Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[N:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([NH:23][C:24](=[O:26])[CH3:25])=[N:20][C:19]=2[CH3:27])=[CH:14][C:13]=1[Cl:28]>N1C=CC=CC=1>[Cl:28][C:13]1[CH:14]=[C:15]([C:18]2[S:22][C:21]([NH:23][C:24](=[O:26])[CH3:25])=[N:20][C:19]=2[CH3:27])[CH:16]=[N:17][C:12]=1[NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(N)c(Cl)c2)s1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(C)c(-c2cnc(NS(=O)(=O)c3ccccc3)c(Cl)c2)s1
Temperature: 25 °C

Procedure:
Phenylsulfonyl chloride (0.108 mL) was added to a stirred solution of N-[5-(6-amino-5-chloropyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (80 mg) in pyridine (1 mL) and the resultant solution was heated to 50° C. for 4 hours. The mixture was cooled to room temperature and concentrated by evaporation. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol as eluent. The material so obtained was triturated under diethyl ether. There was thus obtained the title compound as a white solid (38 mg); 1H NMR Spectrum: (DMSOd6) 2.13 (s, 3H), 2.29 (s, 3H), 7.60 (m, 2H), 7.75 (m, 1H), 7.98 (s, 1H), 8.02 (d, 2H), 8.18 (br s, 1H), 10.95 (br s, 1H); Mass Spectrum: M+H+ 423.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[I:13]I.[OH-].[K+].S(=O)(O)[O-].[Na+].Cl>CN(C=O)C.O>[I:13][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]([OH:12])=[O:11])[CH:5]=2)[NH:1][CH:2]=1
Reactant: II
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: Cl
Agent: O=S([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 192.7 %

Procedure:
To a solution of 1H-indole-5-carboxylic acid (2.08 g, 12.89 mmol, Acros) in DMF (20 mL) was added I2 (3.27 g, 12.89 mmol) and KOH (1.807 g, 32.2 mmol). The reaction was stirred at RT for 1 h then the mixture was poured into ice and H2O (120 mL) containing sodium bisulfite (1.341 g, 12.89 mmol). The mixture was treated with 5 M HCl to pH=4. The resulting yellow solid was collected by filtration, washed with water and dried to give crude 3-iodo-1H-indole-5-carboxylic acid (7.13 g) as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 288.0 (M+1). 1H NMR (400 MHz, MeOH) δ ppm 8.09-8.14 (1H, m), 7.88 (1H, dd, J=8.6, 1.6 Hz), 7.48 (1H, s), 7.45 (1H, d, J=8.6 Hz).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:37][CH3:38])[C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:8]1[N:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[NH:75]1[CH2:80][CH2:79][O:78][CH2:77][CH2:76]1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:37][CH3:38])[C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:8]1[N:13]=[CH:12][C:11]([N:75]2[CH2:80][CH2:79][O:78][CH2:77][CH2:76]2)=[CH:10][N:9]=1
Reactant: C1COCCN1
Reactant: CCN(C(=O)OCc1ccccc1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN(C(=O)OCc1ccccc1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamate (1.28 g) is dissolved in toluene (15 ml), and thereto are added tris(dibenzylideneacetone)dipalladium (159 mg), 2-(di-tert-butylphosphino)biphenyl (208 mg), sodium tert-butoxide (250 mg) and morpholine (230 μl) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added tris(dibenzylideneacetone)dipalladium (159 mg), 2-(di-tert-butylphosphino)biphenyl (208 mg) and sodium tert-butoxide (250 mg) and the mixture is stirred for 3 hours and a half. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give benzyl (2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-carbamate (724 mg). MS (m/z): 742 [M+H]+
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:21][CH2:22][CH2:23][C:16]3=[CH:15][C:14]=2[C:13]=1[C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>[C:1]1([S:7]([NH:11][C:12]2[CH:20]=[CH:19][C:18]3[N:17]4[CH2:21][CH2:22][CH2:23][C:16]4=[CH:15][C:14]=3[C:13]=2[C:24]([O:26][CH3:27])=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1c(N)ccc2c1cc1n2CCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2)ccc2c1cc1n2CCC1
Yield: 48.5 %

