Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[CH:6]=1.S(=O)(=O)(O)O.[C:18]1(C)C=CC=CC=1>Cl.C(O)C>[CH2:1]([O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[CH:6]=1)[CH3:18]
Reactant: Cc1ccccc1
Reactant: COC(=O)Cc1ccnc(C)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)Cc1ccnc(C)c1
Temperature: 25 °C

Procedure:
The mixture of (2-methyl-pyridin-4-yl)-acetic acid methyl ester and the bis adduct (20 g) was dissolved in concentrated hydrochloric acid and heated to reflux for 1 hour. The solution was cooled, diluted with toluene, and concentrated in vacuo to give the crude acid. The acid was dissolved in ethanol, treated with a catalytic amount of sulfuric acid, and heated to reflux for 3 h. The solution was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium chloride solution. The mixture was filtered and the filtrate concentrated to give 14 g of the title compound as a crude oil. MS(ES): m/e (EI*) 180.1 [M+H]
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][NH2:6])[CH3:3].[C:7]1([N:13]=[C:14]=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[C:7]1([NH:13][C:14]([NH:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN(C)CCN
Solvent: Cc1ccccc1
Product: CN(C)CCNC(=O)Nc1ccccc1

Procedure:
88 g of dimethylaminoethylamine are dissolved in 500 l of toluene and then 119 g of phenyl isocyanate are added dropwise in the course of 10 minutes, whereupon the temperature rises to 97° C. The mixture is refluxed for 4 hours. On cooling, the product crystallises and is filtered with suction. The moist product is recrystallised from 1000 ml of ethyl acetate. Yield: 135 g (65.1%); m.p. 141°-142° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[CH3:25])(O)[CH2:10][C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1.S([O-])(O)(=O)=O.[K+]>C(Cl)Cl>[CH3:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[C:9]([C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[CH:10][C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1
Reactant: Cc1ccc(C(O)(Cc2nnnn2C)c2ccc(C)cc2C)c(C)c1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(C(=Cc2nnnn2C)c2ccc(C)cc2C)c(C)c1
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
A mixture of 1,1-bis(2,4-dimethylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol (1.8 g, 5.4 mmoles) and potassium hydrogen sulfate (100 mg) in a 50 ml flask was placed in an oil bath preheated to 190° C. After 15 minutes, the melt was cooled and methylene chloride added to the residue. The insolubles were removed and the solution evaporated. The residue was crystallized from isopropyl ether to give 1.2 g of the title compound; m.p.=143°-143.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:9]1[N:10]=[CH:11][C:12]([CH:36]2[CH2:38][CH:37]2[C:39]([O:41]CC)=[O:40])=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:28])=[CH:22][CH:21]=2)=[N:18][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO.CCOC(C)=O>[C:47]([O:46][C:44]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[N:10]=[CH:11][C:12]([CH:36]2[CH2:38][CH:37]2[C:39]([OH:41])=[O:40])=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH3:28])=[CH:24][CH:25]=2)=[N:18][N:19]=1)=[O:45])([CH3:48])([CH3:49])[CH3:50]
Reactant: CCOC(=O)C1CC1c1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c2nnc(-c3ccc(CN(C)C(=O)OC(C)(C)C)cc3)o2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1ccc(-c2nnc(-c3nc(C4CC4C(=O)O)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
To a solution of ethyl 2-[5-[bis(tert-butoxycarbonyl)amino]-6-[5-[4-[[tert-butoxycarbonyl(methyl)amino]methyl]phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]cyclopropanecarboxylate (825 mg, 1.2 mmol) in THF:MeOH solvent mixture (3.2 mL:1.6 mL) at room temperature was added aqueous NaOH (594 μL, of 4 M, 2.37 mmol) and reaction mixture was heated at 50° C. for 20 minutes. The reaction mixture was cooled to room temperature and diluted with EtOAc and washed with 1M HCl solution. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to obtain 2-[5-[bis(tert-butoxycarbonyl)amino]-6-[5-[4-[[tert-butoxycarbonyl(methyl)amino]methyl]phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]cyclopropanecarboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.73 (s, 1H), 8.07 (d, J=8.2 Hz, 2H), 7.47 (t, J=6.7 Hz, 2H), 4.49 (s, 2H), 2.83 (s, 5H), 1.91 (s, 2H), 1.49-1.33 (m, 27H). LC/MS m/z 567.6 [M+H]+. (less 1 Boc)
Reaction SMILES: [CH3:1][O:2][Si:3]([C:8]12[CH2:14][CH:11]([CH2:12][CH2:13]1)[CH:10]=[CH:9]2)([O:6][CH3:7])[O:4][CH3:5].C([SiH]([CH2:20][CH3:21])CC)C.[CH2:22](O)[CH3:23]>ClCCl.C1COCC1.C1(C)C=CC=CC=1>[CH2:22]([C:8]12[CH2:14][CH:11]([CH2:12][CH2:13]1)[CH:10]=[CH:9]2)[CH2:23][CH2:20][CH3:21].[CH3:1][O:2][Si:3]([C:8]12[CH2:14][CH:11]([CH2:12][CH2:13]1)[CH:10]=[CH:9]2)([O:4][CH3:5])[O:6][CH3:7]
Reactant: CC[SiH](CC)CC
Reactant: CCO
Agent: CO[Si](OC)(OC)C12C=CC(CC1)C2
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCC12C=CC(CC1)C2
Temperature: 80 °C

