Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[CH:14][C:13]([CH2:16][C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[N:19]([Si](C(C)C)(C(C)C)C(C)C)[CH:18]=2)=[CH:12][CH:11]=1.BrC1N=CC(CC2C3C(=NC=CC=3)N([Si](C(C)C)(C(C)C)C(C)C)C=2)=CC=1>>[CH2:1]([NH:8][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[CH:14][N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(Cl)nc2)c2cccnc21
Agent: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(Br)nc2)c2cccnc21
Product: c1ccc(CNc2ccc(Cc3c[nH]c4ncccc34)cn2)cc1

Procedure:
The following table indicates the amine used in Step 1 in place of benzyl amine in Column 3, and whether 3-(6-Chloro-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine or 3-(6-Bromo-pyridin-3-ylmethyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine was used in Step 1 in Column 2 (Cl or Br, respectively), with the compound structure in Column 4, experimental mass spectrometry result in Column 5, and compound number in Column 1.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:26])=[C:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=3[O:21][C:22]([F:25])([F:24])[F:23])C=O)[CH:11]=2)[C:6]([CH3:28])([CH3:27])[CH2:5][C:4]1=[O:29])[CH3:2].[CH2:30]([CH:32](P(O)(O)=O)/[C:33](/CC)=[C:34](\CC)/[C:35]([O-:37])=[O:36])C>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:26])=[C:10]([C:13]3[CH:14]=[C:15]([CH:30]=[CH:32][CH:33]=[CH:34][C:35]([OH:37])=[O:36])[CH:18]=[CH:19][C:20]=3[O:21][C:22]([F:24])([F:25])[F:23])[CH:11]=2)[C:6]([CH3:28])([CH3:27])[CH2:5][C:4]1=[O:29])[CH3:2]
Reactant: CC/C(C(=O)[O-])=C(/CC)C(CC)P(=O)(O)O
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OC(F)(F)F)cc21
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=CC=CC(=O)O)ccc3OC(F)(F)F)cc21

Procedure:
Compound 24 was prepared from Compound 2A using procedures similar to those described for Example 20B and 20C, except using triethyl-4-phosphonocrotonate in step 20B. MS (electrospray): mass calculated for C26H26F3NO4, 473.18; m/z found 474.2 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH2:10][CH2:11][CH:12]([C:18]1[CH:27]=[CH:26][C:21]([C:22](OC)=[O:23])=[CH:20][CH:19]=1)[C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)[CH3:9].O.C(O)(=O)/C=C\C(O)=O>O1CCCC1.CO>[CH3:7][N:8]([CH2:10][CH2:11][CH:12]([C:18]1[CH:19]=[CH:20][C:21]([CH2:22][OH:23])=[CH:26][CH:27]=1)[C:13]1[NH:17][CH:16]=[CH:15][N:14]=1)[CH3:9]
Reactant: COC(=O)c1ccc(C(CCN(C)C)c2ncc[nH]2)cc1
Agent: O=C(O)/C=C\C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN(C)CCC(c1ccc(CO)cc1)c1ncc[nH]1
Reaction time: 2 h

Procedure:
Lithium aluminum hydride (0.4 g) was added slowly to a stirred solution of 4-[3-(N,N-dimethylamino)-1-(imidazol-2-yl)propyl]benzoic acid, methyl ester (1.0 g) in dry tetrahydrofuran (40 ml) under nitrogen. After stirring for 2 hr., water (3 ml) was added, and the granular suspension was filtered off. The filtrate was evaporated to dryness to give a colourless gum which was dissolved in methanol (5 ml) and treated with a solution of maleic acid (0.4 g) in methanol (5 ml). Solvent was removed and the residual gum was triturated with dry ether to give the maleate salt hemihydrate of the title compound as a glassy, hygroscopic solid, m.p. 65°-66° (1.1 g); τ(D2O)2.4-2.65(4H,m,aromatic),2.70(2H,s,imidazole),5.33, ##STR35## 6.7-7.6(10H,m,CH2CH2N(CH3)2),7.08 (6H,s,N(CH3)2).
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].C([O:7][C:8](=O)[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[C:16]1=[O:30])C.C(OCC)(=O)C>C(OCC)C.CCCCCC.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[OH:7][C:8]1([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=3)[C:16]2=[O:30])[CH2:2][CH2:1]1
Reactant: CCOC(=O)c1ccncc1N1CCN(c2cccc(C(F)(F)F)c2)C1=O
Reactant: CC[Mg+]
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Br-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C1N(c2cccc(C(F)(F)F)c2)CCN1c1cnccc1C1(O)CC1
Reaction time: 1.5 h
Yield: 6.7 %

