Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][NH:10][C:11]2[N:20]=[C:19]([N:21]([CH3:23])[CH3:22])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH2:5][CH2:4]1.[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[C:27]([O:33][C:34]([F:37])([F:36])[F:35])[CH:26]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:1][CH2:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([CH2:9][NH:10][C:11]3[N:20]=[C:19]([N:21]([CH3:23])[CH3:22])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=3)[CH2:5][CH2:4]2)=[C:27]([O:33][C:34]([F:35])([F:36])[F:37])[CH:26]=1
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CN)CC2)nc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)c1nc(NC[C@H]2CC[C@H](CNCc3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of trans-N2-(4-aminomethyl-cyclohexylmethyl)-N4,N4-dimethyl-quinazoline-2,4-diamine (500 mg, 1.59 mmol) in CH2Cl2 (5 mL) were added 4-bromo-2-trifluoromethoxy-benzaldehyde obtained in step A of example 13 (428 mg, 1.59 mmol), acetic acid (95 mg, 1.59 mmol), and NaBH(OAc)3 (505 mg, 2.38 mmol). The reaction mixture was stirred at ambient temperature for 4 hr. The reaction was quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 50% EtOAc in hexane) to give trans-N2-{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexylmethyl}-N4,N4-dimethyl-quinazoline-2,4-diamine (783 mg, 89%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH:6](=[N:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC.C1COCC1.[Cl-].[Na+].O>[C:7]1([CH:6]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH2:3][CH:2]=[CH2:1])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(N=Cc1ccccc1)c1ccccc1
Reactant: C=CC[Mg]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(NS(=O)(=O)c1ccccc1)c1ccccc1
Yield: 64.8 %

Procedure:
A solution of allyl magnesium bromide (12 mmol) in Et2O (1.0 M, 12 mL) was added dropwise over 10 min to a stirred solution of N-benzylidenebenzene sulfonamide (2.5 g, 10.2 mmol) in THF (40 mL) under N2. After 2 h the mixture was poured into brine and extracted with EtOAc. These extracts were washed with H2O and brine then dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with CH2Cl2 to give the benzenesulfonamide as a white solid (1.9 g, 65%). 1H NMR (360 MHz, CDCl3) δ 2.44–2.48 (2H, m), 4.39–4.45 (11H, m), 4.79 (11H, d, J=5.6 Hz), 5.04–5.10 (2H, m), 5.46–5.58 (1H, m), 7.04–7.07 (2H, m), 7.15–7.19 (3H, m), 7.32–7.37 (2H, m), 7.43–7.48 (1H, m), 7.64–7.67 (2H, m).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:39])([CH3:38])[C@@H:14]([O:30]CC1C=CC=CC=1)[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]>[Pd].CO>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:39])([CH3:38])[C@@H:14]([OH:30])[C:15]([O:17][CH2:18][CH2:19][O:20][C:21]([O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)OC1CCCCC1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCCOC(=O)OC1CCCCC1
Reaction time: 8 h
Yield: 79.4 %

Procedure:
Following the general procedure of hydrogenolysis of benzyl ethers of Description 18, a mixture of (cyclohexyloxycarbonyloxy)ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate (43c) (0.19 g, 0.34 mmol) and 0.13 g of 10 wt.-% of palladium on activated carbon in 10 mL of methanol (MeOH) was stirred overnight under a hydrogen atmosphere. After purification by mass-guided preparative HPLC, 0.13 g (80% yield) of the title compound (43) was obtained as a colorless, viscous oil. 1H NMR (400 MHz, DMSO-d6, both diastereomers): δ=0.89-0.90 (2s, 3H), 0.93-0.94 (2s, 3H), 1.31-1.47 (br. m, 9H), 1.60-1.68 (br. m, 2H), 1.78-1.83 (br. m, 7H), 3.10-3.15 (m, 2H), 3.28-3.35 (m, 2H), 3.89-3.92 (m, 2H), 4.05-4.08 (2d, J=9.2, 9.6 Hz, 1H), 4.52-4.58 (m, 1H), 5.78-5.85 (2d, J=5.6, 5.6 Hz, 1H), 6.66-6.72 (m, 1H), 7.89-7.92 (br. m, 1H) ppm. MS (ESI) m/z: 482.07 (M+H)+, 503.83 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])[NH:7][C:8]([O:10][CH2:11][CH2:12]Cl)=[O:9])=[O:5].[H-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]([N:6]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])[N:7]1[CH2:12][CH2:11][O:10][C:8]1=[O:9])=[O:5]
Reactant: COCC(=O)N(NC(=O)OCCCl)c1c(C)cccc1C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCC(=O)N(c1c(C)cccc1C)N1CCOC1=O
Reaction time: 0.5 h

Procedure:
11.8 g (0.0375 mol) 2-Chloroethyl 2-(methoxyacetyl)-2-(2,6-dimethylphenyl)-hydrazinecarboxylate are added portion-wise to a suspension of 2.0 g sodium hydride (in form of about 55% by weight in mineral oil) in 100 ml absolute toluene at room temperature under a blanket of nitrogen. The reaction temperature rises gradually during this addition up to 40°. After the addtion is complete the mixture is stirred during 30 minutes without cooling and afterwards cooled to 10°. The unreacted sodium hydride is then destroyed with ethanol, the obtained solution washed with water dried with MgSO4 and the solvent removed in vacuo to give the end title compound which is recrystallised from ethanol to yield the title compound as colourless crystals, m.p. 103°-104°.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][C:7]([CH3:15])=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].CO.[CH3:18][N:19]1[CH:21](SC)[CH:20]1[N+:24]([O-:26])=[O:25].COCCOC>C(OCC)(=O)C.CO.[OH-].[NH4+]>[CH3:3][N:2]([CH2:4][C:5]1[S:6][C:7]([CH3:15])=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:21]([NH:19][CH3:18])=[CH:20][N+:24]([O-:26])=[O:25])[N:9]=1)[CH3:1]
Reactant: CSC1C([N+](=O)[O-])N1C
Reactant: Cc1sc(CN(C)C)nc1CSCCN
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CO
Product: CNC(=C[N+](=O)[O-])NCCSCc1nc(CN(C)C)sc1C
Reaction time: 8 h

Procedure:
Following the procedure of Example 5, a stirred solution of 1.38 g. of 2-([2-(dimethylaminomethyl)-5-methyl-4-thiazolyl]methylthio)ethylamine in 10 ml. of methanol was treated with N-methyl-1-methylthio-2-nitroethyleneamine. The reaction mixture was kept at room temperature overnight by which time all solids had dissolved. Thin layer chromatography over silica using a 10:10:1 ethyl acetate-methanol-ammonium hydroxide solvent system indicated substantially a single product. The reaction mixture was concentrated by evaporation of the methanol and the resulting gummy yellow residue was triturated with several portions of cold ether, thus providing an off-white gum. Repeated tritration with cold 1,2-dimethoxyethane yielded N-2-([2-(dimethylaminomethyl)-5-methyl-4-thiazolyl]methylthio)ethyl-N'-methyl-2-nitro-1,1-ethenediamine formed in the above reaction melting at about 104°-106° C.
