Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:22])[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=1.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:23]([O:27][C:28](=[O:29])[NH:30][C@H:31]([C:32](=[O:33])[NH:21][C:20]1[C:15]([NH:14][C:10]2[CH:9]=[C:8]([CH3:22])[CH:13]=[CH:12][CH:11]=2)=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:35])([CH3:24])([CH3:25])[CH3:26]
Reactant: Cc1cccc(Nc2ncccc2N)c1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(Nc2ncccc2NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (1.7 mL, 12.0 mmol) was added to a mixture of N2-m-tolylpyridine-2,3-diamine (600 mg, 3.01 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.03 g, 5.42 mmol), HOAt (740 mg, 5.42 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.04 g, 5.42 mmol) in anhydrous DCM (25 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 15 min then slowly warmed to RT. Stirring at RT was continued for 16 h. After re-cooling the mixture to 0° C., additional amounts of (S)-2-tertbutoxycarbonylaminopropionic acid (220 mg, 1.20 mmol), HOAt (160 mg, 1.20 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (230 mg, 1.20 mmol) and triethylamine (0.41 mL, 3.01 mmol) were added. The reaction mixture was stirred at 0° C. for 15 min then slowly warmed to RT. Stirring at RT was continued for 72 h. The reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was extracted with DCM (×3) and the combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo to afford the title compound as an off-white foam. The crude material was used without further purification in the following step. Yield assumed to be quantitative. LCMS (Method C): RT 2.70 min [M+H]+ 371.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[N:20][C:21]([N:24]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]5)=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)[N:3]=1.Cl.O1CCOCC1>O>[CH3:43][N:40]1[CH2:41][CH2:42][N:37]([C:4]2[CH:5]=[C:6]([N:8]3[CH2:17][CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:18]5[CH:19]=[N:20][C:21]([N:24]6[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]6)=[N:22][CH:23]=5)=[CH:13][CH:14]=4)[CH2:9]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:38][CH2:39]1
Reactant: CN1CCN(c2cc(N3CCc4ccc(-c5cnc(N6CCN(C(=O)OC(C)(C)C)CC6)nc5)cc4C3)nc(N)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(c2cc(N3CCc4ccc(-c5cnc(N6CCNCC6)nc5)cc4C3)nc(N)n2)CC1

Procedure:
A mixture of tert-butyl 4-(5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}pyrimidin-2-yl)piperazine-1-carboxylate (10 mg, 0.02 mmol, Example 8) and a solution of hydrogen chloride in 1,4-dioxane (0.01704 mL, 0.06817 mmol, 4 M) with a few drops of water was stirred at r.t. for 2 hours. The solution was concentrated. The residue was dissolved in MeOH and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=487.4.
Reaction SMILES: [C:1]1([C:7]([CH:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)=[CH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd]>[C:1]1([CH:7]([CH:16]2[CH2:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:24]2)[CH2:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCN(CC)CCC=C(c1ccccc1)C1Cc2ccccc2C1
Agent: [Pd]
Product: CCN(CC)CCCC(c1ccccc1)C1Cc2ccccc2C1