Procedure:
2.5 M Solution of EtMgBr (0.8 mL, 1.974 mmol) was added drop wise to a solution of titanium(IV)isopropoxide (187.3 mg, 0.659 mmol) in diethyl ether (10 mL) for a period of 15 minutes at −78° C. under nitrogen atmosphere. The resulting mixture was stirred for 90 minutes. This was followed by the addition of 3-[2-oxo-3-(3-trifluoromethyl-phenyl)-imidazolidin-1-yl]-isonicotinic acid ethyl ester (I-36c: 125 mg, 0.329 mmol) in diethyl ether (3 mL) at −78° C. and continued stirring at room temperature overnight. The reaction was monitored by TLC (80% ethyl acetate in hexane). The reaction mixture was cooled and partitioned between ethyl acetate and 1N HCl. The organic layer was concentrated to yield crude product which was purified by preparative HPLC to afford 8 mg of the product (6% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH:16][S:17]([C:20]3[CH:24]=[C:23](C)O[C:21]=3C)(=[O:19])=[O:18])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:29][N:30]1C=C(S(Cl)(=O)=O)C(C)=[N:31]1.FC1C=CC(OC)=C(C2C=CC(C(N)C)=CC=2)C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH:16][S:17]([C:20]3[C:24]([CH3:23])=[N:31][N:30]([CH3:29])[CH:21]=3)(=[O:19])=[O:18])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1nn(C)cc1S(=O)(=O)Cl
Reactant: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2cc(C)oc2C)cc1
Agent: COc1ccc(F)cc1-c1ccc(C(C)N)cc1
Product: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2cn(C)nc2C)cc1

Procedure:
Prepared in a similar manner to (R)-2,5-dimethyl-furan-3-sulfonic acid [1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 10) starting with 1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride and 1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. Title compound: 1H NMR (400 MHz, CDCl3): δ 7.41, 7.20 (a/b, 4H), 7.39 (s, 1H), 7.05-6.88 (m, 3H), 4.70 (d, 1H), 4.55 (m, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 2.33 (s, 3H), 1.52 (d, 3H) ppm; MS (ESI) m/z: 404 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.[CH2:28]([C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[F:20][C:17]1([F:21])[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=[C:2]([N:31]2[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=[C:30]2[CH2:28][CH3:29])[N:10]=3)[CH2:15][CH2:16]1
Reactant: Cn1c(CCN2CCC(F)(F)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN3CCC(F)(F)CC3)n(C)c2n1
Temperature: 120 °C
Yield: 61.2 %

