Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)C>C(OCC)C>[N:14]1([C:2]2[S:3][C:4]3[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)c1cccc2nc(Br)sc12
Reactant: C1CCNCC1
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)c1cccc2nc(N3CCCCC3)sc12
Temperature: 72.5 °C
Reaction time: 2.5 h
Yield: 90 %

Procedure:
A mixture of ethyl ester of 2-bromobenzothiazole-7-carboxylic acid (572 mg, 2.00 mmol), piperidine (5 ml) and ethanol (1 ml) was stirred at 70-75° C. for 2.5 hrs. Diethyl ether (15 ml) was added to the mixture at room temperature and the precipitates were filtered off and washed with diethyl ether. The filtrate and washings were combined and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform) to give ethyl ester of 2-piperidinobenzothiazole-7-carboxylic acid (526 mg, 90%) as pale orange crystals.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:9]C1C(=O)C(Br)=CC(Br)(Br)C=1.[OH-].[Na+]>C(Cl)Cl>[Br:9][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[CH:8]=1
Reactant: Nc1ccccc1F
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Nc1ccc(Br)cc1F

Procedure:
To a solution of o-fluoroaniline (3.9 g) in methylene chloride (50 ml), cooled to -20° under nitrogen, is added a solution of 2,4,4,6-tetrabromocyclohexadienone (35 mmol) in methylene chloride. After several hours, reaction is poured into 15% NaOH solution. The layers are separated and the organic fraction shaken against 15% NaOH solution. The methylene chloride fraction is washed with saturated NaCl solution, dried over calcium sulfate and evaporated to yield 4-bromo-2-fluoroaniline.
Reaction SMILES: C([O:5][C:6]([CH2:8][NH:9][C@@H:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C@H:11]1[NH:19][C:20]([C:22]1[NH:26][C:25]2[C:27]([Cl:31])=[C:28]([Cl:30])[S:29][C:24]=2[CH:23]=1)=[O:21])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:6]([CH2:8][NH:9][C@@H:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C@H:11]1[NH:19][C:20]([C:22]1[NH:26][C:25]2[C:27]([Cl:31])=[C:28]([Cl:30])[S:29][C:24]=2[CH:23]=1)=[O:21])([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.4 %

Procedure:
N-{(1R,2R)-1-[(tert-Butoxycarbonylmethyl) amino]-2,3-dihydro-1H-inden-2-yl}-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Example 29; 100 mg, 0.21 mmol) dissolved in DCM (10 mL). TFA (1 mL) added and the reaction stirred at ambient temperature for 6 hours. Evaporation under reduced pressure, co-evaporation with CHCI3 (2×10 mL) and drying gave the title compound (85 mg, 36%) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)[C@H]1C[C@@H](O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1C[C@@H](C(=O)OCc2ccccc2)C1
Reaction time: 1 h

Procedure:
To a solution of cis-3-hydroxycyclobutane carboxylic benzyl ester (see WO03000657A1)(18.0 g, 87.5 mmol) in dichloromethane (155 m/L) was added triethylamine (18.3 mL, 131 mmol), and then thereto was added dropwise a solution of methanesulfonyl chloride (8.16 mL, 105 mmol) in dichloromethane (20 mL) at 0° C. for 15 minutes. The mixture was stirred for 1 hour, and then the reaction solution was washed with aqueous saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the titled compound (24.9 g, quant.).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][O:54][C:55]1[CH:60]=[C:59]([O:61][CH3:62])[CH:58]=[CH:57][C:56]=1[C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([NH2:69])[CH:64]=1>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:60]=[C:59]([O:61][CH3:62])[CH:58]=[CH:57][C:56]=1[C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([NH:69][C:24]([C:19]2[C:20](=[O:23])[O:21][C:22]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:64]=1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: COc1ccc(-c2cccc(N)c2)c(OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)c(OC)c1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.018 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′,4′-dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.022 g of product in 70% yield: LCMS (ESI) m/z 486 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[C:6]([F:15])[C:3]=1[C:4]#[N:5].O[CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[NH2:19][CH2:18][CH2:17][N:13]1[CH:12]=[CH:11][C:10]([C:8]2[CH:7]=[C:6]([F:15])[C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)=[N:14]1
Reactant: N#Cc1c(F)cc(-c2ccn[nH]2)cc1F
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1c(F)cc(-c2ccn(CCN)n2)cc1F
Yield: 19.8 %