Reaction SMILES: C(C1OC[C@H](C(C)(C)C)N=1)(C1OC[C@H](C(C)(C)C)N=1)(C)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:31][CH2:32][C@H:33]2[O:37][C@@H:36]([N:38]3[CH:45]=[CH:44][C:42](=[O:43])[NH:41][C:39]3=[O:40])[C@H:35]([OH:46])[C@@H:34]2[OH:47])=[CH:26][CH:25]=1.[C:62]1([N:68]=[C:69]=[O:70])[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)OC[C@H]2O[C@@H](N3C=CC(=O)NC3=O)[C@H](OC(=O)NC3C=CC=CC=3)[C@@H]2O)=CC=1>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2].C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([C:54]2[CH:55]=[CH:56][C:57]([O:60][CH3:61])=[CH:58][CH:59]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:31][CH2:32][C@H:33]2[O:37][C@@H:36]([N:38]3[CH:45]=[CH:44][C:42](=[O:43])[NH:41][C:39]3=[O:40])[C@H:35]([OH:46])[C@@H:34]2[O:47][C:69](=[O:70])[NH:68][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[CH:28][CH:29]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Cu+2]
Agent: CC(C)(C1=N[C@@H](C(C)(C)C)CO1)C1=N[C@@H](C(C)(C)C)CO1
Agent: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OC(=O)Nc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2OC(=O)Nc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The THF solution (1 ml) containing 2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (0.03 mmol, 8.9 mg) and Cu(OTf)2 (II) (0.03 mmol, 11.1 mg) was stirred for 2 hours at room temperature. After the reaction mixture was cooled to 0° C., the THF solution (1 ml) of 5′-O-[bis(4-methoxyphenyl)phenylmethyl]uridine (0.3 mmol, 164 mg) and the THF solution of phenyl isocyanate (0.3 mmol, 35.7 mg) were added thereto. After the mixture was continuously stirred at 0° C. overnight, the mixture was analyzed with high-performance liquid chromatography. As a result, it was found that 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-2′-O-phenylcarbamoyl-uridine and 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-3′-O-phenylcarbamoyl-uridine were produced at the ratio of 72:28, and the transformation ratio of the reaction was 95%.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([CH:6]=[C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])=[C:13]([CH:19]=1)[O:14][CH2:15][C:16]([OH:18])=[O:17])[CH3:8])=[O:5])[CH3:2].[CH:31](O)([CH3:33])[CH3:32].Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:29]([N:3]([CH2:1][CH3:2])[C:4](/[CH:6]=[C:7](/[C:9]1[CH:10]=[CH:11][C:12]([O:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])=[C:13]([CH:19]=1)[O:14][CH2:15][C:16]([O:18][CH:31]([CH3:33])[CH3:32])=[O:17])\[CH3:8])=[O:5])[CH3:30]
Reactant: CCN(CC)C(=O)C=C(C)c1ccc(OC(C)c2ccccc2)c(OCC(=O)O)c1
Reactant: CC(C)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)/C=C(\C)c1ccc(OC(C)c2ccccc2)c(OCC(=O)OC(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of [5-(2-diethycarbamoyl-1-methylvinyl)-2-(1-phenylethoxy)-phenoxy]-acetic acid (300 mg, 0.97 mmol), 4-dimethylaminopyridine (12 mg, 0.097 mmol) and isopropanol (117 mg, 1.95 mmol) in methylene chloride (30 mL) is cooled to 0° C., and 1-(3-dimethylaminopropyl)-3-etbylcarbodiimide.HCl (205 mg, 1.07 mmol) is added in one portion. The mixture is then allowed to stir at room temperature for 18 hours. After washing with water (50 ml), the organic layer is washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated in vacuo. Chromatography (silica, 1:1 EtOAc/hexane) yields isopropyl (E)-[5-(2-diethylcarbamoyl-1-methylvinyl)-2-(1-phenylethoxy)-phenoxy]-acetate MS: 454 (M++1), 350 (M+-PhCHCH3+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[O:25]1CCOCC1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[OH-].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[NH:3][C:2](=[O:25])[CH:7]=[N:6][C:5]=2[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1)=[O:16]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: C1COCCO1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(=O)[nH]c12
Temperature: 100 °C
Reaction time: 15 h
Yield: 51 %

Procedure:
A mixture of 1-[2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.067 g, 0.16 mmol), 0.4 mL dioxane, 0.4 mL water, Pd2(dba)3 (0.009 g, 0.01 mmol), 2-di-t-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (0.008 g, 0.02 mmol), and freshly ground KOH (0.038 g, 0.67 mmol) in a sealed tube under N2 was stirred at 100° C. for 15 h. The resulting orange-black mixture was partitioned between 5 mL of ethyl acetate and 5 mL of water, with a few drops of ethanol added to reduce emulsions. The aqueous layer was extracted with 5 mL of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated to an orange oil. Silica gel chromatography (20→40% EtOAc/hexanes) afforded 0.029 g (51%) of 7-(2,2-dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-1,5-dihydro-pyrrolo[2,3-b]pyrazin-2-one as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](OC)=O)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[NH:20][C:18](=[O:19])[C:3]3[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:24][CH:23]=1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Product: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(Cc3ccc(Cl)cc3)nc21

Procedure:
Analogously to the procedure of Example 5, the title compound is prepared from 1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 1.83 g (10.7 mmol) of methyl 4-chlorophenylacetate.
