH:42]=[O:43])C>C1COCC1.O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:4]2[C:3]=1[CH:42]([OH:43])[N:7]([C:8]([CH3:16])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9])[C:5]2=[O:6]
Reactant: CC(C)(NC(=O)c1cccc(Cl)c1)c1ccccc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(c1ccccc1)N1C(=O)c2cccc(Cl)c2C1O
Reaction time: 2.5 h
Yield: 88.8 %

Procedure:
3-Chloro-N-(1-methyl-1-phenylethyl)benzamide (7.00 g, 25.6 mmol) was dissolved in THF (280 mL), and the solution was added with TMEDA (12.4 mL, 81.9 mmol), then added with sec-butyllithium-hexane solution (0.99 mol/L, 82.7 mL, 81.9 mmol) by drops at −78° C. for 40 minutes under argon atmosphere, followed by stirring at the same temperature for 2.5 hours. Then, the mixture was added with DMF (4.36 mL, 56.3 mmol) and warmed from −78° C. to room temperature over 2 hours. The reaction mixture was added with water, extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by slurry using diisopropyl ether to obtain 4-chloro-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (6.86 g, yield 89%).
Reaction SMILES: [C:1]([C@@:5]1([OH:29])[C@@H:9]([CH2:10][O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[O:8][C@@:7]([SiH:26]([CH3:28])[CH3:27])([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21])[C:19]=3[N:18]=[CH:17]2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C[OH:31]>CCO.O.C(Cl)Cl>[C:1]([C@@:5]1([OH:29])[C@@H:9]([CH2:10][O:11][C:12]([CH3:15])([CH3:13])[CH3:14])[O:8][C@@:7]([SiH:26]([CH3:27])[CH3:28])([N:16]2[C:25]3[N:24]=[CH:23][N:22]=[C:20]([NH2:21]=[O:31])[C:19]=3[N:18]=[CH:17]2)[CH2:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CO
Reactant: C[SiH](C)[C@]1(n2cnc3c(N)ncnc32)C[C@@](O)(C(C)(C)C)[C@@H](COC(C)(C)C)O1
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: C[SiH](C)[C@]1(n2cnc3c([NH2+][O-])ncnc32)C[C@@](O)(C(C)(C)C)[C@@H](COC(C)(C)C)O1
Reaction time: 48 h
Yield: 39 %

Procedure:
To a solution of 3',5'-O-bis-tert.-butyldimethylsilyl-2'-deoxyadenosine (Ogilvie, K. K. (1973) Can. J. Chem. 51, 3799-3807.)(6.0 g, 12.5 mmol) in a mixture of EtOH and H2O (2.5:1) was added at RT monopermaleic acid (24 mmol). After 2 days, another 6 equiv. of monopermaleic acid were added, and the reaction continued for two weeks. Continuous monitoring (TLC on SiO2, 10% MeOH in CH2Cl2) showed that the reaction did not proceed to completion even though peracid was still detectable (KI test). After two weeks, CH2Cl2 was added, the organic phase extracted with saturated NaHCO3, and 3',5'-O-bis-tert.-butyldimethylsilyl-2'-deoxyadenosine N-oxide (3.41 g, 55%) isolated by chromatography (SiO2, EtOAc:hexane 4:1) together with starting material (2.33 g, 39%).
Reaction SMILES: C([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@:16]4([C:37]#[N:38])[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]4)[C:11]1([CH3:40])[CH3:39])(=O)C1C=CC=CC=1.O>[OH-].[K+]>[C:37]([C@:16]12[C:15]3[CH2:14][CH2:13][C@@H:12]4[C@:32]([CH3:35])([CH2:33][CH2:34][C@H:10]([OH:9])[C:11]4([CH3:40])[CH3:39])[C:31]=3[CH2:30][CH2:29][C@:28]1([CH3:36])[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]2)#[N:38]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@@]2(C#N)C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@@]2(C#N)C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
3β-benzoyloxy-14α-cyano-4,4-dimethyl-5α-cholest-8-ene (Compound 16a) (45.3 mg, 83.4 μmol) was dissolved in 1 N ethanolic potassium hydroxide (30 mL) containing 5% water at room temperature. The mixture was stirred for 30 min at 50°, poured into ice water (200 mL) and extracted with dichloromethane (3×200 mL). The combined extracts were dried over anhydrous magnesium sulfate and solvent removed by evaporation under reduced pressure. The residue was subjected to MPLC (80 psi, 50 cm×1.2 cm), using 8% ethyl acetate in toluene as the eluting solvent, to afford 33.0 mg (90%) of Compound 17a.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH:19][C:20]([NH2:22])=[S:21])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=1.Cl[CH2:24][CH:25]=O>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH:19][C:20]2[S:21][CH:24]=[CH:25][N:22]=2)=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=1
Reactant: O=CCCl
Reactant: COCCOc1cc(Oc2cccnc2)cnc1NC(N)=S
Solvent: CN(C)C=O
Product: COCCOc1cc(Oc2cccnc2)cnc1Nc1nccs1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 37 %

