Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[C:10]([CH2:15][CH3:16])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].II>C(Cl)Cl.[Pd]>[C:1]([O:5][C:6]([NH:8][NH:9][CH:10]([CH2:15][CH3:16])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(=NNC(=O)OC(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: II
Solvent: ClCCl
Product: CCC(NNC(=O)OC(C)(C)C)C(C)(C)C

Procedure:
Approximately 10.3 g N′-(1-ethyl-2,2-dimethyl-propylidene)-hydrazinecarboxylic acid tert-butyl ester was mixed with 4.14 g (3.9 mmol) 10% Pd/C in CH2Cl2 under an atmosphere of hydrogen in a Pan shaker for four hours. The reaction was monitored by TLC (I2 indicator), and the crude product was twice chromatographed using 10% ether in hexane to yield N′-(1-ethyl-2,2-dimethyl-propyl)-hydrazinecarboxylic acid tert-butyl ester. 1H NMR (CDCl3, 500 MHz) δ (ppm): 6.05 (br, 1H), 3.9 (br, 1H)), 2.45 (m, 1H), 1.6 (m, 1H), 1.5 (s, 9H), 1.25 (m, 1H), 1.1 (t, 3H), 0.92 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[C:7]([CH3:12])=[C:6]([CH3:13])[C:3]=1[CH2:4]Cl.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C1COCC1>[CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[C:7]([CH3:12])=[C:6]([CH3:13])[C:3]=1[CH2:4][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: C1CNCCN1
Reactant: Cc1c(C)c(C)c(CCl)c(C)c1C
Solvent: C1CCOC1
Product: Cc1c(C)c(C)c(CN2CCNCC2)c(C)c1C

Procedure:
Synthesized according to General Procedure A: 2,3,4,5,6-pentamethylbenzyl chloride (4{14}, 5 g, 25.4 mmol, 1 equiv.), piperazine (13.1 g, 152.5 mmol, 6 equiv.), THF (55.5 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{14} (5.31 g, 85%) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 3.52 (s, 2H), 2.80 (t, 4H, J=4.8 Hz), 2.45 (br s, 4H), 2.32 (s, 6H), 2.25 (s, 3H), 2.23 (s, 6H), 1.63 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 133.9, 133.7, 132.3, 131.9, 57.2, 54.1, 46.5, 17.0, 16.8, 16.6.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8]1.[CH3:22][O:23][C:24](Cl)=[O:25]>O.C(Cl)Cl>[CH3:22][O:23][C:24]([NH:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8]1)=[O:25]
Reactant: N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 6 h
Yield: 64 %

