Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].Cl.[F:7][C:8]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:9]=1[CH2:10][C:11]1[N:16]=[CH:15][C:14]2[C:17]([CH3:21])([CH3:20])[CH2:18][NH:19][C:13]=2[CH:12]=1.C(N(CC)CC)C.[C:34]([O:38][C:39]([N:41]1[CH2:46][C@H:45]([CH2:47][OH:48])[NH:44][CH2:43][C@H:42]1[CH3:49])=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[C:34]([O:38][C:39]([N:41]1[CH2:46][C@H:45]([CH2:47][OH:48])[N:44]([CH2:2][C:3]([N:19]2[C:13]3[CH:12]=[C:11]([CH2:10][C:9]4[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:8]=4[F:7])[N:16]=[CH:15][C:14]=3[C:17]([CH3:21])([CH3:20])[CH2:18]2)=[O:4])[CH2:43][C@H:42]1[CH3:49])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: C[C@@H]1CN[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)CCl
Reactant: CC1(C)CNc2cc(Cc3ccc(F)cc3F)ncc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccc(F)cc4F)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.1 %

Procedure:
Chloroacetyl chloride (0.995 mL, 12.0 mmol) was added dropwise to a stirred solution of 6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine hydrochloride (3.10 g, 10.0 mmol) and triethylamine (4.6 mL, 33.0 mmol) in anhydrous DCM (50 mL) and the mixture was stirred at room temperature for 16 hours. (2R,5R)-5-Hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.76 g, 12.0 mmol) was added and the mixture was stirred at room temperature for a further 16 hours. Further triethylamine (1 mL) and (2R,5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (700 mg) were added and the mixture stirred for a further 16 hours. The mixture was diluted with DCM, washed with water, the organic layer separated and the solvent removed in vacuo. Chromatography (silica, elution with 30-100% ethyl acetate in petroleum ether) afforded (2R,5R)-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (4.36 g, 80%) as a pale tan foam. MS: [M+H]+ 545. Methanesulfonyl chloride (0.78 mL, 10.0 mmol) was added dropwise to a stirred solution of (2R,5R)-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (4.36 g, 8.0 mmol) and triethylamine (1.67 mL, 12.0 mmol) in anhydrous DCM (40 mL) and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM, washed successively with saturated aqueous sodium hydrogen carbonate and then water. The organic layer was separated and the solvent removed in vacuo to afford the title compound (4.0 g, 71%) as a pale yellow foam. MS: [M+H]+=563, 565.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=2)[CH2:10]1)=O)(C)(C)C.[ClH:19].O1CCOCC1>C(O)(=O)C>[ClH:19].[NH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(O)cc2C1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: NC1Cc2ccc(O)cc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 2-(tert-butoxycarbonylamino)-5-hydroxyindan (130 mg, 0.50 mmol) synthesized in the above Preparation Example 1 was added 4N hydrochloric acid-dioxane (2.3 ml) and acetic acid (6.9 ml), and the mixture was stirred at room temperature for 10 minutes. By distilling off the solvent under reduced pressure, 2-amino-5-hydroxyindan hydrochloride was obtained as a crude product. This was dissolved in ethanol (3 ml). Using triethylamine (0.14 ml, 1.0 mmol), 4-chloro-5-methylthieno[2,3-d]pyrimidine (83 mg, 0.60 mmol), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (methylene chloride:ethyl acetate=2:1) to obtain the title compound (17 mg, 0.057 mmol) having the following physical properties:
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][C@@H:8]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH:26][C:27](=[O:47])[C@H:28]([CH:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[NH:29][C:30]([O:32][CH3:33])=[O:31])[O:7][CH2:6]1)=[N+:2]=[N-:3].[C:48]1([C:54]#[CH:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CCN(C(C)C)C(C)C>O1CCCC1.[Cu]I>[CH3:33][O:32][C:30]([NH:29][C@H:28]([C:27]([NH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][CH2:18][C@H:8]1[O:7][CH2:6][C@@H:5]([CH2:4][N:1]2[CH:55]=[C:54]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:3]=[N:2]2)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:9]1)=[O:47])[CH:34]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:31]
Reactant: C#Cc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CN=[N+]=[N-])CO1)C(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](Cn2cc(-c3ccccc3)nn2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
To a solution of tert-butyl (2R,5R)-5-(azidomethyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (1 eq.) in tetrahydrofuran (0.033M) were added phenylacetylene (3.9 eq.) and Hunig's base (5 eq.). Nitrogen was then bubbled for 5 minutes through the reaction mixture which was placed in a sealed tube. Copper(I) iodide (1.5 eq.) was added to the reaction mixture and the temperature was raised to 70° C. for 16 hrs. The reaction mixture was evaporated to dryness and the evaporation residue was purified by automated silica gel flash chromatography system eluted with a gradient 0% to 10% of MeOH/CH2Cl2.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])C)(=[O:12])[CH2:4][C:5](OC(C)(C)C)=O.[CH2:18]([O:20][C:21]([C:23]1[C:32](=[O:33])[N:31]2[C:26]([C:27](C)=[C:28](Cl)[C:29]([F:34])=[CH:30]2)=[C:25]([CH:37]2[CH2:39][CH2:38]2)[CH:24]=1)=[O:22])[CH3:19].O>CN(C=O)C>[CH2:18]([O:20][C:21]([C:23]1[C:32](=[O:33])[N:31]2[C:26]([C:27]([CH3:28])=[C:5]([CH2:4][C:3]([O:13][CH:14]([C:16]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]3[CH:37]=[CH:25][CH:24]=[CH:23][CH:21]=3)=[O:12])[C:29]([F:34])=[CH:30]2)=[C:25]([CH:37]2[CH2:39][CH2:38]2)[CH:24]=1)=[O:22])[CH3:19]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(CC(=O)OC(c3ccccc3)c3ccccc3)c(F)cn2c1=O

