Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][C:5]=1[CH3:16].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15][S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[S:13][CH:14]=2)=[CH:6][C:5]=1[CH3:16]
Reactant: COc1ccc(-c2csc(N)n2)cc1C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2csc(NS(=O)(=O)c3ccc(C)cc3)n2)cc1C

Procedure:
A mixture of 0.5 g of 4-(4-methoxy-3-methyl-phenyl)-thiazol-2-ylamine hydrobromide with 0.5 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored solution was poured into 50 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a hot mixture of 20 ml of ethanol and 50 ml of water. 0.06 g of N-[4-(4-methoxy-3-methyl-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide separated as beige crystals upon cooling.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:23]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:24])=[CH:4][CH:3]=1.[CH:31](OCC)(OCC)OCC>>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]2[NH:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][CH3:31])=[CH:7][CH:6]=3)=[C:9]([C:23]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)=[O:24])[N:10]=2)=[CH:18][CH:17]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)c1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(N)cc3)[nH]2)cc1
Product: CNc1ccc(-c2[nH]c(-c3ccc(C(C)(C)C)cc3)nc2C(=O)Nc2nccs2)cc1

Procedure:
5-(4-Aminophenyl)-2-(4-tert-butylphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (0.5 g) obtained in Example 77 was refluxed in triethyl orthoformate overnight and concentrated. Thereto were added ethanol and tetrahydrof uran, and sodium borohydride (0.4 g) was added. The mixture was refluxed under heating for 2 hr. After refluxing, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with saturated brine and dried. After drying, the residue was concentrated to give 2-(4-tert-butylphenyl)-5-(4-methylaminophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (0.5 g). This was converted to hydrochloride to give 2-(4-tert-butylphenyl)-5-(4-methylaminophenyl)-N-(2-thiazolyl) imidazole-4-carboxamide hydrochloride (0.24 g), melting point 257-259° C. (decomposition).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][CH2:15][C:16]1[N:17]2[CH:23]=[N:22][CH:21]=[C:18]2[S:19][CH:20]=1.[CH2:24]([O:27][C:28]([NH:30][S:31]([NH2:34])(=[O:33])=[O:32])=[O:29])[CH:25]=[CH2:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.O1CCCC1>[CH2:24]([O:27][C:28]([N:30]([CH2:14][CH2:15][C:16]1[N:17]2[CH:23]=[N:22][CH:21]=[C:18]2[S:19][CH:20]=1)[S:31]([NH2:34])(=[O:33])=[O:32])=[O:29])[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)NS(N)(=O)=O
Reactant: OCCc1csc2cncn12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCOC(=O)N(CCc1csc2cncn12)S(N)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
Under an argon atmosphere at -38° C., 0.77 ml of diethyl azodicarboxylate was added dropwise to 10 ml of an anhydrous tetrahydrofuran solution containing 550 mg of 3-(2-hydroxyethyl)imidazo[5,1-b]thiazole, 884 mg of N-allyloxycarbonyl-N-aminosulfonylamine and 1286 mg of triphenylphosphine, and the mixture was then stirred at -38° C. to -32° C. for 30 minutes and further stirred for 10 minutes while the solution was heated up to 0° C. The solvent was evaporated under reduced pressure to obtain an oil, and this oil was then dissolved in 50 ml of dichloromethane. Further, extraction was carried out with 2N hydrochloric acid (20 ml×2), and the combined aqueous layer was then washed with 10 ml of dichloromethane. Afterward, the solution was adjusted to pH 9 with anhydrous potassium carbonate, and then subjected to extraction with dichloromethane (30 ml×2). The dichloromethane extract was dried (anhydrous magnesium sulfate:anhydrous potassium carbonate=1:1) and then filtered, and the solvent was evaporated under reduced pressure. Afterward, the resulting oil was purified by a silica gel column chromatograph to obtain 548 mg of the title compound as a milky white amorphous.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].Cl[CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22]>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:21]([CH:20]=[CH2:19])(=[O:23])=[O:22])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: O=S(=O)(Cl)CCCl
Agent: Cl
Product: C=CS(=O)(=O)N[C@H]1CCN(Cc2cccc(C#N)c2)C1=O

