Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19]C(C(=O)N(C)C)=CC=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[C:28]([O:32][C:33]([C:35]1N=CC(Br)=[CH:37][N:36]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29].COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[C:28]([O:32][C:33]([C:35]1[N:19]=[CH:18][C:17]([O:16][C:14]2[C:8]3[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=3[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:15]=2)=[CH:37][N:36]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)c1ncc(Br)cn1
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2c(c1)OC(C)(C)C2
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2cnc(C(=O)OC(C)(C)C)nc2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161b, from 5-bromo-pyrimidine-2-carboxylic acid tert-butyl ester (171a) (497 mg, 1.92 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (426 mg, 1.92 mmol) to give a yellow oil (83 mg, 11% yield). 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 2 H) 7.30 (d, J=1.26 Hz, 1 H) 7.19 (d, J=1.26 Hz, 1 H) 3.88 (s, 3 H) 2.92 (s, 2 H) 1.68 (s, 9 H) 1.50 (s, 6 H); LCMS for C21H24N2O6 m/z 345.00 (M-tBu+H+).
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH3:20])[C:6]1=[O:21])=[O:4].[NH2:22][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][CH:38]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:27]>>[Br:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:26]([C:25]2[CH:24]=[C:23]([NH:22][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH3:20])[C:6]3=[O:21])=[O:4])[CH:38]=[CH:37][CH:36]=2)=[O:27])=[CH:30][CH:31]=1
Reactant: Nc1cccc(C(=O)Nc2ccc(Br)cc2)c1
Reactant: COC(=O)C1C(=O)N(C)c2ccc(C3(C)OCCO3)cc21
Product: CC(=O)c1ccc2c(c1)C(C(=O)Nc1cccc(C(=O)Nc3ccc(Br)cc3)c1)C(=O)N2C

Procedure:
Prepared as in Example 1 from 1-methyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-(4-bromo-phenyl)-benzamide. Purified by flash-chromatography (hexanes/acetone, 1:1).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:35]=[CH:34][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:20]([C:30]([F:33])([F:32])[F:31])[CH:19]=3)[S:17][C:13]=2[CH:12]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:32][C:30]([F:31])([F:33])[C:20]1[CH:19]=[C:18]([C:16]2[S:17][C:13]3[CH:12]=[C:11]([CH2:10][NH:9][CH2:8][CH2:7][C:6]([OH:36])=[O:5])[CH:35]=[CH:34][C:14]=3[N:15]=2)[CH:23]=[CH:22][C:21]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)CCNCc1ccc2nc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCNCc1ccc2nc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
3-{[2-(2-Trifluoromethyl-biphenyl-4-yl)-benzothiazol-6-ylmethyl]-amino }-propionic acid tert-butyl ester (31 mg, 0.0605 mmol) is dissolved in TFA/CH2Cl2 (1/1) (1 mL). The solution is stirred at room temperature for an hour. The mixture is concentrated and purified by reversed phase preparative LC/MS to give 10 mg of 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-benzothiazol-6-ylmethyl]-amino}-propionic acid: 1H NMR (CD3OD, 400 MHz) δ 8.54 (s, 1 H), 8.35 (d, 1 H), 8.22 (s, 1 H), 8.18 (d, 2 H),7.58 (d, 1 H), 7.45 (m, 3 H), 7.37 (m, 2 H), 4.44 (s, 2 H), 3.36 (m, 2 H), 2.80 (m, 2 H); MS (ES+) 45.70 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Cl:7].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[CH:23]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([O:45][CH3:46])=[O:44])=[CH:39][CH:38]=1)[CH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[Cl:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[CH:23]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:42]=1)[CH2:24][CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C(=O)OC)cc2)cc1