Procedure:
BuNB (10.97 g, 0.073 mol), Trimethoxysilyl Norbornene (TMSNB, CAS 7538-46-7) (12.95 g, 0.073 mol), triethyl silane (0.34 g, 2.91E-04 mol), ethanol (0.80 g, 1.75E-03 mol) and toluene (170.0 g) were combined in a 500 mL serum bottle and heated to 80° C. in an oil bath to form a solution. To this solution were injected Pd1446 (0.017 g, 1.16E-05 mol) and DANFABA (0.028 g, 3.49E-5 mol), each in the form of a concentrated solution in dichloromethane. After addition, the resulting mixture was maintained at 80° C. for 4 hours. The copolymer was precipitated by adding methanol drop wise into the vigorously stirred reaction mixture. The precipitated copolymer was collected by filtration and dried in an oven at 60° C. under vacuum. After drying, 15.5 g was obtained (65%). The molecular weight of the copolymer was determined by GPC in THF solvent (polystyrene standard) to be Mw=48,000 and Mn=27,000. The composition of the copolymer was determined by 1H-NMR to be (47/53) BuNB/TMSNB copolymer. The refractive indices of this polymer were measured by prism coupling method and determined to be 1.5093 in TE mode and 1.5089 in TM mode at a wavelength of 633 nm. The dried copolymer was dissolved in sufficient toluene to result in a 30 wt % copolymer solution.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C)C=O.[O:28]([C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[OH:1][C:2]1[C:3]([C:8]([NH:39][C:38]2[CH:37]=[CH:36][C:35]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:41][CH:40]=2)=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1O
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1ncccc1O
Reaction time: 8 h
Yield: 40.5 %

Procedure:
3-Hydroxypicolinic acid (1.39 g, 10.0 mmol) and 1.95 g (12.0 mmol) of carbonyldiimidazole were mixed into anhydrous N,N-dimethylformamide (hereinafter referred to as “DMF”) to prepare a suspension (30 ml). An anhydrous DMF solution (25 ml) of 1.85 g (10.0 mmol) of 4-phenoxyaniline was added dropwise to this suspension, and the reaction was allowed to proceed at room temperature overnight. Water (50 ml) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the dried organic layer was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane) to give 1.24 g (yield 41%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:27])[C@H:7]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[NH:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])[CH3:3].[CH2:28]1[O:30][CH2:29]1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>CC#N>[CH3:4][C:2]([O:5][C:6](=[O:27])[C@H:7]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[N:8]([CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:28][CH2:29][OH:30])([CH3:1])[CH3:3]
Reactant: C1CO1
Reactant: CC(C)(C)OC(=O)CN[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(CCO)[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Temperature: -80 °C
Yield: 77.3 %

