Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C@H:2]([C:20]([N:22]1[CH2:61][CH2:60][CH2:59][C@H:23]1[C:24]([NH:26][C@H:27]([C:29]([NH:31][C@H:32]([C:49]([O:51]CC1C=CC=CC=1)=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][CH2:41][C:42]1[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=1[Cl:44])=[O:39])=[O:30])[CH3:28])=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[NH:1]([C:62]([O:64][C:65]([CH3:66])([CH3:68])[CH3:67])=[O:63])[C@H:2]([C:20]([N:22]1[CH2:61][CH2:60][CH2:59][C@H:23]1[C:24]([NH:26][C@H:27]([C:29]([NH:31][C@H:32]([C:49]([OH:51])=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][CH2:41][C:42]1[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=1[Cl:44])=[O:39])=[O:30])[CH3:28])=[O:25])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
At 0° C. to the solution of 500 mg (0.51 mmol) of Boc-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12) in 5 ml of methanol 5 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 15:1) indicated complete disappearance of Boc-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 12). The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 380 mg (84%) of the title compound as a colorless powder. Mp 108–110° C., TOF-MS (m/e) 893.2[M+H]+, 915.5[M+Na]+, 937.2[M+2Na]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].C1C(=O)N([Br:21])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:21][CH:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)Cc1c(F)cccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1c(F)cccc1F
Reaction time: 24 h

Procedure:
Methyl 2,6-difluorophenylacetate (2.141 g, 11.50 mmol), NBS (2.6 g, 14.61 mmol) and AIBN (0.057 g, 0.345 mmol) were taken up in CCl4 (45 mL). The reaction mixture was stirred at reflux for 18 hours. Additional NBS (1.433 g, 8.05 mmol) and AIBN (0.038 g, 0.230 mmol) were added and stirring at reflux continued for 24 hours. Room temperature was attained and the reaction mixture filtered through Celite, washing with DCM. The filtrate was concentrated in vacuo and the residue purified by MPLC (0-10% EtOAc-hexanes) to give methyl bromo(2,6-difluorophenyl)-acetate as a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)([O:13][CH3:14])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:17]1[CH:16]=[C:15]([C:10]2([O:13][CH3:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:20]=[C:19]([F:21])[CH:18]=1
Reactant: COC1(c2cc(F)cc(Cl)c2)CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1(c2cc(F)cc(Cl)c2)CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of tert-butyl-3-(3-chloro-5-fluorophenyl)-3-methoxypyrrolidin-1-carboxylate (1.57 g, 4.77 mmol) in dichloromethane (20 ml), was added trifluoroacetic acid (5 ml). The mixture was stirred for 1 h at ambient temperature after which the solvent was evaporated. Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) gave the title compound (0.845 g, 77%). The amine was converted to the oxalic acid salt and recrystallized from methanol/diethyl ether: M.p. 169-170° C. MS m/z (rel. intensity, 70 eV) 199 (bp), 187 (93), 157 (61), 133 (66), 129 (59).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N:7]([CH3:34])[C:8]1[CH:33]=[CH:32][C:11]([CH:12]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([N:19]=[CH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[C:15]=2SC)=[CH:10][CH:9]=1.[NH3:35].CS.C(OCC)C>CN(C)C=O>[F:1][B-:2]([F:5])([F:4])[F:3].[NH2:35][C:15]1[N:14]([N:13]=[CH:12][C:11]2[CH:32]=[CH:33][C:8]([N:7]([CH3:34])[CH3:6])=[CH:9][CH:10]=2)[CH:18]=[CH:17][N+:16]=1[N:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1
Reactant: N
Reactant: CSc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Agent: CS
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C=Nn2cc[n+](N=Cc3ccc(N(C)C)cc3)c2N)cc1

