Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11](I)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:13]([O:17][C:18](=[O:38])[NH:19][C:20]1[CH:37]=[CH:36][C:23]2[S:24][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:26][C:22]=2[CH:21]=1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[C:11]([C:25]2[S:24][C:23]3[CH:36]=[CH:37][C:20]([NH:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:38])=[CH:21][C:22]=3[CH:26]=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2sc(B3OC(C)(C)C(C)(C)O3)cc2c1
Reactant: COC(=O)c1cnc(N)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N)c(-c2cc3cc(NC(=O)OC(C)(C)C)ccc3s2)c1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
To the degassed mixture of methyl 6-amino-5-iodonicotinate (4.17 g, 15 mmol, 1 eq), {[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[b]thiophen-5-yl]-carbamic acid tert-butyl ester} (6.47 g, 1.15 eq), and aq sodium carbonate (2M, 22.5 mL, 3 eq) in dioxane (30 mL) was added Ph3P (393 mg, 0.1 eq) and Pd(OAc)2 (340 mg, 0.1 eq). The mixture was heated to 50° C. with vigorous stirring for 45 minutes. The reaction mixture was then partitioned between aq NH4Cl and EtOAc. The organic layer was isolated, washed with sat aq NaHCO3, brine, and finally dried with anhydrous sodium sulfate. The upper solution-layer was decanted, concentrated, and the solid residue was treated with EtOAc-Hex (1:4) with stirring at room temperature for 3 hours. methyl 6-amino-5-{5-[(tert-butoxycarbonyl)amino]-1-benzothien-2-yl}nicotinate was obtained upon filtration as a slightly green-yellowish solid.
Reaction SMILES: [C:1]([C:5]1[CH:52]=[CH:51][C:8]2[N:9](COCC[Si](C)(C)C)[C:10]([CH2:12][CH:13]3[CH2:16][CH:15]([CH2:17][N:18]([CH2:22][C@@H:23]4[C@H:27]5[O:28]C(C)(C)[O:30][C@H:26]5[C@H:25]([N:33]5[C:37]6[N:38]=[CH:39][N:40]=[C:41]([NH2:42])[C:36]=6[CH:35]=[CH:34]5)[CH2:24]4)[CH:19]([CH3:21])[CH3:20])[CH2:14]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>CO>[NH2:42][C:41]1[C:36]2[CH:35]=[CH:34][N:33]([C@@H:25]3[CH2:24][C@H:23]([CH2:22][N:18]([CH2:17][CH:15]4[CH2:14][CH:13]([CH2:12][C:10]5[NH:9][C:8]6[CH:51]=[CH:52][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=6[N:11]=5)[CH2:16]4)[CH:19]([CH3:20])[CH3:21])[C@@H:27]([OH:28])[C@H:26]3[OH:30])[C:37]=2[N:38]=[CH:39][N:40]=1
Reactant: CC(C)N(CC1CC(Cc2nc3cc(C(C)(C)C)ccc3n2COCC[Si](C)(C)C)C1)C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Agent: Cl
Solvent: CO
Product: CC(C)N(CC1CC(Cc2nc3cc(C(C)(C)C)ccc3[nH]2)C1)C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O
Yield: 55.2 %

