Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Si:13]([O:20][CH2:21][C:22]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:23]=1[S:24][C:25]1[C:26]([CH2:37]O)=[CH:27][CH:28]=[CH:29][C:30]=1[N:31]2[CH3:36])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Si:13]([O:20][CH2:21][C:22]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:23]=1[S:24][C:25]1[C:26]([CH2:37][N:43]3[C:39](=[O:49])[C:40]4[C:41](=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:42]3=[O:44])=[CH:27][CH:28]=[CH:29][C:30]=1[N:31]2[CH3:36])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CN1c2cccc(CO)c2Sc2c(CO[Si](C)(C)C(C)(C)C)cccc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1c2cccc(CO[Si](C)(C)C(C)(C)C)c2Sc2c(CN3C(=O)c4ccccc4C3=O)cccc21
Reaction time: 3 h
Yield: 78.2 %

Procedure:
1.62 ml (10.34 mmol) of diethyl azodicarboxylate were slowly added dropwise while cooling with ice and under argon to a solution of 3.09 g (7.97 mmol) of [6-(tert-butyl-dimethylsilanyloxymethyl)-10-methyl-phenothiazin-4-yl]-methanol, 1.76 g (11.9 mmol) of phthalimide and 2.30 g (8.75 mmol) of triphenylphosphine in 65 ml of tetrahydrofuran. The reaction mixture was stirred at 0° for 3 hours and then worked-up analogously to that described in Example 2.1.1.ea. The residue was chromatographed on 500 g of silica gel with toluene/ethyl acetate (19:1), whereupon, after crystallization from ethanol/ethyl acetate, 3.22 g (78.2%) of 2-[6-(tert-butyl-dimethylsilanyloxymethyl)-10-methyl-phenothiazin-4-ylmethyl]-2,3-dihydro-1H-isoindole-1,3-dione were obtained as a light yellow solid of m.p. 195°-196°.
Reaction SMILES: [Cl:1][C:2]([Cl:26])=[CH:3][CH2:4][O:5][C:6]1[CH:23]=[C:22]([Cl:24])[C:9]([O:10][CH2:11][CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O)=[C:8]([Cl:25])[CH:7]=1.Cl>C(OCC)C>[ClH:1].[Cl:26][C:2]([Cl:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([Cl:25])[C:9]([O:10][CH2:11][CH2:12][CH2:13][NH2:14])=[C:22]([Cl:24])[CH:23]=1
Reactant: CC(C)(C)OC(=O)NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Solvent: CCOCC
Product: NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
A stirred solution of 2.6 grams (0.0058 mole) of N-{3-[4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenoxy]propyl}(tert-butoxy)carboxamide in 10 mL of anhydrous diethyl ether was cooled to 0° C. and a 2N solution of hydrogen chloride in diethyl ether was added via a syringe. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred during an 18-hour period. A resultant solid precipitate was collected by filtration, yielding when dried, 1.25 grams of the subject compound. The filtrate was taken up in hexanes and allowed to stand during an 18-hour period, during which time a second crop of the subject compound precipitated from the filtrate. The precipitate was collected by filtration and dried, yielding an additional 0.83 gram of the subject compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])Cl.[CH2:13]([O:15][C:16](=[O:20])[C:17]#[C:18][CH3:19])[CH3:14].C(N(CC)CC)C>C(OCC)C>[CH2:13]([O:15][C:16]([C:17]1[C:4]([C:3]2[CH:8]=[CH:9][C:10]([Br:12])=[CH:11][C:2]=2[F:1])=[N:6][O:7][C:18]=1[CH3:19])=[O:20])[CH3:14]
Reactant: ON=C(Cl)c1ccc(Br)cc1F
Reactant: CC#CC(=O)OCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2ccc(Br)cc2F)noc1C
Yield: 83.1 %

