Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](O)=[O:20])[CH2:17][C:6]=2[CH:5]=1.[C:30]1([C:36]2[NH:37][C:38](=[O:47])[N:39]([CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[CH:40]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.ClC1C2NN=CC=2C2CN(CC(C)(C)C)C(=O)[C@H](CC(=O)N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)CC=2C=1>>[Cl:3][C:4]1[C:12]2[NH:11][N:10]=[CH:9][C:8]=2[C:7]2[CH2:13][N:14]([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:15](=[O:22])[C@H:16]([CH2:18][C:19](=[O:20])[N:44]3[CH2:43][CH2:42][CH:41]([N:39]4[CH:40]=[C:36]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[NH:37][C:38]4=[O:47])[CH2:46][CH2:45]3)[CH2:17][C:6]=2[CH:5]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Reactant: O=c1[nH]c(-c2ccccc2)cn1C1CCNCC1
Agent: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Yield: 30 %

Procedure:
(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride (100 mg, 0.23 mmol) and 4-phenyl-1-(piperidin-4-yl)-1H-imidazol-2(3H)-one (60 mg, 0.28 mmol) were reacted following a procedure analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 30% yield. MS m/e (M+H)+=610.3. 1H NMR (500 MHz, DMSO-D6): δ=13.46 (s, 1H), 10.68 (d, J=4.27, 1H), 8.30 (d, J=3.97, 2H), 8.23 (s, 1H), 7.50 (d, J=7.93, 1H), 7.45 (d, J=7.63, 1H), 7.31 (m, 2H), 7.22 (s, 1H), 7.14 (m, 4H), 5.41 (d, J=16.78, 1H), 4.66 (m, 3H), 4.55 (m, 1H), 4.13 (m, 2H), 3.99 (m, 1H), 3.33 (m, 1H), 3.18 (m, 1H), 3.05 (dd, J1=16.02, J2=8.70, 1H), 2.94 (m, 1H), 2.68 (m, 1H), 2.44 (m, 1H), 1.81 (m, 3H), 1.62 (m, 1H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[Br:40][C:41]1[CH:42]=[C:43]([CH:47]=[C:48]([N+:50]([O-:52])=[O:51])[CH:49]=1)[C:44](O)=[O:45]>CN(C=O)C.C(OCC)(=O)C>[Br:40][C:41]1[CH:42]=[C:43]([C:44]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:45])[CH:47]=[C:48]([N+:50]([O-:52])=[O:51])[CH:49]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Br)cc([N+](=O)[O-])c1)N1CCOCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
HATU (927 mg, 2.44 mmol), morpholine (0.212 mL, 2.44 mmol), and diisopropylethylamine (0.532 mL, 3.05 mmol) were added sequentially to a solution of 3-bromo-5-nitrobenzoic acid (500 mg, 2.03 mmol) in DMF (10 mL) at 0° C. The reaction mixture was stirred for 2 hours at 0° C., then the mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous NaHCO3 (50 mL) followed by 1:1 water: brine (2×30 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) provided (3-bromo-5-nitrophenyl)(morpholin-4-yl)methanone as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.43 (t, J=1.9 Hz, 1H), 8.28-8.12 (m, 1H), 7.89 (t, J=1.5 Hz, 1H), 3.74 (br m, 8H).
