Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([CH3:25])=[N:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][CH2:26][C:16]1([C:19]2[CH:24]=[N:23][C:22]([CH3:25])=[N:21][CH:20]=2)[CH2:17][CH2:18][C:13]([F:12])([F:28])[CH2:14][CH2:15]1)=[O:6]
Reactant: Cc1ncc(C2(CN)CCC(F)(F)CC2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C2(CNC(=O)c3cccc(Cl)c3Cl)CCC(F)(F)CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and C-[4,4-difluoro-1-(2-methyl-pyrimidin-5-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=414.1, tR (minutes, Method F)=2.57
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[O:12][C@@H:11]([N:23]2[C:51]3[N:50]=[C:45]([NH:46][C:47](=[O:49])[NH2:48])[N:44]=[C:27]([O:28][C:29](=[O:43])[N:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)(C(C)(C)C)(C)C.COC1C=CC(C(OC[C@H]2O[C@@H](N3C4N=C(NC(=O)NC)N=C(OC(=O)N(C5C=CC=CC=5)C5C=CC=CC=5)C=4N=C3)C[C@@H]2O)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.C1(C)C=CC=CC=1>O1CCCC1>[C:47]([NH:46][C:45]1[N:44]=[C:27]([O:28][C:29](=[O:43])[N:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:26]2[N:25]=[CH:24][N:23]([C:51]=2[N:50]=1)[C@@H:11]1[O:12][C@H:13]([CH2:14][OH:15])[C@@H:9]([OH:8])[CH2:10]1)(=[O:49])[NH2:48]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(OC(=O)N(c4ccccc4)c4ccccc4)nc(NC(N)=O)nc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CNC(=O)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](COC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)O3)c2n1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: NC(=O)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.5 %

Procedure:
The above-obtained 3′,5′-bis-O-(tert-butyldimethylsilyl)-2-N-carbamoyl-6-O-diphenylcarbamoyldeoxyguanosine (1.53 g, 2.09 mmol) was azeotroped with anhydrous tetrahydrofuran three times and dissolved in anhydrous tetrahydrofuran (10 mL), and triethylamine 3 hydrogen fluoride (1.02 mL, 6.27 mmol) was added thereto. The mixture was stirred at room temperature overnight, and then toluene (10 mL) was added thereto. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (N60: spherical neutral silica gel) with methanol/4% to 10% chloroform to give 2-N-carbamoyl-6-O-diphenylcarbamoyldeoxyguanosine (1.21 g, quant).
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:34])[C@H:15]([CH2:19][C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[N:25][N:26]2[CH2:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:22][CH:21]=1)[CH:16]([CH3:18])[CH3:17])C1C=CC=CC=1.OO.[Li+].[OH-].[O-:39]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[CH3:33][O:32][CH2:31][CH2:30][CH2:29][N:26]1[C:27]2[C:23](=[CH:22][CH:21]=[C:20]([CH2:19][C@H:15]([CH:16]([CH3:17])[CH3:18])[C:14]([OH:34])=[O:39])[CH:28]=2)[CH:24]=[N:25]1
Reactant: O=S([O-])[O-]
Reactant: COCCCn1ncc2ccc(C[C@@H](C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)C(C)C)cc21
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCn1ncc2ccc(C[C@@H](C(=O)O)C(C)C)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 81 %

Procedure:
To a solution of (R)-4-benzyl-3-((R)-2-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutanoyl)oxazolidin-2-one (230 mg, 0.5 mmol) in 3:1 THF/H2O (8 mL) cooled in an ice-water bath, were added 30% aq H2O2 (0.5 mL, 3.5 mmol) and LiOH (60 mg, 1.1 mmol). The mixture was stirred at rt for 12 h. The mixture was cooled to 0° C. and 10% aq Na2SO3 (5 mL) was added dropwise. The solvent was removed in vacuo and the aqueous phase was washed with Et2O. The pH of the aqueous layer was adjusted to 3 by addition of 1 N aq HCl. The mixture was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated to give (R)-2-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutanoic acid (123 mg, 81%). 1H NMR (400 MHz, CDCl3): 1.07 (m, 6H), 1.99 (m, 1H), 2.56 (m, 1H), 3.00 (m, 2H), 3.24 (m, 2H), 2.99 (s, 3H), 4.10 (m, 1H), 4.40 (m, 2H), 6.98 (m, 1H), 7.23 (m, 1H), 7.59 (m, 1H), 7.92 (m, 1H). MS: 305 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[K+].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([OH:22])=[O:21]>O.[Cu]>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(S)cc1Cl