Procedure:
A solution of 23.5 g. of 1-phenyl-1-(2-indanyl)-4-diethylamino-1-butene in 375 cc. of 95 percent (v/v) ethanolbenzene was stirred while 1.5 g. of 5 percent palladium on carbon was added in one portion. The reaction mixture was stirred for six hours at 24°C. under a hydrogen gas atmosphere at 60 p.s.i. After filtering off the hydrogenation catalyst, the filtrate was concentrated to dryness under reduced pressure to provide 1-phenyl-1-(2-indanyl)-4-diethylaminobutane.
Reaction SMILES: O.[CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])[CH3:3].[N+:12]([O-])([OH:14])=[O:13]>CCOCC>[CH:2]([C:5]1[C:6]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: O
Product: CC(C)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred mixture of 200 ml of water, 200 ml of ether and 20.0 g of 2-isopropylphenol was added dropwise 22.0 ml of 61% nitric acid, and then the mixture was reacted with stirring at room temperature for 2 days. The reaction mixture was extracted with 200 ml of ethyl acetate and dried with anhydrous sodium sulfate. After, the drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform-n-hexane (1:1)] to give 7.69 g of 6-isopropyl-2-nitrophenol.
Reaction SMILES: [C@@H:1]1([N:10]2[CH2:17][CH2:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[BH4-].[Na+]>O>[OH:15][CH:14]1[CH2:16][CH2:17][N:10]([C@@H:1]2[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[C:11](=[O:12])[NH:13]1
Reactant: O=C1CCN([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C(=O)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=C1NC(O)CCN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice cold solution of 246.2 mg. (1.0 mmole) of 5,6-dihydrouridine in 10 ml. of water at pH 7.5-8 was added 37.8 mg. (1.0 mmole-4.0 equivalents) of sodium borohydride. After 35 minutes the reaction mixture was set in a freezer overnight and put into an ice bath the next morning. The excess sodium borohydride was destroyed by addition of dilute acetic acid, the mixture was filtered and the filtrate lyophilized to give 4-hydroxy-1-β-D-ribofuranosyl-tetrahydro-2(1H)-pyrimidinone and a small amount of 1-β-D-ribofuranosyl-tetrahydro-2(1H)-pyrimidinone.
Reaction SMILES: [O:1]1[C@@H:3]2[C@H:4](O)[C@@H:5]3[C@@H:14]([C@@:15]4([CH3:27])[CH2:16][CH2:17][C@H:18]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:19][C@@:2]124)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]3[C@@H:7]2[CH2:29][C@@H:8]2[C:9]1=[O:28].[Cl:31]C(Cl)(Cl)C(C(Cl)(Cl)Cl)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:31][C@@H:4]1[C@H:3]2[O:1][C@:2]32[C@:15]([CH3:27])([CH2:16][CH2:17][C@H:18]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:19]3)[C@@H:14]2[C@@H:5]1[C@H:6]1[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C:9](=[O:28])[C@H:8]2[CH2:29][C@@H:7]12
Reactant: O=C(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3[C@@H](O)[C@H]3O[C@]32C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3[C@H](Cl)[C@H]3O[C@]32C1
Temperature: 1 °C
Reaction time: 1 h

Procedure:
A solution of 5,6β-epoxy-7β-hydroxy-15β,16β-methylen-3β-pivaloyloxy-5β-androstan-17-one (1.66 g, 0.004 mol) in dichloromethane (8 mL) is treated with hexachloroacetone (2 mL, 0.013 mol) and cooled to 0-2° C. Triphenylphosphine (1.53 g, 0.0044 mol) in dichloromethane (4 mL) is added dropwise and the mixture is stirred for one hour at 3-4° C., then for an additional hour at 10-15° C.
Reaction SMILES: N(OCCC(C)C)=O.[Cl:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][CH:15]=1.[Cl:18][C:19]1[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[CH:22][C:20]=1N>>[Cl:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][C:15]=1[C:20]1[CH:22]=[C:23]([Cl:27])[C:24]([Cl:26])=[CH:25][C:19]=1[Cl:18]
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Reactant: COc1cccc(Cl)c1
Agent: CC(C)CCON=O
Product: COc1ccc(-c2cc(Cl)c(Cl)cc2Cl)c(Cl)c1
Reaction time: 18 h

Procedure:
Isoamyl nitrite (18.8 mL, 0.140 mol) was added portionwise over the course of 1 hour to a mixture of 3-chloroanisole (100 g, 0.70 mol) and 2,4,5-trichloroaniline (13.75 g, 0.070 mol) at 120° C. under nitrogen and the reaction was allowed to stir an additional 18 hours, and then distilled (0.2 mmHg, 160-185° C.) to yield 14.07 g (62%). A 300 mg portion of the distillate was further purified via flash chromatography (silica gel, hexane eluent). Fraction 1 (32.2 mg, Rf=0.33; GC RT=14.44 minutes) was identified as 2′,4,4′,5′-tetrachloro-2-methoxybiphenyl. Fraction 2 (75.2 mg, Rf=0.22) contained a mixture of two products in a 40:60 ratio. Through subsequent demethylation and separation, these were determined to be the 2,2′,4′,5′-tetrachloro-6-methoxy and 2,2′,4′,5′-tetrachloro-4-methoxybiphenyl derivatives (GC retention time=14.01, 14.69 minutes respectively).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH:12]=O)[N:11]=[C:4]2[N:3]=1.[CH:14]1([C:19]2([CH2:27][CH2:28][C:29]3[CH:34]=[C:33]([F:35])[C:32]([OH:36])=[C:31]([CH2:37][CH3:38])[CH:30]=3)[O:24][C:23](=[O:25])[CH2:22][C:21](=[O:26])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[CH:14]1([C:19]2([CH2:27][CH2:28][C:29]3[CH:34]=[C:33]([F:35])[C:32]([OH:36])=[C:31]([CH2:37][CH3:38])[CH:30]=3)[O:24][C:23](=[O:25])[C:22]([CH2:12][C:10]3[N:11]=[C:4]4[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]4[N:9]=3)=[C:21]([OH:26])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(F)c1O
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Solvent: CO
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)cc(F)c1O
Reaction time: 0.25 h