Procedure:
Benzenesulfonyl chloride (0.092 g) was added to a solution of methyl 7-amino-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (Intermediate 18, 0.100 g) in DCM (4 mL) and pyridine (1 mL) and the resultant mixture was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate and washed with aqueous potassium carbonate solution, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo, then dissolved in toluene and re-evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ammonia in methanol (2M) and DCM, with a gradient of 0-2%. The resultant solid was triturated with diethyl ether to give methyl 7-benzenesulfonylamino-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (0.078 g) as a cream powder.
Reaction SMILES: O=[C:2]1[NH:7][CH:6]=[N:5][C:4]2[S:8][C:9]3[CH2:13][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][C:10]=3[C:3]1=2.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[C:3]2[C:10]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOC(=O)N1Cc2sc3nc[nH]c(=O)c3c2C1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)N1Cc2sc3ncnc(Cl)c3c2C1
Yield: 67 %

Procedure:
In analogy to Example 11A, ethyl 4-oxo-3,4,5,7-tetrahydro-6H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylate from Example 20A (1.70 g, 6.41 mmol) was reacted with phosphoryl chloride to yield 1.23 g (67%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH:3]([C:7]([OH:9])=[O:8])[CH:2]1[C:10]([OH:12])=[O:11].[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.CCC1(C2C=CC(N)=CC=2)C(=O)NC(=O)CC1.C([O-])(=O)C.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>[OH-].[Na+].C(O)(=O)C>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:1]2[CH2:6][CH2:5][NH:4][CH:3]([C:7]([OH:9])=[O:8])[CH:2]2[C:10]([OH:12])=[O:11])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(O)C1NCCNC1C(=O)O
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: CCC1(c2ccc(N)cc2)CCC(=O)NC1=O
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CC(=O)O
Product: O=C(O)C1NCCN(C(=O)c2ccc(Br)cc2)C1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.4 %

Procedure:
##STR11## To an ice cold solution of piperazine-2,3-dicarboxylic acid (1.74 g/0.01 mole) in aqueous sodium hydroxide (1.2 g/20 ml) was added 4-bromobenzoyl chloride (2.2 g/0.01 mole) over 30 min. The resulting solution was stirred at 0° for 2 h, then allowed to warm to room temperature overnight. The solution was applied to a column of Dowex AG-1-acetate resin and the ninhydrin positive fractions of the 3M acetic acid eluate were combined and evaporated to dryness. Recrystallization of the residue from a 50% aqueous ethanol solution yielded 4-(4-bromobenzoyl)-piperazine-2,3-dicarboxylic acid (800 mg) as a white solid m.p., 218°-20°.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=2)[NH:8][N:7]=1.[OH:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[N:12]=[CH:11][N:10]=[C:9]3[NH:8][N:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:35]4[CH2:36][CH2:37][CH:32]([OH:31])[CH2:33][CH2:34]4)[C:14]=23)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: OC1CCNCC1
Reactant: ClCCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: OC1CCN(CCCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Yield: 16 %