Procedure:
0.99 g of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-(methylthio)imidazolium tetrafluoroborate is dissolved in 15 ml of absolute dimethylformamide. Dry ammonia is conducted into the reaction solution at room temperature while stirring until the cleavage of methyl mercaptan is complete. The solution is treated with diethyl ether. The precipitate obtained is washed twice with water and twice with cold methanol and re-precipitated from dimethylformamide/diethyl ether. There is obtained yellow 2-amino-1,3-bis[[p-(dimethylamino)benzylidene]amino]imidazolium tetrafluoroborate with a decomposition point >260°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:18]([OH:20])=O)[CH:7]=[CH:6][C:5]2=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:14]=[C:13]([C:15]([NH2:16])=[O:17])[C:12]2[NH:11][C:10]3[C:5]([C:4]=2[CH:3]=1)=[CH:6][CH:7]=[C:8]([C:18]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])[CH:9]=3
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(C(=O)O)ccc12
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(Br)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
6-Bromo-8-carbamoyl-9H-carbazole-2-carboxylic acid (758 mg, 1.707 mmol, Example 58D) was mixed with morpholine (892 mg, 10.24 mmol), HATU (1947 mg, 5.12 mmol) and DMAP (625 mg, 5.12 mmol) in DMF (8 mL) and stirred for 2 hrs at r.t. The mixture was added slowly to 200 ml H2O while stirring. Resulting mixture was stirred for 10 mins. The resulting yellow precipitate was filtered and air-dried overnight with air-suction to give 546 mg of 3-bromo-7-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide which was used as such in the next step.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][NH:13][C:14]([C:16]2[CH:20]=[CH:19][O:18][N:17]=2)=O)=[N:4][NH:3]1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[CH:12][N:13]=[C:14]([C:16]3[CH:20]=[CH:19][O:18][N:17]=3)[N:4]2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(NCc1n[nH]c(=O)c2ccccc12)c1ccon1
Product: Clc1nn2c(-c3ccon3)ncc2c2ccccc12

Procedure:
The title compound was prepared from isoxazol-3-carboxylic acid (4-oxo-3,4-dihydrophthalazin-1-ylmethyl)amide (Part a) and phosphorus oxychloride according the procedure described in Example 1, Part b. 1H NMR (360 MHz, CDCl3) δ 7.25 (s, 1H), 7.66 (t, J=8 Hz, 1H), 7.86 (t, J=8 Hz, 1H), 7.97 (brs, 1H), 8.09 (d, J=8 Hz, 1H), 8.21 (d, J=8 Hz, 1H), 8.57 (d, J=2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:14]=O)=[N:4][CH:5]=[C:6]([N:8]([CH3:13])[CH:9]([CH3:12])[CH2:10][CH3:11])[N:7]=1.[CH2:16]([NH:23][CH2:24][C@@H:25]([OH:29])[CH2:26][O:27][CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:16]([N:23]([CH2:14][C:3]1[C:2]([Cl:1])=[N:7][C:6]([N:8]([CH3:13])[CH:9]([CH3:12])[CH2:10][CH3:11])=[CH:5][N:4]=1)[CH2:24][C@@H:25]([OH:29])[CH2:26][O:27][CH3:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCC(C)N(C)c1cnc(C=O)c(Cl)n1
Reactant: COC[C@H](O)CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCC(C)N(C)c1cnc(CN(Cc2ccccc2)C[C@@H](O)COC)c(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
To a solution of 3-chloro-5-[methyl(1-methylpropyl)amino]pyrazine-2-carbaldehyde (342 mg), (2R)-1-(benzylamino)-3-methoxypropan-2-ol (351 mg) and acetic acid (258 μl) in acetonitrile (5 mL) was added sodium triacetoxyborohydride (477 mg), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added dropwise saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10-450% ethyl acetate/hexane) to give the title compound (389 mg, 64%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:21]=[N:22][C:23]([C:26]3[C:27](C)=[N:28][N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:30]=3)=[CH:24][CH:25]=2)=[CH:9][N:10](C)[CH:11](C2C=CC=CC=2)C)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH3:11][NH:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)=[CH:24][CH:25]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C(=CN(C)C(C)c2ccccc2)c2ccc(Cl)cc2)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CNCC(c1ccccc1)c1ccc(-c2cn[nH]c2)nc1