Procedure:
The title compound was prepared from 2,6-difluoro-4-(1H-pyrazol-5-yl)-benzonitrile (1.50 g, 7.31 mmol) and tert-butyl N-(2-hydroxyethyl)carbamate (0.96 ml, 6.09 mmol), triphenylphosphine (1.918 g, 7.31 mmol) and DIAD (1.200 ml, 6.09 mmol) using the method of Example 34 (c) affording 0.30 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.60 (m, 2H), 2.94 (t, 2H), 4.14 (t, 2H), 7.01 (d, 1H), 7.79 (m, 2H), 7.88 (d, 1H).
Reaction SMILES: [CH3:1][CH2:2][O:3]CC.Br[C:7]([CH3:13])([CH3:12])[C:8]([O:10][CH3:11])=[O:9].C(OC(=O)C)(=O)C.Cl>[Zn].C1C=CC=CC=1>[CH3:12][C:7]([CH3:13])([C:2](=[O:3])[CH3:1])[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOCC
Reactant: COC(=O)C(C)(C)Br
Agent: Cl
Agent: [Zn]
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(C)(C)C(C)=O

Procedure:
To a mixture of 20.86 g of 20 mesh zinc metal, 165 ml of 120:210 by volumes ether:benzene and 0.05 g of mercuric chloride was added a few drops of a solution of 26.64 g of methyl alpha-bromoisobutyrate and 18.72 g of acetic anhydride followed by brief heating with a heat gun to initiate the reaction. The remaining solution was added slowly at reflux. After addition was complete, the mixture was refluxed for 21/2 hrs, cooled, poured over 12 ml concentrated HCl mixed with ice, and extracted with ether. The combined extract was washed with water, dried (MgSO4) and stripped to give 23.15 g of a yellow oil. Distillation yielded 15.41 g of the desired product as a colorless oil, b.p. 32° C. (1 mm Hg).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>>[Cl:22][CH2:23][C:24]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:10]2[N:9]=[C:8]([C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH3:7])[CH:13]=[CH:12][N:11]=2)=[CH:16][CH:17]=1)=[O:25]
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(N)cc3)n2)s1
Reactant: O=C(Cl)CCl
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CCl)cc3)n2)s1

Procedure:
By treatment of [4-(2,4-dimethylthiazol-5-yl)-pyrimidin-2-yl]-(4-aminophenyl)-amine with chloroacetyl chloride. Mp. 217-219° C. 1H-NMR (DMSO-D6) δ: 2.61 (s, 3H, CH3), 2.64 (s, 3H, CH3), 4.22 (s, 2H, CH2), 7.05 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.50 (d, 2H, J=8.8 Hz, Ph-H), 7.70 (d, 2H, J=8.8 Hz, Ph-H), 8.49 (d, 1H, J=4.9 Hz, pyrimidinyl-H), 9.65 (s, 1H, NH), 10.20 (s, 1H, NH). MS (ESI+) m/z 374.47 [M+H]+ (C17H16ClN5OS requires 373.86).
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[N:29]1[C:33]([CH3:34])=[N:32][CH:31]=[N:30]1)[C:23](O)=[O:24]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([N:29]3[C:33]([CH3:34])=[N:32][CH:31]=[N:30]3)=[C:20]([F:19])[CH:21]=2)[CH2:2][CH2:3]1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Reactant: Cc1ncnn1-c1ccc(C(=O)O)cc1F
Product: Cc1ncnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3nc(C(C)C)no3)CC2)cc1F

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 3-fluoro-4-(5-methyl-[1,2,4]triazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=3.84 min; Mass spectrum (ESI+): m/z=454 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Br:13]([O-])(=O)=O.[K+]>OS(O)(=O)=O>[Br:13][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: N#Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 56.7 %