Procedure:
The procedure described in Example 23 was repeated using 3-(3-chloropropoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 4-hydroxypiperidine to give the title compound in 16% yield; NMR Spectrum: 1.32-1.39 (m, 2H), 1.67-1.70 (m, 2H), 1.93-2.00 (m, 4H), 2.40 (t, 2H), 2.70-2.72 (m, 2H), 4.33 (t, 2H), 5.29 (s, 2H), 7.24 (d, 1H), 7.37 (t, 1H), 7.54-7.58 (m, 2H), 7.87-7.89 (m, 2H), 8.27 (s, 1H), 8.43 (br s, 1H), 8.59 (d, 1H); Mass Spectrum: 510 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.C([Li])CCC.[Cl:23][C:24]1[S:25][C:26]([C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])=[CH:27][CH:28]=1>C1COCC1.O>[Cl:23][C:24]1[S:25][C:26]([C:29]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:6]=[CH:5]3)([OH:34])[C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=1
Reactant: Fc1ccc(-n2ncc3cc(Br)ccc32)cc1
Reactant: O=C(c1ccc(Cl)s1)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1ccc(Cl)s1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
To a chilled (−78° C.) stirred solution of 1.5 g (5.0 mmol) of 5-bromo-1-(4-fluorophenyl)-1H-indazole in THF was added 2.0 mL (5.0 mmol) of n-butyllithium dropwise followed by 1.0 g (4.6 mmol) of 2-chloro-5-trifluoroacetylthiophene in one portion. After 30 minutes, the mixture was diluted with 10 mL of water, warmed to room temperature and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate-hexanes (gradient 10-30%) to afford 300 mg (15.5%) of the title compound. MS m/z 427.82 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[N:6][CH:7]=1.S(Cl)(Cl)=O.CO.[C:24]([O-])(O)=O.[Na+]>C1COCC1>[CH3:24][O:16][C:15](=[O:17])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:9]=1
Reactant: O=C([O-])O
Reactant: O=C(O)Cc1cccc(-c2cncc(Br)c2)c1
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(-c2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [3-(5-bromo-pyridin-3-yl)-phenyl]-acetic acid (Intermediate 94) (1 eq, 4.1 mmol, 1.2 g) in THF (15 ml) is added thionyl chloride (1.5 eq, 6.16 mmol, 0.45 ml), and the resulting mixture is stirred for 30 min at r.t. Then MeOH (3 eq, 12.3 mmol, 0.5 ml) is added and stirring is continued for another 20 h. Addition of 10% aqueous NaHCO3 solution is followed by extraction with EtOAc. The organic layer is dried with MgSO4, filtered, and the solvents are removed in vacuo. Purification or the crude mixture by column chromatography (hexane/EtOAc) gives the title compound; [M+H]+=306/308.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)[CH:6]=[N:7][CH:8]=1.[ClH:19]>C(O)(C)C.O1CCOCC1>[ClH:19].[ClH:19].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[N:7][CH:8]=1
Reactant: COc1cncc(CCNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COc1cncc(CCN)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of tert-butyl (2-(5-methoxypyridin-3-yl)ethyl)carbamate (153 mg, 0.606 mmol) in isopropanol (2 mL) was added 4M HCl in dioxane (2 mL) and the mixture was stirred at room temperature for 16 h. The mixture was concentrated, the residual solid was washed with diethyl ether and dried in vacuum to provide the title compound as a white solid (103 mg, 0.458 mmol, 75%). 1H NMR (500 MHz, CD3OD): δ (ppm) 8.56 (d, J=2.52 Hz, 1H), 8.51 (s, 1H), 8.27 (s, 1H), 4.15 (s, 3H), 3.23-3.38 ppm (m, 4H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)=[N:7][CH:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[N:24]=1.C(N(CC)CC)C>C(#N)C>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:30]([NH:29][C:25]3[N:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[O:31])[CH2:19][CH2:18]2)=[N:7][CH:8]=1
Reactant: Cc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnn4)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
5-Methyl-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine hydrochloride (507 mg, 1.6 mmol, from Example 44, Step 5), phenyl pyridazin-3-ylcarbamate (430 mg, 2.0 mmol) and triethylamine (0.892 mL, 6.4 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 h, the reaction was concentrated and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10%, MeOH:CH2Cl2) to afford the title compound (526 mg) as a foamy white solid. MS APCI M+ 402.1, 281.2 M− 400.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.29 (s, 3H) 2.46 (td, J=5.71, 0.93 Hz, 2H) 2.58 (td, J=5.74, 1.06 Hz, 2H) 3.52-3.61 (m, 2H) 3.65-3.71 (m, 2H) 6.44 (s, 1H) 6.85 (dd, J=8.41, 0.33 Hz, 1H) 6.89-6.96 (m, J=4.21, 4.21, 2.47, 1.01 Hz, 2H) 7.04-7.11 (m, J=7.63, 1.41, 1.04, 0.83 Hz, 1H) 7.31-7.42 (m, 1H) 7.59 (dd, J=9.09, 4.70 Hz, 1H) 7.66 (ddd, J=8.39, 2.49, 0.66 Hz, 1H) 7.97 (td, J=1.63, 0.77 Hz, 1H) 8.12 (d, J=9.32 Hz, 1H) 8.79 (d, J=4.37 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:12][CH2:13][O:14][C:15]2[N:16]([CH3:28])[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=3)[CH:19]=2)[CH3:11])=[CH:4][CH:3]=1.B(Br)(Br)Br.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:12][CH2:13][O:14][C:15]2[N:16]([CH3:28])[N:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)[CH:19]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc(OCCN(C)CCc3ccc(Cl)cc3)n(C)n2)cc1
Agent: BrB(Br)Br
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: ClCCl
Solvent: O
Product: CN(CCOc1cc(-c2ccc(O)cc2)nn1C)CCc1ccc(Cl)cc1
Reaction time: 12 h
Yield: 66.2 %

