Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[NH:7][CH3:8]>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:9]=[C:6]([NH:7][CH3:8])[C:5]([NH2:10])=[CH:4][CH:3]=1
Reactant: CNc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CNc1cc(Br)ccc1N
Reaction time: 0.33 h

Procedure:
An orange solution consisting of 5-bromo-N-methyl-2-nitroaniline (1-2, 10.5 g, 45.4 mmol) in Acetic acid (200 ml) was treated with Zinc dust (8.92 g, 136 mmol, 3.0 eq), generating a mild exotherm. The cloudy maroon reaction mixture was capped and stirred for 20 min. The reaction was >80% complete, so an additional amount of Zinc dust (1.0 g, 16 mmol, 0.35 eq) was added and the reaction was stirred for 15 min. LC/MS showed complete reduction, so the reaction mixture was filtered through Celite and washed with MeOH. The residual filtrate was concentrated in vacuo, then partitioned between EtOAc (2×300 ml) and saturated aqueous NaHCO3 (350 ml). The combined organic layers were dried over Na2SO4 and concentrated, affording the title compound, 4-bromo-N2-methylbenzene-1,2-diamine (1-3), as a brown solid with >90% purity. LRMS m/z: Calc'd for C7H9BrN2 (M+H) 202.1, found 202.8.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:22][CH3:23])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=1>>[CH:1]1([CH:7]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=2)[C:9]2[C:10]([CH2:22][CH3:23])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(-c2ccc(OC)cc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: CCc1nn(-c2ccc(OC)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 0 %

Procedure:
Using cyclohexyl[3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]methanol (0.5 g) synthesized in Example 50(1) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.40 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.15 mg, 18%) was obtained as a white solid.
Reaction SMILES: BrC1C(C)(C)OC2C(C=1)=CC=C(OC)C=2.BrC1C=CC(OC)=CC=1[N+]([O-])=O.[CH3:28][O:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35]([C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=3[N+:50]([O-])=O)[C:36]([CH3:41])([CH3:40])[O:37]2)=[CH:32][CH:31]=1>>[CH3:49][O:48][C:45]1[CH:46]=[CH:47][C:42]([CH:35]2[CH2:34][C:33]3[C:38](=[CH:39][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[O:37][C:36]2([CH3:41])[CH3:40])=[C:43]([NH2:50])[CH:44]=1
Reactant: COc1ccc2c(c1)OC(C)(C)C(c1ccc(OC)cc1[N+](=O)[O-])=C2
Agent: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: COc1ccc2c(c1)OC(C)(C)C(Br)=C2
Product: COc1ccc(C2Cc3ccc(OC)cc3OC2(C)C)c(N)c1
Yield: 89.7 %

