Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C([O:8][C:9](=O)[CH2:10][NH:11]C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)=C(F)C(F)=C(F)C=1F.CCN(C(C)C)C(C)C.[NH2:43][CH2:44][C:45]([NH:47][C@H:48]([C:56]([NH:58][C@H:59]([C:64]([OH:66])=[O:65])[CH2:60][CH:61]([CH3:63])[CH3:62])=[O:57])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:46]>CN(C=O)C>[NH2:11][CH2:10][C:9]([NH:43][CH2:44][C:45]([NH:47][C@H:48]([C:56]([NH:58][C@H:59]([C:64]([OH:66])=[O:65])[CH2:60][CH:61]([CH3:62])[CH3:63])=[O:57])[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:46])=[O:8]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CN)C(=O)O
Reactant: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN)C(=O)O
Reaction time: 3 h

Procedure:
Fmoc-glycine pentafluorophenyl ester (46 mg, 0.1 mmol) is dissolved in anhydrous DMF (1 mL) containing DIEA (17 μL, 0.1 mmol). About 0.5-1.0 mL of this solution is added to Gly-L-Phe-L-Leu ELAMS™ in a test tube and the tube vortexed for about 3 hours. The ELAMS™ are pelleted and washed with DMF (4×) and methylene chloride (2×). Deprotection can be effected by treatment with a solution of 20% piperidine in DMF for 30 min. The ELAMS™ are then washed with DMF (2×), ethanol (2×) and methylene chloride (2×) and dried at 60° C. for 4 hours. The identifier tag for each ELAMS™ is detected and recorded.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:26][C:10]3=[CH:11][C:12]4[C:13]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:14](=[O:21])[N:15]([CH:18]([CH3:20])[CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>>[CH2:24]([C:13]1([CH2:22][CH3:23])[C:12]2[CH:11]=[C:10]3[NH:26][C:7]([C:3]4[C:2]([NH:1][C:30]([CH:27]5[CH2:29][CH2:28]5)=[O:31])=[CH:6][NH:5][N:4]=4)=[N:8][C:9]3=[CH:17][C:16]=2[N:15]([CH:18]([CH3:20])[CH3:19])[C:14]1=[O:21])[CH3:25]
Reactant: O=C(Cl)C1CC1
Reactant: CCC1(CC)C(=O)N(C(C)C)c2cc3nc(-c4n[nH]cc4N)[nH]c3cc21
Product: CCC1(CC)C(=O)N(C(C)C)c2cc3nc(-c4n[nH]cc4NC(=O)C4CC4)[nH]c3cc21
Yield: 16.6 %

Procedure:
Cyclopropanecarboxylic acid[3-(7,7-diethyl-5-isopropyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-Amino-1H-pyrazol-3-yl)-7,7-diethyl-5-isopropyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.43 mmol) and cyclopropanecarbonyl chloride (45 mg, 0.43 mmol). 30 mg (17%) of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([CH3:38])=[CH:32]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([CH3:38])=[CH:32]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
A solution of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)quinazoline (155 mg, 0.3 mmol), (prepared as described in Example 69), in methylene chloride (5 ml) containing TFA (1 ml) was stirred at ambient temperature for 30 minutes. The volatiles were removed under vacuum and the residue was treated with water and adjusted to pH12 with 2M sodium hydroxide. The mixture was extracted with methylene chloride. The organic layer was dried (MgSO4), and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/ethyl acetate/methanol (5/4/1) followed by methylene chloride/methanol (9/1) and by 3M ammonia in methanol/methanol/methylene chloride (5/15/80). After removal of the solvent by evaporation, the residue was dissolved in the minimum of methylene chloride, ether was added followed by petroleum ether. The precipitate was collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-4-(2-methylindol-5yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (120 mg, 96%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])[CH:22]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:9]=1)=[O:6].C(N([CH2:34][CH3:35])CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:16]([O:15][C:13]([C:35]1[CH:34]=[CH:21][C:22]([O:1][C:2]2[CH:3]=[C:4]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:28])[CH2:25][O:26][CH3:27])[CH:22]=2)[C:5]([NH:7][C:8]2[CH:12]=[CH:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:9]=2)=[O:6])=[CH:2][CH:3]=1)=[O:14])[CH3:17]
Reactant: CCN(CC)CC
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)COC)cc(C(=O)Nc3ccn(C(=O)OC(C)(C)C)n3)c2)cc1
Yield: 39 %