Procedure:
To a solution of {2-(4-Chloro-phenyl)-2-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-vinyl}-methyl-(1-phenyl-ethyl)-amine in ethanol was added palladium, 10 wt. % on activated carbon and the reaction mixture was subjected to a hydrogen atmosphere for 17 hours. The mixture was filtered through Celite®, the mother liquor was concentrated, the residue was purified by column chromatography (SiO2), eluting with dichloromethane: methanol: acetic acid: water (240:20:3:2) to dichloromethane: methanol: acetic acid: water (90:18:3:2) to afford the title compound. LC/MS: (PS-A2) Rt 1.59 [M+H]+ 293.18. 1H NMR (Me-d3-OD) δ 2.35 (3H, s), 2.40 (3H, s), 3.25 (2H, s), 4.15-4.20 (1H, t), 7.10-7.18 (1H, m), 7.25 (4H, m), 7.45 (1H, d), 7.67 (1H, dd), 7.80 (1H, s), 8.38 (1H, s).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[NH2:21][CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[CH2:28][CH3:29]>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:21][CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][N:24]2[CH2:28][CH3:29])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN1CCCC1CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCN1CCCC1CNS(=O)(=O)c1ccc(NC(C)=O)cc1
Temperature: 0 °C

Procedure:
4-Acetylaminobenzenesulphonyl chloride (7.3 g, 0.03 mole) was added portionwise to a well stirred mixture of aqueous sodium carbonate (21.2 g. in 250 ml of water) and 2-aminomethyl-1-ethylpyrrolidine (4.0 g. 0.03 mol) in chloroform (250 ml) at about 10°. The ice bath used for cooling was removed. After 2 hours the chloroform layer was separated, dried (MgSO4) and then evaporated under reduced pressure to give a gum, which slowly crystallised (11.6 g). Recrystallisation from cold ethanol, followed by recrystallisation from water gave the pure title compound m.p. 94°-96° C.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH:14](OC)[O:15]C)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>>[NH:1]([C:8]1[N:13]=[C:12]([CH:14]=[O:15])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)c1ccnc(Nc2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=Cc1ccnc(Nc2ccccc2)n1
Temperature: 50 °C
Yield: 75.3 %

Procedure:
A mixture of 2-anilino-4-(dimethoxymethyl)pyrimidine (Method 2; 26.5 g, 0.108 mol) and 3M hydrochloric acid (108 ml, 0.324 mol) was stirred and heated at 50° C. for 18 hours. The reaction mixture was allowed to cool and the pH of the solution adjusted to 9 by careful addition of solid sodium carbonate. The mixture was extracted with EtOAc (5×100 ml). The combined extracts were washed with water (2×100 ml), dried (Na2SO4) and evaporated to give the title compound (16.2 g, 78%) as a brown solid. NMR: (CDCl3): 7.10 (t, 1H), 7.20 (d, 1H), 7.40 (t, 3H), 7.68 (d, 21), 8.64 (d, 1H), 9.90 (s, 1H), m/z 232 [MH+MeOH]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([NH:21][S:22]([C:25]3[S:26][C:27]([CH3:30])=[CH:28][N:29]=3)(=[O:24])=[O:23])[C:18]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])=[C:17]([O:40][CH3:41])[N:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([NH:21][S:22]([C:25]3[S:26][C:27]([CH3:30])=[CH:28][N:29]=3)(=[O:24])=[O:23])[C:18]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])=[C:17]([O:40][CH3:41])[N:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ncc(C)s2)nc(-c2cccc(OCc3ccccc3)c2)nc1OC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ncc(C)s2)nc(-c2cccc(O)c2)nc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.35 g of 5-methyl-thiazole-2-sulfonic acid [2-(3-benzyloxy-phenyl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide dissolved in CH2Cl2 (40 ml) is cooled to 0° C. and treated dropwise with 4.8 ml of a 1M solution of TiCl4 in CH2Cl2. The orange solution is stirred at 0° C. for 0.5 h until the starting material was consumed according to TLC analysis (Me2Cl2/EtOAc: 4/1). The reaction solution was then poured on ice, the product extracted into Me2Cl2 the organic layer dried over Na2SO4 and the solvent removed in vacuo. The residue was washed with ether/hexane to give 5-methyl-thiazole-2-sulfonic acid [2-(3-hydroxy-phenyl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide as an off-white crystalline solid. ISN mass spectrum, m/e 499.1 (M−1 calculated for C22H20N4O6S2: 499).
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C1C=CC2N(O)N=NC=2C=1.[NH2:36][C@H:37]([C:50]([O:52][CH3:53])=[O:51])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].Cl.CN1CCOCC1.C(N=C=NC(C)C)(C)C.S(=O)(=O)(O)O>C1COCC1.O>[NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@@H:2]([C:13]([NH:36][C@H:37]([C:50]([O:52][CH3:53])=[O:51])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: O=C(N[C@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 100.6 %