Procedure:
[3-(2-Methoxy-ethoxy)-5-(pyridine-3-yloxy)-pyridine-2-yl]-thiourea (0.34 mmol) is dissolved in DMF (1.2 ml) and chloro-acetaldehyde (1.0 eq., 55% in water) is added and stirred 90 minutes at 120° C. After cooling to room temperature the suspension is pored into ice-water and extracted with methyl-tert.-butyl ether. The combined organic phases are washed with brine and dried over MgSO4. The solvent is removed in vacuo. [3-(2-Methoxy-ethoxy)-5-(pyridine-3-yloxy)pyridine-2-yl]-thiazole-2-yl-amine (“A31”) is obtained after reversed phase column chromatography (acetonitrile/water+0.1% TFA) as yellow solid in a yield of 37%. HPLC (method C): 1.17 min; LC-MS (method A): 1.07 min, 345.15 (MH+); 1H-NMR (DMSO-d6, 500 MHz): δ [ppm] 10.403 (s, 1H), 8.477 (d, 1H, J=2.7 Hz), 8.398 (dd, 1H, J=1.3 Hz, J=4.6 Hz), 7.832 (d, 1H, J=2.3 Hz), 7.558-7.533 (m, 1H), 7.500-7.475 (m, 2H), 7.456 (d, 1H, J=2.3 Hz), 7.116 (d, 1H, J=3.7 Hz), 4.279 (t, 2H, J=4.6 Hz), 3.771 (t, 2H, J=4.6 Hz), 3.339 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([N:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([F:48])([F:47])[F:46].C(OCC)(=O)C.[ClH:55]>C(OCC)C>[ClH:55].[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([N:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([F:47])([F:46])[F:48]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCNCC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The 4-[[10,11-dihydro-10-[[2-methyl-2′-trifluoromethyl[1,1′-biphenyl]-4-yl]carbonyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]carbonyl]-1-piperazine carboxylic acid, tert-butyl ester of Step A (0.85 g, 1.29 mmol) was added in one portion to stirred ethyl acetate (10 mL) saturated with hydrogen chloride gas at 0° C. The reaction mixture was stirred for 90 minutes under nitrogen. A precipitate formed after several minutes. The reaction was then warmed to room temperature and diluted with diethyl ether. The precipitated product was collected by filtration and dried under high vacuum to provide 0.65 g of the title compound hydrochloride salt as an off-white foam.
Reaction SMILES: C([O:4][C@H:5]1[CH2:18][C@@H:17]([O:19]C(=O)C)[C@H:16](/[CH:23]=[CH:24]/[CH:25]=[CH:26]/[CH2:27][CH2:28][CH2:29][CH3:30])[C@H:6]1[CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=O)C.[OH-].[Na+]>CO>[OH:4][C@H:5]1[CH2:18][C@@H:17]([OH:19])[C@H:16](/[CH:23]=[CH:24]/[CH:25]=[CH:26]/[CH2:27][CH2:28][CH2:29][CH3:30])[C@H:6]1[CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCCC/C=C/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](OC(C)=O)C[C@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC/C=C/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound 121 obtained above (3.90 g, 9.27 mmole) was dissolved in methanol (40 ml), and 10% aqueous sodium hydroxide was added to the solution, and the mixture was stirred at room temperature for one hour. Then, the mixture was treated following the procedure similar to that of Example 44 to yield a residue (2.84 g). The residue was purified with Lobar column (ethyl acetate:n-hexane:acetic acid=50:50:1), to yield the title compound 122 (2.67 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:22]=2)[CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)cn2)c1

Procedure:
N-tert-Butyl-3-{1-[6-(4-fluoro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(4-fluoro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.79) (0.25 g, 0.57 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.175 g, 0.68 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.52 g) which was subsequently deprotected.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=1[NH:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)=O)[CH2:6][CH2:5]2>P(Cl)(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:5][CH2:6][N:7]3[C:8]2=[C:9]([CH:10]=1)[C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)=[N:18][C:12]1[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=13
Reactant: CN1CCN(C(=O)Nc2cc(Br)ccc2N2CCc3cc(Br)ccc32)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3cc(Br)ccc3N3CCc4cc(Br)cc2c43)CC1
Reaction time: 0.33 h
Yield: 70.3 %

Procedure:
A solution of N-[2-(5-bromo-1-indolinyl)-5-bromophenyl]-4-methyl-1-piperazinecarboxamide (12.3 g, 24.8 mmoles) and phosphorus oxychloride (250 ml) was heated under reflux for 1 hour. The reaction mixture was cooled and then concentrated at 50°-60° C. under vacuum. Ice-chilled sodium hydroxide solution (15%, 500 ml) and dichloromethane (500 ml) was added to the reaction mixture. The mixture was stirred for 20 minutes. The organic phase was separated and the aqueous phase was extracted once with dichloromethane (250 ml). The combined dichloromethane solutions were washed with 1N sodium hydroxide solution (350 ml) and brine (2×350 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated. The residue was purified on a silica gel column (250 gm), eluted with 2% and then 3% methanol:dichloromethane. The appropriate fractions were combined and concentrated to give 8.3 g (70%) of product. Recrystallization from isopropanol gave the analytical sample, mp 215°-216° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:9](=O)[C:8]2=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[CH:16]([C:19]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:20]=1[NH2:21])([CH3:18])[CH3:17]>>[CH:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:19]([CH:16]([CH3:18])[CH3:17])[C:20]=1[N:21]1[C:9](=[O:11])[C:8]2=[CH:14][CH:15]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=[C:7]2[C:12]1=[O:13])([CH3:28])[CH3:27]
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)OC2=O
Reactant: CC(C)c1cccc(C(C)C)c1N
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2ccc(C(C)(C)C)cc2C1=O

Procedure:
0.605 g of 4-tert-butylphthalic anhydride and 0.630 g of 2,6-diisopropylaniline were mixed, and the mixture was reacted at a temperature of 200° C. for 1 hour.