Procedure:
To a mixture of 5 g (30.5 mmol) of 4-hydroxy-3-nitrobenzonitrile in H2SO4 solution (50 mL of concentrated H2SO4+50 mL of H2O) at 25° C., 7.9 g (47.3 mmol) of potassium bromate were added in small portions cooling the flask with an ice-bath and maintaining the temperature between 25 and 35° C. After the addition was completed, the reaction was stirred at room temperature for 22 h and then filtered. The pale yellow solid was washed with water and dried to give 4.2 g (57%) of the title compound. M.p.: 162-164° C.; 1H NMR (CD3OD) δ 8.54 (d, 1H, J=2.0 Hz, H-6), 8.32 (d, 1H, J=2.0 Hz, H-2); 13C NMR (DMSO-d6) δ 153.9 (C-4), 140.8 (C-2), 138.2 (C-5), 130.1 (C-6), 117.0 (CN), 115.9 (C-3), 101.6 (C-1).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:20]([C:27]1[N:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[O:20]([C:27]1[N:32]=[CH:31][C:30]([CH2:33][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=Cc1ccc(Oc2ccccc2)nc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(Oc5ccccc5)nc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 6-phenoxypyridine-3-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(6-phenoxypyridin-3-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[N:17]3[CH:18]=[N:19][CH:20]=[C:16]3[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5])C>C(O)C.[OH-].[Na+]>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[N:17]3[CH:18]=[N:19][CH:20]=[C:16]3[CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(C2CCCc3cncn32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 0.66 g of 5-(p-ethoxycarbonylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in 8.0 ml of ethanol and 8.0 ml 1N sodium hydroxide is refluxed for 3 h, cooled and evaporated. The residue is partitioned between water and ethyl acetate. The aqueous phase is adjusted to pH 5 with concentrated sulfuric acid and the solid is filtered and air-dried to yield the title compound, m.p. 309°-310° (dec.).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17]>ClCCl>[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].[CH3:1][O:2][CH:3]1[CH2:6][NH:5][CH2:4]1
Reactant: COC1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1CNC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 3-methoxyazetidine-1-carboxylate (step 1, 110 mg, 0.57 mmol) in dichloromethane (6.0 mL) was added trifluoroacetic acid (6.0 mL). The resulting solution was stirred at room temperature for 4 h. The volatile materials were removed under the reduced pressure to afford 120 mg (quant.) of the title compound as a highly viscous oil:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:18][CH3:19])=[CH:11][C:12]([Br:17])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH3:28])[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.[Cl-].[NH4+].Cl>C(OCC)(=O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([O:18][CH3:19])=[CH:11][C:12]([Br:17])=[C:13]([CH:14]([C:23]2[CH:24]=[CH:25][C:20]([CH3:28])=[CH:21][CH:22]=2)[OH:15])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(Br)c(C=O)cc1OCc1ccccc1
Reactant: Cc1ccc([Mg]Br)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(Br)c(C(O)c2ccc(C)cc2)cc1OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a mixture of 5-benzyloxy-2-bromo-4-methoxy-benzaldehyde (1 g) and tetrahydrofuran (10 mL) was added p-tolylmagnesium bromide (1 mol/L tetrahydrofuran solution, 3.7 mL) under ice-salt bath cooling. After stirring at same temperature for 10 minutes, to the mixture were added an aqueous solution of ammonium chloride, ethyl acetate and 2 mol/L hydrochloric acid. The separated organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%-50% ethyl acetate/hexane, gradient elution) to give the title compound (1.27 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[B:13](OCCO)([OH:21])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1>>[Cl:20][C:16]1[CH:15]=[C:14]([B:13]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[OH:21])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc([Mg]Br)cc1OC
Reactant: OCCOB(O)c1cccc(Cl)c1
Product: COc1ccc(B(O)c2cccc(Cl)c2)cc1OC