Procedure:
In a four-necked flask cooled to −80° C. equipped with a mechanical stirrer, a thermometer, and a jacketed dropping funnel N-[2-(1,1-dimethylethoxy)-2-oxoethyl]-L-tryptophan 1,1-dimethylethyl ester (5 g; 13.35 mmol) was dissolved in CH3CN (25 mL). In the dropping funnel, cooled at −80° C., ethylene oxide (13 mL; 0.26 mol) was collected from the cylinder and then quickly dropped into the solution. Solid ytterbium triflate (0.83 g; 1.34 mmol) was added and after removal of the cooling bath the temperature was allowed to rise to r.t. The reaction was monitored by HPLC (Chromatographic method of Example 3, A)). After 15 h the solution was diluted with H2O (50 mL) and extracted with Et2O (150 mL). After evaporation of the solvent the crude was purified by flash chromatography (silica gel; n-hexane/ethyl acetate, 7:3 v/v) giving the desired product (4.32 g; 10.32 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][CH:11]=[C:10]3[N:14]([CH3:18])[N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[O:28])[CH:21]=1.FC1C=CC(C)=CC=1N=C=O>>[NH2:17][C:16]1[C:9]2[C:10](=[CH:11][N:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:28])=[CH:7][CH:6]=2)[N:14]([CH3:18])[N:15]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: Cn1nc(N)c2c(-c3ccc(N)cc3)cncc21
Agent: Cc1ccc(F)c(N=C=O)c1
Product: Cn1nc(N)c2c(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)cncc21

Procedure:
The title compound was prepared using the procedure described in Example 1E using the product from Example 6A and 1-fluoro-3-isocyanato-benzene instead of the product from Example 1D and 1-fluoro-2-isocyanato-4-methyl-benzene. MS (ESI(+)) m/e 377 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 3.92 (s, 3H) 4.67 (s, 2H) 6.80 (td, J=8.31, 2.37 Hz, 1H) 7.15 (dd, J=8.31, 1.19 Hz, 1H) 7.32 (q, 1H) 7.48 (d, J=8.48 Hz, 2H) 7.53 (t, J=2.37 Hz, 1H) 7.63 (d, J=8.48 Hz, 2H) 7.95 (s, 1H) 8.87 (s, 1H) 8.95 (s, 1H) 8.99 (s, 1H)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:30]([NH:32][NH2:33])=[O:31])[CH2:24][C:25]1[N:29]=[CH:28][NH:27][CH:26]=1)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:35][C@H](P(=O)(O)O)CC(C)C.[NH2:45][C@H:46]([P:51](=[O:54])([OH:53])[OH:52])[CH2:47][CH:48]([CH3:50])[CH3:49].CN1CCOCC1>CN(C)C=O>[N-:35]=[N+:32]=[N-:33].[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:30]([NH:45][C@H:46]([P:51](=[O:53])([OH:52])[OH:54])[CH2:47][CH:48]([CH3:50])[CH3:49])=[O:31])[CH2:24][C:25]1[N:29]=[CH:28][NH:27][CH:26]=1)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](N)P(=O)(O)O
Reactant: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)P(=O)(O)O
Product: [N-]=[N+]=[N-]
Temperature: 4 °C
Reaction time: 264 h

Procedure:
An azide solution was prepared in the same way as in Example 8 using 0.45 g. (1 mmole) of N-benzyloxycarbonyl-L-phenylalanyl-L-histidine hydrazide. To the solution was added 0.20 g. (1 mmole) of 1(R)-amino-3-methylbutylphosphonic acid hemihydrochloride (melting at 267°-269.5°) prepared according to the method of J. R. Chambers and A. F. Isbell [J. Org. Chem., 29, 832 (1964)], followed by 0.11 g. of N-methylmorpholine. The mixture was stirred at 4° C. for 11 days. Insoluble matter was removed by filtration and the filtrate was treated in a conventional manner. There was obtained 0.47 g. of the desired compound as a white powdery solid, melting at 159°-167° C.; [α]22 -15.6° (C=0.5, dimethylformamide).
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1.CN(C)C=O.[CH2:19]([Si:21](Cl)([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:20].N1C=CN=C1>C(OCC)(=O)C>[CH3:12][C:2]([O:13][Si:21]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:19][CH3:20])([CH3:1])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[N:5]1
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC(C)(O)Cn1ccc([N+](=O)[O-])n1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(C)(C)Cn1ccc([N+](=O)[O-])n1
Temperature: 0 °C
Yield: 71.5 %