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using 2-chloroethanesulfonyl chloride in place of 6-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography in a gradient of 10% EtOAc/CH2Cl2 to 40% EtOAc/CH2Cl2 to afford the title compound as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:29][N:30]([CH3:45])[C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][CH:35]=[C:36]2[S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:29][N:30]([CH3:45])[C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][CH:35]=[C:36]2[S:41]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1)(=[O:43])=[O:42]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cccc2c(S(=O)(=O)N3CCC(NC(=O)Nc4ccc(OC(F)(F)F)cc4)CC3)cccc12

Procedure:
Intermediate 42 (200 mg, 0.7 mmol) was dissolved in DCM (7 mL) and triethylamine (100 μL, 0.7 mmol) added followed by 5-(dimethylamino)-1-naphthalenesulfonyl chloride (207 mg, 0.77 mmol). The reaction was evaporated, reconstituted in EtOAc and washed with 1N HCl and 1N K2CO3. Flash chromatography eluted with 2:1 EtOAc:hexanes afforded compound 59 (338 mg, 93%) as a tan solid: Mp 102-107° C. 1H NMR (500 MHz, DMSO-d6□ 8.52 (d, J=8.5 Hz, 1H), 8.45 (s, 1H), 8.28 (d, J=8.7 Hz, 1H), 8.14 (d, J=7.3 Hz, 1H), 7.67 (t, J=7.5 Hz, 1H), 7.62 (t, J=8.1 Hz, 1H), 7.43 (d, J=9.1 Hz, 2H), 7.28 (d, J=7.5 Hz, 1H), 7.19 (d, J=8.7 Hz, 2H), 6.24 (d, J=7.5 Hz, 1H), 3.60-3.53 (m, 3H), 2.88 (t, J=10.5 Hz, 2H, obscured by s δ 2.84), 2.84 (s, 6H), 1.84 (dd, J=12.9, 3.0 Hz, 2H), 1.38 (dq, J=10.6, 3.6 Hz, 2H). Purity 97%. HRMS calculated for C25H27F3N4O4S+H+ 537.1783. found (ESI(+), [M+H]) 537.1785.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27](=[O:33])[N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27](=[O:33])[N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:17]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCC(=O)N3CCCC3)ncc2[N+](=O)[O-])CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CNc2nc(NCC(=O)N3CCCC3)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
(4-{[5-Nitro-2-(2-oxo-2-pyrrolidin-1-yl-ethylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester (19 mg, 0.04 mmol) was dissolved in CH2Cl2 (5 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The solution was treated with saturated NaHCO3 and the organic phase was separated. The aqueous phase was extracted with CH2Cl2 and the combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 10:1:0.3 CH2Cl2:MeOH:Et3N as an eluant to afford 13 mg of the title compound as a light yellow solid (83%), m/z 376.3 [M−1]+.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1>ClCCl>[CH3:1][NH:2][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: ClCCl
Product: CNc1ccc([N+](=O)[O-])cn1
Yield: 80 %

