Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1([O:37][C:38](=O)[NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]3[N:50]([CH3:51])[N:49]=[N:48][N:47]=3)[CH:41]=2)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:38]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]3[N:50]([CH3:51])[N:49]=[N:48][N:47]=3)[CH:41]=2)=[O:37])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 19 h
Yield: 74.8 %

Procedure:
In a dry flask (3R,4R)-4-amino-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (350 mg, 0.834 mmol) was dissolved in dimethylformamide (5 mL) and [3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester (285 mg, 0.965 mmol) was added. The reaction mixture was stirred for 19 hours. The reaction mixture was diluted with ethyl acetate and extracted three times with water. The combined aqueous extracts were extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with 70-100% ethyl acetate/hexanes to give a solid (387 mg, 75%). A small amount was further purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (33 mg, 62%). 1H NMR (300 MHz, CDCl3), δ: 7.88 (m, 1H), 7.49 (m, 2H), 7.40 (m, 1H), 7.19 (m, 1H), 7.01 (m, 1H), 6.95 (m, 1H), 6.86 (m, 1H), 4.31 (m, 1H), 4.17 (s, 3H), 4.03 (m, 4H), 3.16 (m, 1H), 3.05 (m, 1H), 2.88 (m, 3H), 2.67 (m, 1H), 2.50 (m, 2H), 2.37 (m, 1H), 1.95 (m, 1H), 1.65 (m, 5H), 1.47 (s, 9H), 1.23 (m ,1H). HRMS (ESI), C32H42FN8O4 m+/z: calc.=621.3313, found=621.3337.
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[CH3:18][NH2:19].[BH4-].[Na+].CO>C1COCC1>[CH3:18][NH:19][C@H:4]1[CH2:5][CH2:6][C@H:1]([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reaction time: 1.5 h

Procedure:
To a suspension of ketone 5 (10.4 g, 0.045 mol) in 2-PrOH (520 mL) was added methylamine (33.7 mL of a 2.0 M solution in THF, 0.067 mol). A clear, amber solution formed after ca 15 minutes, and a precipitate gradually formed a few minutes later. After 1.5 hours, the reaction mixture was cooled in an ice/water bath, NaBH4 (2.6 g, 0.067 mol) was added, and stirring was continued at 0° C. for 35 minutes. The reaction mixture was stirred at room temperature for 15 hours. MeOH (ca 2 mL) was added to quench any excess NaBH4 (no gas evolution was observed), and the solvents were removed under reduced pressure. The residue was partitioned between 1N HCl (500 mL) and EtOAc (250 mL). The aqueous layer was separated, adjusted to pH 7-8 with solid NaHCO3, and washed with EtOAc (200 mL). A precipitate formed during the wash, which was collected by vacuum filtration and dried to give 6-[trans-4-(methylamino)cyclohexyl]-3H-benzoxazol-2-one 15 (5.0 g, 46%). The organic layer was separated, and TLC analysis (89:10:1 CH2Cl2:MeOH:NH4OH) showed it contained compound 15. Compound 15 was also shown by TLC analysis to be present in the initial EtOAc extraction. The organic extracts were combined, concentrated under reduced pressure, dissolved in a minimal amount of MeOH, and a solid was precipitated out with diethyl ether. The solid was collected by vacuum filtration and dried to give 15 (1.6 g, 13%) as the HCl salt. To the aqueous layer (ca 1L), which also showed the presence of additional 15 by TLC, was added solid NaCl (ca 80 g), and the solution was concentrated under reduced pressure to approximately half its original volume. A solid formed and was collected by vacuum filtration and dried to give 15 (1.3 g, 12%). The solids were combined to give 6-[trans-4-(methylamino)cyclohexyl]-3H-benzoxazol-2-one 15 (7.9 g, 73%): 1H NMR (500 MHz, CD3OD): δ 7.10 (d, J=1.5 Hz, 1H), 7.03 (dd, J=8, 1.5 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 2.67-2.52 (m, 2H), 2.49 (s, 3H), 2.15-2.12 (m, 2H), 1.97-1.94 (m, 2H), 1.61-1.52 (mi, 2H), 1.38-1.30 (m, 2H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5]Cl.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1
Reactant: CN(C)CCCl
Reactant: CC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCN(C)C)cc1
Yield: 63.6 %