Reactant: O=C(O)Cc1ccccc1I
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccccc1Sc1ccc(F)c(Cl)c1
Yield: 72 %

Procedure:
The thiophenol from the preceding experiment (34.5 g) is added at 50° C. to a solution of potassium hydroxide (40 g) in water (425 ml) and this mixture is stirred until it becomes homogeneous. Then, o-iodophenylacetic acid (55.0 g) and copper powder (2.0 g) are added and the mixture refluxed for 24 hours. While still warm, the solution is filtered with charcoal, the filtrate diluted with water and acidified with hydrochloric acid. The separated crude oily acid is extracted with benzene, the solvent evaporated and the residue crystallized from aqueous ethanol, yielding 45.2 g (72%) of 2-(3-chloro-4-fluorophenylthio)phenylacetic acid which in the pure state melts at 85°-87° C. (cyclohexane-hexane).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:21][CH2:20][NH:28][C:2]2[CH:7]=[C:6]([C:8]3[N:12]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[N:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCc1ccccc1
Reactant: Fc1ccc(-n2nccc2-c2ccnc(Cl)c2)cc1
Product: Fc1ccc(-n2nccc2-c2ccnc(NCCc3ccccc3)c2)cc1
Temperature: 190 °C
Yield: 70 %

Procedure:
A mixture of 2-chloro-4-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]pyridine (Example 46; 0.6 g, 0.002 mol) and phenethylamine (20 mL) was heated at 190° C. for 24 hours. The excess amine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 2:8) to give 0.55 g (70% yield) of product as a yellow oil: Anal. Calc'd. for C22H19FN4: C, 73.72; H, 5.34; N, 15.63. Found: C, 73.33; H, 5.46; N, 15.22.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[NH2:28][C:29]1[N:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:42])[CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])=[CH:31][CH:30]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:40][N:39]([CH3:41])[CH2:38][CH2:37][N:36]([CH2:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=3[F:22])=[CH:14][CH:15]=2)=[O:3])=[N:34][CH:33]=1)[CH3:42]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: CN(C)CCN(C)Cc1ccc(N)nc1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN(C)CCN(C)C)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 5 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (prepared as described in Example 26 but using N,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2 and purified by column chromatography), 1.5 equiv of trimethyl aluminum, stirring the reaction mixture for 5 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. The title compound: ESI-MS: 537.1 [M+H]+; tR=3.31 min (System 1); TLC: Rf=0.13 (DCM/MeOH, 95:5).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)=[CH:8][CH:7]=1)([OH:5])[CH3:4].FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@H]2CC2C=CC=C(F)C=2)=CC=1)(O)C.FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@@H]2CC2C=CC=C(F)C=2)=CC=1)(O)C.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[F:35][C:2]([F:1])([F:34])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@H:13]2[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)=[CH:8][CH:7]=1)([OH:5])[CH3:4]
Reactant: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2Cc2cccc(F)c2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2Cc2cccc(F)c2)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2Cc2cccc(F)c2)cc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2Cc2cccc(F)c2)cc1)C(F)(F)F

Procedure:
(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(3-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(3-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(3-fluorobenzyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, CD3OD) δ 7.86 (dd, J=1.2, 5.1 Hz, 1H), 7.64-7.59 (m, 1H), 7.55-7.48 (m, 2H), 7.36-7.15 (m, 2H), 7.11-6.77 (m, 5H), 4.17-4.09 (m, 1H), 3.84 (d, J=10.0 Hz, 1H), 3.61 (d, J=11.3 Hz, 1H), 3.55-3.43 (m, 1H), 3.42-3.34 (m, 1H), 3.19-3.04 (m, 1H), 2.69-2.48 (m, 3H), 1.70 (s, 3H). m/z (ESI, +ve ion) 529.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.802 μM; GK-GKRP EC50 (LC MS/MS)=1.09 μM.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:11][N:10]=2)[CH2:5][CH2:4]1.[CH3:20][N:21]1[CH:30]=[CH:29][C:28]2[N:27]=[C:26]([C:31]3[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=3)[C:25]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:24][C:23]=2[C:22]1=[O:45].C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH3:20][N:21]1[CH:30]=[CH:29][C:28]2[N:27]=[C:26]([C:31]3[CH:38]=[CH:37][C:34]([CH2:35][N:3]4[CH2:8][CH2:7][CH:6]([C:9]5[N:13]=[C:12]([C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=6)[NH:11][N:10]=5)[CH2:5][CH2:4]4)=[CH:33][CH:32]=3)[C:25]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:24][C:23]=2[C:22]1=[O:45]
Reactant: Cn1ccc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cc2c1=O
Reactant: c1ccc(-c2nc(C3CCNCC3)n[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cn1ccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cc2c1=O
Temperature: 25 °C

Procedure:
To a solution of 2-(3-piperidin-4-yl-1H-1,2,4-triazol-5-yl)pyridine dihydrochloride (142 mg, 10.47 mmol) and 4-(6-methyl-5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzaldehyde (5141 mg, 0.415 mmol) in dry DMF (1.5 mL) was added triethylamine (0.21 mL, 1.5 mmol). After stirring for 10 minutes acetic acid (0.26 mL, 4.5 mmol) was added and the mixture was stirred at room temperature over night. Then sodium triacetoxy borohydride (110 mg, 0.52 mmol) was added in one portion and stirred for eight hours. After monitoring by LC/MS determined the reaction was not complete additional sodium triacetoxy borohydride (46 mg, 0.21 mmol)) were added and the reaction was stirred over night. This reaction mixture was adsorbed on silica gel and purified by column chromatography eluting with 1-7% methanol/ethyl acetate (sat'd NH3). The appropriate fractions were combined, the solvents removed in vacuo, and the residue digested in acetonitrile containing a little methanol to give pure title compound. 1H NMR (500 MHz, CDCl3): δ 8.69 (1H, s), 8.65 (1H, d, J=4.4 Hz), 8.15 (1H, d, J=7.8 Hz), 7.83 (1H, t, J=7.6 Hz), 7.31-7.39 (5H, m), 7.22-7.25 (6H, m), 6.86 (1H, d, J=6.5 Hz), 3.66 (3H, s), 3.53 (2H, s), 2.95 (2H, br d, J=10.7 Hz), 2.85 (1H, m), 2.06-2.15 (4H, m), 1.92-2.01 (2H, m). m/e (m+1): 554.3, 277.9 [(m+2)/2].
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][C:11]1[O:15][C:14]([C@@H:16]2[CH2:22][CH2:21][C@@H:20]3[CH2:23][N:17]2[C:18](=[O:32])[N:19]3[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:13][N:12]=1.[C:33]([O:37][C:38]([NH:40][C:41](=[N:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])N1C=CC=N1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>CO>[C:50]([O:49][C:48]([N:47]=[C:41]([NH:40][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[NH:8][CH2:9][CH2:10][C:11]1[O:15][C:14]([C@@H:16]2[CH2:22][CH2:21][C@@H:20]3[CH2:23][N:17]2[C:18](=[O:32])[N:19]3[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:13][N:12]=1)=[O:54])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: NCCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N=C(NCCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
TEA (77 mg, 0.764 mmol) was added to a 0° C. solution of (2S,5R)-2-(5-(2-aminoethyl)-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one TFA salt from the previous step in MeOH (3.0 mL). Tert-Butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (65 mg, 0.209 mmol) was then added at 0° C. and the reaction mixture was stirred at 0° C. for 4 hrs. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (gradient elution 30%-50% EtOAc/petroleum ether) to give (2S,5R)-2-(5-((2,3-bis(tert-butoxycarbonyl)guanidino)ethyl)-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one (80 mg, 70% in 2 steps) as a colorless oil. ESI-MS (EI+, m/z): 586.3 [M+H]+.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][O:38][CH3:39])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][N:35]([CH2:36][CH2:37][O:38][CH3:39])[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: O=C(O)CO