Reactant: ClCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCCl)Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1.84 g (9.9 mmol) of 1-bromo-5-chloropentane [CAS Reg. No. 586-78-7] and 6.45 g (19.8 mmol) of anhydrous cesium carbonate are added to a solution of 1.1 g (2.47 mmol) of methyl 4-{(4E)-5-(2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (racemate; Example 18A) in 16.5 ml of dry toluene, and the mixture is then stirred at 60° C. for 18 h. The mixture is then filtered, and the filtrate is evaporated to dryness. The crude product obtained is taken up in ethyl acetate and washed twice with saturated sodium bicarbonate solution, and the organic phase is dried over sodium sulfate and concentrated. The crude product is then purified by flash chromatography on silica gel (mobile phase: dichloromethane). This gives 1.00 g (1.82 mmol, 73.6% of theory) of a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:17])=[CH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:5])[CH3:2].C(N(CC)CC)C.F[B-](F)(F)F.C(C(=NOC(N(C)C)=[N+](C)C)C(OCC)=O)#N.[CH2:47]([NH2:51])[CH:48]([CH3:50])[CH3:49]>CN(C)C=O>[CH2:47]([NH:51][C:10]([C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[CH:7]=[C:6]([CH3:17])[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:12])[CH:48]([CH3:50])[CH3:49]
Reactant: CC(C)CN
Reactant: CCOC(=O)C(C)=Cc1ccccc1C(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=Cc1ccccc1C(=O)NCC(C)C
Yield: 79.5 %

Procedure:
Ethyl 3-(2-isobutylcarbamoylphenyl)-2-methylacrylate is prepared as described in Example 30, starting with 1.17 g (5.0 mmol) of 2-(2-ethoxycarbonylpropen-1-yl)benzoic acid in 10 cm3 of dimethylformamide, a solution of 0.69 cm3 (5.0 mmol) of triethylamine, 1.64 g (5.0 mmol) of O-[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (“TOTU”) in 6 cm3 of dimethylformamide and a second solution consisting of 366 mg (5.0 mmol) of isobutylamine, 0.69 cm3 (5.0 mmol) of triethylamine in 10 cm3 of dimethylformamide. 1.15 g of ethyl 3-(2isobutylcarbamoylphenyl)-2-methylacrylate are thus obtained in the form of a yellowish oil, which can be reacted in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][S:10]2=[O:14])=[CH:4][N:3]=1.I.[N-:16]=[N+]=[N-].[Na+]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][S:10]2(=[O:14])=[NH:16])=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=S1CCCC1Cc1ccc(Cl)nc1
Agent: I
Agent: [Na+]
Product: N=S1(=O)CCCC1Cc1ccc(Cl)nc1

Procedure:
2-[(6-Chloropyridin-3-yl)methyl]tetrahydro-1H-1λ4-thiophen-1-imine-1-oxide was prepared from 2-chloro-5-[(1-oxidotetrahydrothien-2-yl)methyl]-pyridine by the method as described in Example I-H using NaN3 as the iminating agent.
Reaction SMILES: [O-]P(OP([O-])([O-])=O)(=O)[O-].C1C(=O)NC(=O)N([C@@H]2O[C@H](COP([O:28][P:29]([O:32][C@H:33]3[O:38][C@H:37]([CH2:39][OH:40])[C@@H:36]([OH:41])[C@H:35]([OH:42])[C@H:34]3[OH:43])([OH:31])=[O:30])(O)=O)[C@@H](O)[C@H]2O)C=1.P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O>>[CH2:39]([OH:40])[C@H:37]1[O:38][CH:33]([O:32][P:29]([OH:31])([OH:30])=[O:28])[C@H:34]([OH:43])[C@@H:35]([OH:42])[C@@H:36]1[OH:41]
Reactant: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])OP(=O)([O-])[O-]
Product: O=P(O)(O)OC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
The multi-enzyme system (Scheme 15) started with 1-13C-Gal, [99 Atom Percent, purchased from Isotec Inc., Miamisburg, Ohio), GlcNAcβOallyl (Compound 40), (Lee et al., Carbohydr. Res., 37:193 (1974)] phosphoenolpyruvate (PEP), and catalytic amounts of Glc-1-P, ATP and UDP. UDP was converted into UTP with pyruvate kinase (PK; EC 2.7.1.40) and PEP, and UTP reacted with Glc-1-P catalyzed by UDPGP to produce UDP-Glc. The byproduct inorganic pyrophosphate (PPi) was decomposed by inorganic pyrophosphatase (PPase; EC 3.6.1.1). With Gal-1-P UT, UDP-Glc reacted with 13C-Gal-1-P, generated from 13C-Gal and ATP in the presence of GK, to give UDP-13C-Gal and Glc-1-P. The 13C-Gal of UDP-13C-Gal was transferred onto the acceptor (GlcNAcβOallyl) by GalT to give [Gal-1-13C]-containing LacNAcβOallyl (Compound 41). The produced UDP was again converted to UTP by a reaction of PK and PEP, which reacted with the released Glc-1-P to regenerate UDP-Glc. Using this multienzyme system, [Gal-1-13C]-LacNAcβOallyl was obtained in 54 percent yield. The same procedure was also used in the preparation of unlabelled LacNAc and analogs. Exemplary analogs 41a-c are illustrated in the scheme.