Procedure:
7-[(3aS,4R,6R,6aR)-6-{[({3-[(5-tert-butyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)methyl]cyclobutyl}methyl)(propan-2-yl)amino]methyl}-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (58.7 mg, 0.08 mmol) was dissolved in cone. HCl solution (5 ml) and methanol (5 ml) and heated to 40° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue partitioned between sat. NaHCO3(aq) (10 ml) and EtOAc (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2×10 ml), the combined organics were then dried (MgSO4) and concentrated. The crude material was purified by prep TLC, eluting with 10% 2M NH3 in MeOH in DCM to afford the title compound (24.7 mg, 55%) as a colourless gum: MS (ESI+) for C32H45N7O2 m/z 560.4 [M+H]+; LC purity 100% (UV), (ret. time, 5.10 min); 1H NMR (500 MHz, Acetone) δH 8.12 (s, 1 H), 7.30-7.60 (m, 2 H), 7.13-7.28 (m, 2 H), 6.54 (d, J=3.5 Hz, 1 H), 6.33 (br. s., 1 H), 4.85-5.07 (m, 1 H), 4.36 (t, J=6.2 Hz, 1 H), 4.08 (t, J=5.2 Hz, 1 H), 3.01 (d, J=7.7 Hz, 1 H), 2.93 (d, J=7.4 Hz, 2 H), 2.78 (br. s., 2 H), 2.59-2.73 (m, 2 H), 2.15-2.56 (m, 7 H), 1.68 (dt, J=12.4, 9.7 Hz, 1 H), 1.44-1.62 (m, 2 H), 1.35 (s, 9 H), 0.90-1.07 (m, 6 H).
Reaction SMILES: [CH3:1][C:2]1[S:3](=[O:21])(=[O:20])[O:4][C:5]2[C:11]([S:12]([NH:15][C:16](NC)=[O:17])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.C(Cl)(Cl)=O>ClC1C=CC=CC=1>[CH3:1][C:2]1[S:3](=[O:21])(=[O:20])[O:4][C:5]2[C:11]([S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1
Reactant: CNC(=O)NS(=O)(=O)c1cccc2c1OS(=O)(=O)C(C)=C2
Agent: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: CC1=Cc2cccc(S(=O)(=O)N=C=O)c2OS1(=O)=O

Procedure:
5.0 g of N-(3-methyl-2,2-dioxo-1,2-benzoxathiin-8-ylsulfonyl)-N'-methylurea are dispersed in 150 ml of absolute chlorobenzene and the dispersion is saturated with phosgene at 130° C. A clear solution forms during this addition. The solvent is subsequently distilled off in vacuo with the exclusion of moisture. The 3-methyl-2,2-dioxo-1,2-benzoxathiin-8-ylsulfonylisocyanate obtained as oily residue can be used without further purification for the preparation of the pyrimidinylureas and triazinylureas of the formula I.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:19]=[C:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]3[N:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[C:20]([C:24]1[S:31][C:30]2[C:29](=[O:32])[N:28]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35](B4OC(C)(C)C(C)(C)O4)[C:34]=3[CH3:48])[CH2:27][C:26]=2[CH:25]=1)([CH3:23])([CH3:22])[CH3:21].O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.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>[C:20]([C:24]1[S:31][C:30]2[C:29](=[O:32])[N:28]([C:33]3[C:34]([CH3:48])=[C:35]([C:2]4[CH:3]=[C:4]([NH:9][C:10]5[CH:19]=[C:13]6[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]6[N:11]=5)[C:5](=[O:8])[NH:6][N:7]=4)[CH:36]=[CH:37][CH:38]=3)[CH2:27][C:26]=2[CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CN1CCn2nc(Nc3cc(Cl)n[nH]c3=O)cc2C1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
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: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)[nH]n2)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Temperature: 25 °C

Procedure:
In a dried pressure flask was placed 0.968 mmol of 101m, 1.065 mmol of 101g, and 56 mg (5 mol %) of tetrakis(triphenylphosphine)palladium(0), The flask was evacuated under vacuum, then filled with nitrogen. This procedure was repeated twice more, then 8 mL of anhydrous dioxane and 2.4 mL (2.5 equivalents) of 1 M aqueous sodium carbonate solution were added, and the mixture was heated at 100° for 18 h. The mixture was cooled to room temperature, then diluted with ethyl acetate, washed with saturated aqueous saturated NaCl solution four times, dried over anhydrous Na2SO4, and purified by chromatography on a Biotage 25M KP NH column to afford 101. 1H NMR (400 MHz, DMSO) δ 12.96 (s, 1H), 9.19 (s, 1H), 7.78 (s, 1H), 7.54-7.32 (m, 3H), 7.15 (s, 1H), 5.97 (s, 1H), 4.78 (s, 2H), 3.97 (t, J=5.3, 2H), 3.52 (s, 2H), 2.80 (t, J=5.4, 2H), 2.36 (s, 3H), 2.11 (d, J=12.1, 3H), 1.42 (s, 9H). ESIMS m/z=530.2 (M+1).
Reaction SMILES: C(Cl)(=O)C.[C:5]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15](=[O:23])[CH2:14]1)(=[O:12])[C:6]1C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[C:5]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15](=[O:23])[CH2:14]1)(=[O:12])[CH3:6]
Reactant: O=C1CN(C(=O)c2ccccc2)c2ccccc2N1
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(=O)Nc2ccccc21
Reaction time: 1 h

