Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:24])=[C:9]([CH2:19][C:20]([O:22]C)=[O:21])[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[S:5][C:4]=1[CH3:25])[CH3:2].[O-2].[Li+].[Li+].Cl>O1CCOCC1.O>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:24])=[C:9]([CH2:19][C:20]([OH:22])=[O:21])[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[S:5][C:4]=1[CH3:25])[CH3:2]
Reactant: CCc1c(C)sc2nc(C)c(CC(=O)OC)c(-c3ccc(C)cc3)c12
Agent: Cl
Agent: [Li+]
Agent: [O-2]
Solvent: O
Solvent: C1COCCO1
Product: CCc1c(C)sc2nc(C)c(CC(=O)O)c(-c3ccc(C)cc3)c12
Temperature: 60 °C
Yield: 64.9 %

Procedure:
To a solution of methyl 2-(3-ethyl-2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.045 g; 0.127 mmol) in dioxane (3 mL) and water (0.8 mL) was added a 1N lithium oxide solution (0.8 mL; 0.80 mmol). The reaction mixture was heated at 60° C. for 2 h. After cooling to room temperature, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.028 g (65%) of the title compound as a beige solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:12]=1[CH2:13][NH2:14])=O)(C)(C)C.C(OC([NH:27][C@@H:28]([C:36]([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40](O)=[O:41])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=O)(C)(C)C>>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][C@H:28]([C:36]([N:38]1[CH2:45][CH2:44][CH2:43][C@H:39]1[C:40]([NH:14][CH2:13][C:12]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=1[CH2:10][CH2:9][NH2:8])=[O:41])=[O:37])[NH2:27]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Cl)cc1CN
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccn1)C(=O)N1CCC[C@H]1C(=O)O
Product: NCCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H](N)Cc1ccccn1

Procedure:
The title compound was prepared from 2-(2-(tert-butoxycarbonylamino)ethyl)-5-chlorobenzyl amine from Step 4 and N-(tert-butoxycarbonyl)-3-pyridin-2-yl-D-alanyl-L-proline from Step 5 using a similar coupling, deprotection, and purification procedures as described in Steps 7 and 8 of Example 15: 1H NMR (DMSO-d6, 400 MHz): δ 8.84 (t, 1H, J=5.8 Hz), 8.72-8.62 (br m, 4H), 8.12-8.00 (br m, 4H), 7.54 (d, 2H, J=7.9 Hz), 7.33-7.19 (m, 4H), 4.58 (br s, 1H), 4.40-4.20 (m, 3H), 3.88-3.80 (m, 2H), 3.43-3.28 (m, 3H), 2.96 (br s, 4H), 1.90-1.75 (br m, 2H); MS (Electrospray): M+H=430.2; TLC Rf=0.13 (80/10/1 of methylene chloride/methanol/concentrated ammonium hydroxide).
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:11]=1)[C:8](Cl)=[O:9]>O1CCCC1.[Cl-].[Na+].O>[Br:2][C:3]1[CH:11]=[C:7]([C:8]([NH2:1])=[O:9])[CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cncc(Br)c1
Reactant: N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In an amount of 555 mg of 5-bromonicotinoyl chloride was dissolved in 5.5 ml of tetrahydrofuran, added with 768 μl of 28% aqueous ammonia under ice cooling, stirred for 40 minutes, then warmed to room temperature, and further stirred at room temperature for 20 minutes. The reaction system was added with 15% brine, and extracted with tetrahydrofuran, and the organic layer was dried over anhydrous magnesium sulfate, and filtered. Then, the filtrate was concentrated under reduced pressure until about half amount of crystals were deposited, and added with ethyl acetate until the deposition of crystals was terminated, and the crystals were taken by filtration to obtain 374 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][N:9]=2)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].C1(P(O[NH2:40])(C2C=CC=CC=2)=O)C=CC=CC=1.CN(C=O)C>C1COCC1.CCOC(C)=O>[NH2:40][N:10]1[N:9]=[C:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:18]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]nc(-c2ccc(Cl)nc2)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nn1nc(-c2ccc(Cl)nc2)c2ccccc2c1=O
Reaction time: 1 h
Yield: 42.2 %