Reaction SMILES: CC(C)=O.[OH:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]1.CC(O)C>O>[CH2:15]([O:14][C:12]([CH:9]1[CH2:10][CH2:11][C:6](=[O:5])[CH2:7][CH2:8]1)=[O:13])[CH3:16]
Reactant: CCOC(=O)C1CCC(O)CC1
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C1CCC(=O)CC1
Reaction time: 0.33 h

Procedure:
120 ml of a Jone's reagent was added dropwise into a solution of 800 ml of acetone containing 81.1 g of ethyl 4-hydroxycyclohexane carboxylate over 30 minutes in an ice bath. After stirring at the same temperature for 20 minutes, 2-propanol was added thereto. The reaction solution was poured into water, followed by extracting with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed, to give 80.0 g of the target compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH:16]1([NH:24][C:25]([NH:27][CH:28]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[S:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[ClH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:26][C:25](=[N:24][CH:16]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[N:27]2[CH:28]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: NS(=O)(=O)c1cc(C(=O)CCl)ccc1Cl
Reactant: S=C(NC1CCCCCCC1)NC1CCCCCCC1
Product: Cl
Product: NS(=O)(=O)c1cc(C2(O)CSC(=NC3CCCCCCC3)N2C2CCCCCCC2)ccc1Cl

Procedure:
5.2 g of 2,4'-dichloro-3'-sulfamoylacetophenone and 5.8 g of 1,3-dicyclooctylthiourea were reacted according to the prescription made in Example 12 and worked up according to the prescription of Example 42. Colorless solid body, decomposition beginning at 118° C., γ C=N 1600 cm-1.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH2:9][C:10]([O-:12])=[O:11])=[CH:7][O:8][C:4]=2[CH:3]=1.[CH3:15][O-].[Na+].[H][H]>CO>[OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C@H:6]([CH2:9][C:10]([O:12][CH3:15])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: C[O-]
Reactant: O=C([O-])Cc1coc2cc(O)ccc12
Reactant: [H][H]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C[C@@H]1COc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of (1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (656 mg) and (S,S)-Et-FerroTANE (620 mg) was added methanol (200 mL) sufficiently substituted by argon gas, and the mixture was stirred at room temperature 15 min. To a mixture of (6-hydroxy-1-benzofuran-3-yl)acetate (26.1 g) and sodium methoxide (3.8 g) was added methanol (500 mL) sufficiently substituted by argon gas. The methanol solution prepared earlier was added thereto, and the mixture was stirred at room temperature for 2 hr under 0.7 MPa hydrogen atmosphere. The reaction mixture was quantified by HPLC. As a result, the enantiomeric excess was 90.8%, the yield was quantitative.
Reaction SMILES: C1COCC1.O.[OH:7][C@@H:8]([CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:20]2[C@@H:14]([O:15][CH2:16][C@@H:17]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:19]2)[CH2:13][C@H:12]1[O:30]C1CCCCO1>C(O)(=O)C>[OH:30][C@@H:12]1[CH2:13][C@@H:14]2[O:15][CH2:16][C@@H:17]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:19][C@@H:20]2[C@H:11]1/[CH:10]=[CH:9]/[C@@H:8]([OH:7])[CH2:37][O:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)OC(=O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/[C@@H](O)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2OC1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)OC(=O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/[C@@H](O)COc3ccccc3)[C@H](O)C[C@@H]2OC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
THF (400 μL) and water (400 μL) were added to an acetic acid solution (800 μL) of the compound (151 mg, 0.259 mmol) produced in Example 15, and the mixture was stirred at 60° C. for 3 hours and 30 minutes. The reaction solution was concentrated under reduced pressure, and purified with a column apparatus (Hiflash-SI, Size S, ethyl acetate: hexane=1:1→ethyl acetate) manufactured by Yamazen Corporation to obtain a titled compound (74 mg) having the following physical property values. TLC: Rf 0.28 (dichloromethane: methanol=20:1);
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([S:9]([OH:12])(=[O:11])=[O:10])[C:5]([O:7][CH3:8])=[O:6].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C>[N:13]([CH2:2][CH2:3][CH:4]([S:9]([OH:12])(=[O:11])=[O:10])[C:5]([O:7][CH3:8])=[O:6])=[N+:14]=[N-:15]
Reactant: COC(=O)C(CCBr)S(=O)(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCN=[N+]=[N-])S(=O)(=O)O
Yield: 95 %