Procedure:
tert-Butyl 3-({3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoyl}amino)-1H-pyrazole-1-carboxylate (391 mg, 1 mmol), ethyl-4-boronic acid benzoate (388 mg, 2.0 equiv), copper (II) acetate (363 mg, 2.0 equiv) and triethylamine (0.7 mL; 5.0 equiv) were suspended in dry DCM over freshly activated powdered 4A molecular sieves (ca. 1 g) for 7 hours under an ambient atmosphere. Reaction mixture filtered through diatomaceous earth was washed with DCM (×3). Filtrate concentrated in vacuo, taken up in ethyl acetate and washed with 1M hydrochloric acid, saturated sodium hydrogen carbonate, saturated brine and dried (MgSO4). Filtered, filtrate concentrated in vacuo and chromatographed (0-50% ethyl acetate/isohexane) to give a brown oil (210 mg, 39%).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH3:28])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH3:13])[CH2:9]1)=O)(C)(C)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[NH:8]1[CH2:9][CH:10]([N:12]([CH3:13])[C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH3:28])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:11]1
Reactant: Cc1cc2c(cc1N(C)C1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1N(C)C1CNC1)N1C(=NNC(=O)C1C)CO2
Yield: 56 %

Procedure:
A solution of 3-[(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-methyl-amino]-azetidine-1-carboxylic acid tert-butyl ester (0.018 g, 0.043 mmol) in TFA (0.5 mL) and DCM (3 mL) was stirred at 25° C. for 2 h. The solvent was removed in vacuo to give 6-(azetidin-3-yl-methyl-amino)-4,7-dimethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (0.010 g, 56%). LC/MS (Table 1, Method 5) Rt=1.994 min.; MS m/z: 316 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C@H:3]([OH:36])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[CH2:7][CH:6]1[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31].CCN(C(C)C)C(C)C.[CH3:48][NH2:49].C(N=C=NCCCN(C)C)C>CO>[CH3:48][NH:49][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[C:27]([CH:6]2[CH2:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:24])([F:25])[F:26])[CH:17]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:5]2[CH2:4][C@@H:3]([OH:36])[C:2]([F:1])([F:38])[F:37])[CH:28]=1
Reactant: CN
Reactant: O=C(O)c1cccc(C2CN(Cc3cccc(OC(F)(F)F)c3)c3ccccc3N2C[C@@H](O)C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(C2CN(Cc3cccc(OC(F)(F)F)c3)c3ccccc3N2C[C@@H](O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-{1-[(R)-3,3,3-trifluoro-2-hydroxypropyl]-4-[3-(trifluoromethoxy)benzyl]-1,2,3,4-tetrahydroquinoxalin-2-yl}benzoic acid (100 mg, 0.185 mmol) (from Scheme A12) was dissolved in MeOH (925 μl), Hunig's Base (97 μl, 0.555 mmol), methylamine (93 μl, 0.185 mmol), and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine (106 mg, 0.555 mmol) were added, and the mixture was stirred at 25° C. overnight. The product was purified on a reverse phase column, 10-90% MeCN/H2O gradient, 0.1% TFA modifier, yielding Example 19, N-methyl-3-{1-[(R)-3,3,3-trifluoro-2-hydroxypropyl]-4-[3-(trifluoro-methoxy)benzyl]-1,2,3,4-tetrahydro quinoxalin-2-yl}benzamide. MS m/z=554.04.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1.[NH2:12][C:13]1[C:14]([C:18]2[N:19]([CH2:29][CH3:30])[C:20]3[C:25]([CH:26]=O)=[CH:24][N:23]=[CH:22][C:21]=3[N:28]=2)=[N:15][O:16][N:17]=1>>[NH2:12][C:13]1[C:14]([C:18]2[N:19]([CH2:29][CH3:30])[C:20]3[C:25]([CH2:26][NH:11][CH:8]4[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:9]4)=[CH:24][N:23]=[CH:22][C:21]=3[N:28]=2)=[N:15][O:16][N:17]=1
Reactant: CCn1c(-c2nonc2N)nc2cncc(C=O)c21
Reactant: COCCN1CCC(N)CC1
Product: CCn1c(-c2nonc2N)nc2cncc(CNC3CCN(CCOC)CC3)c21