Procedure:
A mixture of the product from Example 4A (0.527 g, 2.04 mmol) and potassium 2-methylpropan-2-olate (0.299 g, 2.66 mmol) in THF (6 mL) was stirred for 1 h, and O-(diphenylphosphoryl)hydroxylamine (0.621 g, 2.66 mmol) and DMF (2 mL) were added, stirred at room temperature for 2 hours, diluted with EtOAc, washed with 1N NaOH and brine, dried (Na2SO4), filtered, and chromatographed (20-60% EtOAc/DCM) to give 235 mg of title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.67 (dd, J=2.4, 0.5, 1H), 8.38 (s, 1H), 8.14 (dd, J=8.2, 2.5, 1H), 8.02-7.82 (m, 2H), 7.81-7.65 (m, 2H), 6.54 (s, 2H).
Reaction SMILES: [O:1]=[C:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[H][H]>C(O)C.[C].[Pd]>[OH:1][CH:2]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]2)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: O=C1CCc2cc(C(=O)CCN3CCC(c4ccccc4)CC3)ccc2N1
Agent: [Pd]
Solvent: CCO
Product: O=C1CCc2cc(C(O)CCN3CCC(c4ccccc4)CC3)ccc2N1

Procedure:
2.2 Grams of 6-[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyril and 0.5 g of 5%-palladium carbon were dispersed in 80 ml of ethanol and stirred under 2 atmospheric pressure of hydrogen gas at a room temperature for 5 hours. The reaction mixture was filtered to remove the palladium black and the mother liquor was concentrated under a reduced pressure. The residue thus obtained was recrystallized from ethanol to obtain 1.5 g of 6-[1-hydroxy-3-(4-phenyl-1-piperidyl)-propyl]-3,4-dihydrocarbostyril in colorless plate-like crystals.
Reaction SMILES: CC([N:5]([C@H:9]([CH3:31])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[C:25]3[C:26]([CH3:30])([CH3:29])[CH2:27][O:28][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:30][C:26]1([CH3:29])[C:25]2[C:20]([O:19][C:16]3[N:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:31])[NH2:5])=[CH:18][CH:17]=3)=[CH:21][CH:22]=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: C[C@H](C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)nc1)N(C(=O)[O-])C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 119.1 %

Procedure:
To a solution of 1,1-dimethylethyl[(1R)-2-({6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 60, 35 mg) in dry dichloromethane (3 ml), TFA (0.189 ml, 2.456 mmol) was slowly added at 0° C. and the reaction mixture was stirred for 1.5 hours at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified with an SCX cartridge. The cartridge was washed with 3 CV of methanol, then the compound was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N). This afforded the title compound (32 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[CH:22]=2)([F:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:40]>C(Cl)Cl.O1CCOCC1>[ClH:40].[ClH:40].[CH2:36]([C:20]1[N:19]=[N:18][C:17]([O:16][CH2:15][C:11]2([F:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:22][C:21]=1[C:23]1[CH:24]=[CH:25][C:26]([O:29][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)=[CH:27][CH:28]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCc1nnc(OCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1nnc(OCC2(F)CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester (0.15 mmol, 85 mg) in DCM (1 mL) was added 4 N HCl in dioxane (1.5 mL) and the reaction was stirred for 30 min. The volatiles were removed in vacuo and the residue was triturated with anhydrous ethyl ether (2×3 mL) and dried under high vacuum to provide 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4-fluoro-piperidin-4-ylmethoxy)-pyridazine dihydrochloride (0.078 g).
Reaction SMILES: C(O[C:9]([N:11](C)[C@@H:12]([C:20]([N:22]1[CH2:49][CH2:48][CH2:47][C@H:23]1[C:24]([NH:26][C@H:27]([CH:45]=[O:46])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:44])[NH:33]C(OCC1C=CC=CC=1)=O)=[O:25])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.O.[S:52](=[O:56])(=[O:55])([OH:54])[OH:53].C(OCC)(=O)C.N1C=CC=CC=1CC(O)=O.O>C(O)C.[Pd]>[S:52]([OH:56])([OH:55])(=[O:54])=[O:53].[CH3:9][NH:11][C@@H:12]([C:20]([N:22]1[CH2:49][CH2:48][CH2:47][C@H:23]1[C:24]([NH:26][C@H:27]([CH:45]=[O:46])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:33])[NH2:44])=[O:25])=[O:21])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C(=O)OCc1ccccc1)[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@H](C=O)CCCNC(=N)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=C(O)Cc1ccccn1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@H](C=O)CCCNC(=N)N