Procedure:
To a solution of 23.7 g Z-D-Trp-OH in 230 ml THF are added 9.5 g HOBt at RT. A clear colorless solution is formed. Then 20.8 g H-Lys(BOC)-OMe.HCl are added at RT, followed by 7.7 ml N-methylmorpholine. The fine suspension is cooled down to 0° and 11.4 ml diisopropylcarbodiimide added. Stirring 1 hour at 0°, then 3 hours at RT. A solution of 7.0 g sulfuric acid conc. in 120 ml water is added to the suspension. Extraction with 150 ml ethyl acetate, separation of the phases and washing of the organic phase consecutively with 100 ml brine saturated, 100 ml brine 25%, 5% sodium hydrogencarbonate solution. Then the organic phase is dried over MgSO4 and evaporated. The residue is taken up in 250 ml isopropyl acetate and stirred 2 hours at RT. Filtration and drying at 40° gives 40.9 g Z-D-Trp-Lys(BOC)-OMe, white substance. HPLC-conditions: MN Nucleosil 100 A/C 18; 5 micron; 250×4 mm; phase A: 0.24% phosphoric acid, phase B acetonitrile; gradient: from 20 to 80% B in 30 minutes; wavelength 220 nm; flow rate 1.3 ml/min; Temperature 35°: purity 97.8% b.a. (24.2 min).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[C:9]1([C:15]2[CH:16]=[C:17]([CH2:21][CH2:22][C:23](OCC)=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>O1CCCC1.O>[O:24]=[C:23]([CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=1)[CH2:2][C:1]#[N:3]
Reactant: CCOC(=O)CCc1cccc(-c2ccccc2)c1
Reactant: CC#N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: N#CCC(=O)CCc1cccc(-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 2.3 mL (0.044 mole) of acetonitrile in 50 mL of tetrahydrofuran was cooled to about -80° C., and 17.7 mL (0.044 mole) of n-butyllithium (2.5M in hexanes) was added dropwise at a rate to maintain the reaction mixture temperature below -75° C. Upon completion of addition, the reaction mixture was stirred at -78° C. for 30 minutes. After this time a solution of 10.3 grams (0.040 mole) of ethyl 3-(3-phenylphenyl)propanoate in 100 mL of tetrahydrofuran was added dropwise at a rate to maintain the reaction mixture temperature below -75° C. Upon completion of addition, the reaction mixture was stirred at -78° C. for one hour. After this time the reaction mixture was allowed to warm to ambient temperature, then was cooled to about 0° C., and 30 mL of aqueous 6N hydrochloric acid was added dropwise. Upon completion of addition, the reaction mixture was allowed to Warm to ambient temperature where it was stirred for 30 minutes. The mixture was poured into 200 mL of water, and then it was extracted with two 100 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. NMR analysis of the residual oil indicated that it was impure. The oil was dissolved in 10:1 methylene chloride and acetone, and the solution was passed through a column of basic alumina that was deactivated to Level III with water. The eluate was concentrated under reduced pressure, yielding 5.9 grams of 3-oxo-5-(3-phenylphenyl)pentanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](OS(C)(=O)=O)[CH2:10][CH:11]=[CH2:12])=[CH:5][C:4]=1[F:18])#[N:2].[CH3:19][C:20]1[NH:21][CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:21]2[CH:22]=[CH:23][N:24]=[C:20]2[CH3:19])[CH2:10][CH:11]=[CH2:12])=[CH:5][C:4]=1[F:18])#[N:2]
Reactant: Cc1ncc[nH]1
Reactant: C=CCC(OS(C)(=O)=O)c1ccc(C#N)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCC(c1ccc(C#N)c(F)c1)n1ccnc1C
Temperature: 100 °C