Procedure:
The title compound was prepared from the product of Step 2 the product of Example 310 using the method of Example 149; MS (ES+) m/e 401 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][C:5]=1[F:13])(=[O:3])[CH3:2].C(O)(=O)C.[Br:18]Br>CO>[Br:18][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][C:5]=1[F:13])=[O:3]
Reactant: CC(=O)c1ccc(B(O)O)cc1F
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CO
Product: O=C(CBr)c1ccc(B(O)O)cc1F
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
An oven-dried, 500-milliliter, 3-necked, round-bottomed flask was charged with 5 grams (27.4 millimole) of 4-acetyl-3-fluorophenyl boronic acid and 25 milliliters of methanol under a nitrogen atmosphere. The solution was cooled to 0° C. using an ice bath. To this solution was added 0.2 milliliters (0.55 equivalents) of glacial acetic acid. In a 100 milliliters Erlenmeyer flask was taken 1.27 milliliters (3.95 grams, 24 millimole, 0.9 equivalents) of elemental bromine dissolved in 4 milliliters of cold methanol. The bromine solution was added dropwise to the above solution at 0° C. using an addition funnel. With the addition of Br2, the solution slowly turned light orange and finally to dark orange when addition was complete. After about 5-6 hours, the progress of the reaction was monitored by NMR. Depending on the progress of reaction, another 10-20 mole % of bromine was added after cooling the solution to 0° C. Total reaction time was approximately 24 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@H]4CCCNC4)ncnc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC[C@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 88.3 %

Procedure:
To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3S)-piperidin-3-yl]-9H-purin-6-amine (15.3 mg, 0.035 mmol, 1 eq.) in 2 mL of THF was added methanesulfonyl chloride (0.005 mL, 0.07 mmol, 2 eq.) and triethylamine (0.015 mL, 0.11 mmol, 3 eq.). The mixture was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 16 mg (89%) of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3S)-1-methanesulfonylpiperidin-3-yl]-9H-purin-6-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.63-2.02 (m, 4 H) 2.77 (s, 3 H) 2.98-3.19 (m, 2 H) 3.31 (br. s., 1 H) 3.71 (d, J=10.55 Hz, 1 H) 4.56 (br. s., 1 H) 6.01 (d, J=7.54 Hz, 1 H) 6.97-7.56 (m, 8 H) 8.37 (s, 1 H), [M+H]+ 517.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:9][O:10]C)[C:3]=1OC.S(=O)(=O)(O)O.[CH2:22]1COCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH:12]2[CH2:14][CH2:13]2)[CH:9]=[O:10])[C:3]=1[CH3:22]
Reactant: COC=C(c1nccc(Cl)c1OC)C1CC1
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Product: Cc1c(Cl)ccnc1C(C=O)C1CC1

Procedure:
1.02 g of 2-(4-chloro-3-methoxy-2-pyridyl)-2-cyclopropyl-1-methoxyethene (XI) was dissolved in 10 ml of THF and 10 ml of dilute sulfuric acid was added to the resulting mixture and the resulting mixture was concentrated at 50° C. under reduced pressure. The resulting mixture was poured into water and neutralized with saturated sodium bicarbonate solution, and thereafter, extracted with chloroform. The resulting organic layer was washed with saturated salt water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 0.81 g of 2-(4-chloro-3-methyl-2-pyridyl)-2-cyclopropylethanal (XII).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.Cl.[NH2:27][C@@H:28]([C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([Br:38])[CH:32]=1)[CH2:29][OH:30].C(Cl)CCl.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:27][C@@H:28]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([Br:38])[CH:32]=3)[CH2:29][OH:30])=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: N[C@H](CO)c1cc(F)cc(Br)c1
Reactant: Nc1ncc([C@H]2CC[C@H](O)[C@@H](F)C2)nc1-c1ccc(C(=O)O)c(F)c1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncc([C@H]2CC[C@H](O)[C@@H](F)C2)nc1-c1ccc(C(=O)N[C@H](CO)c2cc(F)cc(Br)c2)c(F)c1
Reaction time: 15 h
Yield: 33.3 %