Procedure:
23.1 g (0.03 mole) of N-benzyloxycarbonyl-N-methyl-D-phenylalanyl-L-prolyl-Nω -benzyloxycarbonyl-L-arginine-aldehyde (Example 1, Step 2) are dissolved in 150 ml of ethanol, 50 ml of deionized water and 48 ml of N sulfuric acid are added and the mixture is submitted to hydrogenolysis in the presence of 3 g of a 10 percent Pd/C catalyst. The progress of the hydrogenolysis is monitored by thin-layer chromatography in a developing solvent of ethyl acetate-pyridine-acetic acid-water-30:20:6:11 (Rf values of the starting material, intermediary and final product about 0.9, 0.7 and 0.4, respectively). After completed reaction the catalyst is filtered and washed three times with 30 ml of deionized water. The filtrate and washings are combined and concentrated to about 100 ml in a rotary evaporator. The aqueous residue is diluted to about 200 ml with deionized water and its pH is controlled. If it is not between 6.0 and 6.5, it is adjusted with 0.1N sulfuric acid or an ion-exchange resin in OH cycle (i.e. AG 1X8), then the solution is freeze-dried. Yield 12.4 g (75%).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:24]([O:26]CC)=[O:25])[N:21]([CH3:23])[CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>>[CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:24]([OH:26])=[O:25])[N:21]([CH3:23])[CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1cc(C(=O)OCC)n(C)c1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCNc1cc(C(=O)O)n(C)c1

Procedure:
A mixture of 1.0 g. of ethyl 4-hexadecylamino-1-methyl-2-pyrrolecarboxylate and 10 ml. of 40% aqueous sulfuric acid is heated under reflux for 24 hours, allowed to cool and neutralized with sodium acetate. The mixture is extracted with chloroform and the extract is dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a silica gel column by elution with chloroform-acetic acid mixtures. Evaporation of the eluate affords the product.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:25]([O:32][C:33]([C@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:25]([O:32][C:33]([C@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[CH2:16][C:13]1[S:12][C:11]([NH:10][C:8]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:9])=[N:15][CH:14]=1)=[O:34])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: O=C(OCc1ccccc1)[C@H]1CCCN1Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Yield: 78.6 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (75 mg. 0.223 mmol), pyrrolidine-2 (R)-carboxylic acid benzyl ester hydrochloride (73 mg, 0.31 mmol) and sodium triacetoxyborohydride (71 mg, 0.335 mmol) to afford 92 mg (78%) of the desired product after purification.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Pd]>[C:1]([O:4][CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: Cc1ccccc1
Agent: [Pd]
Product: CC(=O)OCc1ccccc1

Procedure:
Using a catalyst consisting of 0.6% Pd, 0.5% Au and 1.0% Bi, without added promoter, under the following reaction conditions: 150° C.; 1100 psig air pressure, reaction time: 3 hours and 1:1 molar ratio of acetic acid to toluene, 1016 grams of benzyl acetate per gram Pd are obtained.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: C1CCNC1
Product: N#Cc1ccc(N2CCCC2)c2ccccc12
Reaction time: 0.25 h