Procedure:
Synthesized from 3-bromo-7-methoxy-2,2-dimethyl-2H-chromene and 4-bromo-3-nitroanisole according to an analogous synthetic method to Preparation Example 107 described below, 7-methoxy-3-(4-methoxy-2-nitrophenyl)-2,2-dimethyl-2H-chromene (1.2 g) was used according to an analogous synthetic method to Example 30 to provide the title compound (988 mg).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[Si](C)(C)C.CC([Mg]Cl)C.[C:22]1(=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[NH2:11][C:6]1[C:5]2=[CH:4][CH:3]=[C:2]([C:22]3([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[N:10]2[N:9]=[CH:8][N:7]=1
Reactant: Nc1ncnn2c(Br)ccc12
Reactant: O=C1CCCCC1
Agent: CC(C)[Mg]Cl
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: Nc1ncnn2c(C3(O)CCCCC3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-Bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (1.20 g, 5.63 mmol) was dissolved in THF (25 mL) under argon at room temperature. Chlorotrimethylsilane (1.43 mL, 11.27 mmol) was added, and the mixture was stirred at room temperature for 3 h. Then, it was cooled to 0° C., 2-propyl magnesium chloride (11.8 mL of a 2.0 M solution in THF, 23.7 mmol) was added, and stirring was maintained for another 3 h while the reaction mixture was allowed to warm to room temperature. Then, cyclohexanone (0.88 mL, 8.45 mmol) was added, and stirring was continued for 16 h. The reaction was quenched with a mixture (1:1) of concentrated aqueous ammonium chloride solution and ice until the pH reached 6-7. The mixture was extracted with two portions of ethyl acetate, and the combined organic extracts were dried over anhydrous sodium carbonate and concentrated to dryness. The product thus obtained was used without further purification (purity 68% by HPLC). Yield: 1.87 g (97% of th.).
Reaction SMILES: [CH:1]1([C:5]([OH:7])=O)[CH2:4][CH2:3][CH2:2]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.Cl.Cl.[NH2:34][CH2:35][C:36]1[N:41]=[C:40]([C:42]2[N:43]=[C:44]([N:47]=[C:48]([NH2:50])[NH2:49])[S:45][CH:46]=2)[CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([C:5]([NH:34][CH2:35][C:36]2[N:41]=[C:40]([C:42]3[N:43]=[C:44]([N:47]=[C:48]([NH2:50])[NH2:49])[S:45][CH:46]=3)[CH:39]=[CH:38][CH:37]=2)=[O:7])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)C1CCC1
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(N)=Nc1nc(-c2cccc(CNC(=O)C3CCC3)n2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of cyclobutanecarboxylic acid (0.5 ml), 1-hydroxybenzotriazole hydrate (0.8 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.0 g) in N,N-dimethylformamide (5 ml) was stirred for 1 hour at ambient temperature. The above mixture was added to a mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (1.5 g) and triethylamine (1.8 ml) in N,N-dimethylformamide (15 ml) and the mixture was sitrred for 20 hours at ambient temperature. The reaction mixture was added a mixture of ethyl acetate tetrahydrofuran and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was removed by concentration and the residue was recrystallized from a mixture of N,N-dimethylformamide and ethyl acetate to give 4-(6-cyclobutanecarbonylaminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.86 g).
Reaction SMILES: Br[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[C:11]1(=[O:24])[C:16]2[CH:17]=[C:18]3[N:23]([C:15]=2[CH2:14][CH2:13][NH:12]1)[CH2:22][CH2:21][CH2:20][CH2:19]3.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:10][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([N:12]2[CH2:13][CH2:14][C:15]3[N:23]4[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]4)=[CH:17][C:16]=3[C:11]2=[O:24])[N:9]=[CH:8][CH:7]=1
Reactant: O=C1NCCc2c1cc1n2CCCC1
Reactant: O=Cc1c(Cl)ccnc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=Cc1c(Cl)ccnc1N1CCc2c(cc3n2CCCC3)C1=O
Temperature: 80 °C
Yield: 50 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (50 mL), 2-bromo-4-chloronicotin-aldehyde 103a (1.4 g, 6.4 mmol), 3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-1(2H)-one 112d (0.6 g, 3.2 mmol), Pd2(dba)3 (293 mg, 0.32 mmol), XantPhos (370 mg, 0.64 mmol), and potassium carbonate (627 mg, 6.4 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 80° C. overnight. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM/CH3OH (20:1, V/V) to afford 139a (528 mg, 50%) as a yellow solid. MS: [M+H]+ 330. 1H NMR (500 MHz, CDCl3) δ 10.09 (s, 1H), 8.37 (d, J=5.5, 1H), 7.16 (d, J=5.5, 1H), 6.25 (s, 1H), 4.29-4.32 (m, 2H), 3.83-3.86 (m, 2H), 2.96-2.99 (m, 2H), 2.75-2.78 (m, 2H), 2.00-2.07 (m, 2H), 1.82-1.85 (m, 2H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]([O:13]C)=[O:12])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]([OH:13])=[O:12])[CH2:9][CH2:10]2)[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)C1(c2cncc(Br)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C1(c2cncc(Br)c2)CC1
Temperature: 25 °C