Procedure:
A mixture of 2-chloro-8-[2-(4,4-difluoropiperidin-1-yl)ethyl]-9-methyl-6-morpholin-4-yl-9H-purine (30 mg, 0.08 mmol), 2-ethylbenzimidazole (12 mg, 0.08 mmol), Pd2(dba)3 (1.7 mg, 2.5 mol %), Xphos (3.6 mg, 10 mol %) and Cs2CO3 (37 mg, 0.11 mmol) in dioxane (1.0 mL) was purged with argon gas then heated at 120° C., for 20 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 30-90%) to give 540 (25 mg, 64%) as a beige solid. LCMS: (Method I): RT 2.61 min; [M+H]+ 511.2. 1H NMR (400 MHz, CHCl3-d): δ 8.01-7.96 (m, 1 H), 7.78-7.74 (m, 1 H), 7.29-7.23 (m, 2 H), 4.68-4.02 (m, 4 H), 3.86 (t, J=4.8 Hz, 4 H), 3.78 (s, 3 H), 3.35 (q, J=7.5 Hz, 2 H), 3.12-2.99 (m, 4 H), 2.81-2.65 (m, 4 H), 2.15-1.99 (m, 4 H), 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[CH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15][B:14]([OH:24])[C:13]=2[CH:12]=[C:11]([OH:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:33]1[CH:38]=[N:37][CH:36]=[CH:35][N:34]=1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:17]2[CH:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15][B:14]([OH:24])[C:13]=2[CH:12]=[C:11]([O:25][C:33]2[CH:38]=[N:37][CH:36]=[CH:35][N:34]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cnccn1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(OCc3ccccc3)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OCc3ccccc3)c21
Temperature: 90 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
To a mixture of ethyl 2-(4-(benzyloxy)-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.00 g, 2.9 mmol) and anhydrous Cs2CO3 (1.12 g, 5.84 mmol) in DMF (10 mL) was added 2-chloropyrazine (0.40 g, 3.5 mmol). The reaction mixture was stirred at 90° C. for 1 h and quenched by addition of water (15 mL). The resulting mixture was extracted by EtOAc and the combined organic layers were washed with water (20 mL) and brine (25 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow oil (0.74 g, Yield: 61%).
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:31]([N:38]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[N:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:38]1[CH:42]=[C:41]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)[CH:40]=[N:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1cnn(Cc2ccccc2)c1
Yield: 43 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a brown solid (43% yield); 1H-NMR (d6-DMSO) 1.12 (9H, s), 3.61 (2H, t), 4.02 (2H, t), 5.24 (2H, s), 6.31 (1H, s), 7.27-7.33 (6H, m), 7.64 (1H, s); 13C-NMR (CDCl3) 27.8, 41.9, 56.2, 66.5, 125.5, 128.1, 128.2, 128.8, 130.9, 136.9; MS ES(+) 342.0 (M++1); HRMS m/z calcd for C19H23N3O3+H+ 342.1818 [M+H+]. Found 342.1826. IR λmax=1697 cm−1.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH2:6]([O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH3:7].C(N(CC)CC)C>ClCCl>[CH2:6]([O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:1](=[O:4])[CH:2]=[CH2:3])=[CH:12][CH:11]=1)[CH3:7]
Reactant: C=CC(=O)Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Nc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
To a solution of acryloyl chloride (1.08 mL, 13.32 mmol) in dry dichloromethane (10 mL) was slowly added dropwise, via addition funnel, a solution of 4-aminobenzoic acid ethyl ester (2.0 g, 12.11 mmol) and triethylamine (1.86 mL, 13.32 mmol) in dry dichloromethane (5 mL) over about 30 minutes. The reaction was stirred at room temperature for 16 hours. The solution was then partitioned between dichloromethane and water in a separatory funnel. The organic layer was washed with 2 N HCl, dried with sodium sulfate, and concentrated in vacuo to dryness. The resulting residue was triturated with hexane, and vacuum filtered to yield 2.02 g (76%) of 4-acryloylaminobenzoic acid ethyl ester as a solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12]Br.Cl.[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:26](=[O:27])[C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[S:23]2(=[O:33])=[O:32])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)C.C(O)(C)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12][N:16]1[CH2:17][CH2:18][CH:19]([N:22]2[C:26](=[O:27])[C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[S:23]2(=[O:32])=[O:33])[CH2:20][CH2:21]1
Reactant: O=C1c2ccccc2S(=O)(=O)N1C1CCNCC1
Reactant: OC(CBr)C1COc2ccccc2O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC(C)O
Product: O=C1c2ccccc2S(=O)(=O)N1C1CCN(CC(O)C2COc3ccccc3O2)CC1