Procedure:
To a suspension of NaH in DMF with ice bath cooling is added di-t-butyl malonate. After the addition, 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester from Example 253i above is added. The reaction is then heated to 50° to 60° C., and the mixture is poured into water and acidified. The product is extracted into methylene chloride and dried over MgSO4. The residue, after removal of the solvent, is dissolved in methylene chloride and trifluoroacetic acid at room temperature. The solvent is removed under vacuum, and the product is treated with diphenyldiazomethane in methylene chloride and methanol. When the reaction is finished, the solvents are removed under vacuum, and the product is purified by column chromatography to give the title compound.
Reaction SMILES: C[CH:2]1[CH:7](C)[CH2:6][CH2:5][CH:4]([NH:9][C:10](=[O:45])[C@H:11]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:33][CH:32]=2)[NH:12][C:13](=[O:29])[C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][CH:15]=2)[CH2:3]1.O1CCCC1.C(N(CC)CC)C>CN(C)C=O>[CH:4]1([NH:9][C:10](=[O:45])[C@H:11]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:33][CH:32]=2)[NH:12][C:13](=[O:29])[C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[CH:18][CH:19]=2)[CH2:5][CH2:6][CH2:7][CH2:2][CH2:3]1
Reactant: CC1CCC(NC(=O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)CC1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)NC2CCCCC2)cc1
Reaction time: 0.5 h