Procedure:
To a solution of the title compound from Example 71 Step B (100 mg, 0.390 mmol) in tetrahydrofuran (2.0 mL) was added aqueous 1 N sodium hydroxide solution (0.390 ml, 0.390 mmol). After stirring for several hours at room temperature, the reaction was concentrated under reduced pressure to provide the title compound: LCMS m/z 241.95 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.58 (s, 1H), 8.53 (s, 1H), 7.86 (s, 1H), 1.76-1.74 (m, 2H), 1.29-1.27 (m, 2H).
Reaction SMILES: [Si](O[C@@H](CC)C(O)=O)(C(C)(C)C)(C1C=CC=CC=1)[C:2]1C=CC=CC=1.[NH2:25][CH2:26][CH2:27][CH2:28][C@:29]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:33]([C:34](=[O:39])[C@@H:35]([O:37][CH3:38])[CH3:36])[N:32]=[C:31]([C:40]2[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=2[F:47])[S:30]1>>[NH2:25][CH2:26][CH2:27][CH2:28][C@@:29]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:33]([C:34](=[O:39])[C@@H:35]([O:37][CH3:38])[CH2:36][CH3:2])[N:32]=[C:31]([C:40]2[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=2[F:47])[S:30]1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1
Reactant: CC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Product: CC[C@H](OC)C(=O)N1N=C(c2cc(F)ccc2F)S[C@]1(CCCN)c1ccccc1

Procedure:
Prepared as in Example 71 using (S)-2-(tert-butyldiphenylsilyloxy)butanoic acid in place of (S)-2-(tert-butyldiphenylsilyloxy)propanoic acid. MS APCI (+) m/z 434 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.46 (m, 3H), 7.36 (app t, 2H, J=8 Hz), 7.13 (m, 2H), 4.54 (dd, 1H, J=8 Hz, 4 Hz), 3.31 (s, 3H), 3.23 (m, 1H), 2.84 (m, 2H), 2.44 (m, 1H), 1.94 (m, 2H), 1.78 (m, 1H), 1.48 (m, 1H), 1.08 (t, 3H, J=7 Hz). Stereochemistry was assigned by comparison to (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[N:8]([C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)CCN(c1ccc([N+](=O)[O-])cc1)C2Cc1ccc(OCc2ccccc2)cc1
Temperature: 120 °C
Yield: 89.1 %

Procedure:
A solution of 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (2.10 g, 5.84 mmol) and 1-fluoro-4-nitrobenzene (1.65 g, 11.7 mmol) in 40 mL of DMSO was treated with powdered K2CO3 (1.62 g, 11.7 mmol) and the reaction mixture was warmed at 120° C. for 12 h. The reaction mixture was cooled to room temperature and 300 mL of water was added. The aqueous layer was extracted with CH2Cl2 and the combined organic layer was washed with water, dried over MgSO4, then concentrated under reduced pressure. The crude product was purified by flash chromatography to provide the title compound (2.50 g, 89%). ES-MS, (m/z) 481 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.CN1CCOCC1>CO>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: COc1ccc(CN)cc1
Solvent: CN1CCOCC1
Solvent: CO
Product: COc1ccc(CNS(=O)(=O)c2ccc3nc(-c4c(C)n[nH]c4N)sc3c2)cc1
Yield: 11.6 %

Procedure:
the title compound (15 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), 4-methoxybenzylamine (79 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 430.5 (M+1, 100%). Yield=11%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:17])(C)C)[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][OH:17])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C(C)(C)O)cc(-c3ccc(Cl)cc3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(CO)cc(-c4ccc(Cl)cc4)nc23)cc1

Procedure:
The title compound was prepared from 2-[5-(4-chloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidin-7-yl]-propan-2-ol (example C.13) (28 mg, 0.10 mmol) and 4-bromo-benzenesulfonamide (24 mg, 0.10 mmol) according to general procedure II. Obtained as a yellow solid (12 mg, 27%). MS (ISP) 439.0 [(M+H)+]; mp 238-240° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]([OH:30])[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:14][CH:13]=1)(C)(C)C.[H][H]>[Pd].CO>[C:26]([O:25][C:23](=[O:24])[NH:22][CH2:21][CH:20]([OH:30])[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])=[CH:13][CH:14]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(OCC(O)CNC(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(O)COc1ccc(CCCCN)cc1
Yield: 123.3 %