Reactant: COCCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: COCCN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)CO
Yield: 27 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{2-[(2-methoxyethyl)amino]ethoxy}quinazolin-4-amine (obtained as described in Example 24, preparation of starting materials) to give the title compound in 27% yield; NMR spectrum (DMSO-d6) 3.18 (s, 1H), 3.24 (s, 2H), 3.48 (s, 3H), 3.55-3.60 (m, 1H), 3.86-3.98 (m, 2H), 4.10-4.15 (m, 2H), 4.32 (t, 1H), 4.43 (t, 1H), 4.51-4.57 (m, 1H), 5.31 (s, 2H), 7.17 (d, 1H), 7.25 (d, 1H), 7.33-7.40 (m, 2H), 7.57-7.63 (m, 2H), 7.71-7.76 (m, 1H), 7.86-7.91 (m, 1H), 7.99-8.05 (m, M1H), 8.46 (s, 1H), 8.60 (d, 1H), 9.84 (s, 1H); Mass spectrum MH+ 538.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH2:30][C:31](O)=[O:32])[CH:22]=1)([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[N:9]=[CH:8]2)[OH:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:48][S:49]([NH2:52])(=[O:51])=[O:50].[H-].[Na+]>CN(C=O)C>[F:1][C:2]([F:34])([F:35])[C:3]([C:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH2:30][C:31]([NH:52][S:49]([CH3:48])(=[O:51])=[O:50])=[O:32])[CH:22]=1)([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[N:9]=[CH:8]2)[OH:4]
Reactant: O=C(O)Cn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2cccnc21
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)Cn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 107 mg (0.22 mmol) of (3-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}pyrrolo[2,3-b]pyridin-1-yl)acetic acid in 3 mL of DMF was added 108 mg (0.66 mmol) of N,N-carbonyldiimidazole. The mixture stirred for 5 minutes and then 63 mg (0.66 mmol) of methanesulfonamide was added. After 30 minutes, the reaction was monitored by LCMS indicating only starting material [MS m/z 485.29 (MH+)]. To the mixture was added sodium hydride and the mixture stirred for 1.5 hours. The mixture was monitored by LCMS indicating desired product [MS m/z 562.37 (MH+)]. TLC (ethyl acetate or methanol-dichloromethane) indicated a new product. The mixture was diluted with saturated aqueous ammonium chloride and extracted with five 10 mL portions of ethyl acetate. The combined organic layers were washed with two 7 mL portions of saturated aqueous ammonium chloride, two 7 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The oily residue was chromatographed on silica gel using dichloromethane to load the sample and then methanol-dichloromethane (1-10%) to afford some mixed factions and clean fractions. Fractions containing product were chromatographed on four prep. plate (1 mm, methanol-dichloromethane 15:85). The most polar band was recovered eluting from the silica gel with 20% methanol-dichloromethane. The material was triturated with ether-hexanes to afford 42 mg (33%) of the title compound as a tan solid. MS m/z 562.39 (MH+).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O.CCOC(C)=O>CN(C=O)C>[CH3:15][S:16]([NH:2][C@H:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:18])=[O:17]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NS(C)(=O)=O
Reaction time: 16 h
Yield: 49.4 %

Procedure:
To a stirring solution of 2.51 g (20.0 mmol) of methyl L-phenylalaninate hydrochloride and 6.7 mL (48 mmol) of TEA in 50 mL of DMF was added 1.86 mL (24 mmol) of methanesulfonyl chloride. After 16 hours, the reaction mixture was added to 200 mL of H2O and 200 mL of EtOAc. The resulting layers were separated, and the organic layer was washed with 3x 200 mL of H2O and dried. The resulting residue was chromatographed to yield 2.54 g (49%) of N-(methylsulfonyl)-L-phenylalanine, methyl ester (13), which was a clear colorless glass. Analysis calculated for C11H15NO4S (M.W. 257.30): C, 51.35; H, 5.88; N, 5.44; S, 12.46. Found: C, 50.92; H, 5.92; N, 5.38; S, 12.55.