Procedure:
Sodium bicarbonate (2.073 g, 24.68 mmol) was dissolved in a mixture of water (20.00 mL) and DCM (20 mL), and phenylmethyl (3S)-3-amino-1-pyrrolidinecarboxylate (2.88 g, 11.22 mmol) was added followed by methylchloroformate (0.953 mL, 12.34 mmol). This mixture was stirred for 6 h. The biphasic mixture was then separated, and the aqueous phase was extracted once with DCM. The combined organics were dried over sodium sulfate, filtered and evaporated. The residual material was then purified via silica gel chromatography (0-100% EtoAc in hexane) yielding phenylmethyl (3S)-3-{[(methyloxy)carbonyl]amino}-1-pyrrolidinecarboxylate (2 g, 64%) as a clear oil. LCMS: (M+H)+: 278.9.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:43]1[CH2:44][CH2:45][N:40]([C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([Cl:33])[CH:35]=2)[CH2:41][CH2:42]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: Clc1cccc(N2CCNCC2)c1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2cccc(Cl)c2)CC1
Yield: 7.9 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(3-chloro-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (5.6 mg, 7.9%) as light yellow oil. MS m/e=525.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([OH:9])=O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.[Cl:43][C:44]1[C:45]([NH:73][C:74](=[O:94])[C:75]2[CH:80]=[CH:79][C:78]([N:81]3[CH2:86][CH2:85][N:84]([C:87](=[O:92])[C:88]([CH3:91])([CH3:90])[CH3:89])[CH2:83][C@H:82]3[CH3:93])=[N:77][CH:76]=2)=[CH:46][C:47]([O:68][C:69]([F:72])([F:71])[F:70])=[C:48]([C:50]2[CH:55]=[CH:54][C:53]([C:56]3[N:57]=[C:58]([C@@H:61]4[CH2:65][C@H:64]([O:66][CH3:67])[CH2:63][NH:62]4)[NH:59][CH:60]=3)=[CH:52][CH:51]=2)[CH:49]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@@H:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([N:62]1[CH2:63][C@@H:64]([O:66][CH3:67])[CH2:65][C@H:61]1[C:58]1[NH:59][CH:60]=[C:56]([C:53]2[CH:54]=[CH:55][C:50]([C:48]3[CH:49]=[C:44]([Cl:43])[C:45]([NH:73][C:74]([C:75]4[CH:76]=[N:77][C:78]([N:81]5[CH2:86][CH2:85][N:84]([C:87](=[O:92])[C:88]([CH3:90])([CH3:91])[CH3:89])[CH2:83][C@H:82]5[CH3:93])=[CH:79][CH:80]=4)=[O:94])=[CH:46][C:47]=3[O:68][C:69]([F:71])([F:72])[F:70])=[CH:51][CH:52]=2)[N:57]=1)=[O:9]
Reactant: CO[C@@H]1CN[C@H](c2nc(-c3ccc(-c4cc(Cl)c(NC(=O)c5ccc(N6CCN(C(=O)C(C)(C)C)C[C@H]6C)nc5)cc4OC(F)(F)F)cc3)c[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](OC)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)C(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
To a solution of (S)-methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (9.4 mg, 0.046 mmol; Preparation 29) in DMA (1 mL) was added HATU (6.4 mg, 0.017 mmol). The reaction mixture was stirred at RT for 15 min, and N-{5-chloro-4′-[2-((2S,4S)-4-methoxy-pyrrolidin-2-yl)-1H-imidazol-4-yl]-2-trifluoromethoxy-biphenyl-4-yl}-6-[(R)-4-(2,2-dimethyl-propionyl)-2-methyl-piperazin-1-yl]-nicotinamide tri-HCl (12.0 mg, 0.014 mmol; Preparation 32) was added followed by DIPEA (12.3 μL, 0.07 mmol). The reaction mixture was stirred at RT overnight, concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide the di-TFA salt of the title compound (9 mg, 56% yield). (m/z): [M+H]+ calcd for C46H54ClF3N8O8 939.37. found 939.8.
Reaction SMILES: [CH3:1][C:2]1[C:6]([I:7])=[C:5]([CH3:8])[NH:4][N:3]=1.[H-].[Na+].[CH:11]1(OS(C)(=O)=O)[CH2:15][CH:14]=[CH:13][CH2:12]1.O>CN(C=O)C>[CH:14]1([N:3]2[C:2]([CH3:1])=[C:6]([I:7])[C:5]([CH3:8])=[N:4]2)[CH2:13][CH:12]=[CH:11][CH2:15]1
Reactant: CS(=O)(=O)OC1CC=CC1
Reactant: Cc1n[nH]c(C)c1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C2CC=CC2)c(C)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of 3,5-dimethyl-4-iodo-1H-pyrazole (5.00 g, 22.5 mmol) in DMF (15 mL) was added NaH (60%, 1.08 g, 27 mmol) in portions and stirred at room temperature for 1 h. To this was added methanesulfonic acid cyclopent-3-enyl ester (4.00 g, 24.7 mmol) and heated at 60° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate (60 mL). The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by column chromatography using 5-10% ethyl acetate in hexane to give the title compound as an oil. 1H NMR (300 MHz, CDCl3): δ=5.75 (s, 2H), 4.97 (m, 1H), 2.79 (d, 4H, J=7.2 Hz), 2.28 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([S:16][CH3:17])[CH:15]=2)=[CH:6][C:5]([N:18]=[CH:19][N:20](C)C)=[C:4]([C:23]#[N:24])[CH:3]=1.[CH:25](N)([CH3:27])[CH3:26].ClCCl.CO>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([S:16][CH3:17])[CH:15]=1)[N:18]=[CH:19][N:20]=[C:23]2[NH:24][CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: CSc1cncc(COc2cc(N=CN(C)C)c(C#N)cc2Br)c1
Solvent: CO
Solvent: ClCCl
Product: CSc1cncc(COc2cc3ncnc(NC(C)C)c3cc2Br)c1
Yield: 77 %

Procedure:
According to GWP 5, the reaction of N′-(4-bromo-2-cyano-5-{[5-(methylsulphanyl)-pyridin-3-yl]methoxy}phenyl)-N,N-dimethylformimidamide (540 mg, 1.33 mmol) with isopropylamine (0.14 mL, 1.6 mmol) and chromatography (silica gel, dichloro-methane/methanol: 0→30% methanol) gives the desired product in 77% yield (430 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]([CH2:18][CH:19](OC)OC)[CH3:17])=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl>O>[CH3:17][N:16]1[CH:18]=[CH:19][N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=3)=[CH:12][CH:11]=2)[C:14]1=[O:15]
Reactant: COC(CN(C)C(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1)OC
Agent: Cl
Solvent: O
Product: Cn1ccn(-c2ccc(Oc3ccc(Cl)cc3)cc2)c1=O