Reaction SMILES: [CH2:1]1[CH2:6]CC(N=C=NC2CCCCC2)C[CH2:2]1.[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.C(O)CC>[I:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O:23][CH2:2][CH2:1][CH3:6])=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCCO
Product: CCCOC(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
DCC (13.4 g) was added in one portion to 4-iodobenzoic acid (15.0 g), n-propanol (7.2 g) and 4-(dimethylamino)pyridine (0.6 g) in MC (50 ml) at 0° under nitrogen. The mixture was stirred at 0° for 10 min and at room temperature for 3 h, diluted with ER (50 ml), filtered and evaporated. The residue was treated with CX (50 ml), filtered and the filtrate evaporated to give the title compound as a pale yellow oil (16.2 g). T.l.c. (CX-ER 3:1) Rf 0.8.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](I)[CH3:23].[H-].[Na+].Cl>CN(C=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:22][CH3:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)OC)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To 82 mg (0.28 mmol) of 1-benzyloxycarbonyl-4-(methoxycarbonylamino)piperidine from Step A and 0.045 mL (0.56 mmol) of ethyl iodide in 4 mL of DMF under nitrogen was added 22 mg (0.56 mmol) of 60% sodium hydride in mineral oil. The reaction was stirred at rt for 1 h and was then poured into water containing 1 mL of 2 N hydrochloric acid and extracted twice with ether. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 50% ethyl acetate in hexanes to afford 87 mg of title compound.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][C:13]=2[CH2:25][S:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:10]=1)C.[OH-].[Li+]>CO.O>[C:27]([S:26][CH2:25][C:13]1[CH:14]=[C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH:10]=[C:6]([CH2:5][C:4]([OH:31])=[O:3])[CH:7]=[N:8]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)Cc1cnn(Cc2ccc(NC(=O)C(C)(C)C)cc2CSC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1Cn1cc(CC(=O)O)cn1

Procedure:
{1-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-benzyl]-1H-pyrazol-4-yl}-acetic acid ethyl ester (0.038 g, 0.09 mmol) in MeOH and H2O was hydrolyzed with lithium hydroxide to give the title compound.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[C:17]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]3[CH2:12][N:13]([S:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:37])=[O:36])[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2CN(S(=O)(=O)c3ccccc3)CCN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (50 mg, 0.17 mmol) in chloroform (2 mL) were sequentially added pyridine (0.5 mL) and benzenesulfonyl chloride (43 mg, 0.24 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) and crystallized from diisopropyl ether to obtain the title compound (27 mg, yield 37%).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:12]=[C:11]([C:22]2[CH:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([N:36]4[CH2:41][CH2:40][N:39]([CH:42]([CH3:44])[CH3:43])[CH2:38][CH2:37]4)=[O:35])=[CH:30][CH:29]=3)[CH:25]=[N:26][CH:27]=2)[CH:10]=1)C1C=CC=CC=1.C[Si](I)(C)C>C(Cl)Cl>[OH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:12]=[C:11]([C:22]2[CH:23]=[C:24]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([N:36]4[CH2:37][CH2:38][N:39]([CH:42]([CH3:44])[CH3:43])[CH2:40][CH2:41]4)=[O:35])=[CH:32][CH:33]=3)[CH:25]=[N:26][CH:27]=2)[CH:10]=1