Procedure:
5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.2 g, 0.57 mmol) was added to a solution of 6-Cyclopentyl-6-[2-(3-ethyl-5-fluoro-4-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione (0.2 g, 0.53 mmol) in MeOH (6 mL). The reaction mixture was stirred for 15 mins and then treated with borane-dimethylamine complex (50 mg, 0.86 mmoL). After 15 hours the reaction mixture was quenched with 1N HCl and extracted with 10% MeOH in CH2Cl2. The combined organic layers were concentrated and recrystallized from EtOAc to give the product as a white soild (0.15 g, 52%). 1H NMR (400 MHz, DMSO-d6): δ 1.09 (t, J=7.3 Hz, 3 H), 1.43–1.72 (br m, 8 H), 2.05–2.17 (m, 2 H), 2.43 (m, 1 H), 2.48–2.58 (m, 10 H), 2.66 (d, J=17.4 Hz, 1 H), 2.81 (d, J=17.4 Hz, 1 H), 3.74 (d, J=16.2 Hz, 1 H), 3.85 (d, J=16.2 Hz, 1 H), 6.76 (s, 1 H), 6.84 (d, J=11.6 Hz, 1 H) 7.07 (s, 1 H), 9.08 (s, 1 H), 11.01 (s, 1 H). MS: C28H32N4O4F (M+H+) 509.10.
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22](=[O:27])[C:23]([O:25]C)=[O:24])[C:16]([CH3:20])=[CH:17][C:18]=2[Br:19])=[C:6]([CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33])[C:5]=1[OH:36])(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22](=[O:27])[C:23]([OH:25])=[O:24])[C:16]([CH3:20])=[CH:17][C:18]=2[Br:19])=[C:6]([CH2:30][CH2:31][C:32]([F:33])([F:34])[F:35])[C:5]=1[OH:36])(=[O:3])[CH3:2]
Reactant: COC(=O)C(=O)Nc1cc(OCCCOc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)c(Br)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1ccc(OCCCOc2cc(NC(=O)C(=O)O)c(C)cc2Br)c(CCC(F)(F)F)c1O

Procedure:
A suspension of 1.75 g (3 mmol) of methyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-bromo-6-methyl-phenyl}}-oxamate (Example 2) in 30 ml of methanol and 3.2 ml of N sodium hydroxide solution is refluxed for 60 minutes. the reaction mixture is concentrated under reduced pressure, the residue is dissolved in acetone and dilute sodium hydroxide solution and the solution is acidified with dilute hydrochloric acid. The product which has precipitated is filtered off and washed neutral with water. N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-bromo-6-methyl-phenyl}}-oxamic acid of melting point 207°-209° is thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](O)=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=2[N:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][N:52]([CH3:58])[CH2:53][CH2:54][CH2:55][NH:56][CH3:57]>ClCCl>[CH3:51][N:52]([CH3:58])[CH2:53][CH2:54][CH2:55][N:56]([CH3:57])[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:17]3[NH:21][C:20]4[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:19]=4[N:18]=3)[CH:4]=2)[CH2:13][CH2:12]1)=[O:15]
Reactant: O=C(O)C1CCN(c2ccc(Cl)c(-c3nc4cc(F)ccc4[nH]3)c2)CC1
Reactant: CNCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)CCCN(C)C(=O)C1CCN(c2ccc(Cl)c(-c3nc4cc(F)ccc4[nH]3)c2)CC1
Temperature: 35 °C
Yield: 48.9 %