Procedure:
N-[4-(4-Chlorophenoxy)phenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea (0.02 mole), water (30 ml) and concentrated hydrochloric acid (3 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. The mixture is refluxed for a period of about 30 minutes and then cooled and extracted with ethyl acetate. The extract is washed with dilute aqueous sodium bicarbonate, with two portions of water, and dried. The ethyl acetate is removed by mild warming at reduced pressure to yield the desired product 1-methyl-3-[4-(4-chlorophenoxy)phenyl]-4-imidazolin-2-one.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH2:15][C@@H:16]([OH:23])[CH2:17][NH:18][C:19](=[O:22])[CH2:20][OH:21])=[C:9]([CH2:24][CH3:25])[CH:8]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:24]([C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([CH3:13])[C:10]=1[O:14][CH2:15][C@@H:16]([OH:23])[CH2:17][NH:18][C:19](=[O:22])[CH2:20][OH:21])[C:6]([OH:26])=[O:5])[CH3:25]
Reactant: CCc1cc(C(=O)OC(C)(C)C)cc(C)c1OC[C@@H](O)CNC(=O)CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(C(=O)O)cc(C)c1OC[C@@H](O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
To a cooled (0° C.) solution of 3-ethyl-4-[(S)-2-hydroxy-3-(2-hydroxy-acetylamino)-propoxy]-5-methyl-benzoic acid tert-butyl ester (5.94 g, 16.2 mmol) in DCM (100 mL), TFA (5 mL) is added. The mixture is warmed to rt and stirred for 2 h. The mixture is concentrated, dissolved in acetonitrile/water (6 mL) and separated by prep. HPLC to give the title compound (2.20 g) as a white powder; LC-MS: tR=0.41 min; [M+H]+=312.18.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]([CH2:30][C@@H:31]([OH:33])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:41]([NH:48][CH2:49][C:50](O)=[O:51])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:44]([O:43][C:41]([NH:48][CH2:49][C:50]([O:33][C@@H:31]([CH3:32])[CH2:30][N:27]1[C:28]([CH3:29])=[C:24]([C:22](=[O:23])[NH:21][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[C:2]([F:1])[CH:3]=2)[C:25](=[O:40])[N:26]1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:51])=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@H](C)O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@H](C)OC(=O)CNC(=O)OC(C)(C)C)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 113.4 %

Procedure:
To a mixture of (S)—N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-1-(2-hydroxylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1.0 g, 1.84 mmol), N-Boc-glycine (0.644 g, 3.68 mmol, ABCR) and DMAP (0.45 g, 3.68 mmol, Aladdin) in 12 mL of CH2Cl2 at 0° C. was added EDC solid (1.0582 g, 5.52 mmol, Aladdin) in portions. After stirring at 0° C. for 2 hrs, the reaction mixture was warmed up to room temperature and continued to stir overnight. The reaction mixture was diluted with CH2Cl2 (100 mL), and the result solution was washed with 0.1 N HCl (10 mL×2), followed by saturated NaHCO3 (10 mL×2) and water (20 mL), the aqueous phase was extracted with EtOAc (15 mL×3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc:hexane=2:1) to give the desired compound as a yellow solid (1.46 g, 70.1%).
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:18]1[CH:22]([CH2:23][CH2:24][CH2:25][CH2:26][C:27](N)=[O:28])SS[CH2:19]1>CCCCCC>[C:27]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:18][CH2:19][CH2:1]/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: NC(=O)CCCCC1CCSS1
Solvent: CCCCCC
Product: CCC/C=C\CCCCCCCCC(=O)OCCCCCCCCCCCCCCCC
Yield: 88 %