Procedure:
2-(Dimethylamino)ethyl chloride hydrochloride (3.49 g, 23.2 mmol, 1.1 eq.) was added to a solution of 4′-hydroxyacetophenone (3.00 g, 22.0 mmol, 1 eq.) in acetone (100 mL), followed by the addition of potassium carbonate (9.12 g, 66.0 mmol, 3 eq.). The reaction mixture was heated under reflux overnight, cooled, and filtered; and the filtrate was concentrated and water (50 mL) was added, forming a cloudy solution. Hydrochloric acid (0.1N, 20 mL) was added, and the resulting clear solution was extracted three times with ethyl acetate. The aqueous phase was made basic with aqueous sodium hydroxide, forming a cloudy mixture, which was extracted with ethyl acetate (5×50 mL), then the ethyl acetate layer dried over magnesium sulfate and the ethyl acetate evaporated to give 4′-[2-(dimethylamino)ethoxy]acetophenone (2.90 g) as a light yellow oil, with identity and purity verified by LC-MS. Bromine (1.62 g, 10.1 mmol, 1.4 eq.) was added dropwise to a solution of the 4′-[2-(dimethylamino)ethoxy]acetophenone (1.5 g, 7.24 mmol) in acetic acid (5 mL) and the reaction mixture stirred at 24° C. for 3 hours, giving a dark red solution. The reaction mixture was cooled, water (5 mL) was added, and the mixture was lyophilized overnight. The crude 2-bromo-4′-[2-(dimethylamino)ethoxy]acetophenone was purified by preparative HPLC, followed by lyophilization of the appropriate fractions, to give 2-bromo-4′-[2-(dimethylamino)ethoxy]acetophenone (0.7 g) as an off-white solid.
Reaction SMILES: [CH2:1]([N:5]([CH3:26])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:25])[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][C:22]([OH:24])=O)[N:20]=1)[CH:2]([CH3:4])[CH3:3].[CH3:27][NH2:28]>>[CH2:1]([N:5]([CH3:26])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:25])[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][C:22]([NH:28][CH3:27])=[O:24])[N:20]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)cs2)c(N(C)CC(C)C)c1
Reactant: CN
Product: CNC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2N(C)CC(C)C)n1
Yield: 65 %