Procedure:
In a round bottomed flask was placed 2-methyl-1-(3-nitro-pyrazol-1-yl)-propan-2-ol (170 mg, 0.92 mmol) and N,N-dimethylformamide (5 mL) and it was placed in an ice bath and cooled to 0° C. To this stirred solution was added triethylsilyl chloride (169 mL, 1.01 mmol) and imidazole (156 mg, 2.30 mmol) and it was stirred at 0° C. and slowly warmed to 25° C. and stirred for two days. The reaction was then diluted with ethyl acetate (15 mL) and washed with a saturated aqueous brine solution (10 mL). The aqueous layer was then extracted with ethyl acetate (2×15 mL). The organic layers were then combined and dried over sodium sulfate, filtered and concentrated in vacuo. Purification by AnaLogix Intelliflash system (4 g column, 5% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) afforded 1-(2-methyl-2-triethylsilanyloxy-propyl)-3-nitro-1H-pyrazole (197 mg, 72%) as a clear colorless oil: ES-HRMS m/e calcd for C13H25N3O3Si (M+H)+ 300.1738, observed 300.1737; 1H NMR (300 MHz, CDCl3) δ ppm 0.58 (q, J=8.0 Hz, 6H, 3×SiCH2), 0.92 (t, J=8.0 Hz, 9H, 3×CH3), 1.26 (s, 6H, 2×CH3), 4.12 (s, 2H, NCH2), 6.89 (d, J=2.5 Hz, 1H, Ar), 7.56 (d, J=2.5 Hz, 1H, Ar).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]>>[F:29][C:26]([F:27])([F:28])[O:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:15]2[CH:14]=[CH:13][C:12]([S:9](/[CH:8]=[CH:2]/[C:1]([O:5][CH2:6][CH3:7])=[O:4])(=[O:11])=[O:10])=[CH:17][CH:16]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)C=O
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Product: CCOC(=O)/C=C/S(=O)(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared from ethyl glyoxalate and 4-(4′-trifluoromethoxyphenyloxy)-phenyl methyl sulfone following the procedures of Examples 126A, 126B and 75B.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[C:15]([C:10]1([NH:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:14][CH2:13][CH2:12][CH2:11]1)#[N:16]
Reactant: N#CC1(N)CCCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1(C#N)CCCC1
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
To a stirred mixture of 20.2 g (0.2 mole) triethylamine and 200 ml chloroform cooled in an ice bath, 14.7 g (0.1 mole) 1-amino-1-cyanocyclopentane hydrochloride (the product of Example 14) were spooned in over ten minutes to give a red solution. To that mixture, 11.5 g (0.1 mole) methanesulfonyl chloride in 25 ml chloroform were added dropwise over 30 minutes. The reaction mixture was stirred 30 minutes. The reaction mixture was washed with 25 ml concentrated hydrochloric acid which had been diluted to 50 ml with ice water. The layers were phase separated. The organic layer was washed twice with 50 ml ice water, dried over magnesium sulfate and stripped to give 13 g of the above-identified amber oily product.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)=[C:15]([O:29][CH3:30])[CH:14]=1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:30][O:29][C:15]1[CH:14]=[C:13]([CH:11]=[CH2:1])[CH:18]=[CH:17][C:16]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)c1ccc(-c2ccc(C=O)cc2OC)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2ccc(C(=O)OC)cc2)c(OC)c1
Reaction time: 0.5 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (785 mg, 2.2 mmoL) in THF (5 mL) was treated with 1M lithium bis(trimethylsilyl)amide in THF (2.2 mL), stirred for 30 minutes, treated with a solution of Example 122I (540 mg, 2.0 mmol) in THF (2 mL), stirred for 1 hour, and filtered through a pad of silica gel (20 g). The pad was rinsed with 1:1 ether/dichlormethane and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20-50% dichloromethane/hexanes to provide the desired product.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[OH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](O)[CH:10]=[CH:9][N:8]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Cl:3][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([OH:6])[C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Product: O=[N+]([O-])c1c(Cl)ccnc1O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Phosphorous oxychloride (63.4 mL, 0.68 mol) was added dropwise to a stirred mixture of 2,4-dihydroxy-3-nitropyridine (28.92 g, 0.17 mol) and benzyl triethylammonium chloride (155 g, 0.68 mol) in acetonitrile (560 mL). The reaction mixture was warmed to 60° C. for 1 h then was heated to reflux for 1 h. The reaction was cooled and the volatiles were evaporated in vacuo. An ice/water slurry (500 mL) was added to the residual oil and the mixture was stirred for 3 h at 0° C. The solids were collected by filtration, washing with water and hexanes to give the title compound as a solid;
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH2:27]([N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)[CH3:28].C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[CH2:27]([N:29]1[CH:33]=[C:32]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]4[CH:17]=[C:16]([N:18]5[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]5)[N:15]=[C:14]([NH2:25])[N:13]=4)[CH2:9]3)=[CH:4][CH:3]=2)[CH:31]=[N:30]1)[CH3:28]
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Solvent: CO
Solvent: O
Product: CCn1cc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.8 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. It was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (5.5 mg). LCMS (M+H)+: m/z=433.3.
Reaction SMILES: [N:1]1([C:30](OC(C)(C)C)=[O:31])[CH2:29][CH2:28][CH2:27][C@H:2]1[C:3]([NH:5][C@H:6]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4].Cl.CCOC(C)=O.[NH:44]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:45](C(ON1C(=O)CCC1=O)=O)[CH3:46]>CCN(CC)CC>[NH:44]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:45]([C:30]([N:1]1[CH2:29][CH2:28][CH2:27][C@H:2]1[C:3]([NH:5][C@H:6]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:16])[NH:12][N+:13]([O-:15])=[O:14])=[O:4])=[O:31])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
The desired compound was prepared from 28.9 g of Boc-Pro-Arg(NO2)-OBzl, 150 ml of 4N HCl-AcOEt, 8 ml of Et3N and 16.3 g of Boc-Ala-OSu in the same manner as in Example 8-(1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[NH2:20][C:21]1[C:22]([C:33]#[N:34])=[N:23][CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:26]=1.Cl.O1CCOCC1>CN1C(=O)CCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:20][C:21]3[C:22]([C:33]#[N:34])=[N:23][CH:24]=[C:25]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH:26]=3)=[C:3]([CH3:19])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: N#Cc1ncc(N2CCOCC2)cc1N
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1C#N