Procedure:
(3-Chlorophenyl)(3,4-dimethoxyphenyl)borinic acid was prepared from 3,4-dimethoxyphenylmagnesium bromide and 3-chlorophenylboronic acid ethylene glycol ester by the procedure described in Example 6a. The title complex product was made by the methodology described in Section 5.3.7.1, and obtained as yellow crystals. MS (ESI, positive): m/z=404 (M+1); 1H NMR (DMSO-d6, 300 MHz): δ 9.17 (d, 1H), 8.78 (d, 1H), 7.90 (dd, 1H), 7.70 (t, 1H), 7.43 (d, 1H), 7.30-7.17 (m, 5H), 6.89-6.80 (m, 3H), 3,66 (s, 3H) and 3.62 (s, 3H) ppm.
Reaction SMILES: C([O-])(=O)C.[C:5]([C:8]1[CH:46]=[CH:45][C:11]([C:12]([NH:14][C@H:15]([C:28]([N:30]2[CH2:35][CH2:34][CH:33]([O:36][CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[CH2:32][CH2:31]2)=[O:29])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]C(C)(C)C)=[CH:19][CH:18]=2)=[O:13])=[CH:10][CH:9]=1)(=[NH:7])[NH2:6].FC(F)(F)C([O-])=O>O.CO>[C:5]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][C@H:15]([C:28]([N:30]2[CH2:35][CH2:34][CH:33]([O:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:32][CH2:31]2)=[O:29])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[O:13])=[CH:45][CH:46]=1)(=[NH:6])[NH2:7]
Reactant: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@H](Cc2ccc(OC(C)(C)C)cc2)NC(=O)c2ccc(C(=N)N)cc2)CC1
Agent: CC(=O)[O-]
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Solvent: O
Product: N=C(N)c1ccc(C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N2CCC(OCC(=O)O)CC2)cc1

Procedure:
From 2.5 g of the acetate of t-butyl [[1-[N-(p-amidinobenzoyl)-3-(p-t-butoxyphenyl)-L-alanyl]-4-piperidinyl]oxy]-acetate there is obtained in analogy to Example 1, after chromatography (silylated silica get RP-18, water/methanol gradient), 1.0 g of [[1-[N-(p-amidinobenzoyl)-L-tyrosyl]-4-piperidinyl]oxy]acetic acid as the trifluoroacetate. M.p. 125°-130° C. (ethyl acetate, decomposition). MS (FAB): 469 (M+H)+.
Reaction SMILES: [H-].[Al+3].[H-].[H-].[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:13][CH2:14][C:15]([C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[O:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][C:28]=2[F:36])[NH:19][CH:18]=1)=[O:16])=O>COCCOC>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:24]2[CH:23]=[CH:22][N:21]=[C:20]3[NH:19][CH:18]=[C:17]([CH:15]([OH:16])[CH2:14][OH:13])[C:25]=23)=[C:28]([F:36])[CH:29]=1
Reactant: O=COCC(=O)c1c[nH]c2nccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Product: Nc1ccc(Oc2ccnc3[nH]cc(C(O)CO)c23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
To a suspension of anhydrous aluminum hydride (266 mg, 2.0 mmol, Alfa Aesar) in 5 mL of 1,2 dimethoxyethane at 0° C. was added lithium aluminum hydride (1 M soln. in THF, 1.0 mL, 1.0 mmol). A solution of 2-(4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxoethyl formate (72 mg, 0.2 mmol) in 5 mL of 1,2-dimethoxyethane was added dropwise. The reaction mixture was stirred at rt for 2 h and quenched by the addition of 5 mL of cold water. The mixture was extracted with EtOAc (3×30 mL) and the combined organic extracts were dried (MgSO4), concentrated in vacuo and purified by flash column chromatography (ISCO RediSep® silica gel cartridge, etuting with 2-10% MeOH in dichloromethane) to give 1-(4-(4-amino-2-fluorophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-diol (27 mg, 45%): MS(ESI+) m/z 304.3(M+H)+ and 2-(4-(4-amino-2-fluorophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol (10 mg, 18%): MS(ESI+) m/z 288.3 (M+H)+.
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=2[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[C:1]([C:9]1[O:10][C:11]2[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2c(C(=O)c3ccccc3)oc3ccccc23)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1oc2ccccc2c1-c1ccc(O)cc1