Procedure:
2-(2-{3-[2-(Isobutyl-methyl-amino)-4-methyl-phenyl]-ureido}-thiazol-4-yl)-N-methyl-acetamide (63 mg, 65%) was prepared from (2-{3-[2-(isobutyl-methyl-amino)-4-methyl-phenyl]-ureido}-thiazol-4-yl)-acetic acid (95 mg, 0.25 mmol) and methylamine following the general procedure K.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1.Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>C(#N)C>[C:13]([O:12][C:10](=[O:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:4][CH:5]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)Cc1ccc(CN)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNCc1ccc(CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl [4-(aminomethyl)phenyl]acetate (1.00 g) in acetonitrile (15.0 mL) were added tert-butyl bromoacetate (0.668 mL) and triethylamine (0.693 mL), followed by stirring at room temperature for 4 hours. The reaction suspension was concentrated under reduced pressure, and then to the residue was added ethyl acetate. The organic layer was washed with 0.1 M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-[4-(2-tert-butoxy-2-oxoethyl)benzyl]glycinate (747 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3ccccc3)c2n1C
Temperature: 140 °C
Yield: 57.6 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), phenylboronic acid (0.041 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.013 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 min, then heated for 30 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH then the product eluted with 2M NH3/MeOH. then concentrated in vacuo. The resulting residue was purified by chromatography (SiO2, 0-7% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water). The relevant fractions were concentrated to approximately ⅓ volume and partitioned between DCM (3×) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to give 424 as a white solid (0.058 g, 58%). LCMS (Method K): RT 3.55 min [M+H]+ 388.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.03 (1H, s), 7.66-7.62 (2H, m), 7.52-7.41 (5H, m), 7.30 (2H, s), 7.13 (1H, m), 5.61 (1H, m), 3.15 (3H, s), 1.57 (3H, d, J=6.72 Hz)
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][OH:12])[C:5]=2[CH:6]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C.C(OCC)(=O)C>[Si:18]([O:12][CH2:11][CH2:10][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[NH:9][CH:8]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
A solution of tryptophol (5.0 g, 31 mmol) in DMF (30 ml) was treated with imidazole (4.64 g, 68 mmol) and cooled to 0° C. tert-Butyldimethylsilyl chloride (5.14 g, 34.1 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was then diluted with ethyl acetate (100 ml) and washed with water (2×100 ml) and the aqueous solutions were extracted with ethyl acetate (200 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatogaphy (30% ether/petroleum ether) yielded the title compound (8.43 g, 99% yield) as a colorless oil: IR (CCl4) 3910 (s), 3060 (w), 2960 (s), 2930 (s), 2850 (s), 1450 (m), 1370 (w), 1260 (s), 1100 (s), 900 (m), 840 (s), 780 (s), 750 (s) cm−1; 1H NMR (500 MHz, CDCl3) δ 8.26 (br s, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.64-7.50 (m, 4H), 4.28 (t, J=7.3 Hz, 2H), 3.38 (t, J=7.3 Hz, 2H), 1.29 (s, 2H), −0.43 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 136.08, 127.62, 122.08, 121.75, 119.12, 118.79, 112.84, 111.04, 63.89, 28.98, 25.98, 18.34, −5.29; high resolution mass spectrum (Cl, NH3) m/z 276.1750 [(M+H)+; calcd for C16H25NOSi: 276.1783].
Reaction SMILES: [F:1][CH:2]([F:50])[C:3]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N:36]3[C:40]([C:41]([F:44])([F:43])[F:42])=[C:39]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:38]=[N:37]3)[N:31]=2)[C:4]=1[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=2)=[CH:9][CH:8]=1.[H][H]>CCOC(C)=O.[Pt]=O>[F:50][CH:2]([F:1])[C:3]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N:36]3[C:40]([C:41]([F:44])([F:43])[F:42])=[C:39]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:38]=[N:37]3)[N:31]=2)[C:4]=1[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cccc(C(F)F)c3OCc3ccc(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)c1C(F)(F)F
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(C(F)F)c3OCc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)n2)c1C(F)(F)F
Reaction time: 0.75 h

Procedure:
To a degassed solution of the title compound from Example 7 Step E (115 mg, 0.17 mmol) in EtOAc (5 mL) was added platinum oxide (22 mg). The reaction flask was fitted with a hydrogen balloon attached to a 3-way adapter. The reaction mixture was then evacuated and back-filled with hydrogen. After this process was repeated three times, the reaction mixture was placed under a hydrogen atmosphere, and was stirred vigorously. After 45 min, the reaction mixture was filtered though Celite, rinsing with EtOAc. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (0 to 30% EtOAc in hexanes, 30 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 701.0 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.15 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 8.01-7.92 (m, 2H), 7.68 (dd, J=8.0, 6.0 Hz, 2H), 7.39 (t, J=8.0 Hz, 1H), 7.15 (dd, J=12.5, 8.5 Hz, 4H), 6.94 (t, 2JH-F=55.5 Hz, 1H), 4.57 (s, 2H), 4.40 (q, J=7.0 Hz, 2H), 4.34-4.16 (br m, 2H), 2.90-2.72 (br m, 2H), 2.68-2.60 (m, 1H), 1.86-1.74 (m, 2H), 1.66-1.56 (m, 2H), 1.49 (s, 9H), 1.40 (t, J=7.0 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=O.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1.C(#N)C>CN1C(=O)CCC1>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]2[O:19][CH:2]=[C:3]([C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=3)[N:20]=2)=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: NC(=O)c1ccc(Br)cc1
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: N#Cc1ccc(-c2coc(-c3ccc(Br)cc3)n2)cc1
Temperature: 135 °C
Reaction time: 3 h
Yield: 17.5 %