Procedure:
Method H—Step a To a vial with 1-[4-Chloro-3-(5-fluoro-1H-benzoimidazol-2-yl)-phenyl]-piperidine-4-carboxylic acid (obtained as described in general method 3,4, step e) (0.10 g, 0.26 mmol) and HATU (0.10 g, 0.27 mmol) in dichloromethane (2 mL), TEA (0.07 mL, 0.54 mmol) and N,N,N′-trimethyl-1,3-propanediamine (0.32 mmol, 0.05 mL) were added. The reaction mixture was heated at 35° C. overnight, solvent was removed and the crude was purified by PrepHPLC and SCX column to obtain 0.06 g of the title compound (49%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[N:7]=[C:6]2[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[N+]([NH:31][C:32](N)=[O:33])([O-])=O.O>CN(C=O)C>[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=1)[N:7]=[C:6]2[CH:22]1[CH2:27][CH2:26][N:25]([C:32]([NH2:31])=[O:33])[CH2:24][CH2:23]1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: Fc1ccc2c(c1)c(C1CCNCC1)nn2-c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)N1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
To a solution of 5-fluoro-1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole free base of Example 124 (6.3 g, 0.017 moles) in DMF (100 ml) was added nitrourea (2.2 g, 0.021 moles). The mixture was warmed on a steam bath until gas began to evolve and was then stirred at ambient temperature for 4 hours. The mixture was then poured into H2O and the product extracted (dichloromethane), dried (MgSO4), and concentrated to yield 6.9 of an oil. The oil was triturated with water to produce 6.9 of a solid. The product was purified by high pressure liquid chromatography (silica gel 100% ethyl acetate) followed by recrystallization from isopropyl alcohol to yield 2.75 g (39%) of 4-[5-fluoro-1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboxamide, mp 172°-174°.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:14]3[C:9]([C:10]([NH2:15])=[N:11][CH:12]=[N:13]3)=[C:8]([C:16]3[CH:17]=[CH:18][C:19]4[C:23]([CH:24]=3)=[N:22][N:21]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=4)[CH:7]=2)[CH2:2]1.[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:25]([N:21]1[CH:20]=[C:19]2[C:23]([CH:24]=[C:16]([C:8]3[CH:7]=[C:6]([CH2:5][CH:3]4[CH2:4][N:1]([C:35](=[O:36])[CH2:34][N:33]([CH3:38])[CH3:32])[CH2:2]4)[N:14]4[C:9]=3[C:10]([NH2:15])=[N:11][CH:12]=[N:13]4)[CH:17]=[CH:18]2)=[N:22]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ncnn2c(CC3CNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CC(Cc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.2 %

Procedure:
A mixture of 7-(azetidin-3-ylmethyl)-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.20 mmol), N,N-dimethylglycine (24 mg, 0.23 mmol), EDCl (41 mg, 0.22 mmol), HOBt (29 mg, 0.22 mmol), and N,N-diisopropylethylamine (102 μL, 0.59 mmol) in DMF (1.8 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 30% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 21 mg (22%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.90 (s, 1 H), 7.79 (d, 1 H), 7.58 (s, 1 H), 7.26-7.39 (m, 5 H), 7.13 (dd, 1 H), 6.62 (s, 1 H), 5.65 (s, 2 H), 4.26 (t, 1 H), 4.00 (t, 1 H), 3.90 (dd, 1 H), 3.66 (dd, 1 H), 3.31-3.21 (m, 4 H), 2.99-3.11 (m, 1 H), 2.30 (s, 6 H); ES-MS m/z 495.47 [M+H]+, HPLC RT (min) 2.03.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:66][CH2:67][C:68]([NH:70][C@@H:71]([C:79]([OH:81])=[O:80])[CH2:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1)=[O:69]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([NH:66][CH2:67][C:68]([NH:70][C@@H:71]([C:79]([OH:81])=[O:80])[CH2:72][CH:73]4[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]4)=[O:69])=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(Cl)cc2)cc1
Reactant: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(Cl)cc2)cc1)NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a stirred solution of {4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-oxoethyl]thio}-1-(4-chlorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (35.4 mg, 0.067 mmol)) in DMF (3 ml) was added N-methylmorpholine (35 μl, 0.23 mmol). TBTU (29.3 mg, 0.091 mmol) was added and the reaction mixture was stirred at 30° C. for 1 hour. Glycyl-3-cyclohexyl-D-alanine (18.4 mg, 0.081 mmol) was added and the mixture was stirred at ambient temperature for 60 hours. The formation of the ketone of the title compound was confirmed. M/z: 736.67 (M+1) and 734.71 (M−1). Without further purification, methanol (2 ml) and sodium borohydride (28.0 mg, 0.740 mmol) was added and the mixture was stirred for 20 minutes. Ammonium acetate (38.4 mg) was added and the solution was purified with preparative HPLC on a C8 column, UV 240/260 nm. A gradient from 20 to 45 MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The remaining water solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The organic phase was passed through a phase separator and concentrated under reduced pressure. The residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained 1H-NMR (400 MHz, DMSO-d6): 0.70-1.68 (m, 13H), 2.78-2.88 (m, 2H), 3.75 (d, 2H), 4.13-4.21 (m, 1H), 4.23-4.28 (m, 1H), 4.49 (s, 2H), 4.56-4.64 (m, 1H), 5.02 (d, 0.5H), 5.04 (d, 0.5H), 5.56 (b, 1H), 6.70-6.79 (m, 2H), 6.82 (s, 1H), 6.96 (d, 2H), 7.18 (d, 2H), 7.30-7.37 (m, 4H), 8.04 (b, 1H), 8.20 (t, 1H). M/z: 736.69 (M−1).
Reaction SMILES: C([O:5][C:6](=[O:38])[C@@H:7]1[CH2:11][C@H:10]([CH2:12][N:13](C(OC(C)(C)C)=O)[C:14]([NH2:23])=[N:15]C(OC(C)(C)C)=O)[CH2:9][N:8]1C(OC(C)(C)C)=O)(C)(C)C.[ClH:39]>O1CCOCC1>[ClH:39].[ClH:39].[NH:13]([CH2:12][C@@H:10]1[CH2:9][NH:8][C@H:7]([C:6]([OH:38])=[O:5])[CH2:11]1)[C:14]([NH2:23])=[NH:15]
Reactant: CC(C)(C)OC(=O)N=C(N)N(C[C@H]1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)NC[C@@H]1CN[C@H](C(=O)O)C1

