Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][C:8]2[C:11]([C:15]([OH:17])=[O:16])=[CH:12][CH:13]=[CH:14][C:7]1=2.[Br:18][C:19]1[CH:20]=[N:21][C:22]([Cl:25])=[N:23][CH:24]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.Cl>C1COCC1.C(O)(=O)C>[Br:18][C:19]1[C:20]([C:10]2[S:6][C:7]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[C:8]=3[CH:9]=2)=[N:21][C:22]([Cl:25])=[N:23][CH:24]=1
Reactant: O=C(O)c1cccc2sccc12
Reactant: Clc1ncc(Br)cn1
Agent: Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 42 %

Procedure:
Butyllithium (2.5 M in hexane, 14.1 mL) is added dropwise to a stirred solution of benzo[b]thiophene-4-carboxylic acid (3.00 g, 16.8 mmol) in anhydrous THF (50 mL) at −78° C. under nitrogen. The resultant mixture is allowed to stir for 45 minutes at −78° C. before it is added, via cannula, to a stirred cold solution of 5-bromo-2-chloropyrimidine (3.26 g, 16.8 mmol) in anhydrous THF (50 mL) at −30° C. Upon the completion of the addition, the reaction mixture is stirred for 30 minutes at −30° C., then at ambient temperature for another 1.5 hours. Acetic acid (2.4 mL) is added to the reaction mixture, after 5 minutes, followed by the addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4.01 g, 17.7 mmol) dissolved in THF (10 mL). The mixture is allowed to stir for 10 minutes before it is treated dropwise with HCl (37%, 30 mL), then the mixture is stirred for another 1 hour. THF is evaporated off and the mixture becomes a suspension. The solid is filtered off, washed with water (100 mL×2), and then dried under vacuum. The dry solid is suspended in dichloromethane (45 mL) and ethanol (5 mL) and stirred for 30 minutes. After filtration, the solid is resuspended in ether (50 mL) and the suspension is stirred for another 30 minutes. After filtration and vacuum drying, the title compound is obtained as a yellow solid. (2.64 g, 42% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:31][CH2:30][N:11]2[C:12](=[O:29])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([C:19]#[C:20][Si](C)(C)C)=[CH:15][C:14]=3[C:25]([F:28])([F:27])[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)C1OC=CC=1)CCC.C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:31][CH2:30][N:11]2[C:12](=[O:29])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][C:14]=3[C:25]([F:27])([F:28])[F:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(C#C[Si](C)(C)C)cc3C(F)(F)F)[C@@H]2C1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Reaction time: 0.08 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-trimethylsilylethynyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one, prepared according to procedures described in Example 29 with substitution of tributyl(trimethylsilylethynyl)tin for 2-(tributylstannyl)furan (44 mg, 0.1 mmol in MeOH (1.0 mL) was added potassium carbonate (13 mg, 0.1 mmol). The reaction was stirred for 5 min and then quenched with brine. The reaction was extracted with EtOAc (2×5 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a pale yellow oil. The oil was purified by radial chromatography (silica gel, 30% EtOAc in hexanes) to give 27 mg of the desired product as a pale yellow oil.
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.[CH2:7]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]1)=[O:12])[CH:8]=[CH2:9].C([Mg]Br)C.[Cl-].[NH4+]>ClCCl.O1CCCC1.C(N(CC)CC)C.CS(C)=O>[CH2:7]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH:19]([OH:20])[CH2:1][CH3:2])[CH2:15][CH2:14]1)=[O:12])[CH:8]=[CH2:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCOC(=O)N1CCC(CO)CC1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CCC(C(O)CC)CC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of oxalyl chloride (7.7 ml) in dichloromethane (200 ml) was added dropwise dimethyl sulfoxide (7.7 ml) at -78° C. After stirring at -78° C. for 20 minutes, to the mixture was added dropwise a solution of 1-allyloxycarbonyl-4-hydroxymethylpiperidine (14 g) in dichloromethane (20 ml). After stirring at -78° C. for 30 minutes, to the mixture was added dropwise triethylamine (35 ml) and the resulting mixture was allowed to stir at 0° C. The solution was washed with brine and dried. Evaporation of the solvent gave an oil, which was dissolved in tetrahydrofuran (100 ml). To the solution was added 1N-ethylmagnesium bromide in tetrahydrofuran solution (35 ml) at 0° C. After stirring for 1 hour at 0° C., to the solution was added saturated aqueous ammonium chloride, and the organic layer was separated. The dried organic layer was evaporated, and the residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1, V/V) to give 1-allyloxycarbonyl-4-(1-hydroxypropyl)piperidine (12.8 g).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(OCC)(=O)C>CC#N.CCCCCC>[C:1]1([CH:7]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[CH:8]2[CH2:9][CH2:10][N:11]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: CCOC(=O)CBr
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CN1CCC(C(c2ccccc2)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
To a solution of 4-(phenyl(4-(trifluoromethyl)phenyl)methyl)piperidine (0.4 g, 1.25 mmol) in MeCN (15 mL) was added triethyl amine (0.45 mL, 3.2 mmol) at rt. After stirring at rt for 10 min, it was cooled to 0° C. and ethyl bromoacetate (0.27 mL, 1.62 mmol) was added dropwise. After stirring at rt for 16 h, the solvent was removed under vacuum and the residue was diluted with water, extracted with ethyl acetate, the combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afforded the crude product. Column chromatography (SiO2, 5-10% ethyl acetate in hexane) afforded ethyl 2-(4-(phenyl(4-(trifluoromethyl)phenyl)methyl)piperidin-1-yl)acetate (0.25 g, 52% yield) as a pale yellow solid. MS (ESI, pos. ion) m/z: 406 (M+1).
Reaction SMILES: [CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:8][NH:7][C:6](=O)[CH:5]([CH3:10])[O:4]1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>CCOCC.O>[CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[O:4][CH:5]([CH3:10])[CH2:6][NH:7][CH2:8]1)[CH3:2]
Reactant: CCC1(c2cccc(OC)c2)CNC(=O)C(C)O1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CCC1(c2cccc(OC)c2)CNCC(C)O1