Procedure:
The above compound (III) was suspended in dimethylformamide (10 ml)--tetrahydrofuran (10 ml) solution, and triethylamine (0.4 ml) and trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarboxylic acid mixed acid anhydride were added under ice-cooling, followed by stirring for 30 minutes. Further, the reaction was carried out at room temperature for 3 hours. After a conventional post-treatment, N-[trans-4-(t-butyloxycarbonyl)aminomethylcyclohexylcarbonyl]-4-(3-cyanobenzyloxy)-L-phenylalanine 4-acetylanilide (IV) (1.31 g) was obtained. The above compound (IV) (1.31 g) was allowed to react with 4N-hydrogen chloride/dioxane solution (10 ml) for 1 hour, and the crystalline substance precipitated by addition of hexane was collected by filtration. The product was recrystallized from an ethanol-ether solution to obtain N-(trans-4-aminomethylcyclohexylcarbonyl)-4-(3-cyanobenzyloxy)-L-phenylalanine 4-acetylanilide hydrochloride (1.1 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8](B(O)O)[CH:9]=1)[CH3:2].Br[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C@H:21]2[CH2:25][CH2:24][C@:23]3([CH2:29][CH2:28][N:27]([CH3:30])[C:26]3=[O:31])[N:22]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:16]=1[CH3:39].C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C@H:21]3[CH2:25][CH2:24][C@:23]4([CH2:29][CH2:28][N:27]([CH3:30])[C:26]4=[O:31])[N:22]3[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[C:16]=2[CH3:39])[CH:9]=1)[CH3:2]
Reactant: Cc1c(Br)ccnc1[C@H]1CC[C@]2(CCN(C)C2=O)N1C(=O)OC(C)(C)C
Reactant: CCOc1ccc(F)c(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(F)c(-c2ccnc([C@H]3CC[C@]4(CCN(C)C4=O)N3C(=O)OC(C)(C)C)c2C)c1
Temperature: 140 °C
Yield: 28.9 %

Procedure:
To a microwave vial containing a solution of (5-ethoxy-2-fluoro-phenyl)boronic acid (121.99 mg, 0.6600 mmol) in MeCN (3 mL) and water (0.6000 mL) was added tert-butyl (2R,5R)-2-(4-bromo-3-methyl-2-pyridyl)-7-methyl-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (which may be prepared as described in Description 98) (225.1 mg, 0.5300 mmol), sodium carbonate (112.41 mg, 1.06 mmol) and bis(triphenyl-phosphine)palladium (II) dichloride (18.39 mg, 0.0300 mmol). The microwave vial was sealed and heated at 140° C. for 20 minutes. The reaction was concentrated in vacuo, and the residue was purified on silica (25 g, SNAP cartridge), eluting with EtOAc in isohexane from 0% to 100%. Fractions containing desired product were combined and concentrated in vacuo to give tert-butyl (2R,5R)-2-[4-(5-ethoxy-2-fluoro-phenyl)-3-methyl-2-pyridyl]-7-methyl-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D100) (74.2 mg, 0.1534 mmol, 28.9% yield) as a colourless oil;
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH2:33][C:34]#[N:35])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:36]1[C:34]([CH2:33][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13]([C:10]3([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)[CH2:11][CH2:12]3)=[O:14])=[CH:21][C:20]=2[C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:24][CH:23]=2)=[N:35][N:38]=[N:37]1
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2CC#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2Cc2nnn[nH]2)cc1
Yield: 25.7 %

Procedure:
5′-(1-(Benzo[d][1,3 ]dioxol-5-yl)cyclopropanecarboxamido)-2′-(cyanomethyl)-N,N-dimethylbiphenyl-4-carboxamide (32 mg, 0.070 mmol), sodium azide (55 mg, 0.84 mmol), and ammonium chloride (45 mg, 0.84 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) and irradiated in the microwave at 100° C. for 2 hours. After cooling, the mixture was filtered and purified by reverse phase HPLC to yield 2′-((1H-tetrazol-5-yl)methyl)-5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropane carboxamido)-N,N-dimethylbiphenyl-4-carboxamide (9.2 mg, 26%). ESI-MS m/z calc. 510.2, found 511.5 (M+1)+; Retention time 2.68 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][C:13](CO)([C:15]([OH:17])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([CH2:15][O:17][S:21]([CH3:20])(=[O:23])=[O:22])[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)N1CC(CO)(C(=O)O)C1
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CN(C(=O)OCc2ccccc2)C1