Procedure:
To a solution of the methanesulfonate from Step I (17.3 mmol) in 20 mL of DMF was added 2-methylimidazole (4.25 g, 51.8 mmol) and potassium carbonate (7.15 g, 51.8 mmol). The reaction was heated to 100° C. for 3 hours, then cooled to room temperature. The solution was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (3-6% MeOH/CH2Cl2) provided the titled compound.
Reaction SMILES: N1C=CC=CC=1C(O)=O.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:32][C:33]1[CH:38]=[CH:37][C:36](I)=[C:35]([CH3:40])[CH:34]=1>[Cu]I.CS(C)=O>[F:32][C:33]1[CH:38]=[CH:37][C:36]([O:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]3[C:11]([NH2:10])=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:18][CH:19]=2)=[C:35]([CH3:40])[CH:34]=1
Reactant: Cc1cc(F)ccc1I
Reactant: Nc1ncccc1-c1ccc(O)cc1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1Oc1ccc(-c2cccnc2N)cc1
Temperature: 130 °C
Reaction time: 5 h
Yield: 44.8 %

Procedure:
Copper(I) iodide (102 mg) was added to a mixture of picolinic acid (66.1 mg), 4-(2-aminopyridin-3-yl)phenol (500 mg), tripotassium phosphate (1710 mg), 4-fluoro-1-iodo-2-methylbenzene (761 mg) and DMSO (8 mL). The mixture was stirred at 130° C. under nitrogen for 5 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). Water was added and the extracted organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (354 mg) as a yellow solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:33][CH:34]1[CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH:36]1[CH2:37][CH:34]([NH:33][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CNC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a solution of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (100 mg, 0.22 mmol) in DMF (1 mL) was added tert-butyl 3-aminoazetidine-1-carboxylate (41.3 mg, 0.24 mmol), HATU (125 mg, 0.33 mmol), and DIEA (80 μL, 0.44 mmol). The reaction mixture was stirred for 1 h. It was then poured into 100 mL of rapidly stirring water. A peach solid forms and was filtered, washed with water and dried. This solid was treated with TFA in DCM (3 mL 1:1) for 30 minutes. The solvent was then removed, and the product purified by reverse phase HPLC, free based and lyophilized to yield a white solid (37.4 mg, 34% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49-1.79 (m, 6 H) 1.93 (br. s., 2 H) 3.52-3.66 (m, 4 H) 3.94 (s, 3 H) 4.05 (t, J=14.02 Hz, 2 H) 4.56-4.84 (m, 2 H) 7.45-7.58 (m, 2 H) 7.98 (s, 1 H) 8.26 (s, 1 H) 8.28 (d, J=8.34 Hz, 1 H) 8.75 (d, J=7.07 Hz, 1 H). [M+H] calc'd for C24H29F2N7O3, 502; found 502.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].[C-:15]#[N:16].[K+].C(=O)(O)[O-].[Na+]>CCO.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:15]#[N:16])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12]
Reactant: [C-]#N
Reactant: FC(F)(F)Oc1cc(CBr)ccc1Br
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Br)c(OC(F)(F)F)c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
A mixture of 1-bromo-4-(bromomethyl)-2-(trifluoromethoxy)benzene (1 g, 3.0 mmol) in EtOH (20 mL) and water (5 mL) was added potassiumcyanide (390 mg, 6 mmol). The resulting mixture was stirred at 85° C. for 2 h. Sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to afford the crude title product (800 mg, 2.86 mmol). MS (ESI) m/z 279.9 M+, 281.1 [M+2]+.