Procedure:
The crude 6-ethyl-6-(3-methoxyphenyl)-2-methyl-3-morpholinone was added in ether to a cooled suspension of lithium aluminium hydride (12 g) in ether and then refluxed for 6 h. A solution of potassium sodium tartrate (132 g) in water (300 ml) was slowly added to the cooled suspension. The ether layer was washed and dried giving the title compound as a yellow oil (12.3 g). Both this and the parent morpholinone were mixtures of equal proportions of diastereoisomers in >95% purity.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=O.S(Cl)(Cl)=O.[CH3:17][N:18]([CH3:26])[CH:19]=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)CC)C>C1(C)C=CC=CC=1.O1CCCC1.CCCCCC.CN(C)C=O>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([C:20](=[CH:19][N:18]([CH3:26])[CH3:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:6]
Reactant: Cc1c(F)ccc(C(=O)[O-])c1F
Reactant: CCOC(=O)C=CN(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(F)c(C)c1F
Temperature: 80 °C
Reaction time: 14 h
Yield: 78 %

Procedure:
2,4-Difluoro-3-methylbenzoate (4.97 g, 28.9 mmol) was dissolved in toluene (50 ml), and after adding N,N-dimethylformamide (0.1 ml) and thionyl chloride (3.16 ml, 43.4 mmol) thereto, it was stirred for 14 hours in an oil bath of 80° C. The reaction solution was then cooled and thereafter concentrated under a reduced pressure. After adding toluene to the residue and repeating concentration under a reduced pressure, the residue obtained was dissolved in tetrahydrofuran (10 ml). This solution was added dropwise while cooling with ice to a solution in which ethyl 3-dimethylaminoacrylate (4.97 g, 34.7 mmol) and triethylamine (5.04 ml, 36.1 mmol) were dissolved in tetrahydrofuran (20 ml). After completion of dripping, the reaction solution was heated under reflux for 10 hours. After completion of the reaction, the reaction solution was filtered, the triethylamine hydrochloride salt was removed (by diethyl ether washing), and the filtrate was concentrated under a reduced pressure. The residue obtained was applied to a short silica gel chromatography and 6.70 g (78%) of the title compound was obtained in the form of a yellow powder from an n-hexane:ethyl acetate=1:1 eluate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=1.C(OC([N:28]1[C:36]2[N:31]([C:32](=[O:38])[N:33]=[C:34](Cl)[CH:35]=2)[CH2:30][C:29]1([CH3:40])[CH3:39])=O)(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[N:13][C:12]([C:15]([F:17])([F:18])[F:16])=[N:11][CH:10]=1)[CH2:19][O:20][C:34]1[CH:35]=[C:36]2[NH:28][C:29]([CH3:40])([CH3:39])[CH2:30][N:31]2[C:32](=[O:38])[N:33]=1