Procedure:
In a fashion similar to that described for preparation 15, 2-fluoro-4-bromo-benzoyl chloride oxime (2.00 g, 7.92 mmol), ethyl-2-butynoate (1.33 g, 11.9 mmol), triethylamine (2.2 ml, 15.8 mmol) in diethyl ether (10 ml), and diethyl ether (20 ml) gave 4-ethoxycarbonyl-5-methyl-3-(2-fluoro-4-bromophenyl)isoxazole (2.16 g, 83%) after column chromatography (silica gel, hexanes/diethyl ether gradient). 1H NMR (400 MHz, CDCl3) δ 7.36-7.29 (m, 3H), 4.16 (q, 2H, J=6.8 Hz), 2.70 (s, 3H), 1.15 (t, 3H, J=6.9 Hz)ppm.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:20]([NH:22][CH2:23][C:24]([N:26]([CH2:42][CH3:43])[C@H:27]([C:35]([NH:37][NH:38][C:39]([CH3:41])=[O:40])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])=[O:21])[CH2:15][CH2:16][S:17]([CH3:19])=[O:18])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.NCC(O)=O.N[C@H](C(O)=O)CCSC.N[C@H](C(O)=O)CC1C=CC(O)=CC=1>>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:20]([NH:22][CH2:23][C:24]([N:26]([CH2:42][CH3:43])[C@H:27]([C:35]([NH:37][NH:38][C:39]([CH3:41])=[O:40])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])=[O:21])[CH2:15][CH2:16][S:17]([CH3:19])=[O:18])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CCN(C(=O)CNC(=O)[C@@H](CCS(C)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(C)=O
Agent: CSCC[C@H](N)C(=O)O
Agent: NCC(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCN(C(=O)CNC(=O)[C@@H](CCS(C)=O)NC(=O)[C@@H](N)Cc1ccc(O)cc1)[C@@H](Cc1ccccc1)C(=O)NNC(C)=O
Reaction time: 0.17 h

Procedure:
To 0.20 g of BOC-Tyr-(D)-Met(O)-Gly-EtPhe-NHNHCOCH3 were added 0.2 ml of anisole and 4 ml of TFA, and the mixture was shaken for 10 minutes. Then, the solvent was distilled off and ether was added to the residue of thereby recover by filtration the product in the form of powder. The product was subjected to ion exchange with Amberlite IRA 410 (acetic acid type) and then poured on a column (2.2×120 cm) of Sephadex LH-20. The elution was conducted with 0.1 N acetic acid, and the fractions of 285 to 340 ml were collected and lyophilized. Yield: 0.14 g, [α]D24 +20.4° (c=0.50, MeOH), Rf2 0.22. Amino acid analysis (4% thioglycolic acid/6 N hydrochloric acid hydrolysis): Gly 0.99(1), Met 1.00(1), Tyr 1.04(1).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:18]=[C:17]4[N:19]([C:24]5[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=5[F:31])[C:20](=[O:23])[NH:21][CH2:22][C:16]4=[C:15](Cl)[N:14]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C(=O)([O-])[O-].[K+].[K+].[F:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:65])[C:49]2[CH:54]=[CH:53][C:52]([CH3:55])=[C:51](B3OC(C)(C)C(C)(C)O3)[CH:50]=2)=[CH:43][CH:42]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:14]=[C:15]([C:51]4[CH:50]=[C:49]([CH:54]=[CH:53][C:52]=4[CH3:55])[C:48]([NH:47][C:44]4[CH:45]=[CH:46][C:41]([F:40])=[CH:42][CH:43]=4)=[O:65])[C:16]4[CH2:22][NH:21][C:20](=[O:23])[N:19]([C:24]5[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=5[F:31])[C:17]=4[N:18]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1NCc2c(Cl)nc(N3CCC(N4CCCCC4)CC3)nc2N1c1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N2CCC(N3CCCCC3)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 49.6 %