Procedure:
Acetyl chloride (0.36 ml) is added to 1,2,3,4-tetrahydroquinoxalin-2-one (IV, EXAMPLE 1, 0.676 g) and triethylamine (0.76 ml) in THF (8 ml) at 0°. After stirring for 1 hr, the solvent is removed under reduced pressure and the residue is partitioned between dichloromethane and aq. sodium bicarbonate. The layers are separated, the organic phase is filtered through sodium sulfate and concentrated. The concentrate is crystallized from methanol/methylene chloride/hexane to give the title compound, mp 164°-165°; NMR (CDCl3) 2.28, 4.54, 7.00, 7.11, 7.21 and 9.19 δ.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:15])[C:13]#[N:14])[CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH2:47](O)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]>C1COCC1>[CH2:47]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:15])[C:13]#[N:14])[CH:6]=[CH:5]2)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCCCCO
Reactant: CC(C#N)c1ccc2cc(O)ccc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc2cc(C(C)C#N)ccc2c1
Temperature: 5 °C

Procedure:
Into 20 ml of dry THF, were dissolved 1.5 g of oa (6-hydroxy-2-naphthyl)-propanonitrile and 3.0 g of triphenylphosphine, and cooled to 5° C. To this solution, were added dropwise 2.0 g of diethyl azodicarboxylate and then 1.2 g of n-decyl alcohol, and stirred at room temperature for 12 hours. The resulting reaction mixture was extracted with ether, followed by washing three times the ether phase with water and then distilling off the ether. The resulting oily product was extracted with hexane, and the hexanesoluble matter was recrystallized with methanol to obtain 0.7 g of oa (6-n-decyloxy-2-naphthyl)propanonitrile (Compound No. 1-10) of this invention.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[CH3:19][C:20]1[O:24][N:23]=[C:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]2)[N:21]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CC(C)=O.CN(C=O)C>[CH3:19][C:20]1[O:24][N:23]=[C:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][N:26]2[C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]2[CH:7]=[C:6]3[C:11](=[N:10][CH:9]=2)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]3)[N:21]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: Cc1nc(C2CCCCN2)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C2CCCCN2C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (30 mg, 0.12 mmol), DMF (3 mL), 2-(5-methyl-1,2,4-oxadiazol-3-yl)piperidine hydrochloride (29 mg, 0.14 mmol; which may be prepared as described in Step 3), DIPEA (48 μL, 0.28 mmol) and EDAC (27 mg, 0.14 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified on preparative TLC (eluent: dichloromethane/NH3 7N in MeOH, 2.5%) to give an oil. This oil was taken up in acetone, diethyl ether and concentrated. The resulting wax was finally dissolved in dichloromethane, concentrated and dried to give the title compound (15 mg, 34%) as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([NH:27][C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])[C@@H:24]([OH:38])[C@H:23]3[OH:39])=[C:15]([NH:40][CH2:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:14]=2)[CH2:9]1)(C)(C)C.Cl>CO.O1CCOCC1>[CH2:31]([O:30][C:28](=[O:29])[NH:27][C@H:25]1[CH2:26][C@@H:22]([N:19]2[CH:18]=[N:17][C:16]3[C:20]2=[N:21][C:13]([N:10]2[CH2:11][CH2:12][C@@H:8]([NH2:7])[CH2:9]2)=[N:14][C:15]=3[NH:40][CH2:41][CH:42]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@H:23]([OH:39])[C@@H:24]1[OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)OCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)OCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of {(R)-1-[9-((1R,2S,3R,4S)-4-benzyloxycarbonylamino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Intermediate L5) (1.24 g, 1.7 mmol) in MeOH (3 ml) is treated with 4M HCl in dioxane (5 ml) and stirred at room temperature for 2 hours. The solvent is removed in vacuo and purification is carried out by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water −0.1% HCl). The fractions are collected and the MeCN is removed in vacuo. The remaining aqueous portion is basified with saturated sodium bicarbonate solution and extracted with DCM. The combined organic extracted are dried (MgSO4) and concentrated in vacuo to afford the title product. MS (ES+) m/e 649 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[S:3])[NH2:2].[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](=O)[CH2:21]Br)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]2[N:2]=[C:1]([C:4]3[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=3)[C:7]([O:9][CH3:10])=[O:8])[S:3][CH:21]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1cccc(C(N)=S)c1
Reactant: COc1ccc(C(=O)CBr)cc1
Product: COC(=O)c1cccc(-c2nc(-c3ccc(OC)cc3)cs2)c1
Yield: 74 %