Reactant: OCc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CC1(C)Cn2c(cc(OCc3ccc(Oc4cnc(C(F)(F)F)nc4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol and tert-buty-7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C1C=CC=CC=1.[CH2:36]([O:38][C:39](=[O:47])[C:40]1[CH:45]=[CH:44][C:43](I)=[CH:42][CH:41]=1)[CH3:37]>C(N(CC)CC)C.[Cu]I.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>[CH2:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:43]3[CH:44]=[CH:45][C:40]([C:39]([O:38][CH2:36][CH3:37])=[O:47])=[CH:41][CH:42]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(N(Cc3ccccc3)Cc3ccccc3)CC2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(N(Cc4ccccc4)Cc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure F; dibenzyl-[1-(4-ethynylphenyl)-cyclopropyl]-amine (Intermediate 129, 40.0 mg, 0.12 mmol) and ethyl-4-iodo benzoate (Reagent A, 60.0 mg, 0.22 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (8.0 mg, 0.04 mmol) and sparged with argon for 5 minutes. Dichlorobis (triphenylphosphine)palladium(II) (27 mg, 0.04 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded the title compound as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]2[CH:22]=[N:21][C:20]([C:23]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[OH:24])=[N:19]2)[CH2:13][CH2:12]1.[CH2:37]([O:44][C:45]1[CH:46]=[CH:47][C:48]([C@@H:56]([O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH2:57]Br)=[C:49]2[C:54]=1[NH:53][C:52](=[O:55])[CH:51]=[CH:50]2)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([O:44][C:45]1[CH:46]=[CH:47][C:48]([C@@H:56]([O:59][Si:60]([C:63]([CH3:64])([CH3:66])[CH3:65])([CH3:62])[CH3:61])[CH2:57][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([CH2:17][N:18]3[CH:22]=[N:21][C:20]([C:23]([CH:31]4[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]4)([OH:24])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:19]3)[CH2:15][CH2:16]2)=[C:49]2[C:54]=1[NH:53][C:52](=[O:55])[CH:51]=[CH:50]2)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: NCCCCCCCCCN1CCC(Cn2cnc(C(O)(c3ccccc3)C3CCCCC3)n2)CC1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCCCCN1CCC(Cn2cnc(C(O)(c3ccccc3)C3CCCCC3)n2)CC1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Yield: 24 %

Procedure:
The title compound was prepared from (1-{[1-(9-aminononyl)piperidin-4-yl]methyl}-1H-1,2,4-triazol-3-yl)(cyclohexyl)phenylmethanol (Preparation 22, 150 mg, 0.303 mg) and 8-(benzyloxy)-5-[(1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]quinolin-2(1H)-one (WO05/09286, 148 mg, 0.303 mmol) using the same method as described in preparation 7, to give a clear oil, in 24% yield, 66 mg.
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[C:25]([C:27]3[O:31][N:30]=[C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:28]=3[C:38]([F:41])([F:40])[F:39])[O:24][N:23]=2)=[CH:18][CH:17]=1)[C:3]([NH:5][CH2:6][CH2:7][NH:8]C(=O)OC(C)(C)C)=[O:4].[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>ClCCl>[NH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH:2]([OH:1])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[C:25]([C:27]3[O:31][N:30]=[C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:28]=3[C:38]([F:41])([F:40])[F:39])[O:24][N:23]=2)=[CH:18][CH:17]=1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.5 h