Procedure:
3-Hydroxymethyl-azetidine-1,3-dicarboxylic acid monobenzyl ester (6.6 g) was dissolved in CH2Cl2 (100 mL) and brought to −15 C. While stirring, TEA was added (3 eq, 9.43 g) followed by methanesulphonic chloride (2.0 eq, 7.69 g) and allowed to come to RT and stirred for 1 h. The resulting organic solution was extracted with water (3×100 mL). The organic layer was dried over Na2SO4 and evaporated to give the desired product as a clear oil which was used without further purification.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH2:18])[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=O)C.[Li+].[OH-]>CC(O)C.C1COCC1.O>[NH2:18][C:16]1[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=[C:12]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([N:21]3[CH2:32][CH2:31][N:30]4[C:23](=[CH:24][C:25]5[CH2:26][C:27]([CH3:33])([CH3:34])[CH2:28][C:29]=54)[C:22]3=[O:35])[C:6]=2[CH2:5][OH:4])[CH:17]=1
Reactant: CC(=O)OCc1c(-c2cc(N)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc(N)c1=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
A mixture of 103c (1.1 g, 2.3 mmol) and LiOH (450 mg, 11.0 mmol) in iPrOH/THF (1:1, 10 mL) and H2O (2.5 mL) was stirred at 40° C. for 0.5 h. The mixture was evaporated in vacuo. The residue was partitioned between EtOAc and water. The combined EtOAc extract was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 10:1 dichloromethane/methanol to afford 103d (350 mg, 36%) as a pale yellow solid. MS-ESI: [M+H]+ 434.3. 1H NMR (500 MHz, CDCl3) δ 8.44 (d, J=5.0 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.21 (d, J=5.0 Hz, 1H), 6.83 (s, 1H), 6.82 (d, J=2.0 Hz, 1H), 5.04-5.03 (m, 1H), 4.63-4.62 (m, 1H), 4.50-4.48 (m, 1H), 4.30-4.28 (m, 1H), 4.16-4.10 (m, 3H), 3.87-3.85 (m, 1H), 3.65 (s, 3H), 2.57-2.56 (m, 2H), 2.50 (s, 2H), 1.26 (s, 6H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f22) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[C:10]([C:27]2[O:31][C:30]([CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[N:29][N:28]=2)=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:13][N:14]=1>C(Cl)Cl>[NH2:8][C:9]1[C:10]([C:27]2[O:31][C:30]([CH2:32][C:33]([OH:35])=[O:34])=[N:29][N:28]=2)=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:13][N:14]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(CC(=O)OC(C)(C)C)o3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(CC(=O)O)o3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.9 %

Procedure:
TFA (500 μL, 6.490 mmol) was added to a stirred solution of tert-butyl 2-(5-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)acetate (45 mg, 0.083 mmol) in CH2Cl2 (5 mL) and the reaction stirred at ambient temperature for 18 h. The solvent was removed in vacuo and the residue azeotroped with CH2Cl2 (2×5 mL) and ether (2×5 mL). The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3 CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a yellow solid (16.7 mg, 49%); 1H NMR (400 MHz, DMSO) d 1.19 (d, 6H), 3.45 (m, 1H), 4.27 (s, 2H), 7.85 (br s, 2H), 7.96 (d, 2H), 8.30 (d, 2H), 9.04 (s, 1H) and 13.30 (s, 1H) ppm; MS (ES+) 404.2
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[F:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([NH:19][NH2:20])=O.Cl.C(N(CC)CC)C>CC1C=CC(C)=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][C:5]2[N:4]([C:17]([C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=3[F:14])=[N:19][N:20]=2)[N:3]=1
Reactant: NNC(=O)c1ccccc1F
Reactant: Clc1cc(-c2cccs2)c(Cl)nn1
Agent: Cl
Solvent: Cc1ccc(C)cc1
Solvent: CCN(CC)CC
Product: Fc1ccccc1-c1nnc2cc(-c3cccs3)c(Cl)nn12
Yield: 26 %