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([F:28])[C:26]=1[OH:27])[CH:22]=O>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:22][C:21]3[CH:20]=[C:19]([F:18])[C:26]([OH:27])=[C:25]([F:28])[CH:24]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cc(F)c(O)c(F)c1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1cc(F)c(O)c(F)c1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and 3,5-difluoro-4-hydroxybenzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C.Cl[C:23]([C:25]1[CH:26]=[C:27]([CH2:31][NH:32][C:33]([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([O:43][C:44](=[O:58])[NH:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:39][CH2:38]2)=[O:34])[CH:28]=[CH:29][CH:30]=1)=[O:24].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:23]([C:25]2[CH:26]=[C:27]([CH2:31][NH:32][C:33]([CH2:35][CH2:36][N:37]3[CH2:38][CH2:39][CH:40]([O:43][C:44](=[O:58])[NH:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=4[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH2:41][CH2:42]3)=[O:34])[CH:28]=[CH:29][CH:30]=2)=[O:24])=[CH:8][CH:7]=1
Reactant: O=C(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)NCc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(C2OCCO2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)NCc1cccc(C(=O)Nc2ccc(C3OCCO3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 4-(1,3-dioxolan-2-yl)phenylamine (0.0826 g, 0.500 mmol) and N,N-diisopropylethylamine (348 μL, 2.00 mmol) in DCM (2.0 mL) at room temperature was added a solution of biphenyl-2-ylcarbamic acid 1-{2-[(3-chlorocarbonylphenyl)methylcarbamoyl]ethyl}piperidin-4-yl ester (0.260 g, 0.500 mmol) in DCM (1.0 mL). The resulting mixture was stirred at room temperature for 1 h. LC-MS (Method 10-90) showed product was present (Rt 3.41 min; m/z 649.4 [M+H]+. Saturated aqueous sodium bicarbonate solution was added and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-5% MeOH in DCM) to give the title compound (345 mg containing some solvent residue, ca. 100% yield) as a brown oil.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[C:5]([O:9][CH3:10])(=[O:8])[CH:6]=O.CO.C(OC(=O)C)(=O)C>N(CC(O)=O)C>[CH:1](/[C:2](/[CH3:3])=[CH:6]\[C:5]([O:9][CH3:10])=[O:8])=[O:4]
Reactant: COC(=O)C=O
Reactant: CCC=O
Agent: CNCC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: COC(=O)/C=C(/C)C=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
688 g (11.9 mol) of propionaldehyde were added within 45 min to a mixture of 968 g (11 mol) of methyl glyoxylate, 352 g (11 mol) of methanol and 9.6 g (0.11 mol) of sarcosine at 50° C. After the addition was complete, the mixture was stirred at 80° C. for 1 h and then 2805 g (27.5 mol) of acetic anhydride were added. Distillation was carried out under atmospheric pressure with a column until the top temperature was 105° C., to remove some of the methyl acetate/acetic acid, and then up to 125° C. to remove a mixture of methyl acetate, acetic acid, acetic anhydride and methyl 3-formylcrotonate. Distillation was then continued under 250 mbar up to 105° C. and then under 30 mbar until the top temperature was 90° C. The combined distillates were redistilled to give 1184 g (9.3 mol) of methyl 3 -formylcrotonate, corresponding to a yield of 84% of theory.