Procedure:
In the same manner as in Example 28, methyl 3-thiocarbamoylbenzoate was reacted with 4-methoxyphenacyl bromide to obtain methyl 3-[4-(4-methoxyphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 74%. Pale yellow prisms. Melting point: 108 to 109° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:13]=[C:12]([CH:14]([OH:16])[CH3:15])[O:11][N:10]=1.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14](=[O:16])[CH3:15])[O:11][N:10]=1
Reactant: CC(O)c1cc(-c2c(F)cccc2Cl)no1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1cc(-c2c(F)cccc2Cl)no1
Temperature: 5 °C

Procedure:
To a solution of 30 g (124 mmol) of 1-[3-(2-chloro-6-fluorophenyl)-5-isoxazolyl]-ethanol in 187 ml of acetic acid maintained under stirring at 5° C. were added dropwise 9.07 (90.7 mmol) of CrO3 in 9.34 of water and 132 ml of acetic acid.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:3]=1.Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[NH:24][C@H:25]1[CH2:30][CH2:29][C@@H:28]([NH2:31])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:14]1[CH2:15][CH2:16][N:11]([C:4]2[CH:3]=[C:2]([NH:31][C@H:28]3[CH2:27][CH2:26][C@@H:25]([NH:24][C:19]4[N:18]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:30][CH2:29]3)[C:10]3[C:6]([CH:5]=2)=[N:7][O:8][N:9]=3)[CH2:12][CH2:13]1
Reactant: Brc1cc(N2CCOCC2)cc2nonc12
Reactant: N[C@H]1CC[C@@H](Nc2ncccn2)CC1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1cnc(N[C@H]2CC[C@@H](Nc3cc(N4CCOCC4)cc4nonc34)CC2)nc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
As shown in step 5-iii of Scheme 5, a mixture of 4-bromo-6-morpholinobenzo[c][1,2,5]oxadiazole (compound 1012, 147 mg, 0.5 mmol), (cis)-N1-(pyrimidin-2-yl)cyclohexane-1,4-diamine hydrochloride (120 mg, 0.6 mmol), (rac)-BINAP (32 mg, 0.05 mmol), Pd2(dba)3 (24 mg, 0.026 mmol), and cesium carbonate (506 mg, 1.55 mmol) in toluene (5 mL) was flushed with nitrogen gas and stirred overnight at 90° C. under an atmosphere of nitrogen. The mixture was filtered though a layer of diatomaceous earth, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0 to 80% EtOAc/hexanes gradient) to provide (cis)-N1-(6-morpholinobenzo[c][1,2,5]oxadiazol-4-yl)-N4-(pyrimidin-2-yl)cyclohexane-1,4-diamine (compound 23) as an orange solid: 1H-NMR (300 MHz, CDCl3) δ 8.20 (d, J=4.9 Hz, 2H), 6.46 (t, J=4.8 Hz, 1H), 6.05 (d, J=1.6 Hz, 1H), 5.82 (s, 1H), 5.24 (s, 1H), 4.82 (d, J=7.0 Hz, 1H), 3.98 (s, 1H), 3.85-3.72 (m, 4H), 3.60 (s, 1H), 3.23-3.06 (m, 4H), 1.95-1.62 (m, 8H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:8]=[CH:7]2)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].O1CCOCC1>O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH:14]=[CH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2nc(C=Cc3ccccc3)ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc2nc(C=Cc3ccccc3)ccc2c1