Reaction SMILES: [N+](C1C=CC(C(Cl)=O)=CC=1)([O-])=O.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]1[N:23]([C:24](=[O:34])C2C=CC([N+]([O-])=O)=CC=2)[CH2:22][CH2:21][NH:20][C:19]1=[O:35]>>[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]1[N:23]([CH:24]=[O:34])[CH2:22][CH2:21][NH:20][C:19]1=[O:35]
Reactant: O=C1NCCN(C(=O)c2ccc([N+](=O)[O-])cc2)C1c1cccs1
Agent: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: O=CN1CCNC(=O)C1c1cccs1

Procedure:
Using 4-nitrobenzoyl chloride: 3-(2-thienyl)-4-(4-nitrobenzoyl)-piperazin-2-one, yield: 83% of theory, melting point: 204° C.
Reaction SMILES: [N+:1]([C:4]1[C:13]([Cl:14])=[C:12]([Cl:15])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:17])[C:8](=[O:16])[NH:9]2)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[C:13]([Cl:14])=[C:12]([Cl:15])[CH:11]=[C:10]2[C:5]=1[NH:6][C:7](=[O:17])[C:8](=[O:16])[NH:9]2
Reactant: O=c1[nH]c2cc(Cl)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a stirred mixture of 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (110 mg, 0.40 mMol) in ethanol (6 mL) was added SnCl2.2H2O (448 mg, 2.0 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring for 1 h to form a clear solution and continually refluxed for another 3 h. The mixture was then cooled to room temperature and the yellow precipitate was collected by filtration and washed with cold ethanol (2×1 mL) to give 61 mg (62%) of crude title compound (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 43 mg of pure title compound as bright yellow needles, mp >350° C. (dec.), changed color from 320° C. IR (KBr, cm-1): 3468; 3389; 3057; 1695; 1636; 1596; 1397. NMR (1H, DMSO-d6): δ 5.935 (s, 2H); 6.595 (s, 1H); 11.317 (s, 1H); 11.868 (s, 1H). Purity >98.95% by HPLC. HRMS: calcd for C8H5N3O2Br2 (M+) m/z: 244.9757; found 244.9740. Potency relative to DCK: 323%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH2:7][OH:8].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[Cl:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=[O:8]
Reactant: OCc1sc2ccccc2c1Cl
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1sc2ccccc2c1Cl
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
A solution of alcohol 12 (4.32 g, 21.6 mmol) in 40 mL of CH2Cl2 was treated with 4 A molecular sieves, NMO (3.81 g, 32.5 mmol), and TPAP (381 mg, 1.08 mmol). The reaction was stirred for 10 min. and then was evaporated to dryness. Purification by flash chromatography on silica gel (2% ethyl acetate/hexane) gave 3.52 g (18.3 mmol, 84%) of the aldehyde (13).
Reaction SMILES: [Si](OC[C@@H](N)C([CH:13]1[CH2:15][CH2:14]1)=C)(C(C)(C)C)(C)C.BrCC(N(OC)C)=O.[Si:25]([O:32][CH2:33][C@@H:34]([N:37]([CH2:45][C:46]([N:48]([O:50][CH3:51])[CH3:49])=[O:47])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:35]=[CH2:36])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>>[Si:25]([O:32][CH2:33][C@@H:34]([N:37]([CH2:45][C:46]([N:48]([O:50][CH3:51])[CH3:49])=[O:47])[C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])[C:35]([CH:13]1[CH2:15][CH2:14]1)=[CH2:36])([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:26])[CH3:27]
Reactant: C=C(C1CC1)[C@H](N)CO[Si](C)(C)C(C)(C)C
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Agent: CON(C)C(=O)CBr
Product: C=C(C1CC1)[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from (S)-1-(tert-butyldimethylsilyloxy)-3-cyclopropylbut-3-en-2-amine (Intermediate 234, 4.61 g, 19.09 mmol) and 2-bromo-N-methoxy-N-methylacetamide (Intermediate 4, 3.16 g, 17.36 mmol) following the procedure described for Intermediate 5. The desired product was obtained as a light yellow oil (4.94 g, 64%).