Procedure:
Methylamine gas was bubbled through a stirred solution of 2-chloro-5-nitropyridine (4 g, 25.2 mmol) in dichloromethane (60 mL), at room temperature, until saturation had occurred. The resulting yellow precipitate was then filtered off, washed with dichloromethane and dried under vacuum to afford the title compound as a yellow solid in 80% yield, 3.07 g.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([C:32]1[CH:33]=[CH:34][C:35]2[C:36]([CH:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)=[C:37]3[C:43]4[CH:44]=[CH:45][C:46]([O:48][CH3:49])=[CH:47][C:42]=4[CH:41]=[C:40]([C:50]([OH:52])=O)[CH2:39][N:38]3[C:53]=2[CH:54]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.Cl.[CH3:63][N:64]1[CH2:70][CH:69]2[NH:71][CH:66]([CH2:67][CH2:68]2)[CH2:65]1>CN(C=O)C.O>[CH:55]1([C:36]2[C:35]3[CH:34]=[CH:33][C:32]([C:30]([O:29][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:31])=[CH:54][C:53]=3[N:38]3[CH2:39][C:40]([C:50]([N:71]4[CH:66]5[CH2:67][CH2:68][CH:69]4[CH2:70][N:64]([CH3:63])[CH2:65]5)=[O:52])=[CH:41][C:42]4[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=4[C:37]=23)[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]1
Reactant: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Reactant: CN1CC2CCC(C1)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)C=C(C(=O)N1C3CCC1CN(C)C3)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
HATU (680 mg, 1.8 mmol) was added to a stirring solution of 10-(tert-butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (670 mg, 1.37 mmol) and 3-methyl-3,8-diazabicyclo[3.2.1]octane di HCl salt (560 mg, 2.81 mmol) in DMF (6 mL) and TEA (1.2 mL, 8.2 mmol) and the reaction was stirred for 30 min (complete by LCMS). The reaction mixture was diluted with water (˜35 mL) (precipitate formed) and stirred ON. The precipitate was collected by filtration, flushed with water and dried under high vacuum at 55° C. to yield tert-butyl 13-cyclohexyl-3-methoxy-6-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (775 mg, 1.30 mmol, 95% yield) as a light yellow solid. The material was used without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 1.14-3.95 (m, 24H), 1.59 (s, 9H), 3.86 (s, 3H), 4.21-5.26 (m, 2H), 6.82 (s, 1H), 6.88 (d, J=2.6 Hz, 1H), 7.01 (dd, J=8.8, 2.6 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.66 (dd, J=8.4, 1.1 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 8.02 (br s, 1H). LC-MS retention time: 3.72 min; m/z 596 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 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 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:31]([N:33]1[CH2:37][CH:36]([CH2:38]O)[CH2:35][S:34]1(=[O:41])=[O:40])[CH3:32].CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:31]([N:33]1[CH2:37][CH:36]([CH2:38][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH2:35][S:34]1(=[O:41])=[O:40])[CH3:32]
Reactant: CCN1CC(CO)CS1(=O)=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1CC(CN2C(=O)c3ccccc3C2=O)CS1(=O)=O
Temperature: 25 °C

Procedure:
To a stirred solution of phthalimide (133 mg, 1 equiv) in tetrahydrofuran (4.5 ml) was added triphenylphosphine (237 mg, 1 equiv) and (2-Ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-yl)-methanol (0.905 mmol). This solution was cooled down to 0° C. for the dropwise addition of diisopropylazodicarboxylate (0.18 ml, 1 equiv). The reaction mixture was stirred at room temperature over the weekend. It was then concentrated, and stirred in diethyl ether for 5 hours. Volatiles were removed in vacuo. Flash chromatography eluting with cyclohexane/ethyl acetate (7/3) afforded 261 mg (0.85 mmol, 94%). LCMS (Method E) 1.40 min, M+H 309. 1H-NMR (CDCl3, 400 MHz): 7.93-7.84 (m, 2H), 7.83-7.72 (m, 2H), 3.89 (dd, 2H), 3.41-3.23 (m, 2H), 3.17-2.98 (m, 5H), 1.22 (t, 3H).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19][OH:20])[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:22])([CH3:21])[N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19][O:20][S:31]([CH3:30])(=[O:33])=[O:32])[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:22])([CH3:21])[N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CO)no3)cc2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(COS(C)(=O)=O)no3)cc2)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
A methylene chloride solution (20 ml) of (4S,5R)-tert-butyl 4-(fluoromethyl)-5-(4-(3-(hydroxymethyl)isoxazol-5-yl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate (876 mg, 2.16 mmol) is cooled to 0° C. and methanesulfonyl chloride (250 mg, 2.16 mmol) is added followed by diisopropylethylamine (278 mg, 2.16 mmol). The reaction is stirred for one hour at 0° C. The reaction is diluted with methylene chloride (20 ml) and washed with water (2×10 ml). The organic phase is dried over sodium sulfate and concentrated to give the title compound (987 mg): m/z (Cl) 485 ([M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[CH:24]=[C:23]([CH3:25])[S:22][CH:21]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:26])[N:3]=1.B([C:30]1[CH:41]=[CH:40][C:33]([CH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[NH2:36])=[CH:32][CH:31]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[NH2:36][C@@H:35]([CH2:34][C:33]1[CH:40]=[CH:41][C:30]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH:24]=[C:23]([CH3:25])[S:22][CH:21]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:26])[N:3]=2)=[CH:31][CH:32]=1)[C:37]([OH:39])=[O:38]
Reactant: Cc1cc(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)cs1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(-c2ccccc2C(Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)cs1
Temperature: 150 °C
Yield: 25.5 %