Procedure:
A mixture of 3,6-dichloro-4-(thien-2-yl)pyridazine from above (0.5 g, 2.1 mmol), 2-fluorobenzhydrazide (0.66 g, 4,3 mmol) and triethylamine hydrochloride (0.59 g, 4,3 mmol) in p-xylene (10 ml) was stirred and heated at reflux under nitrogen for 30 hours. Upon cooling the volatiles were removed in vacuo. The residue was partly purified by chromatography on silica gel eluting with 50%→66%→100% ethyl acetate-hexane to give the title compound as a yellow solid (0.19 g, 26%). MS (ES+) m/e 331 [MH]+, 333 [MH]+. This material was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[C:17]([Cl:30])[CH:16]=2)[NH:7][N:6]=1.[OH:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:30][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:35]4[CH2:36][CH2:37][CH:32]([OH:31])[CH2:33][CH2:34]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)c1
Reactant: OC1CCNCC1
Product: OC1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Yield: 39 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and 4-hydroxypiperidine to give the title compound in 39% yield; NMR Spectrum: 1.32-1.39 (m, 2H), 1.66-1.69 (m, 2H), 2.15 (t, 2H), 2.75-2.80 (m, 4H), 3.40-3.44 (m, 1H), 4.40 (t, 2H), 4.53 (br s, 1H), 5.25 (s, 2H), 7.18 (t, 1H), 7.23 (d, 1H), 7.29-7.33 (m, 2H), 7.44-7.47 (m, 1H), 7.56 (d, 1H), 7.90 (s, 1H), 8.29 (s, 1H), 8.50 (br s, 1H); Mass Spectrum: 513 (MH+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=O.S(=O)(=O)(O)O.S(OS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>C(O)C>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2[CH:1]=[C:2]([C:4]3[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=3)[CH:1]=[C:2]([C:4]3[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=3)[CH:1]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OS(=O)(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: Brc1ccc(-c2cc(-c3ccc(Br)cc3)cc(-c3ccc(Br)cc3)c2)cc1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A mixture of 0.8 kg of 4-bromoacetophenone by Sigma-Aldrich Japan, KK., 40 ml of sulfuric acid and 1.2 kg of potassium disulfate was stirred at 180° C. for 18 hours. After stirring, 3.0 L of ethanol was added to the mixture, which was heated to reflux for 7 hours. It was then allowed to naturally cool to room temperature, producing a precipitate which was filtered out. After adding 3.0 L of water to the filtered precipitate and heating to reflux for 1 hour, the reaction mixture was allowed to naturally cool to room temperature. The reaction mixture was filtered and rinsed with 0.5 L of ethanol. In this manner there was obtained 0.58 kg of 1,3,5-tris(p-bromophenyl)benzene.
Reaction SMILES: [OH-:1].[Na+].Cl.Cl[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]>O>[OH:1][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: [OH-]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a 5-liter, 3-necked, round-bottom flask is added 532 g of NaOH in 3 liters of water and 520 g of 4-chloro-3-nitrobenzoic acid. The solution is heated to reflux (100° C.) under nitrogen and stirred for 10 hours. Upon completion, the reaction is cooled to room temperature and neutralized with concentrated hydrochloric acid. The product is isolated by filtration, washed with 3 liters of cold water and dried in a vacuum oven at 30° C. overnight at 3 mm Hg. The yield is 430 g (90 percent) of 4-hydroxy-3-nitrobenzoic acid with a melting point of 182° C.-183° C.
Reaction SMILES: FC1C(C)=C(F)C(F)=C(F)C=1F.[OH-].[Na+].[CH:15]([O:18][C:19]1[C:35]([F:36])=[C:34]([F:37])[C:22]([CH2:23]OC2C=CC(C(=O)C)=CC=2)=[C:21]([F:38])[C:20]=1[F:39])([CH3:17])[CH3:16].[Br:40]N1C(=O)CCC1=O>O.C(O)(C)C>[CH:15]([O:18][C:19]1[C:35]([F:36])=[C:34]([F:37])[C:22]([CH2:23][Br:40])=[C:21]([F:38])[C:20]=1[F:39])([CH3:17])[CH3:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc(OCc2c(F)c(F)c(OC(C)C)c(F)c2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: Cc1c(F)c(F)c(F)c(F)c1F
Solvent: O
Product: CC(C)Oc1c(F)c(F)c(CBr)c(F)c1F

Procedure:
This compound can be prepared by reacting pentafluorotoluene with isopropanol and sodium hydroxide in water, as described for the preparation of compound 38, followed by bromination with N-bromosuccinimide.