Reaction SMILES: C(C[C@H](O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]Br)=[CH:9][CH:8]=1)C)C.[CH3:16][C@H:17]([NH2:26])[C@H:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:8]([CH2:9][C@H:10]([CH2:13][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][NH:26][C@@H:17]([CH3:16])[C@H:18]([OH:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][CH:12]=1)[CH3:11])[CH3:7]
Reactant: CCC[C@@H](C)Oc1ccc(CCBr)cc1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC[C@@H](C)Cc1ccc(CCN[C@@H](C)[C@H](O)c2ccccc2)cc1

Procedure:
A compound ethyl(R)-2-[4-(2-bromoethyl)phenoxy]propane (450 mg, 1.5 mM) and (1R,2S)-Norephedrine in DMF (5 ml) it is maintained in agitation in nitrogen atmosphere at a temperature of 70° C. for 72 hours. Then the reaction mixture is diluted with ethyl acetate, washed with a saturated solution of NaCl and dried with anhydrous Na2SO4. The solvent is removed at reduced pressure and the product is isolated from the residue by column chromatography (silica gel; mobile phase: dichloromethane/ethanol=40:1). 145 mg of ethyl (R)-2-[4-[2-((1R,2S)-1-hydroxy-1-phenylpropan-2-yl-amino)ethyl]benzyl]propane is obtained as clear yellow oil (52% of yield). [α]D=−0.6 (c 1.1, CH Cl3). FT-IR (neat): 3262, 3055, 2986, 2930, 1748, 1613, 1559, 1511, 1451, 1270, 1241, 1196, 1136, 1098, 1051, 1016, 743, 703 cm−1. 1NMRs (500 MHz, CDCl3, δ): 7.32-7.22 (m, 5H, aromatic protons); 7.11-7.09 (2H, aromatic protons); 6.80-6.78 (2H, aromatic protons); 5.15-5.14 (d, 1H, J=4.0 Hz, CHOH); 4.76 (bs, 2H, OH and NH: exchanged with D2O); 4.71-4.67 (q, 1H, J=6.7 Hz, CH3CHCO); 4.22-4.18 (q, 1H, J=7.2 Hz, CH2CH3); 3.71-3.67 (q, 1H, J=7.0 Hz, CH3CHNH); 3.20-2.91 (m, 4H, CH2CH2); 1.60-1.59 (d, 3H, J=6.7 Hz, OCHCH3); 1.25-1.20 (m, 3H, CH3CH2); 0.96-0.94 (m, 3H, J=7.0 Hz, CH3CHNH). 13C NMRs (125 MHz CDCl3, δ): 172.23, 161.34, 156.25, 129.69, 128.13, 127.60, 127.17, 126.10, 125.88, 115.22, 75.80, 72.62, 72.40, 61.23, 58.98, 49.72, 48.09, 34.28, 18.51, 14.08. MS-ESI m/z (%): 372 [M+H]+(100). MS-MS (372): 354 (100), 221 (55), 147 (24), 121 (7).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[C:25]([O:32][CH3:33])[N:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:24]=[C:25]([O:32][CH3:33])[C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@@H:14]5[CH3:18])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:27][N:28]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: OB(O)c1cncnc1
Product: COc1ncc(-c2ccc3nc([C@H]4C[C@@H](N5CCC[C@@H]5C)C4)sc3c2)c(OC)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 19A for the product of Example 1E and substituting 2,6-dimethoxy-5-pyrimidineboronic acid for pyrimidine-5-boronic acid. 1H NMR (400 MHz, CDCl3) δ ppm 8.31 (s, 1H) 7.91-8.03 (m, 2H) 7.55 (dd, J=8.44, 1.69 Hz, 1H) 4.06 (s, 3H) 4.05 (s, 3H) 3.55-3.70 (m, 1H) 3.15-3.29 (m, 1H) 3.02-3.14 (m, 1H) 2.72-2.88 (m, 1H) 2.60-2.71 (m, 1H) 2.43-2.56 (m, 3H) 2.30-2.40 (m, 1H) 1.91-2.02 (m, 1H) 1.79-1.88 (m, 1H) 1.66-1.77 (m, 1H) 1.44-1.55 (m, 1H) 1.16 (s, 3H). MS: (M+H)+=411.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:11])=[O:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13](=[O:15])[CH3:14])=[CH:4][C:3]=1[S:9]([OH:12])(=[O:10])=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(N)c(S(=O)(=O)O)c1
Product: CC(=O)Nc1ccc(N)c(S(=O)(=O)O)c1

Procedure:
That is, 2,5-diaminobenzenesulfonic acid is acetylated with acetic anhydride to obtain 2-amino-5-acetylaminobenzenesulfonic acid, which is then diazotized in an ordinary manner and coupled with 2,5-xylidine to thereby obtain the compound [E] shown below.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH3:30])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH3:30])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)=[O:33])[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: CCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Product: CCOC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-ethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A175) and ethyl chloroformate the title compound was obtained as colorless solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:12]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=3[C:14](O)=[O:15])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.O.[NH2:24][NH2:25]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:12]4[C:13](=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[C:14](=[O:15])[NH:25][N:24]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NN
Reactant: COc1ccc(C(=O)c2ccc3c(c2)OCO3)c(C(=O)O)c1
Solvent: O
Product: COc1ccc2c(-c3ccc4c(c3)OCO4)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-(1,3-benzodioxol-5-yl)carbonyl-5-methoxybenzoic acid unpurified with hydrazine hydrate.