Procedure:
Preparation of hexadecyl cis-10-tetradecenoate, 8 was carried out according to the Scheme 2. Methyl undecenoate, 5 (10.21 g, 0.0515 mol) in dichloromethane (150 ml) was cooled to −78° C. and ozone gas was bubbled into the reaction mixture for 1 hr. The reaction was quenched by adding dimethyl sulphide (DMS, 5 ml) and was stirred for 6 hr at 25° C. The solvents were removed under vacuum and the residue 6 thus obtained was used directly further preparation of cis-10-myristoleate, 7. n-Butyl-triphenyl phosphonium bromide salt (10.0 g, 0.0251 mol) was taken in dry THF (50 ml) and cooled to 0° C. To this slurry, n-Butyl lithium (17.0 ml, 1.6 M in hexane) was added and stirred for 0.5 hr. 1-Al-methyl deaconate containing crude product 6 (5.01 g, 0.025 mol) dissolved in dry THF (50 ml) was added slowly to the above contents and allowed the reaction mixture to warm to roam temperature and then heated to reflux temperature to reflux for 4 hr. THF was removed from the reaction product under reduced pressure, and to the residue distilled water (25 ml) was added and extracted with ether (25 ml×3 times). The combined ether layer was dried over anhydrous sodium sulphate and solvent was evaporated and dried under vacuum to get the product and was further purified by column chromatography using hexane and ethyl acetate (98:2) as eluent to obtain cis-10-myristoleate, 7 (3.35 g, 0.014 mol) in 56% yield with 97% purity by GC. cis-10-Myristoleate, 7 (3.35 g, 0.014 mol) was enzymatically transesterified with cetyl alcohol (4.07 g, 0.0168 mol) in the presence of Lipozyme TL IM (0.745 g, 10 wt % of the total substrate), at 65° C. for 8 hr. The reaction was monitored by TLC and after completion of reaction, hexane (50 ml) was added and the lipase, was separated by filtration and the solvent was evaporated to get the crude product and was purified by column chromatography to obtain hexadecyl cis-10-tetradecenoate, 8 (5.55 g, 0.0123) in 88% yield with 95% purity by GC. The structure of hexadecyl cis-10-tetradecenoate, 8 was confirmed by 1H NMR, IR, and GC-MS.
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[CH2:25][CH2:24][C:23]5[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:22]=5[NH:21][C:20]4=[O:32])[CH2:15][CH2:14]3)[CH:8]=2)=[CH:4][C:3]=1[CH3:35].[CH3:36][C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.O>CN(C=O)C>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:22]2[NH:21][C:20](=[O:32])[N:19]([CH:16]3[CH2:15][CH2:14][N:13]([C:9]4[N:10]=[CH:11][N:12]=[C:7]([O:6][C:5]5[CH:33]=[CH:34][C:2]([NH:1][C:37](=[O:38])[CH3:36])=[C:3]([CH3:35])[CH:4]=5)[CH:8]=4)[CH2:18][CH2:17]3)[CH2:25][CH2:24][C:23]=2[CH:26]=1
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc(N)c(C)c4)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc(NC(C)=O)c(C)c4)ncn3)CC1)C(=O)N2

Procedure:
80 mg (0.17 mmol) 3-(1-(6-(4-amino-3-methylphenoxy)pyrimidin-4-yl)piperidin-4-yl)-7-methoxy-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one, 0.02 mL (0.35 mmol) AcOH, 120 mg (0.37 mmol) TBTU and 0.06 mL (0.43 mmol) TEA in 2.0 mL DMF were stirred for 2 h at RT. Water was added to the reaction mixture. The precipitate was suction filtered and purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:12]=1[CH2:13][NH2:14])=O)(C)(C)C.C(OC([NH:27][C@@H:28]([C:36]([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40](O)=[O:41])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=O)(C)(C)C>>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][C@H:28]([C:36]([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([NH:14][CH2:13][C:12]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=1[CH2:10][CH2:9][NH2:8])=[O:41])=[O:37])[NH2:27]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccn1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Cl)cc1CN
Product: NCCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H](N)Cc1ccccn1

Procedure:
The title compound was prepared from 2-(2-(tert-butoxycarbonylamino)ethyl)-5-chlorobenzyl amine from Step 4 and N-(tert-butoxycarbonyl)-3-pyridin-2-yl-D-alanyl-L-proline from Step 5 using a similar coupling, deprotection, and purification procedures as described in Steps 7 and 8 of Example 15: 1H NMR (DMSO-d6, 400 MHz): δ 8.84 (t, 1H, J=5.8 Hz), 8.72-8.62 (br m, 4H), 8.12-8.00 (br m, 4H), 7.54 (d, 2H, J=7.9 Hz), 7.33-7.19 (m, 4H), 4.58 (br s, 1H), 4.40-4.20 (m, 3H), 3.88-3.80 (m, 2H), 3.43-3.28 (m, 3H), 2.96 (br s, 4H), 1.90-1.75 (br m, 2H); MS (Electrospray): M+H=430.2; TLC Rf=0.13 (80/10/1 of methylene chloride/methanol/concentrated ammonium hydroxide).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([N:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:7]([O:9]C)=[O:8]>CO>[Cl:3][C:4]1[C:5]([N:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:21])=[C:6]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)N(C)c1c(C(=O)OC)ccc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N(C)c1c(C(=O)O)ccc(Cl)c1Cl
Yield: 108 %