Procedure:
To a solution of 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (20 mg, 0.057 mmol) in DMF (573 μL) was added (S)-2-amino-2-(3-bromo-5-fluorophenyl)ethanol HCl salt (18.59 mg, 0.069 mmol), aza-HOBt (11.69 mg, 0.086 mmol), EDC (21.95 mg, 0.115 mmol), and DIEA (30.0 μl, 0.172 mmol). The reaction mixture was stirred for 15 h. Water was added, and the reaction mixture was extracted with EtOAc three times. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by HPLC. Pure fractions were lyophilized to provide 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (12.9 mg, 0.019 mmol, 32.8%) as a TFA salt. LCMS (m/z): 565.1/567.1 (MH+), 0.72 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.78 (s, 2H), 7.63-7.47 (m, 2H), 7.37 (s, 1H), 7.22-7.02 (m, 2H), 5.15-5.03 (m, 1H), 4.43-4.15 (m, 1H), 3.77 (t, J=5.7 Hz, 2H), 3.62-3.47 (m, 1H), 2.76 (br. s., 1H), 2.19 (dd, J=3.1, 6.3 Hz, 1H), 2.02-1.92 (m, 1H), 1.89-1.66 (m, 2H), 1.56 (dd, J=3.3, 12.3 Hz, 1H), 1.42 (br. s., 1H). The absolute stereochemistry was determined based on the information of X-ray co-structure of 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-hydroxyethyl)-2-fluorobenzamide.
Reaction SMILES: C[N:2]1[N:6]=[C:5]2[CH:7]=[CH:8][C:9]([NH:11][N:12]=[C:13]3[C:17]([NH2:18])=[N:16][N:15]=[C:14]3[NH2:19])=[CH:10][C:4]2=[N:3]1.CN1N=C2C=CC(N)=CC2=N1.CN1N=C2C=CC([N+]([O-])=O)=CC2=N1.C(#N)CC#N.O.NN>>[N:6]1[NH:2][N:3]=[C:4]2[CH:10]=[C:9]([NH:11][N:12]=[C:13]3[C:14]([NH2:19])=[N:15][N:16]=[C:17]3[NH2:18])[CH:8]=[CH:7][C:5]=12
Reactant: Cn1nc2ccc(NN=C3C(N)=NN=C3N)cc2n1
Agent: Cn1nc2ccc(N)cc2n1
Agent: Cn1nc2ccc([N+](=O)[O-])cc2n1
Agent: NN
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccc2n[nH]nc2c1

Procedure:
In a similar manner, 4-[(2-methyl-2H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine was prepared from 2-methyl-2H-benzotriazol-5-ylamine (which was prepared from methyl-5-nitro-2H-benzotriazole (2.0 g) in a manner similar to that described above) (0.24 g), malononitrile (0.2 g) and hydrazine hydrate (0.2 g) to yield 0.181 g. MS (m/z, ES+): 258 (M+1, 100%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH:24]([CH3:26])[CH3:25]>>[CH3:25][CH:24]([CH3:26])[CH2:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: CC(C)COc1ccccc1CBr
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Product: CC(C)COc1ccccc1Cn1cnc(-c2cc(C#N)ccn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 4) and 1-(bromomethyl)-2-(2-methylpropoxyl)benzene according to the procedure for the preparation of Example 43, part A using room temp. [M+H] Calc'd for C20H20N4O, 333. Found, 333.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C@@H:11]2[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=3)=[O:17])[CH2:12]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:32][C:33]([O:36][C:37]([NH:39][C:40]([C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1)=[NH:41])=[O:38])([CH3:35])[CH3:34]>>[CH3:35][C:33]([O:36][C:37]([NH:39][C:40]([C:42]1[CH:43]=[CH:44][C:45]([C:46]([N:14]2[CH2:15][C@@H:11]([N:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)[CH2:12][C@H:13]2[C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:21][CH:20]=2)=[O:17])=[O:47])=[CH:49][CH:50]=1)=[NH:41])=[O:38])([CH3:32])[CH3:34]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2C[C@H](N3CCN(S(C)(=O)=O)CC3)CN2)cc1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(C(=O)O)cc1
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(C(=O)N2C[C@@H](N3CCN(S(C)(=O)=O)CC3)C[C@H]2C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)cc1

Procedure:
Following the procedure described in Example 8, the compound prepared in Example 6 was treated with the compound prepared in Example 18 to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[C:7]2[C:8](=[C:13]([CH3:17])[N:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1>>[OH:2][CH2:1][CH2:3][NH:4][C:6]1[C:7]2[C:8](=[C:13]([CH3:17])[N:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: NCCO
Reactant: Cc1cc(Cl)c2nn(C)c(C)c2n1
Product: Cc1cc(NCCO)c2nn(C)c(C)c2n1