Procedure:
A suspension of 41 (0.8 g, 1.69 mmol) with 10% palladium on carbon (0.40 g, wet) in methanol (30 mL) was stirred for 3 h at room temperature under atmospheric pressure of hydrogen. The mixture was then filtered through a silica gel pad; the solvent was evaporated to provide 42 (0.705 g, 99%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.55 (m, 4H), 2.58 (m, 4H), 2.71 (m, 2H), 3.29 (m, 1H), 3.45 (m, 2H), 3.92 (m, 2H), 4.10 (br s, 1H), 5.10 (br s, 1H), 6.81 (d, 2H), 7.08 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:56][C:57]1[CH:62]=[CH:61][C:60]([C:63]2([NH2:66])[CH2:65][CH2:64]2)=[CH:59][CH:58]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O.CC(=O)OCC>[Br:56][C:57]1[CH:58]=[CH:59][C:60]([C:63]2([NH:66][C:21]([C:20]3[C:14]4[C:15](=[N:16][CH:17]=[C:12]([C:6]5[C:5]6[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=6)[N:8]([CH3:11])[N:7]=5)[N:13]=4)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[CH:19]=3)=[O:23])[CH2:64][CH2:65]2)=[CH:61][CH:62]=1
Reactant: NC1(c2ccc(Br)cc2)CC1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2(c4ccc(Br)cc4)CC2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Yield: 91.2 %

Procedure:
To a stirred suspension of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (150 mg, 0.34 mmol) in DMF (5 mL) were added HATU (258 mg, 0.68 mmol) and 1-(4-bromo-phenyl)-cyclopropanamine (108 mg, 0.51 mmol) followed by DIPEA (0.24 mL, 1.36 mmol) at room temperature under nitrogen atmosphere. The resulting light yellow solution was stirred for 15 h by which time TLC analysis (Hex:EA, 1:1, Rf=0.5) indicated the presence of a new spot. Then, the reaction mixture was diluted with water and the organic compound was extracted into EtOAc (3×25 mL). The combined extracts were washed with brine solution and then dried over anhydrous MgSO4. Filtration of the drying agent and concentration of the filtrate gave the crude product which was purified using by ISCO column chromatography (40 g) eluting with EtOAc in hexanes (0-60%) in 10 minutes. The desired fractions were combined and the solvent was removed under vacuum to obtain 197 mg (91%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(4-bromo-phenyl)-cyclopropyl]-amide as a off-white solid.
Reaction SMILES: C(OC(=O)[N:10]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][C:43]=1[CH3:49])[CH2:11][C@H:12]([NH:18][C:19](=[O:40])[CH2:20][C:21](=[O:39])[NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([NH:33][C:34]([NH:36][CH2:37][CH3:38])=[O:35])[CH:24]=1)[C@@H:13]([OH:17])[CH2:14][CH2:15][CH3:16])C1C=CC=CC=1>CO.[Pd]>[CH3:49][C:43]1[CH:44]=[C:45]([CH3:48])[CH:46]=[CH:47][C:42]=1[CH2:41][NH:10][CH2:11][C@H:12]([NH:18][C:19](=[O:40])[CH2:20][C:21]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([NH:33][C:34]([NH:36][CH2:37][CH3:38])=[O:35])[CH:24]=1)=[O:39])[C@@H:13]([OH:17])[CH2:14][CH2:15][CH3:16]
Reactant: CCC[C@H](O)[C@H](CN(Cc1ccc(C)cc1C)C(=O)OCc1ccccc1)NC(=O)CC(=O)Nc1cc(NC(=O)NCC)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CCC[C@H](O)[C@H](CNCc1ccc(C)cc1C)NC(=O)CC(=O)Nc1cc(NC(=O)NCC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound (2,4-dimethyl-benzyl)-[(2S,3S)-2-{2-[3-(3-ethyl-ureido)-5-trifluoromethyl-phenylcarbamoyl]-acetylamino}-3-hydroxy-hexyl]-carbamic acid benzyl ester was dissolved in MeOH (2 mL). This solution was charged with 5% Pd/C, Degussa style (11 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=566.3.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.C(=O)(O)[O-].[Na+].[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27].O>C(Cl)(Cl)Cl>[Br:9][C:7]1[CH:6]=[CH:5][C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[C:3]([NH:2][C:26]([N:25]([CH3:29])[CH3:24])=[O:27])[CH:8]=1
Reactant: Nc1cc(Br)ccc1N1CCc2ccccc21
Reactant: CN(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)C(=O)Nc1cc(Br)ccc1N1CCc2ccccc21
Reaction time: 0.17 h
Yield: 40.3 %