Procedure:
(4S)-1-(tert-Butyloxycarbonyl)-4-[N,N'-bis(tert-butyloxycarbonyl)guanidinomethyl]-L-proline tert-butyl ester (81 mg, 0.149 mmol) was treated with 4N HCl in dioxane (1 mL) at room temperature overnight. The reaction mixture was evaporated under diminished pressure, coevaporated several times with diethyl ether and several times with methanol. The product was dried under high vacuum; yield 38.7 mg (100%). Mass spectrum: m/z 187 (M+1); 400 MHz 1H NMR (CD3OD): δ1.85 (m, 1H); 2.61-2.80 (m, 2H); 3.13 (dd, 1H); 3.58 (dd, 1H); 4.47 (dd, 1H).
Reaction SMILES: Br[C:2]1[C:3](Br)=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:19]1([CH3:28])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]([C:3]2[CH:2]=[CH:12][CH:11]=[CH:10][C:4]=2[CH3:5])=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(Br)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2C)c(C(=O)OCC)cc1-c1ccccc1C

Procedure:
60 g (160 mmol) of diethyl dibromoterephthalate, 43 g (320 mmol) of o-tolylboronic acid, 365 mg (0.32 mmol) of Pd(PPh3)4 and 92 g (660 mmol) of K2CO3 are heated at the boil for 4 h in 300 ml of toluene and 300 ml of water. The mixture is subsequently partitioned between toluene and water, and the organic phase is washed three times with water and dried over Na2SO4. The residue remaining is recrystallised twice from heptane to give colourless crystals. The yield is 51 g (127 mmol, 81%).
Reaction SMILES: [Br:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[C:4](O)=[O:5].C1(C(Cl)(Cl)[Cl:18])C=CC=CC=1>>[Br:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[C:4]([Cl:18])=[O:5]
Reactant: ClC(Cl)(Cl)c1ccccc1
Reactant: O=C(O)C(F)(F)C(F)(F)Br
Product: O=C(Cl)C(F)(F)C(F)(F)Br
Yield: 70.8 %

Procedure:
A mixture of 375.9 g (1.67 mol) of 3-bromotetrafluoropropionic acid, 10 g of ferric chloride, and 488.7 g (2.50 mol) of benzotrichloride was refluxed for 1.5 h, then crude product was removed, bp about 60°. Redistillation gave 287.9 g (71%) of 3-bromotetrafluoropropionyl chloride, bp 67°-68°. IR (CCl4): 5.53 (C=O). ##STR44##
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]2[C:12]([I:13])=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>CN(C)C=O>[Cl:3][C:4]1[N:5]=[C:6]2[C:12]([I:13])=[CH:11][N:10]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:7]2=[N:8][CH:9]=1
Reactant: Clc1cnc2[nH]cc(I)c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydride (140 mg, 3.5 mmol) was added to an ice-cold solution of 2-chloro-7-iodo-5H-pyrrolo[2,3-b]pyrazine (5) (820mg, 2.9mmol) in dimethylformamide (7 ml) under nitrogen. After 30 minutes tosyl chloride (570mg, 3mmol) was added to the reaction mixture and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then quenched with water (15 ml). An off white solid was filtered off and dried in vacuo (950 mg, 75%). MS(ES+) 434.