Procedure:
To a stirring solution of 4-(2-bromoacetyl)benzonitrile (7.13 g, 31.8 mmol) in NMP (15 mL) was added 4-bromobenzamide (5.31 g, 26.5 mmol) and the reaction mixture heated to 135° C. for 18 h. The reaction mixture was allowed to cool to room temperature then treated with acetonitrile (25 mL) and stirred for 3 h. The precipitate was collected by filtration and washed with acetonitrile (2×5 mL) to afford 1.51 g (17%) of 4-(2-(4-bromophenyl)oxazol-4-yl)benzonitrile INT-42 as a light brown powder. LCMS-ESI (m/z) calculated for C16H9BrN2O: 324; found 325 [M+H]+, tR=2.86 min (Method 10). 1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.03 (d, J=8.2 Hz, 2H), 7.98-7.91 (m, 4H), 7.76 (d, J=8.5 Hz, 2H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:30]([O-])=O)[C:18]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[Cl-].[NH4+]>[Fe].O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH2:30])[C:18]([NH:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:24][CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 80 °C

Procedure:
A suspension of trans (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(4-methanesulfonyl-cyclohexyl)-amine (585 mg, 1.20 mmol) and ethanol (4 mL, IMS grade) was treated with water (1.3 mL) followed by ammonium chloride (393 mg, 7.30 mmol) and iron powder (274 mg, 4.90 mmol). The mixture was heated to 80° C. for 45 minutes. The resulting solid was isolated and washed repeatedly with ethanol/water. The filtrate was partially concentrated under vacuum and then diluted with DCM and water. The phases were separated and the aqueous phase was extracted with DCM (×2). The combined organic extracts were washed with brine, dried with sodium sulfate and concentrated under vacuum to give 505 mg (92%) of trans 1-benzenesulfonyl-N*4*-(4-methanesulfonyl-cyclohexyl)-1H-pyrrolo[2,3-b]pyridine-4,5-diamine as a pale brown solid that was used without further purification. 1H NMR (400 MHz, DMSO) δ: 8.01 (dd, 2H), 7.70-7.64 (m, 1H), 7.55 (m, 3H), 7.47 (d, 1H), 6.76 (d, 1H), 5.13 (d, 1H), 3.72 (br s, 1H), 3.06 (m, 1H), 2.93 (s, 3H), 2.09 (m, 4H), 1.63 (m, 2H), 1.33 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](Br)=[CH:9][S:10][C:6]=2[C:5]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>COCCOC.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>[NH2:1][C:2]1[C:7]2[C:8]([C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=3)=[CH:9][S:10][C:6]=2[C:5]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2cnc(N)c3c(Br)csc23)cc(OC)c1OC
Reactant: OB(O)c1ccc(Cl)cc1
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: [Na+]
Solvent: COCCOC
Product: COc1cc(-c2cnc(N)c3c(-c4ccc(Cl)cc4)csc23)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 14 h
Yield: 47.8 %