Procedure:
The title compound was prepared from ethanolamine and 7-chloro-2,3,5-trimethylpyrazolo[4,3-b]pyridine in an analogous manner to the preparation of Example 2 giving a white crystalline solid, m.p. 186°-189° C. after recrystallisation from ether/methanol.
Reaction SMILES: [CH2:1]([C@H:8]([NH:28][C:29](=[O:45])[O:30][CH2:31][CH:32]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@@H:9]([OH:27])[CH2:10][C@@H:11]([NH:19]C(OC(C)(C)C)=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[NH2:19][C@@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:10][C@H:9]([OH:27])[C@@H:8]([NH:28][C:29](=[O:45])[O:30][CH2:31][CH:32]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=2[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing the product of Example 3A (0.92 g, 1.5 mmol) in dioxane (5 mL) was treated with HCl solution (15 mL, 4 N in dioxane) at 0° C., stirred at 25° C. for 1 hour and concentrated. The residue was triturated with hexanes to give the title compound as the hydrochloride salt (0.82 g).
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[SH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][S:10][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1)[CH3:16]
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Reactant: CCOC(=O)CS
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1c[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-bromo-2,4(1H,3H)-pyrimidinedione (15 g, 79 mmol) and ethyl mercaptoacetate (8.58 ml, 79 mmol) in DMF (200 mL) was treated with tetrabutylammonium hydrogen sulfate (6.67 g, 19.64 mmol) and potassium carbonate (23.88 g, 173 mmol) and stirred at ambient temperature overnight. The solution was filtered and concentrated under reduced pressure to yield crude title compound as a yellow oil which foams up under reduced pressure.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]([NH:14][C:15](=[O:31])[CH2:16][C:17]2[N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:20]=[N:19][CH:18]=2)[CH2:11][CH:10]([C:32]([O:34][CH3:35])=[O:33])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:35][O:34][C:32]([C@H:10]1[CH2:11][C@@H:12]([NH:14][C:15](=[O:31])[CH2:16][C:17]2[N:21]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[CH:27][CH:28]=3)[CH:20]=[N:19][CH:18]=2)[CH2:13][NH:8][CH2:9]1)=[O:33]
Reactant: COC(=O)C1CC(NC(=O)Cc2cncn2Cc2ccc(C#N)cc2)CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CNC[C@H](NC(=O)Cc2cncn2Cc2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(t-Butoxycarbonyl)-3-methoxycarbonyl-5-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-yl)acetylamino]piperidine (44.6 mg, 0.093 mmol) was dissolved in CH2Cl2 (6 mL). Trifluoroacetic acid (3 mL) was added and the solution was stirred at ambient temperature for 4 h. The solution was concentrated under reduced pressure to give the title compound without further purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6](Cl)(Cl)[C:7]([F:10])([F:9])[F:8].[CH2:13]([C:15]1[CH:30]=[C:29]([O:31][CH2:32][CH:33]=[C:34]([Cl:36])[Cl:35])[CH:28]=[C:27]([CH2:37][CH3:38])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH:25]=O)[CH3:14].C(OC(=O)C)(=O)C>[Zn].CN(C)C=O>[CH2:13]([C:15]1[CH:30]=[C:29]([O:31][CH2:32][CH:33]=[C:34]([Cl:35])[Cl:36])[CH:28]=[C:27]([CH2:37][CH3:38])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24]/[CH:25]=[C:6](\[Cl:5])/[C:7]([F:10])([F:9])[F:8])[CH3:14]
Reactant: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCCOCC=O
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCCOC/C=C(\Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 192.5 %

Procedure:
To a mixture of 0.12 g of aluminum chloride and 50 ml of N,N-dimethylformamide was added 3.04 g of 1,1,1-trichlorotrifluoroethane. After stirring at room temperature for 1 hour, 1.21 g of 5-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetaldehyde was added, and the reaction mixture was further stirred at room temperature for 4 hours, to which 1.38 g of acetic anhydride was added. After stirring at room temperature for 1 hour, 0.88 g of zinc dust was added, and the reaction mixture was stirred at room temperature for 12 hours and filtered. The filtrate was poured into 50 ml of diluted hydrochloric acid and extracted twice with 100 ml of diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then evaporated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 2.91 g of (Z)-3,5-diethyl-1-(3,3-dichloro-2-propenyloxy)-4-(5-(3-chloro-4,4,4-trifluoro-2-butenyloxy)pentyloxy)benzene (yield, 72%), nD26.0 1.4958.