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (93 mg, 0.34 mmol), 3-amino-5-morpholinopicolinonitrile (70 mg, 0.34 mmol) and a 4.0M solution of HCl in dioxane (0.08 mL, 0.34 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification 3-((7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-5-(4-morpholinyl)-2-pyridinecarbonitrile was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, dt, J=3.1, 1.6 Hz), 7.76-8.00 (5H, m), 7.31-7.49 (2H, m), 6.46 (1H, s), 5.92 (1H, d, J=2.3 Hz), 3.68-3.84 (4H, m), 3.00-3.19 (4H, m), 2.42 (3H, s). Mass Spectrum (ESI) m/e=441.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[C:20]1[C:24]([C:25](Cl)=[O:26])=[C:23](C)[O:22][N:21]=1.[CH2:29](N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:29][C:10]1[CH:9]=[C:6]([CH2:7][NH2:8])[CH2:5][C:4]([C:25]([C:24]2[C:20]([C:14]3[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=3[Cl:12])=[N:21][O:22][CH:23]=2)=[O:26])([N+:1]([O-:3])=[O:2])[CH:11]=1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: CCN(CC)CC
Reactant: NCc1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1=CC(C(=O)c2conc2-c2c(F)cccc2Cl)([N+](=O)[O-])CC(CN)=C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Nitrobenzylamine (511 mg, 2.71 mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxaz-4-oyl chloride (742 mg, 2.71 mmol) were suspended in 10 mL of dichloromethane and triethylamine was added (0.95 mL, 6.78 mmol). The reaction went clear and was stirred at room temperature for 2 hours. The reaction was then diluted with 100 mL of ethyl acetate and the organic layer was washed twice each with 1N aqueous hydrochloric acid and 1N aqueous sodium hydroxide. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.12 g of the title compound. (>100). MS(IE) m/z 390 (M+1). IR 3280, 1648, 1532, 1349, 1251 cm−1.