Procedure:
Methyl 4-bromo-2-sulfo-butyrate (1.07 g, 4.11 mmol) and sodium azide (0.70 g (10.7 mmol) in DMF (50 ml) was stirred overnight. The mixture was evaporated and purified by SiO2 chromatography and eluted with 1:5:0.01 CH3OH/CH2Cl2/HAc and crystallized with CH3OH/Toluene/Hexane to afford 1.00 g (95%) of the title compound. m.p=267-272° C. (decomp). 1H NMR (DMF-d7): 12.06 (br, 1H), 3.65 (s, 3H), 3.59 (dd, 1H, J=5.4, 8.9 Hz), 3.47 (m, 2H), 2.24 (m, 2H). 13C NMR 171.10, 64.29, 52.24, 50.64, 21.35. ESI MS m/z+267.9 (M+2Na—H), m/z−222.0 (M−H). HRMS m/z−(C5H9N3O5S—H) calcd 222.0185. found 222.0179.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[CH3:9].F.F.F.C(N(CC)CC)C.[B-](F)(F)(F)[F:22].CCN([S+](F)F)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([F:22])[CH3:9]
Reactant: F[B-](F)(F)F
Reactant: CC(O)c1ccccc1Br
Agent: CCN(CC)[S+](F)F
Agent: F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(F)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-bromophenyl)ethanol (1 g, 4.97 mmol) in DCM (12 mL) was added triethylamine trihydrofluoride (1.621 mL, 9.95 mmol) and XtalFluor-E® (1.708 g, 7.46 mmol) dropwise over 5 min. After addition the resulting mixture was stirred at room temperature for 1 h and then cooled to 0° C. and quenched by addition of sat. aq. NaHCO3. The layers were separated and the aqueous was extracted with DCM (2×). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford 1-bromo-2-(1-fluoroethyl)benzene. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.54 (dt, J=8.0, 1.2 Hz, 1H), 7.50 (dd, J=7.8, 1.8 Hz, 1H), 7.38 (td, J=7.6, 1.3 Hz, 1H), 7.19 (td, J=7.7, 1.7 Hz, 1H), 5.90 (dq, J=46.6, 6.4 Hz, 1H), 1.60 (dd, J=3-24.2, 6.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[C:4](=[O:15])[N:3]=1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH:9]2[CH2:13][CH2:12][CH:11]([O:14][C:23](=[O:24])[C:22]3[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=3)[CH2:10]2)[C:4](=[O:15])[N:3]=1
Reactant: Nc1nc(=O)n(C2CCC(O)C2)cc1F
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: Nc1nc(=O)n(C2CCC(OC(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1F

Procedure:
4-Amino-5-fluoro-1-(3-hydroxy-cyclopentyl)-1H-pyrimidin-2-one was inverted via the Mitsunobu reaction (General Method A) with 4-nitrobenzoic acid to provide 4-nitro-benzoic acid 3-(4-amino-5-fluoro-2-oxo-2H-pyrimidin-1-yl)-cyclopentyl ester 28.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9]C)[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[O:15][C:5]3[C:6](=[C:7]([OH:9])[CH:8]=[C:3]([OH:2])[CH:4]=3)[CH:13]=2)=[CH:17][CH:18]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: O=C(CBr)c1ccc(F)cc1
Product: Oc1cc(O)c2cc(-c3ccc(F)cc3)oc2c1
Yield: 80 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(4-fluorophenyl)ethanone: Yield 80% following procedures A.2 and A.5; m.p. 189-190° C.; IR 3332, 1614, 1500, 1243, 1125, 1072 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 9.85 (s, 1H), 9.36 (s, 1H), 7.82 (dd, J=8.7 Hz, 5.4 Hz, 2H), 7.27 (t, J=8.9 Hz, 2H), 7.21 (s, 1H), 6.42 (s, 1H), 6.19 (d, J=1.7 Hz, 1H); 13C-NMR (126 MHz, δ ppm, CD3OD) 163.85 (d, J=246.0 Hz), 158.8, 158.0, 153.3, 152.5, 129.0 (d, J=3.3 Hz), 127.1 (d, J=8.1 Hz), 116.8 (d, J=22.2 Hz), 112.9, 99.7, 98.9, 90.9.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH2:22][C:23]([NH2:25])=[NH:24].[ClH:26].C[O-].[Na+]>CO.O>[NH2:24][C:23]([NH2:25])=[N:22][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:11][C:2]=1[CH3:1].[ClH:26]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(N2CCCCC2)cc1C
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cc(N2CCCCC2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Reaction time: 1 h

Procedure:
A solution of 20 g of methyl 2-methyl-4-piperidino-5-methylsulfonylbenzoate [obtainable by reacting piperidine with 2-methyl-4-chloro-5-methylsulfonylbenzoic acid followed by esterification] and 30 g of guanidine, which has been liberated beforehand from the guanadine hydrochloride using sodium methylate, is stirred in 160 ml of methanol at 50° over a period of twenty hours. After cooling to 0°, water is added, stirring is continued for 1 hour and the precipitate which forms is separated off. Recrystallization from dichloromethane/methanol gives N-diaminomethylene-2-methyl-4-piperidino-5-methylsulfonylbenzamide, m.p. 222°-224°, hydrochloride m.p. 275°-276°.