Procedure:
1.8 g of 3-{2-[N-(2- (4-chlorophenyl)-ethyl)-N-methylamino]-ethyloxy}-5-(-4-methoxyphenyl)-2-methylpyrazole (see Example 24) were dissolved in 100 ml of dichloromethane. 10 ml of a 1 molar solution of boron tribromide in dichloromethane were added to the solution. The reaction mixture was allowed to stand for 12 hours and then placed in water and extracted with dichloromethane. The aqueous phase was separated, rendered alkaline and extracted three times with a mixture of dichloromethane and methanol, and the combined organic phases were dried and concentrated. The crude title compound obtained as an oil was purified by chromatography on silica gel using dichloromethane/methanol. The purified title compound was reacted in accordance with the method described in Example 4 C) with an equimolar quantity of L-(+)-tartaric acid to form a salt, and the resulting salt was crystallized from a mixture of diethyl ether and isopropanol. 1.15 g of 3-{2-[N-(2-(4-chlorophenyl)-ethyl)-N-methylamino]-ethyloxy}-5-(4-hydroxyphenyl)-2-methylpyrazole×1.3 hydrogen tartrate were obtained having a melting point of 90° to 91° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[ClH:10].[CH2:11]([OH:13])[CH3:12]>>[ClH:10].[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:13][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 92 %

Procedure:
Into a solution of 4-fluorobenznitrile (50.9 g, 0.420 mol) in ethanol (500 mL) was blown hydrogen chloride to saturation under ice-cooling and the mixture was stirred at room temperature for 21 hours. The solvent was evaporated under reduced pressure and the obtained crystals were washed with ether and dried in vacuo to give ethyl 4-fluorobenzimidate hydrochloride as white crystals (78.8 g, 92%).
Reaction SMILES: [Cl-].[Zn+2:2].[Cl-].[O:4]1[CH2:9][CH2:8][CH2:7][O:6][CH:5]1[CH2:10][CH2:11][Mg]Br>C1COCC1>[O:4]1[CH2:9][CH2:8][CH2:7][O:6][CH:5]1[CH2:10][CH2:11][Zn:2][CH2:11][CH2:10][CH:5]1[O:6][CH2:7][CH2:8][CH2:9][O:4]1
Reactant: Br[Mg]CCC1OCCCO1
Reactant: [Zn+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C1COC(CC[Zn]CCC2OCCCO2)OC1

Procedure:
To a solution of zinc chloride (274 mg, 2.0 mmol) in THF (4 mL) was added (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide (8.8 mL, 4.4 mmol, 0.5M THF) to provide bis(2-(1,3 dioxan-2-yl)ethyl)zinc. In a separate reaction vessel, a mixture of compound 1C (348.6 mg, 1.0 mmol) and potassium carbonate (276 mg, 2.0 mmol) in DMF (5 mL) was stirred at rt for 3 h. After this time, argon was bubbled through the mixture for 5 minutes and then the bis(2-(1,3 dioxan-2-yl)ethyl)zinc and Pd(dppf)Cl2[CH2Cl2] (81.7 mg, 0.10 mmol) were added. Upon completion of addition, the reaction vessel was flushed with argon, capped, and then heated at 90° C. for 16 h. After this time, the reaction mixture was partitioned between diethyl ether and water and stirred vigorously for 15 minutes. The organic phase was separated, dried over Na2SO4 and concentrated in vacuo to yield a residue. The residue was purified via flash chromatography (SiO2, 0-100% ethyl acetate/hexanes) followed by purification via preparative HPLC (Phenomenex Axia Luna column (30×100 mm); 0-100% B over 15 min, then 3 min B hold @40 mL/min; Solvent A=10% MeCN, 90% H2O; Solvent B=90% MeCN, 10% H2O) to afford compound 4A (289 mg, 75%) as a pale-yellow foam. LC/MS (m/z)=384 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][CH3:14])=[O:12])[CH:6]=1)([CH3:4])[CH3:3].[CH:15]([CH:17]=[O:18])=[O:16].[OH-].[Na+]>C(O)C>[CH3:4][C:2]([C:5]1[O:9][N:8]=[C:7]([N:10]2[CH:15]([OH:16])[CH:17]([OH:18])[N:13]([CH3:14])[C:11]2=[O:12])[CH:6]=1)([CH3:1])[CH3:3]
Reactant: O=CC=O
Reactant: CNC(=O)Nc1cc(C(C)(C)C)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)N(c2cc(C(C)(C)C)on2)C(O)C1O
Reaction time: 8 h