Reaction SMILES: O.[C:2]1([C:8]2[NH:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+].[CH3:19]O>C(OC(=O)C)C>[C:2]1([C:8]2[NH:9][CH:10]=[C:11]([C:13]([O:15][CH3:19])=[O:14])[N:12]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1c[nH]c(-c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c[nH]c(-c2ccccc2)n1
Temperature: 25 °C

Procedure:
2-Phenyl-1H-imidazole-4-carboxylic acid mono hydrate (2.00 g) was suspended in methanol (30 mL) and concentrated hydrochloric acid (10.0 mL) was added and the reaction mixture heated at reflux overnight. The reaction mixture was cooled to room temperature and diluted with ethylacetate and the aqueous basified with 1 N sodium hydroxide. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound. The title compound was used without further purification, having the following physical data.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@H:24]([C:26]([O:28]C)=O)[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH3:43]>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@H:24]([C:26]([NH2:43])=[O:28])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:8]=1
Reactant: COC(=O)[C@@H]1CC[C@@]2(CCN(C(=O)N(C)[C@@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Reactant: N
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CC[C@@H](C(N)=O)N2)CCN1C(=O)N(C)[C@@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 97 %

Procedure:
In a sealed tube a solution of methyl (2S,5S,7R)-8-{[{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 29, 80 mg, 0.133 mmol) in 7M methanolic ammonia (5 ml, 35.0 mmol) was shaken overnight. The solvent was evaporated and the crude was purified was purified by flash-chromatography (Si cartridge 5 g; from 1:0 to 95:5 DCM/MeOH) to give the title compound (76.1 mg, 0.129 mmol, 98% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.94 (s, 1H) 7.56 (s, 2H) 7.24 (s, 1H) 7.15-7.21 (m, 1H) 6.84-6.96 (m, 2H) 6.71-6.81 (m, 1H) 5.30-5.40 (m, 1H) 4.09-4.18 (m, 1H) 3.47-3.57 (m, 1H) 3.24-3.40 (m, 1H) 2.83 (s, 3H) 2.59-2.78 (m, 2H) 2.31 (s, 3H) 2.03-2.17 (m, 1H) 1.42-1.85 (m, 10H). HPLC: Rt=4.91 mins; MS: m/z=589 [M+H]+ and 611 [M+Na]+.
Reaction SMILES: [C:1](=[O:12])([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:2][CH2:3]Cl.[C:13]([NH:16][C:17]1[C:18]([I:33])=[C:19]([N:28]([C:30](=[O:32])[CH3:31])[CH3:29])[C:20]([I:27])=[C:21]([C:24]([O-:26])=[O:25])[C:22]=1[I:23])(=[O:15])[CH3:14].[K+].[I-].[Na+]>CN(C=O)C>[C:13]([NH:16][C:17]1[C:18]([I:33])=[C:19]([N:28]([C:30](=[O:32])[CH3:31])[CH3:29])[C:20]([I:27])=[C:21]([C:24]([O:26][CH2:3][O:2][C:1]([O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:12])=[O:25])[C:22]=1[I:23])(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: O=C(OCCl)Oc1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OCOC(=O)Oc2ccccc2)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Chloromethyl phenyl carbonate (0.50 g, 2.7 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (1.62 g, 2.4 mmol) and sodium iodide (0.038 g, 0.25 mmol) in dry DMF (15 ml). After stirring at 50° C. for 5 hours and at room temperature for 18 hours the solvent was removed at reduced pressure. The residue was suspended in chloroform (25 ml) and washed four times with a saturated sodium hydrogen carbonate solution and finally twice with water. After drying with magnesium sulfate the solution was evaporated to dryness. Yield: 0.67 g Purity by HPLC: 99.2% 1H-NMR(DMSO-d6): delta=1.68 (NCH3COCH3); 2.06 (NHCOCH3); 2.97 (NCH3); 6.08 (CH2); 7.28-7.49 (phenyl); 10.14 ppm (NH). FAB/MS: 779 ((M+H)+).