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[N:8]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:9]=[C:10]([C:12]([CH2:16][F:17])([CH3:15])[CH2:13][F:14])[CH:11]=1.CCN(C(C)C)C(C)C.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([C:50]2[CH:55]=[CH:54][C:53]([NH2:56])=[C:52]([CH3:57])[N:51]=2)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].O>CS(C)=O>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][N:47]([C:50]2[CH:55]=[CH:54][C:53]([NH:56][C:5]([NH:6][C:7]3[N:8]([C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)[N:9]=[C:10]([C:12]([CH2:13][F:14])([CH3:15])[CH2:16][F:17])[CH:11]=3)=[O:4])=[C:52]([CH3:57])[N:51]=2)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38]
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reactant: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2C)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Add [5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (2.7 mmol, 1.2 g) and DIEA (2.9 mmol, 0.5 mL) over a solution of 4-(5-amino-6-methyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.9 mmol, 0.9 g) in 4 mL of DMSO and stir at 85° C. overnight. Cool down, add water and extract with CH2Cl2. Combine the organic layers and wash with saturated aq. sodium chloride solution. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give 4-(5-{3-[5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-6-methyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester. Subject residue to silica gel chromatography eluting with hexanes/ethyl acetate in gradient (from 10 to 50%). MS(ES+): m/z=584 [M+H]).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([NH:7][C@H:8]([C:16]([NH:18][CH2:19][C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:35]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:51]([NH:53][C@H:54]([C:62]([NH:64][C@H:65]([C:70]([NH:72][CH2:73][C:74]([NH2:76])=[O:75])=[O:71])[C@H:66]([CH2:68][CH3:69])[CH3:67])=[O:63])[CH2:55][CH2:56][CH2:57][NH:58][C:59](=[NH:61])[NH2:60])=[O:52])[CH2:47][C:48](=[O:50])[OH:49])=[O:44])[C@H:39]([CH2:41][CH3:42])[CH3:40])=[O:36])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:34])[NH2:33])=[O:25])=[O:21])=[O:17])[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:6])[CH2:3][SH:4].N[C@H](C(N[C@H](C(NCC(NCC(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(NCC(N)=O)=O)[C@H](CC)C)=O)CCCNC(=N)N)=O)CC(=O)O)=O)[C@H](CC)C)=O)CCCNC(=N)N)=O)=O)=O)CC1CCCCC1)=O)C(S)(C)C.N[C@H](C(N[C@H](C(NCC(NCC(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N)=O)[C@H](CC)C)=O)CCCNC(=N)N)=O)CC(=O)O)=O)[C@H](CC)C)=O)CCCNC(=N)N)=O)=O)=O)CC1CCCCC1)=O)CS>>[NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:16]([NH:18][CH2:19][C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:35]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:51]([NH:53][C@H:54]([C:62]([NH:64][C@H:65]([C:70]([NH:72][CH2:73][C:74]([NH2:76])=[O:75])=[O:71])[C@H:66]([CH2:68][CH3:69])[CH3:67])=[O:63])[CH2:55][CH2:56][CH2:57][NH:58][C:59](=[NH:60])[NH2:61])=[O:52])[CH2:47][C:48](=[O:49])[OH:50])=[O:44])[C@H:39]([CH2:41][CH3:42])[CH3:40])=[O:36])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:33])[NH2:34])=[O:25])=[O:21])=[O:17])[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:6])[CH2:3][SH:4]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)CNC(=O)[C@H](CC1CCCCC1)NC(=O)[C@H](N)CS)[C@@H](C)CC)C(=O)NCC(N)=O
Agent: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)CNC(=O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)C(C)(C)S)[C@@H](C)CC)C(=O)NCC(N)=O
Agent: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)CNC(=O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)CS)[C@@H](C)CC)C(N)=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)CNC(=O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)CS)[C@@H](C)CC)C(=O)NCC(N)=O

Procedure:
D-Cys-Cha-Gly-Gly-Arg-Ile-Asp-Arg-Ile-GlyNH2 ; L-Pen-Cha-Gly-Gly-Arg-Ile-Asp-Arg-Ile-GlyNH2 ; and Cys-Cha-Gly-Gly-Arg-Ile-Asp-Arg-IleNH2.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[CH2:15][CH2:14]1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (2.5 g, 16 mmol), N-methylpiperazine (2 mL, 18 mmol) and potassium carbonate (2.7 g, 19 mmol) in DMSO (7 mL) was stirred and heated at 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature and then diluted with ethyl acetate (100 mL), washed with water (3×30 mL), brine, dried (MgSO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with dichloromethane—40% methanol/dichloromethane (gradient) to afford the desired title compound as a yellow solid, 3.67 g, 97%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][CH2:21][C:22]3[C:23](=[N:24][C:25]([NH:28][C:29]4[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][C:30]=4[O:38][CH3:39])=[N:26][CH:27]=3)[C:17]=2[N:16]([CH3:40])[N:15]=1)=[O:13])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:72][N:73]1[CH2:78][CH2:77][CH:76]([NH2:79])[CH2:75][CH2:74]1>CN(C=O)C.O>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][CH2:21][C:22]3[C:23](=[N:24][C:25]([NH:28][C:29]4[CH:37]=[CH:36][C:32]([C:33](=[O:35])[NH:79][CH:76]5[CH2:77][CH2:78][N:73]([CH3:72])[CH2:74][CH2:75]5)=[CH:31][C:30]=4[O:38][CH3:39])=[N:26][CH:27]=3)[C:17]=2[N:16]([CH3:40])[N:15]=1)=[O:13])[CH3:10]
Reactant: CN1CCC(N)CC1
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(C(=O)O)cc3OC)nc1-2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)nc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
A solution of 4-({3-[(2,6-diethylphenyl)carbamoyl]-1-methyl-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidin-9-yl}amino)-3-methoxybenzoic acid (50 mg, 0.092 mmol) in anhydrous DMF (0.5 mL) was treated with DIPEA (0.150 mL) and TBTU (50 mg, 0.150 mmol). The mixture was then treated with 1-methylpiperidin-4-amine (18 mg, 1.38 mmol) and was stirred at room temperature for 2 hours. The reaction was diluted with water and extracted twice with DCM. The organic layer was dried over Na2SO4 and the solvent was evaporated to dryness. The crude solid was purified by flash chromatography on silica gel (DCM/MeOH) to afford 43 mg (72% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH:25]=[C:26]([CH3:28])[CH3:27])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].ClC1C=C(C=CC=1)C(OO)=[O:34]>C(Cl)Cl.CCOC(C)=O>[CH3:27][C:26]1([CH3:28])[O:34][CH:25]1[C:14]1[CH:15]=[C:16]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=2)[C:11]([NH:10][C:4]2[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:12][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ncc(Nc2ncc(C=C(C)C)cc2-c2nc(C)nc(N)n2)cc1F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ncc(Nc2ncc(C3OC3(C)C)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-methylprop-1-enyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (380 mg, 0.996 mmol) in DCM (9.9 mL) was cooled to 0° C., and 3-chlorobenzoperoxoic acid (268 mg, 1.196 mmol) was then added. The resulting mixture was stirred at 0° C. for 1.5 h and then allowed to warm to ambient temperature and stir for 2 h. The reaction mixture was then diluted with 200 mL of EtOAc, added to a separatory funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 1 time with 150 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated in vacuo to give the title compound. m/z (ESI, +ve ion) 398.2 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])[CH2:3][CH2:2]1.[Br:15]N1C(=O)CCC1=O>CN(C=O)C>[Br:15][C:11]1[CH:12]=[CH:13][C:8]([NH:7][CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[C:9]([OH:14])[CH:10]=1
Reactant: Oc1ccccc1NC1CCOCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Oc1cc(Br)ccc1NC1CCOCC1
Yield: 46.6 %

Procedure:
A solution of intermediate D7 (0.66 g, 3.415 mmol) and N-bromosuccinimide (0.669 g, 3.757 mmol) in DMF (10 ml) was stirred at r.t. for 1 h. Subsequently, the r.m. was washed with an aqueous saturated NaHCO3 solution. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/EtOAc 8:2 as eluent). The desired fractions were collected and evaporated in vacuo to yield D9 (0.433 g, 46.6%) as a reddish solid.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[CH2:27](O)[CH2:28]/[CH:29]=[CH:30]/[CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl>[I:25][CH2:27][CH2:28]/[CH:29]=[CH:30]/[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCC/C=C/CCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCC/C=C/CCI
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
A mixture of Ph3P (3.205 g, 12.2 mmol), imidazole (1.221 g, 17.9 mmol), and I2 (3.024 g, 11.9 mmol) in CH2Cl2 (38 mL) was stirred at room temperature. After 15 min., a solution of 7-2 (1.283 g, 10.0 mmol) in CH2Cl2 (4.8 mL) was added by cannula, rinsing with 4 mL CH2Cl2. After 3 h, the mixture was filtered through basic alumina, washing with 10% ethyl acetate/hexanes. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel (Isco Combiflash unit) to provide the title compound (2.323 g, 98%).