Procedure:
(R/S)-tert-Butyl 2-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)ethylcarbamate (Example 51, 80 mg, 0.139 mmol) was dissolved in dichloromethane (5 mL). TFA (1 mL, 12.98 mmol) was added. The reaction mixture was stirred for 30 min. All solvent was removed to provide (R/S)-N-(2-aminoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide, TFA (70 mg, 0.116 mmol, 83% yield): LCMS=474.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.62 (1 H, t, J=5.93 Hz), 8.19 (2 H, d, J=8.35 Hz), 7.55-7.76 (7 H, m), 5.20 (1 H, s), 3.39-3.64 (2 H, m), 3.07 (2 H, t, J=6.15 Hz); HPLC peak RT=6.3 min (Method A).
Reaction SMILES: [C:1]([C@H:4]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[NH:34][C:33]2=[O:43])[CH2:28][CH2:27]1)=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:10]=[CH:9]2)(O)=[O:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH3:73][N:74]1[CH2:79][CH2:78][N:77]([CH:80]2[CH2:85][CH2:84][NH:83][CH2:82][CH2:81]2)[CH2:76][CH2:75]1>CN(C=O)C>[CH3:15][C:13]1[CH:14]=[C:6]([CH2:5][C@@H:4]([O:23][C:24]([N:26]2[CH2:27][CH2:28][CH:29]([N:32]3[CH2:38][CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=4[NH:34][C:33]3=[O:43])[CH2:30][CH2:31]2)=[O:25])[C:1]([N:83]2[CH2:82][CH2:81][CH:80]([N:77]3[CH2:76][CH2:75][N:74]([CH3:73])[CH2:79][CH2:78]3)[CH2:85][CH2:84]2)=[O:2])[CH:7]=[C:8]2[C:12]=1[N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[N:10]=[CH:9]2
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2cnn(C(=O)OC(C)(C)C)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc2cnn(C(=O)OC(C)(C)C)c12

Procedure:
A solution of 440 mg tert.-butyl 5-{(R)-2-carboxy-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-ethyl}-7-methyl-indazol-1-carboxylate, 256 mg (0.8 mmol) TBTU, 146 μL (1.0 mmol) triethylamine and 147 mg (0.8 mmol) 1-methyl-4-piperidin-4-yl-piperazine in 8 mL DMF was stirred for 2 h at RT. The reaction solution was filtered through an injection filter and purified directly by HPLC without any further working up. The fractions containing the product were combined, evaporated down i.vac., made alkaline with 15% K2CO3 solution, extracted three times with 30 mL DCM, the combined organic phases were dried over Na2SO4 and the solvent was eliminated i. vac.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][CH:11]1[CH2:13][CH2:12]1>>[CH:11]1([CH2:10][N:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][C:4]2=[NH:8])[CH2:13][CH2:12]1
Reactant: BrCC1CC1
Reactant: Cc1nc(N)sc1C
Product: Cc1sc(=N)n(CC2CC2)c1C
Temperature: 85 °C