Procedure:
Sodium hydroxide solution (2M, 44.6ml) was added dropwise during 5 minutes to a stirred solution of methyl 3,4-dichloro-2-(N-methyl-N-ethoxycarbonylamino)benzoate (9.1 g) in methanol. After 0.5 hours the methanol was evaporated, the residue diluted (water), washed (ether), acidified with potassium bisulphate and extracted (ethyl acetate). The extract was dried (magnesium sulphate) and evaporated to give 3,4-dichloro-2-(N-methyl-ethoxycarbonylamino)benzoic acid (9.38 g) as a brown oil, NMR 1.2(m,3H), 3.1(s,3H), 4.0(m,2H), 7.4(m,1H), 7.9(m,1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:17].C(N(CC)CC)C.[CH:25]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:25]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:17][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([B:8]3[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]3)[C:2]=2[CH3:1])=[O:34])=[CH:31][CH:30]=1)([CH3:27])[CH3:26]
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)c2ccc(OC(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 19 h
Yield: 88 %

Procedure:
To a solution of 117 mg (0.500 mmol) of 2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine, 0.26 mL (1.5 mmol) of triethylamine, and 4-isopropoxybenzoic acid in 2.5 mL of DMF was added HATU at RT. The reaction mixture was stirred at RT for 19 hours then partitioned between 50 mL of EtOAc and 50 mL of water. The organic layer was washed with 50 mL of saturated NaHCO3 solution, dried (MgSO4) and concentrated. Column chromatography (0->30% ethyl acetate/hexanes in 10 minutes) gave 175 mg (0.443 mmol, 88%) of the title compound.
Reaction SMILES: [CH2:1]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[C:2]([CH3:5])([CH3:4])[CH3:3].[F:17]F>C(=O)(O)[O-].[K+]>[F:17][N:6]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:8])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)NCC(C)(C)C)cc1
Reactant: FF
Agent: O=C([O-])O
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)N(F)CC(C)(C)C)cc1
Yield: 56.7 %

Procedure:
N-Neopentyl-p-toluenesulfonamide (2.41 g, 10 mmole) was dissolved in 1:1 fluorotrichloromethanechloroform (450 mL) and the solution was cooled to -78° under nitrogen. Fluorine (approximately 15 mmole, 5% in nitrogen) was bubbled into the solution through a vibrating mixer shaft for 2 h. The cold reaction mixture was poured into aqueous 10% potassium bicarbonate solution (200 mL) and the layers were separated. The organic phase was washed with aqueous 10% sodium thiosulfate (200 mL) and saturated sodium chloride (200 mL) solutions and dried over anhydrous magnesium sulfate. Filtration and removal of solvent under reduced pressure left a solid. Purification of the solid by flash column chromatography (silica, 25% methylene chloride in hexane) yielded N-fluoro-N-neopentyl-p-toluene-sulfonamide as a solid (1.47 g, 57% yield). This material, and additional samples prepared by this procedure, were analyzed and provided the following results: mp 58°-62.5°; IR (KBr) γmax (cm-1) 3440 (b), 2980 (w), 1370 (m), 1175 (s), 734 (m); 1H NMR (80 MHz, CDCl3) δ1.00 (s, 9H, C(CH3)3), 2.50 (s, 3H, CH3), 3.00 (d, J=44 Hz, 2H, NCH2), 7.40 (d, J=8 Hz, 2H, aromatic), 7.83 (d, J=8 Hz, 2H, aromatic); 19F NMR (94.1 MHz, CDCl3) -36.88 (t, J=44 Hz, 1F, NF); HRMS calcd. for C12H18NO2SF: 259.1042; found: 259.1029.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:4]([NH2:16])[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][C:7]=1[CH3:8].[C:27](OCC)(OCC)(OCC)C.Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:8][C:7]1[N:6]=[C:5]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]2[N:16]=[CH:27][N:17]([CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:3]=2[C:2]=1[CH3:1]
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCOc2ccccc2)c1C
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1nc(Oc2ccccc2)c2ncn(CCOc3ccccc3)c2c1C

Procedure:
5,6-Dimethyl-2-phenoxy-N4-(2-phenoxyethyl)pyridine-3,4-diamine (2.41 g), triethyl orthoacetate (1.60 ml), toluene (20 ml), and a catalytic amount of pyridine HCl were combined and heated to reflux for 2 hours. HPLC and MS analysis indicated that the reaction was complete. The reaction mixture was allowed to cool and the resulting solid was filtered and dried. NMR analysis of the dried solid indicated a pure product.