Procedure:
41.6 g of 6-nitro-2-styrylquinoline were added in portions to a mixture containing 69 g of reduced iron, 6.9 g of aluminum chloride, 450 ml of dioxane, and 90 ml of water with heating under reflux. After heating under reflux for a further 5 hours, the solid was filtered using a Nutsche filter in which sellaite is laid. The filtrate was condensed, 130 ml of ethyl acetate were added thereto, and the deposited crystals were filtered. 28 g (74% of the theoretical yield) of the 6 -amino-2-styrylquinoline crystals were produced.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([OH:21])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:22][C@H:23]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][OH:25].C(N1C2=NC=C(C(N[C@H](C3C=CC=CC=3)CO)=O)C(NC3CCOCC3)=C2C=N1)C>>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([NH:22][C@H:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:24][OH:25])=[O:21])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Reactant: N[C@@H](CO)Cc1ccccc1
Agent: CCn1ncc2c(NC3CCOCC3)c(C(=O)N[C@@H](CO)c3ccccc3)cnc21
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)N[C@@H](CO)Cc3ccccc3)cnc21

Procedure:
Intermediate 45 was prepared from Intermediate 17 and (2R)-2-amino-3-phenyl-1-propanol (commercially available from Aldrich) using an analagous method to that for Intermediate 42. LCMS showed MH+=424; TRET=2.59 min.
Reaction SMILES: [Br:1][C@H:2]1[C@@H:8]2[CH2:9][C@@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.[NH3:11].CO>C1COCC1>[Br:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([C:6]([NH2:11])=[O:10])[CH2:9][C@@H:8]1[OH:7]
Reactant: N
Reactant: O=C1O[C@H]2C[C@@H]1CC[C@H]2Br
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)[C@H]1CC[C@@H](Br)[C@@H](O)C1

Procedure:
(1S,4R,5S)-4-Bromo-6-oxabicyclo[3.2.1]octan-7-one (352a) (2.88 g, 14.0 mmol) was taken up in THF (27 mL) and treated with 0.880 ammonia (7.1 mL) at 20° C. for 24 h with stirring. The solvent was then removed in vacuo to give a white solid in quantitative yield; [α]D=−55.4° (c=1, MeOH).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2].[OH:19][C@@H:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21](O)=[O:22]>>[CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH:17][C:21](=[O:22])[CH:20]([OH:19])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCCC(N)C(=O)Nc1cn(C(CC)CC)cn1
Reactant: CC(C)(C)[C@H](O)C(=O)O
Product: CCCC(NC(=O)C(O)C(C)(C)C)C(=O)Nc1cn(C(CC)CC)cn1