Procedure:
Erythro 1-(1,4-Benzodioxan-2-yl)-2-bromoethanol (1.29 g, 0.005 m), 2-(piperid-4-yl)-1,2-benzisothiazolin-3-one-1,1-dioxide hydrochloride (1.44 g, 0.005 m) and triethylamine (4 cm3) were refluxed for 24 hours in ethanol (50 cm3). The solution was cooled, the solvent evaporated and the residue treated with water. The product was extracted with chloroform, washed with water and dried (MgSO4). Evaporation gave a gum which was dissolved in isopropyl alcohol. The crystallised solid was collected by filtration, dissolved in ethanol and treated with ethanolic HCl. Ether was added and the resulting precipitate filtered off and recrystallised from isopropyl alcohol to give the title compound as the hydrochloride salt, m.p. 216°-218° C.
Reaction SMILES: [CH:1]1([CH2:7][O:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NN.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH:1]1([CH2:7][O:8][NH:9][S:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=2)(=[O:32])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1OCC1CCCCC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: NN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NOCC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.7 %

Procedure:
2-(cyclohexylmethoxy)-1H-isoindole-1,3(2H)-dione (11.8 mmol, 3.05 g) was combined with hydrazine (12.9 mmol, 0.41 mL) in anhydrous THF (25 mL) under nitrogen. The reaction immediately formed a white suspension and was allowed to stir at room temperature for 48 hours. The suspension was filtered directly into a flask containing 4-methoxybenzenesulfonyl chloride (9.5 mmol, 1.97 g) and diisopropylethylamine (11.6 mmol, 2.03 mL) was added. After stirring at room temperature for 18 hours, the reaction was concentrated to a solid residue and partitioned between ethyl acetate and 1N HCl. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate, and brine, and dried over magnesium sulfate. The product was concentrated to a solid and purified by silica gel chromatography (2:1 hexanes/ethyl acetate) providing 2.55 g (80%) of a yellow solid. H1-NMR (CDCl3): δ 7.81 (2H,d), 6.97 (2H,d), 6.78 (1H,s), 3.85 (3H,s), 3.75 (2H,d), 1.65-1.55 (6H,m), 1.25-1.07 (3H,m), 0.93-0.85 (2H,m).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([CH3:30])=[C:6]([C:22]2[CH:23]=[N:24][C:25]([CH:28]=[O:29])=[CH:26][CH:27]=2)[C:7]([O:20][CH3:21])=[C:8]([CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])[CH:9]=1>CO>[Cl:3][C:4]1[C:5]([CH3:30])=[C:6]([C:22]2[CH:23]=[N:24][C:25]([CH2:28][OH:29])=[CH:26][CH:27]=2)[C:7]([O:20][CH3:21])=[C:8]([CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])[CH3:11])[CH:9]=1
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1-c1ccc(C=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1-c1ccc(CO)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium tetrahydroborate (2.8 mg, 0.074 mmol) was added to a mixture of tert-butyl {1-[5-chloro-3-(6-formylpyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}carbamate (20 mg, 0.05 mmol) in methanol (2 mL) at 0° C. The reaction was stirred for 1 h at 0° C. The reaction mixture was partitioned between water and EtOAc. The combined organic layers was washed with brine, dried over MgSO4, filtered and concentrated to give crude product. This crude was used for next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][C:19]=1[CH2:42]OS(C)(=O)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:42][C:19]2[CH:20]=[C:21]([O:24][Si:25]([C:38]([CH3:40])([CH3:39])[CH3:41])([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]=[CH:23][C:18]=2[Br:17])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CC(C)(C)[Si](Oc1ccc(Br)c(COS(C)(=O)=O)c1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2Br)C(=O)C1
Reaction time: 1 h

Procedure:
To a solution piperazin-3-one-1-carboxylic acid tert-butyl ester (2.11 g, 10.5 mmol) in dry DMEF (20 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 632 mg, 15.8 mmol). The reaction mixture was stirred for 1 hour, and then a solution of the mesylate from Step C (5.47 g, 10.5 mmol) in DMF (10 mL) was added. The reaction mixture was stirred for 16 hours. The solvent was removed in vacuo and the residue partitioned between methylene chloride (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (20→50% ethyl acetate/hexane) to provide the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[S:8][C:6]=2[N:7]=1.[CH2:29]([C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[CH2:29]([C:31]1[N:32]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:10]=[C:9]([CH2:11][CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[S:8][C:6]=3[N:7]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: CC(C)(O)C1CCN(CCc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN3CCC(C(C)(C)O)CC3)sc2n1
Temperature: 120 °C
Yield: 56 %