Procedure:
2-Benzoyl-3-p-methoxyphenylbenzofuran is demethylated with pyridine hydrochloride as previously described to give 2-benzoyl-3-p-hydroxyphenylbenzofuran, which upon reaction with 3-diethylaminopropyl chloride as described in Example 1, gives the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:21].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CC#N>[N+:18]([C:17]1[C:12]2[N:11]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:2][O:21][C:13]=2[CH:14]=[CH:15][CH:16]=1)([O-:20])=[O:19]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c1N=C(c1ccccc1)CO2
Reaction time: 3 h
Yield: 100.8 %

Procedure:
The 2-bromoacetophenone (3.9 g, 19 mmol) [Aldrich, cat. #115835] was added portion wise to a stirred suspension of 2-amino-3-nitrophenol (2.5 g, 16 mmol) [Aldrich, cat. #297003] and K2CO3 (3.4 g, 24 mmol) in MeCN (100 mL) at room temperature. The reaction was monitored by LC/MS. After stirring for 3 h the reaction was complete and then EtOAc added and solution filtered to remove the solids and the organic layer was washed with water, 1 N HCl, brine, dried over MgSO4, filtered and concentrated to give 5-nitro-3-phenyl-2H-1,4-benzoxazine as a dark oil (4.1 g, 100%). LCMS calc. for C14H11N2O3 (M+H)+: m/z=255.3. found: 255.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19](=[O:60])[NH:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([S:30]([C:33]5[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=5)(=[O:32])=[O:31])[CH:28]=4)[N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:22]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CO>O1CCOCC1>[F:40][C:35]1[CH:34]=[C:33]([S:30]([C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[NH:20][C:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]=2)=[O:60])(=[O:31])=[O:32])[CH:38]=[C:37]([F:39])[CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)Nc3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ccc(S(=O)(=O)c5cc(F)cc(F)c5)cc34)cn2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1n[nH]c2ccc(S(=O)(=O)c3cc(F)cc(F)c3)cc12)c1cnn(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude 4-{4-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-ylcarbamoyl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester was dissolved into 15 mL of 1,4-dioxane and added with 3 mL of 4M hydrochloric acid in 1,4-dioxane and stirred at room temperature overnight. Methanol was then added and the mixture stirred for additional 2 hours. The volatiles were removed under reduced pressure, the residue re-dissolved into ethyl acetate, washed with 10% ammonium hydroxide in water, dried over sodium sulfate and evaporated to dryness. The residue was stirred overnight with diethyl ether/methanol 95:5, filtered, washed with diethyl ether/methanol 9:1 then with diethyl ether and dried in oven at 60° C. affording 170 mg of the title compound.
Reaction SMILES: [C:1]1(=[O:8])[NH:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2]1.[CH2:9]=[O:10]>O>[CH2:9]([N:6]1[C:5](=[O:7])[CH2:4][CH2:3][CH2:2][C:1]1=[O:8])[OH:10]
Reactant: O=C1CCCC(=O)N1
Reactant: C=O
Solvent: O
Product: O=C1CCCC(=O)N1CO
Temperature: 100 °C

Procedure:
Glutarimide (27 g) and a 35% formaldehyde solution (20 ml) were added to water (40 ml), and heated at about 100° C. for 1 hour over an oil bath. The water was completely distilled away from the reaction mixture using a rotary evaporator. Thus, a crude product of N-methylolglutarimide was obtained. This product was added to 200 ml of benzene without purification, and the resulting solution was heated together with phosphorus tribromide (7.5 ml) under reflux for 1 hour. Thereto, water was added and thereby the benzene layer was separated. The crude product obtained by distilling the benzene away from the benzene layer was recrystallized from an ethyl acetate/n-hexane mixture to yield about 25 g of the desired compound. Melting Point: 165° C.