Procedure:
In a microwave vial, 4-chloro-6-{2,2,2-trifluoro-1-[2-(5-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-2-ylamine (30 mg, 0.075 mmol), 4-borono-L-phenylalanine (19 mg, 0.09 mmol), 1 ml of actonitrile and 0.7 ml of water were mixed. 0.3 ml of 1N aqueous sodium carbonate was added to the mixture, followed by 5 mole percent of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep-LC to give 10.1 mg of (S)-2-Amino-3-(4-{2-amino-6-[2,2,2-trifluro-1-(2-(5-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (400 MHz, CD3OD) δ (ppm) 7.83(d, J=8.4 Hz, 2H), 7.63(d, J=7.2 Hz, 1H), 7.34(m, 4H), 7.26(m, 1H), 7.12(d, J=1.2 Hz, 1H), 6.92(q, J=6.8, 1H), 6.82(d, J=1.2 Hz, 1H), 6.64(s, 1H), 4.21(t, J=5.6 Hz, 1H), 3.29(m, 1H), 3.20(m, 1H), 2.47(s, 3H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:15](N(OC)C)=[O:16])=[CH:9][CH:8]=1>C1COCC1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[C:15](=[O:16])[CH2:1][CH2:2][CH3:3])=[CH:11][CH:12]=1
Reactant: CON(C)C(=O)C(Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
A solution of propylmagnesium bromide (29.7 g, 201.6 mmol, 3.0 equiv) in THF (200 mL) was added dropwise with stirring at 0° C. to a solution of the carbamate (26 g, 66.5 mmol, 1.0 equiv) in THF (200 mL). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of aqueous NH4Cl (200 mL). The resulting solution was extracted with EtOAc and the organic layers combined. The resulting mixture was washed with saturated NaHCO3 (200 mL) and saturated aqueous NaCl (200 mL), then dried over anhydrous MgSO4. The residue was applied onto a silica gel column with petroleum ether/EtOAc (5:1) to yield t-butyl 1-(4-bromophenyl)-3-oxohexan-2-ylcarbamate (14 g) as a white solid.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[C:12](/[CH3:28])=[CH:13]/[CH:14]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH:31]=1>>[C:22]1([C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[C:12](\[CH3:28])/[C:11]([NH:40][CH2:39][CH2:38][CH2:37][CH2:36][C:32]2[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=2)=[O:10])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C/C(=C\C=C(c1ccccc1)c1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCc1cccnc1
Product: C/C(=C\C=C(c1ccccc1)c1ccccc1)C(=O)NCCCCc1cccnc1
Yield: 86.3 %

Procedure:
As in Example 134, (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid 4-nitrophenyl ester (1.6 g) was reacted with 3-pyridinebutanamine (0.63 g) for 18 hours at 25° C. The crude amide obtained from the usual work up was purified by HPLC (ethyl acetate) and then crystallized from ether to provide 1.42 g of (E)-5,5-diphenyl-2-methyl-N-[4-(3-pyridinyl)butyl]2,4-pentadienamide mp 93°-94° C. Anal. Calculated for C27H28N2O: C, 81.78; H, 7.12; N, 7.06 Found: C, 81.74; H, 7.02; N, 7.01.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8](Cl)=[N:7][C:6]=12.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.N#N>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:7][C:6]=12
Reactant: Clc1ccn2ncc(Br)c2n1
Reactant: C1CNCCN1
Agent: N#N
Solvent: CCOC(C)=O
Product: Brc1cnn2ccc(N3CCNCC3)nc12
Temperature: 120 °C
Yield: 86.2 %