Procedure:
A mixture of 2-{1-[2-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-yl)ethyl]-piperidin-4-yl}propan-2-ol (56 mg, 0.13 mmol), 2-ethylbenzimidazole (21 mg, 0.15 mmol), Pd2(dba)3 (3.0 mg, 2.5 mol %), Xphos (6.3 mg, 10 mol %) and Cs2CO3 (64 mg, 0.20 mmol) in dioxane (1.0 mL) was purged with argon gas then heated at 120° C., for 18 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PCC, 0-10% MeOH in DCM) to give 433 (39 mg, 56%) as an orange solid. LCMS: (Method I): RT 2.71 min; [M+H]+ 536.4. 1H NMR (400 MHz, CHCl3-d): δ 8.01-7.97 (m, 1 H), 7.76-7.71 (m, 1 H), 7.29-7.24 (m, 2 H), 4.52-4.32 (m, 4 H), 3.90-3.85 (m, 4 H), 3.34 (q, 7.5 Hz, 2 H), 3.35-3.23 (m, 2 H), 3.21-3.10 (m, 2 H), 2.87-2.83 (m, 2 H), 2.17-2.05 (m, 2 H), 1.86-1.75 (m, 2 H), 1.43 (t, J=7.5 Hz, 3 H), 1.38-1.23 (m, 3 H), 1.22 (s, 6 H)
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]2[N:19]([C:20](=[O:22])[CH:21]=1)[CH:18]=[C:17]([CH2:23][NH:24]C(OC(C)(C)C)=O)[CH:16]=[CH:15]2)=[O:11])(C)(C)C.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>ClCCl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[NH2:24][CH2:23][C:17]1[CH:16]=[CH:15][C:14]2[N:19]([C:20](=[O:22])[CH:21]=[C:12]([C:10]([NH:9][CH2:8][CH:7]([NH:32][S:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)(=[O:34])=[O:35])[C:6]([OH:42])=[O:5])=[O:11])[CH:13]=2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc2cc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)OC(C)(C)C)cc(=O)n2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc2cc(C(=O)NCC(NS(=O)(=O)c3ccccc3)C(=O)O)cc(=O)n2c1
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of (S)-2-Benzenesulfonylamino-3-{[7-(tert-butoxycarbonylamino-methyl)-4-oxo-4H-quinolizine-2-carbonyl]-amino}-propionic acid tert-butyl ester (21.2 mg, 0.035 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred overnight, evaporated to dryness and triturated in ether (3×) and dichloromethane (1×). The solid was dried and characterized to yield 62% (10 mg, 0.022 mmol) of the title compound which was characterized by 1HNMR (400 MHz, CD3OD) δ: 9.03 (s, 1H), 7.93-7.83 (m, 3H), 7.64 (dd, 1H, J=9, 1.5 Hz), 7.55-7.45 (m, 3H), 7.26 (s, 1H), 6.92 (d, 1H, J=1.5 Hz), 4.29 (s, 2H), 4.22 (dd, 1H, J=7.5, 5 Hz), 3.81-3.77 (dd, 1H, J=13.5, 5 Hz), 3.55-3.45 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[OH:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([O:22][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][CH:11]([O:12][S:31]([CH3:30])(=[O:33])=[O:32])[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(C(O)CCC(O)c2ccc(Br)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
Dissolved the product from Example 39B (3.68 g, 10.05 mmol) in dichloromethane (167 mL) and cooled the solution in an ice bath followed by the addition of triethylamine (4.20 mL, 30.1 mmol) and methanesulfonyl chloride (1.96 mL, 25.1 mmol) dropwise. After stirring for 15 min, the solution was concentrated to a solid (5.25 g, 100%) that was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:24][CH2:23][CH2:22][C:19]2[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccncc1
Product: Clc1nccc(-c2cccc(CNCCc3ccncc3)c2)n1

Procedure:
Intermediate 1 was coupled with 2-pyridin-4-yl-ethylamine following procedure B. LC-MS showed the product had the expected M+H+ of 325.