Procedure:
2-Amino-pentanoic acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide was coupled with (S)-2-hydroxy-3,3-dimethyl-butyric acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 10.8, 13.9, 19.0, 26.3, 28.8, 35.3, 35.6, 52.7, 62.9, 79.8, 104.8, 132.7, 137.9, 169.2, 172.9; MS 367.1 m/z (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([C:11]([O:10][CH3:9])=[O:19])=[CH:17][CH:16]=2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine (300 mg, 2.0 mmol), 4-aminobenzoic acid methyl ester (302 mg, 2.05 mmol) in acetonitrile (3 mL), DIPEA (0.35 mL, 2.0 mmol) was added. After 30 minutes at room temperature, resulting solid was filtered and washed with acetonitrile and dried to give methyl 4-(4-chloro-1,3,5-triazin-2-ylamino)benzoate (Int-1). MS found for C11H9ClN4O2 as (M+H)+ 265.07. A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)H-imidazo[1,2-a]pyridine (139 mg, 0.57 mmol), Int-1 (150 mg, 0.57 mmol), 2.0M Sodium carbonate solution (0.6 mL, 1.25 mmol), PdCl2(dppf) (14 mg, 0.02 mmol), dioxane (2 mL) was heated in a microwave (Emry's Optimizer) at 125° C. for 15 minutes. The reaction mixture was then poured into water and the resulting solid was filtered and washed with ether and dried to give 5 methyl 4-(4-(H-imidazo[1,2-a]pyridin-3-yl)-1,3,5-triazin-2-ylamino)benzoate (Int-2) which was used without further purification. MS found for C18H14N6O2 as (M+H)+ 347.25. To solid Int-2 in MeOH (5 mL) was added 1N NaOH (5 mL) and stirred at 60° C. for 2 hours. The reaction mixture was concentrated, diluted with water and neutralized with 6N HCl (1.5 mL). The aqueous phase was then extracted with ethyl acetate and the combined organic layers were concentrated to give 4-(4-(H-imidazo[1,2-a]pyridin-3-yl)-1,3,5-triazin-2-ylamino)benzoic acid (Int-3). MS found for C17H12N6O2 as (M+H)+ 333.34. To Int-3 in DMF (6 mL), was added HATU (260 mg, 0.7 mmol), 1,2-phenylenediamine (123 mg, 1.1 mmol) and DIPEA (0.4 mL, 2.3 mmol) and stirred at room temperature for 3 hours. The reaction mixture was diluted with water and acetonitrile and directly purified by preparative HPLC affording the title compound, after lyophilization. MS found for C23H18N8O as (M+H)+ 423.09. 1H NMR (400 MHz, dmso-d6): δ 10.49 (s, 1H); 9.89 (brs, 1H); 9.56 (s, 1H); 8.78 (s, 1H); 8.57 (s, 1H); 7.99-7.77 (m, 6H); 7.54 (t, J=7.6 Hz, 1H); 7.23 (t, J=6.4 Hz, 1H); 7.14 (d, J=7.6 Hz, 1H); 6.94 (m, 1H); 6.75 (d, J=8.0 Hz, 1H); 6.57 (t, J=7.6 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[O:8])[CH:2]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]([C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])[C:10]1=[O:18])(=[O:21])[CH3:20]
Reactant: O=C1Nc2ccccc2C1C(=O)c1cccnc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)C(C(=O)c2cccnc2)c2ccccc21
Yield: 53 %

Procedure:
Acetylation of 3-(3-pyridylcarbonyl)-2-oxindole with acetic anhydride, substantially according to the procedure of Example 1, afforded a 53% yield of the title compound, m.p. 141°-142.5° C.
Reaction SMILES: C(O[C:6]([N:8]([C:40](OC(C)(C)C)=O)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[C:20](=[O:21])[CH2:19][CH2:18][CH:17]2C)[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.[CH3:47][N:48]1[CH2:53]CNC[CH2:49]1>>[CH3:37][C:36]1[C:31]([N:28]2[CH2:27][CH2:26][N:25]([C:23]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:17][CH2:18][CH2:19][C:20]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]3[CH2:6][CH2:49][N:48]([CH3:53])[CH2:47][CH2:40]3)=[O:39])=[O:24])[CH2:30][CH2:29]2)=[N:32][CH:33]=[C:34]([CH3:38])[CH:35]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: CN1CCNCC1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N3CCN(C)CC3)CC2)c(C)c1
Yield: 58.3 %

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-methyl-5-oxopyrrolidin-1-yl)benzamide (80 mg) described in Example 837 and 1-methylpiperazine (52 mg) and by the reaction and treatment in the same manner as in Example 770, the title compound (37 mg) was obtained.