Reactant: Cc1cccc(-c2nc(OCc3ccccc3)cc(-c3cncc(-c4ccc(C(=O)N5CCN(C(C)C)CC5)cc4)c3)n2)n1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: Cc1cccc(-c2nc(O)cc(-c3cncc(-c4ccc(C(=O)N5CCN(C(C)C)CC5)cc4)c3)n2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (4-{5-[6-benzyloxy-2-(6-methyl-pyridin-2-yl)-pyrimidin-4-yl]-pyridin-3-yl}-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone (Example 8) (1 eq, 30 mg) in dry DCM (0.6 ml) under an atmosphere of N2 is treated with trimethylsilyl iodide (12 eq, 83.6 μl). After stirring at RT overnight, the reaction is quenched by addition of MeOH (5 ml) and stirring continued for 45 minutes. The solvent is removed in vacuo and the residue is loaded onto a SCX-2 cartridge (1 g) eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined and concentrated in vacuo and dried under vacuum overnight to afford the title compound [M+H]+=495 as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[S:24][CH:23]=[CH:22][C:4]=2[N:5]([N:14]=CC2C=CC=CC=2)[C:6](=[O:13])[C:7]=1[C:8](OCC)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([NH2:35])(=[O:34])=[O:33].[OH-].[K+].Cl>C1(C)C=CC=CC=1>[NH2:14][N:5]1[C:6](=[O:13])[C:7]([C:8]2[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32](=[O:33])(=[O:34])[N:35]=2)=[C:2]([OH:1])[C:3]2[S:24][CH:23]=[CH:22][C:4]1=2
Reactant: CCOC(=O)c1c(O)c2sccc2n(N=Cc2ccccc2)c1=O
Reactant: Nc1ccccc1S(N)(=O)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Yield: 61.9 %

Procedure:
The product of Example 268C (2.29 g, 6.69 mmol) was reacted with 2-aminobenzenesulfonamide (1.15 g, 6.69 mmol) in toluene (60 mL), and stirred at reflux for 5 hours. The reaction was cooled to 25° C. and the resulting precipitate was collected by filtration and dried (1.95 g, 62%). The resulting solid (1.95 g, 4.2 mmol) was reacted with 10% aqueous KOH (60 mL) at reflux for 24 hours, cooled to 25° C. and acidified with concentrated hydrochloric acid to pH 2. The resulting solid was collected by filtration, washed repeatedly with water and dried to provide the title compound (1.5 g, 98%).(Any sodium salt made?) 1H NMR (300 MHz, DMSO-d6) δ ppm 6.12 (s, 2 H) 7.49 (d, J=5.52 Hz, 1 H) 7.57 (m, 2 H) 7.79 (t, J=7.17 Hz, 1 H) 7.93 (d, J=7.72 Hz, 1 H) 8.34 (d, J=5.52 Hz, 1 H) 14.33 (s, 1 H) 14.68 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[CH3:9][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:15]([C:14]2[CH:19]=[CH:20][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[O:16])[CH:3]=1
Reactant: Cc1cc(Br)ccn1
Reactant: COC(=O)c1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Cc2cc(Br)ccn2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 4-bromo-2-methylpyridine (2.9 g, 16.8 mmol) and methyl 4-methoxybenzoate (2.8 g, 16.8 mmol) in tetrahydrofuran (42 mL) at 0° C. was added dropwise a 1M solution of lithium bis(trimethylsilyl)amide (33.6 mL, 33.6 mmol). The mixture was allowed to warm to room temperature and stirred for 3 days. A saturated solution of ammonium chloride (40 mL) was added and the mixture was diluted with ethyl acetate (50 mL). The separated aqueous layer was then extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford a residue which was purified by automated flash-chromatography (ethyl acetate/hexanes; 15/85). The title compound was obtained as a bright yellow solid (3.8 g, 75%). LCMS m/z 306.0; 308.0 (M+H)+, ret. time=2.48 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)CCCC(CCCNS(=O)(=O)c1ccc(Cl)cc1)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCCC(CCCNS(=O)(=O)c1ccc(Cl)cc1)CCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.083 g (0.18 mmol) of methyl 8-(p-chlorophenylsulfonamido)-5-[2-(3-pyridyl)ethyl]-octanoate, 2 mL dioxane and 0.4 mL (0.4 mmol) 1N aqueous sodium hydroxide is stirred for 16 hours at room temperature. The solvent is evaporated and the residue taken up in water and the pH is adjusted to 5. The aqueous mixture is then extracted with methylene chloride (4×10 mL). Combined organic extract is dried (MgSO4), filtered and evaporated to give an oil which is crystallized from ether to give 8-(p-chlorophenylsulfonamido)-5-[2-(3-pyridyl)ethyl]-octanoic acid, m.p. 83-85°.