Procedure:
To a solution of compound 7-(1,4′-bipiperidin-1′-yl)-5-chloro-1-(2,6-difluorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (18 mg, 0.04 mmol) in dioxane (1.5 mL)/water (0.5 mL) were added potassium carbonate (34 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium(0) (2.3 mg, 0.002 mmol) and N-(4-fluorophenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (22 mg, 0.062 mmol). The reaction mixture was bubbled with N2 for 5 mins, then microwaved at 150° C. for 30 mins. The reaction mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH [7]+NH4OH[3]) provided the title compound as a white solid (13 mg, 51%). LC-MS m/z 656 (M+H)+; 1H-NMR (MeOD) δ 1.37 (m, 2H), 1.48 (m, 2H), 1.60 (m, 4H), 1.80 (m, 2H), 2.33 (s, 3H), 2.56 (m, 5H), 2.72 (t, 2H), 4.17 (m, 2H), 4.46 (m, 2H), 7.12 (m, 4H), 7.52 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].O.Cl.[CH2:10]([N:17]1[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CS(C)=O>[CH2:10]([N:17]1[CH2:22][CH2:21][CH2:20][C:19]2([O:23][CH2:2]2)[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: C[S+](C)C
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CN2CCCC3(CO3)C2)cc1

Procedure:
Trimethylsulfonium iodide (2.13 g, 10.4 mmol) in DMSO (15 mL) was added to NaH (0.4907 g, 20.4 mmol) in DMSO (70 mL). 1-benzyl-3-piperidone hydrochloride hydrate (109) (0.996 g, 4.41 mmol) was taken up in DMSO (15 mL) and was added to the reaction mixture at room temperature. When the reaction was judged complete by TLC (0.5 h), the reaction was poured over ice and the product was extracted with CH2Cl2. The organics were washed with H2O, dried over sodium sulfate, filtered and concentrated in vacuo. Purification with alumina gel chromatography (900:100:3 CH2Cl2:Hexanes:2 N NH3 in EtOH) provided pure 5-benzyl-1-oxa-5-azaspiro[2,5]octane (110). 13C NMR (CDCl3): 137.54, 128.69, 127.83, 126.67, 62.55, 59.28, 53.32, 52.96, 52.48, 30.90, 23.51 ppm.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Reactant: C1CCNC1
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCCC1
Yield: 5.7 %

Procedure:
1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 72A (200 mg, 0.368 mmol) and pyrrolidine (91 μL 1.104 mmol) were reacted in the manner described in Example 73 to yield 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea (12 mg, 6%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.85 (s, 1H), 8.30 (s, 1H), 7.25 (m, 2H), 7.35-7.00 (m, 4H), 6.45 (s, 1H), 4.20 (m, 2H), 3.85 (m, 7H), 3.15 (m, 2H), 2.20-1.85 (m, 6H), 1.30 (s, 9H); LC-MS (ESI) m/z 577 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O.C1C(=O)N([Br:41])C(=O)C1.CCOCC>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]=1[Br:41])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2ccc(C#N)cc2c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2ccc(C#N)cc2c1Br
Temperature: -60 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
A solution of 15 (137 mg, 0.366 mmol) in freshly distilled THF (7.3 mL) and cooled to -78° C. under Ar was treated with 10 μL of a 1 μL/mL solution of H2SO4 in THF and the solution was stirred for 20 min before the addition of NBS (78 mg, 439 mmol, 1.2 equiv). The reaction mixture was allowed to warm to -60° C. and was stirred for 4 h at which time the reaction was complete by TLC. Et2O (7.3 mL) was added and the resulting organic phase was washed with 5% aqueous NaHCO3 (1×10 mL), saturated aqueous NaCl (1×10 mL), dried (MgSO4), and concentrated in vacuo. Chromatography (SiO2, 2×20 cm, 10% EtOAc-hexane) afforded 16 (145 mg, 166 mg theoretical, 87%) as a white crystalline solid: mp 179° C. dec (white needles, 10% EtOAc-hexane); 1H NMR (CDCl3, 250 MHz) δ8.40 (s, 1H, C8-H), 8.26 (d, 1H, J=8.5 Hz), 8.23 (s 1H, C3-H), 7.5-7.3 (m, 6H), 5.23 (s, 2H), 1.58 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ154.4, 152.4, 137.0, 136.0, 132.2, 132.0, 128.7, 128.6, 128.4, 128.0, 124.9, 124.8, 124.2, 119.1, 111.9, 102.0, 81.9, 70.8, 28.3; IR (KBr) vmax 3416, 2978, 2230, 1738, 1623, 1603, 1570, 1498, 1405, 1364, 1335, 1229, 1158, 990, 970, 878, 850, 823, 758, 696 cm-1 ; FABHRMS (NBA-CsI) m/z 584.9793 (M+ +Cs, C23H21BrN2O3 requires 584.9790).
Reaction SMILES: [K].[S:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:12]>CC(C)=O>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11](=[O:12])[CH2:10][N:4]2[C:5](=[O:7])[CH2:6][S:2][C:3]2=[O:8])=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: O=C1CSC(=O)N1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: [K]
Solvent: CC(C)=O
Product: O=C(CN1C(=O)CSC1=O)c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A little at a time, 1.3 g (8.4 mmol) of 1,3-thiazolidine-2,4-dione potassium salt were added to a solution of 2.0 g (8.2 mmol) of 2-bromo-1-(4-nitrophenyl)ethanone in 80 ml of acetone, and the mixture was stirred at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water/dichloromethane. After phase separation, the organic phase was dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. Yield: 2.3 g (98% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10]O)[CH2:7][C:6]=2[CH:12]=1.N1C=CC=CC=1.S(Cl)([Cl:21])=O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][Cl:21])[CH2:7][C:6]=2[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCC1Cc2cc(Cl)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: ClCC1Cc2cc(Cl)ccc2O1
Temperature: 80 °C
Reaction time: 7 h
Yield: 46.2 %