Procedure:
To a solution of 2.0 grams (0.010 mole) of 1-[5-(1,1-dimethylethyl)-3-isoxazolyl]-3-methylurea in 50 milliliters of 95 percent ethanol was added 7.3 grams of a 40 percent aqueous glyoxal solution which had been previously adjusted to pH 7 with dilute sodium hydroxide solution. After standing at room temperature overnight, the solution was topped on a rotary evaporator to give an oily residue which was extracted with two 20 milliliter portions of chloroform. The extract was washed with saturated sodium chloride solution, filtered through silicone-treated paper, and concentrated on a rotary evaporator to give 2.0 grams of oily residue. Crystallization from ether gave 0.4 gram of white crystals of 3-[5-(1,1-dimethylethyl)-3-isoxazolyl]-4,5-dihydroxy-1-methyl-2-imidazolidinone, M.P. 153°-157° C., which had consistent mass, infrared and NMR spectra.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.C(OCC)(=O)C>[CH2:24]([NH:1][C@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[O:7][CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](N)C1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](NCc2ccccc2)C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6R,7S)-6-amino-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) in THF (2 mL) was added benzyl bromide (0.036 mL) at 50° C., and the mixture was stirred at 50° C. overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (80 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][C@H:11]([C:33]([O:35]C(C)(C)C)=[O:34])[CH2:12][NH:13][C:14](=[O:32])[C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](=[O:31])[NH:24][C:25]4[NH:26][CH2:27][CH2:28][CH2:29][N:30]=4)=[CH:17][CH:16]=3)=[N:7][C:6]=2[CH:40]=1.C(O)(C(F)(F)F)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][C@H:11]([C:33]([OH:35])=[O:34])[CH2:12][NH:13][C:14](=[O:32])[C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23](=[O:31])[NH:24][C:25]4[NH:26][CH2:27][CH2:28][CH2:29][N:30]=4)=[CH:19][CH:20]=3)=[N:7][C:6]=2[CH:40]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)Nc1nc2cc(Br)ccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCc1ccc(C(=O)NC[C@H](Nc2nc3cc(Br)ccc3o2)C(=O)O)cc1)NC1=NCCCN1
Yield: 117.9 %

Procedure:
Hydrolysis of the ester is carried out as in the previous examples, but starting from 56 mg of 10-7 and 2.5 ml of TFA in 2.5 ml of dichloromethane. 60 mg of 10-8 is obtained (in the form of the trifluoroacetic acid salt).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][S:13](Cl)(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][NH:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>C(Cl)Cl>[CH2:17]([CH:11]([CH2:12][S:13]([N:32]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)[CH3:31])(=[O:15])=[O:14])[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccccc1)C(Cc1ccccc1)CS(=O)(=O)Cl
Reactant: CNCCc1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCc1ccccn1)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
To the resultant compound from Example 62 (1 mmol) in methylene chloride (10 mL) at -10° C. was added triethylamine (1.2 mmol) and 2-(2-methylaminoethyl)pyridine (1 mmol). After 30 min the mixture was evaporated, suspended in ethyl acetate, washed with saturated NaHCO3 solution, water, and brine, and then dried over Na2SO4 and evaporated. Chromatography of the residue on silica gel afforded the desired product.