Procedure:
A mixture of 4,5-dimethylthiazol-2-amine (0.30 g, 2.3 mmol, Aldrich) and (bromomethyl)cyclopropane (0.63 g, 4.7 mmol, Aldrich) was heated at 85° C. for 16 h. The reaction mixture was cooled to room temperature and triturated with ether to obtain the crude intermediate, hydrobromide salt of (cyclopropylmethyl)-4,5-dimethylthiazol-2(3H)-imine. To a solution of the above intermediate in tetrahydrofuran (10 mL) were added Example 24B (0.71, 2.3 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodimide hydrochloride (0.54, 2.8 mmol, Aldrich), 1-hydroxybenzotriazole (0.43 g, 2.8 mmol, Aldrich) and triethylamine (1.0 mL, 7.0 mmol, Aldrich). The reaction mixture was stirred at 80° C. for 2 h, cooled and then quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 5-100% of triethylamine/MeOH/EtOAc (0.1/1/10) in hexanes) to afford 160 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.32-0.69 (m, 4H), 1.14-1.40 (m, 1H), 1.48-1.75 (m, 3H), 1.78-2.00 (m, 1H), 2.07-2.22 (m, 1H), 2.23 (s, 3H), 2.29 (s, 3H), 2.32 (s, 3H), 2.53-2.64 (m, 1H), 2.86-2.97 (m, 1H), 3.92-4.07 (m, 2H), 4.11 (d, J=7.1 Hz, 2H), 7.28 (d, J=8.7 Hz, 1H), 7.72 (dd, J=8.7, 2.4 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H); MS (ESI+) m/z 468 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[C:8]([C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12]Br)#[N:9].O>CN(C=O)C>[N:1]1([CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[C:8]#[N:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Cn1ccnc1
Reaction time: 0.5 h

Procedure:
To a solution of imidazole (1.0 g, 14.6 mmol) in DMF (10 mL) is added sodium hydride (60% wt. in mineral oil, 0.887 g, 22.17 mmol) at room temperature. The mixture is stirred for 30 min, whereupon 2-cyanobenzyl bromide (2.87 g, 14.6 mmol) is added. After an additional 30 min, water is added and the mixture is extracted with ethyl acetate. The aqueous phase is poured into aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic phase is dried over sodium sulfate, filtered and concentrated in vacuo to give a residue which is purified by silica gel chromatography (dichloromethane-methanol, 19:1) to give 2-imidazol-1-ylmethyl-benzonitrile; MS (ESI) m/z 184.3 (M+H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([N:62]5[CH2:63][CH2:64][N:59]([CH3:58])[CH2:60][CH2:61]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and N-methylpiperazine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27-1.35 (m, 2 H) 1.54-1.67 (m, 3 H) 1.72-1.84 (m, 5 H) 2.83 (s, 3 H) 3.31 (d, J=3.2 Hz, 3 H) 3.91 (d, J=4.6 Hz, 3 H) 3.95-4.33 (m, 10 H) 4.39-4.54 (m, 1 H) 7.06 (dd, J=8.1, 2.0 Hz, 1 H) 7.13 (d, J=110 Hz, 1 H) 8.10-8.18 (m, 1 H) 8.22 (d, J=3.0 Hz, 1 H). [M+H] calc'd for C27H35F2N7O3 544; found 544.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]([C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])[CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])[CH2:18][CH2:17]1>>[F:32][C:31]([F:34])([F:33])[C:30]([C:12]1[CH:13]=[CH:14][C:15]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[C:10]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:11]=1)([OH:39])[C:35]([F:38])([F:37])[F:36]
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Reactant: OB(O)c1ccsc1
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2-c2ccsc2)CC1

Procedure:
Following the procedure outlined for Example 69, 3-thiopheneboronic acid (17.8 mg, 0.139 mmol, Sigma-Aldrich, St. Louis, Mo.) was coupled to 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol, the reaction mixture was filtered, concentrated, and the residue was subjected to reverse-phase preparative HPLC using a Phenomenex Gemini-NX (C18 110 A column (100×21 mm, 5 μm) eluting with 0.1% NH4OH in CH3CN/H2O (5% to 95% over 8 min)) to afford 1,1,1,3,3,3-hexafluoro-2-(3-(3-thiophenyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J=6.2 Hz, 1H), 7.69-7.62 (m, 2H), 7.53 (m, 3H), 7.38-7.29 (m, 2H), 7.19 (d, J=9.7 Hz, 1H), 2.99-2.94 (m, 4H), 2.93-2.87 (m, 4H). m/z (ESI, +ve ion) 557.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=3.50 μM; GK-GKRP EC50 (LC MS/MS)=1.90 μM.