Procedure:
To a solution of (5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol (3 g, 16 mmol) in benzene (50 ml) was added pyridine (1.55 g, 19.6 mmol, 1.2 eq) and thionyl chloride (2.72 g, 23.0 mmol) dropwise with stirring at 0° C. for 7 hours at 80° C. in an oil bath. The reaction mixture was adjusted to ˜pH 8 with aqueous sodium bicarbonate and then extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 3% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 5-chloro-2-(chloromethyl)-2,3-dihydro-1-benzofuran as an off-white solid (1.5 g, 46%); 1H NMR (300 MHz, CDCl3): δ 7.06-7.14 (m, 2H), 6.70 (d, J=8.4 Hz, 1H), 4.99-5.10 (m, 1H), 3.64-3.76 (m, 2H), 3.32-3.40 (dd, J=9.3 Hz, 16.2 Hz, 1H), 3.09-3.17 (dd, J=6.6 Hz, 16.2 Hz. 1H).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][CH:11]([OH:18])[CH2:12][C:13]([CH3:17])([O:15][OH:16])[CH3:14]>C(N(CC)CC)C.CCOCC>[CH:1]1([NH:7][C:8](=[O:9])[O:18][CH:11]([CH3:10])[CH2:12][C:13]([CH3:17])([O:15][O:16][C:8](=[O:9])[NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCCC1
Reactant: CC(O)CC(C)(C)OO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(CC(C)(C)OOC(=O)NC1CCCCC1)OC(=O)NC1CCCCC1
Reaction time: 48 h
Yield: 39 %

Procedure:
A mixture of 18.7 g. (0.15 mole) of cyclohexyl isocyanate, 6.7 g. (0.05 mole) of 1,3-dimethyl-3-hydroperoxybutyl alcohol and 3 drops of triethylamine was stirred for five days at ambient temperature. The reaction vessel was protected with a calcium chloride tube to keep out moisture. Within two days, a solid began to appear, and after the five day stirring period the reaction mixture was stripped in vacuo. The residue was slurried in 100 ml of ether and filtered. The filter cake was washed with an additional 30 ml of ether and air dried. A total of 7.5 grams of a colorless solid was obtained.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([N:23]([CH2:35][CH3:36])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]1)[CH3:22]>>[CH2:35]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH3:36]
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CCN(CC)CCOCCC1CCCCN1
Product: CCN(CC)CCOCCC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 44 %