Procedure:
The mixture of 4-amino-3-bromo-7-(3,4,5-trimethoxyphenyl)-thieno[3,2-c]pyridine (30 mg, 0.076 mmol), Pd(PPh3)4 (17 mg, 10 mol %), 4-chlorobenzeneboronic acid (30 mg, 0.19 mmol) and 2M sodium bicarbonate (0.19 ml, 0.38 mmol) in DME (2 ml) was stirred for 14 hours at 80° C. The crude mixture was directly applied to SCX (Varian, 5 g) and eluted with 1N NH3 in CHCl3 and MeOH. The eluant was collected and concentrated in vacuo. The residue was purified by chromatography on a silica gel column to afford the titled compound (15.5 mg) 1H NMR (400 MHz, DMSO-d6) ppm 7.99 (s, 1H), 7.60 (d, J=8.6 Hz, 2H), 7.58 (s, 1H), 7.51 (d, J=7.3 Hz, 2H), 6.95 ((s, 2H), 5.47 (s, 2H), 3.85 (s, 6H), 3.73 (s, 3H). MS: m/z 427, 429 (M+H)+.
Reaction SMILES: [NH2:1]N.[C:3]1([S:9]([C:12](=[CH:15][N:16](C)C)[C:13]#[N:14])(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCO>[C:3]1([S:9]([C:12]2[C:15]([NH2:16])=[N:1][NH:14][CH:13]=2)(=[O:10])=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)C=C(C#N)S(=O)(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Product: Nc1n[nH]cc1S(=O)(=O)c1ccccc1
Reaction time: 5 h
Yield: 29.2 %

Procedure:
2.05 ml (40.9 mmol) of NH2NH2 were added to a solution of 9.08 g (38.3 mmol) of 2-benzenesulphonyl-3-dimethylamino-acrylonitrile in 60 ml of EtOH and stirred at 40° for 5 hrs. The reaction solution was evaporated and the residue was partitioned between H2O and CH2Cl2. The aqueous phase was washed three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 10:1) yielded 2.5 g (30%) of 4-benzenesulphonyl-1H-pyrazol-3-ylamine as a beige powder, m.p. 159-161°.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]([CH2:18][C@@H:19]([OH:29])[C@@H:20]([NH2:28])[CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH3:32][O:33][C:34]1[C:35](=O)[C:36](=[O:40])[C:37]=1[O:38]C.CCN(CC)CC>CCO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:18][C@@H:19]([OH:29])[C@@H:20]([NH:28][C:35]2[C:36](=[O:40])[C:37](=[O:38])[C:34]=2[O:33][CH3:32])[CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:9]([O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:10])=[CH:30][CH:31]=1)#[N:2]
Reactant: COc1c(OC)c(=O)c1=O
Reactant: C[Si](C)(C)CCOC(=O)N(Cc1ccc(C#N)cc1)C[C@@H](O)[C@@H](N)CC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1c(N[C@@H](CC2CCCCC2)[C@H](O)CN(Cc2ccc(C#N)cc2)C(=O)OCC[Si](C)(C)C)c(=O)c1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of (2R,3S)-1-(N-(4-cyanobenzyl)-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-2-hydroxy-3-amino-4-cyclohexylbutane (764 mg, 1.68 mmol) in EtOH (20 mL) was treated with 3,4-dimethoxycyclobut-3-ene-1,2-dione (300 mg, 2.10 mmol, 1.25 equiv) and Et3N (212 mg, 1.25 equiv). The resulting solution was allowed to stir at rt for 17 h. The excess 3,4-dimethoxycyclobut-3-ene-1,2-dione was removed by flash chromatography on silica gel, eluting with 0-65% EtOAc in hexanes. Analysis of the compound by LC-MS showed that it was of sufficient purity to employ in the subsequent steps.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[N+](=[CH2:13])=[N-]>CO.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:13])=[O:9]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1cnccc1Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cnccc1Cl
Yield: 85 %

Procedure:
4-Chloronicotinic acid, prepared as described by W. C. J. Ross in J. Chem. Soc. (C), 1816 (1966), (2.54 g, 16.1 mmol) in methanol (30 mL) at 0° C. was treated with diazomethane in ether until gas evolution ceased; the ice bath was removed halfway through the esterification. The excess diazomethane was removed with a nitrogen stream and the solvent was removed under reduced pressure. The residue was taken up in saturated sodium bicarbonate solution and extracted with ethyl acetate (2×). The combined organic extracts were washed with 1M aqueous sodium hydroxide solution (2×) and brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford 2.35 g (85%) of the title compound as a yellow oil. A portion (1.47 g) was distilled at b.p. 75°-85° C. at ~1 mm mercury to afford 1.15 g as a pale yellow crystalline solid.