Procedure:
3-Bromo-5-chloro-pyrazolo[1,5-a]pyrimidine (15.4 g, 66.2 mmol) and piperazine [110-85-0] (56.8 g, 659.5 mmol) were ground together in a mortar to an intimate mixture and transferred to a 250 mL round bottomed flask containing a magnetic stir bar. The flask was fitted to a reflux condenser, N2 blanketed, and the reaction pot immersed in an ambient temperature oil bath. While the neat solid mixture stirred, the bath was heated to 120° C. over 0.5 h and held at nominal temperature for a total of 2 h. The bath was removed and the molten reaction allowed to cool to approximately 75° C. Ethyl acetate was cautiously added down the condenser to dissolve the reaction product to prevent its setting up into a solid mass. The reaction solution was transferred to a separatory funnel, further diluted with ethyl acetate, and washed with water. The ethyl acetate extract was dried (MgSO4) and evaporated to obtain 16.1 g of clear yellow oil. The oil was crystallized from methanol to provide 15.8 g of light yellow crystalline powder in two crops, mp. 108-109° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.51 (s, 1 H) 3.16-3.24 (m, 3 H) 3.38 (s, 1 H) 3.93-4.00 (m, 3 H) 6.85 (d, J=7.83 Hz, 1 H) 8.03 (s, 1 H) 8.78 (d, J=8.08 Hz, 1 H) 9.61 (br. s., 1 H). 13C NMR (100 MHz, DMSO-d6) δ ppm 41.25, 42.16, 77.73, 97.78, 136.77, 144.01, 144.18, 155.53. LRMS (ESI) m/z 282.0/284.0 [(M+H)]+, calc'd for C10H12BrN5: 282.14.
Reaction SMILES: BrC1C=CC=C[C:3]=1[C:8]1([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[O:12][CH:11]([CH3:13])[CH2:10][O:9]1.[OH:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:8]1([CH2:3][O:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[O:12][CH:11]([CH3:13])[CH2:10][O:9]1
Reactant: CC1COC(c2ccc(Cl)cc2Cl)(c2ccccc2Br)O1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC1COC(COc2cccnc2)(c2ccc(Cl)cc2Cl)O1
Reaction time: 18 h

Procedure:
A mixture of 2-(bromophenyl)-2-(2,4-dichlorophenyl)-4-methyl-1,3-dioxolane (10 g.), 3-hydroxypyridine (3.8 g.) and potassium carbonate (5.5 g.) in N,N-dimethylacetamide (90 ml.) was refluxed with stirring for 18 hours. After the mixture was allowed to cool, it was poured into water and extracted with toluene. The toluene fraction, thereby obtained, was washed with 5% aqueous sodium hydroxide and evaporated to yield 3-[[2-(2,4-dichlorophenyl)-4-methyl-1,3-dioxolan-2-yl]methoxy]pyridine as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:24]=[CH:23][C:11]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=3)=[CH:10][CH:9]=2)[N:7]=1.CC([O-])(C)C.[K+].[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]=1[C:41]([F:44])([F:43])[F:42]>CN(C=O)C>[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:1][C:2]2[N:3]=[N:4][CH:5]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([O:12][C:13]4[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=4)=[CH:23][CH:24]=3)[N:7]=2)=[O:37])=[CH:34][C:33]=1[C:41]([F:42])([F:43])[F:44]
Reactant: CNC(=O)c1cc(Oc2ccc(-c3cnnc(N)n3)cc2)ccn1
Reactant: O=C(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(-c3cnnc(NC(=O)c4ccc(Cl)c(C(F)(F)F)c4)n3)cc2)ccn1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
108.6 mg (0.337 mmol, 1.0 eq) of 4-[4-(3-amino-[1,2,4]triazin-5-yl)-phenoxy]-N-methylpyridine-2-carboxamide can be dissolved in 2 mL of anhydrous DMF with heating to about 100° C. 45.4 mg (0.405 mmol, 1.2 equivalent) of solid t-BuOK can be added to the solution, followed by 0.405 mmol (1.2 equivalent) of 4-chloro-3-trifluoromethylbenzoyl chloride. It can be allowed to stir at ambient temperature for 1-2 hours. The product can be isolated by a number of methods known to those skilled in the art, such as precipitation or by extraction with a number of solvents, such as ethyl acetate, methylene chloride or diethyl ether or by silica gel column chromatography, or by reverse-phase prep-HPLC chromatography.