Procedure:
To a stirred mixture, under nitrogen, of 28.9 g (0.10 mole) of 1-(2-amino-4-bromophenyl)indoline hydrochloride and 16.8 g (0.20 mole) of anhydrous powdered sodium bicarbonate in 500 ml of chloroform was added a solution of 21.5 g (0.20 mole) of dimethylcarbamyl chloride in 25 ml of chloroform, over a 10 minute period. The mixture was heated under reflux for 7 hours, and 8.4 g (0.10 mole) of sodium bicarbonate and 10.7 g (0.10 mole) of the dimethylcarbamyl chloride were added. After heating under reflux for 2 days, equivalent amounts (8.4 g of sodium bicarbonate and 10.7 g of dimethylcarbamyl chloride) were added. After three days under reflux, the mixture was cooled and 500 ml of water was added. The phases were stirred vigorously for 0.5 hours and separated. The organic phase was washed three times with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in 200 ml of dichloromethane and adsorbed on a chromatography column containing 1 kg of silica gel packed in and eluted with dichloromethane. The fractions containing product were combined and concentrated to afford 14.5 g (40%) of product. Recrystallization from toluene (charcoal)/hexane gave the analytical sample, mp 119-121° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:22]S(C2C=CC(C)=CC=2)(=O)=O)=[N:7][N:8]2[C:13]=1[CH:12]=[N:11][N:10]=[C:9]2[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])([CH3:4])([CH3:3])[CH3:2].[CH3:33][N:34]1[C:38]([CH2:39]O)=[N:37][CH:36]=[N:35]1.[H-].[Na+]>CN(C)C=O>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:9]1[N:8]2[N:7]=[C:6]([O:22][CH2:39][C:38]3[N:34]([CH3:33])[N:35]=[CH:36][N:37]=3)[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:13]2[CH:12]=[N:11][N:10]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4cc(F)ccc4F)nncc3c2C(C)(C)C)cc1
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3cc(F)ccc3F)nncc2c1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from Example 21, step e) (0.4 g, 0.0009 mol) and (2-methyl-2H-[1,2,4]triazol-3-yl)methanol (0.12 g, 0.0011 mol) were dissolved in dry N,N-dimethylformamide (10 ml) under nitrogen and sodium hydride (60% wt in oil) (0.035 g, 0.0009 mol) was added. The solution was stirred at room temperature for 3 h after which solvent was removed in vacuo and the residue was purified using silica gel chromatography with 0%→60% ethyl acetate/dichloromethane as eluent. Trituration with isohexane and recrystallisation from ethyl acetate/isohexane gave the required product (0.137 g, mp=144° C.). Data for the title compound: 1H NMR (400 MHz, CDCl3) δ 1.50 (9H, s), 3.84 (3H, s), 5.48 (2H, s), 7.18-7.26 (1H, m), 7.27-7.35 (1H, m), 7.47 (1H, m), 7.87 (1H, s), 9.41 (1H, s); MS (ES+) m/e 400 [MH]+; Anal. Found: C, 57.30; H, 4.64; N, 24.64%. C19H19F2N7O requires: C, 57.14; H, 4.79; N, 24.55%.
Reaction SMILES: Cl.OC(COC1C=CC([Cl:26])=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.[OH:28][CH:29]([CH2:44][O:45][C:46]1[C:55]2C(=[CH:51][CH:52]=[CH:53][CH:54]=2)C=[CH:48][CH:47]=1)[CH2:30][NH:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.Cl.OC(COC1C=CC(OC)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:26].[OH:28][CH:29]([CH2:44][O:45][C:46]1[CH:55]=[CH:54][C:53]([CH2:52][CH3:51])=[CH:48][CH:47]=1)[CH2:30][NH:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2cccc3ccccc23)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: Cl
Product: CCc1ccc(OCC(O)CNC(C)(C)Cc2ccc(OC)cc2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 342 (M−15,0.1), 237 (15), 236 (100), 163 (5), 121 (19), 114 (7).