Procedure:
Prepared analogously to Example 1 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6- one and 2-[2-[2-(diethylamino)ethoxy]ethyl]piperidine (Bp.0.4 mmHg 95°-99° C.) in a yield of 44% of theory.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:19])[CH:6]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([O:9][CH3:10])=[O:8].[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[N+:36]([O-:38])=[O:37])[CH2:31]I)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCC.CN(C=O)C.O>[CH3:3][O:4][C:5](=[O:19])[C:6]([CH2:31][C:30]1[CH:33]=[CH:34][C:35]([N+:36]([O-:38])=[O:37])=[C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:29]=1)([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])c1ccc(CI)cc1OCc1ccccc1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Sodium hydride (60% in mineral oil, 729 mg, 18.22 mmol) is washed twice with dry hexane and suspended in DMF (15 mL). To the suspension is added dropwise a solution of t-butoxycarbonylamino-malonic acid dimethyl ester (4.92 g, 19.9 mmol) in DMF (15 mL) over a period of 10 min. The mixture is stirred at RT for 40 min and a solution of the title D compound, 3-benzyloxy-4-nitro-benzyl iodide (6.23 g, 16.9 mmol) in DMF (15 mL) is added dropwise over a period of 10 min and the mixture is stirred at RT overnight. The mixture is diluted with water (200 mL) and extracted 3 times with EtOAc. The organic extracts are washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated. The residue is crystallized from ether-hexane to give 2-(3-benzyloxy-4-nitro-benzyl)-2-t-butoxycarbonylamino-malonic acid dimethyl ester: mp=114-116° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[CH:30]=[CH:31][C:32]([C:35]([OH:37])=[O:36])=[N:33][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([OH:37])=[O:36])=[N:33][CH:34]=2)[CH:5]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][N:19]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(=O)O)nc2)c1
Temperature: 130 °C

Procedure:
A mixture of N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (6.5 g, 17.1 mmol), 5-bromopyridine-2-carboxylic acid (3.92 g, 19.4 mmol), aqueous sodium carbonate (2M, 17.1 mL, 34.3 mmol) in dioxanes (57.1 mL) was flushed and purged with Ar(g) (3×). PdCl2(dppf)-dichloromethane adduct (646 mg, 0.791 mmol) was then added to the reaction mixture and heated at 130° C. for 10 hours. Upon cooling, the reaction mixture was filtered through a CELITE pad and washed with dioxane. The crude reaction mixture was concentrated under reduced pressure and diluted with 90% MeCN and 10% 2M HCl (aq). The crude solid was isolated by filtration and was recrystallized from dichloromethane to yield 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-2-carboxylic acid as an off-white powder. MS APC calc'd for C18H14F3N4O2 [M+H]+ 375. found 375. 1H NMR (500 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.95 (s, 1H), 8.84 (d, J=5.4, 1H), 8.18 (d, J=9.6, 1H), 8.12 (d, J=9.3, 1H), 8.05 (s, 1H), 7.28 (s, 2H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=[O:10])=[C:7]([CH3:11])[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=1.[CH2:21]([O:28][C:29]1[C:30]([C:36]([O:38][CH3:39])=[O:37])=[N:31][C:32](Br)=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].CCCCCC>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([O:28][C:29]1[C:30]([C:36]([O:38][CH3:39])=[O:37])=[N:31][C:32]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([CH:9]=[O:10])[C:7]=2[CH3:11])=[CH:33][CH:34]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1nc(Br)ccc1OCc1ccccc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCCCCC
Product: COC(=O)c1nc(-c2ccc(OC)c(C=O)c2C)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 111.5 %

Procedure:
A suspension of the 6-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde produced in Example 4-1 (1.91 g, 6.92 mmol), methyl 3-(benzyloxy)-6-bromopyridine-2-carboxylate (PCT Int. Appl., 2010080478, 15 Jul. 2010) (2.23 g, 6.92 mmol), sodium carbonate (2.20 g, 20.8 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.40 g, 0.35 mmol) in 1,2-dimethoxyethane (38 ml) and water (17 ml) was prepared at room temperature, and the suspension thus prepared was then stirred at 90° C. for 3 hours. After air-cooling, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (ethyl acetate:hexane=2:3, v/v) to obtain the title compound (3.02 g, yield: 112%).