Procedure:
1-Cyano-4-fluoronaphthalene (2.0 g, 11.7 mmol) was transferred to a 25 mL flask and pyrrolidine (4.0 mL) was added. The reaction mixture was stirred for 15 min where after the product precipitated out. The reaction mixture was concentrated in vacuo. The solid was then re-crystallized with MeOH and the crystals washed with EtOH. Yield: 1.6 g (62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[CH:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][C:17]([OH:19])=O.[C:25]([C:29]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[NH2:37])=[CH:32][C:30]=1[NH2:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl.C(OCC)C>[C:25]([C:29]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[NH2:37])=[CH:32][C:30]=1[NH:31][C:17](=[O:19])[CH2:16][CH:15]([C:4]1[CH:5]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCCCCC(CC(=O)O)c1cc(C(=O)OC)c(OC)cc1OC
Reactant: CC(C)(C)c1ccc(C(N)=O)cc1N
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1cc(C(=O)OC)c(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 44, but using 3-(2,4-dimethoxy-5-methoxycarbonylphenyl)octanoic acid (prepared as described in Preparation 37) and 2-t-butyl-5-carbamoylaniline (prepared as described in Preparation 38), the title compound was obtained as crystals, melting at 101°-103° C. (from methylene chloride-diethyl ether).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O=[C:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH:17]1[C:22](OC)=[O:23]>>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]3[C:16]4[CH2:21][CH2:20][NH:19][CH2:18][C:17]=4[C:22](=[O:23])[O:13][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: COC(=O)C1CNCCC1=O
Agent: Cl
Product: O=c1oc2cc(-c3ccccc3)ccc2c2c1CNCC2
Yield: 54.1 %

Procedure:
Prepared by the method described for Example 1 from 3-phenylphenol (17 g, 0.1 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (19.3 g, 0.1 moles). The crude material is washed with water and dried to give the product (15 g), mp 250°-270° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:11]([CH2:12][OH:13])=[CH:10][N:9](CO)[C:5]2=[N:6][C:7]=1[Cl:8]>CC(C)=O>[Br:1][C:2]1[N:3]=[C:4]2[C:11]([CH:12]=[O:13])=[CH:10][NH:9][C:5]2=[N:6][C:7]=1[Cl:8]
Reactant: OCc1cn(CO)c2nc(Cl)c(Br)nc12
Solvent: CC(C)=O
Product: O=Cc1c[nH]c2nc(Cl)c(Br)nc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
To a stirred suspension of (2-bromo-3-chloro-7-hydroxymethyl-pyrrolo[2,3-b]pyrazin-5-yl)-methanol (2.0 g, 6.84 mmol) in acetone (67 mL) was added Jone's reagent (2.12 mL) and the mixture stirred at room temperature for 20 min. The mixture was cooled then filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was diluted with THF (35 mL) and 1 N NaOH solution (18 mL). The resulting mixture was stirred at room temperature for 16 h, then concentrated in vacuo to ˜20 mL and adjusted to pH7 by addition of 1N HCl. The mixture was extracted with ethyl acetate (100 mL×3), dried and concentrated to give 2-bromo-3-chloro-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (1.4 g, 80%) as a brown solid. LC-MS: 260.2 (M−H). This was used directly without further purification.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:31][N:32](C=O)C>CC([O-])=O.CC([O-])=O.[Pd+2].[C-]#N.[C-]#N.[Zn+2]>[O:11]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:31]#[N:32])[CH:10]=2)[CH2:6][NH:7]1
Reactant: O=C1NCc2ccc(Br)cc21
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Product: N#Cc1ccc2c(c1)C(=O)NC2
Temperature: 100 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 6-bromo-2,3-dihydro-1H-isoindol-1-one (150 g, 0.71 mol), Pd(OAc)2 (7.92 g, 0.036 mol), PPh3 (27.9 g, 0.106 mol), Zn(CN)2 (124.6 g, 1.065 mol) and 500 ml of DMF was stirred at 100° C. overnight. Cooled to rt, the solvent was removed and the residue was dissolved in EtOAc. The solid was removed and the filtrate was washed with brine, dried over Na2SO4, evaporated to afford the crude product, which was purified by flash column chromatography on silica gel to afford 3-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (87.5 g, 78% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH:25]([CH3:27])[CH3:26])[CH:19]=[O:20].Cl>C(O)C.O.C(OCC)(=O)C>[CH2:7]([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH:25]([CH3:27])[CH3:26])[CH:19]=[O:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)Oc1ccc(C=O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(C)Oc1ccc(C=O)cc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Potassium carbonate (1.83 g, 13.2 mmol) and benzyl chloride (1.55 mL, 13.5 mmol) were added to a suspension of 3-hydroxy-4-isopropoxybenzaldehyde described in Production Example 171 (1.84 g, 10.2 mmol) in ethanol (20 mL) under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 90° C. for 2 hours. The mixture was cooled to 0° C. and then 2 M hydrochloric acid, ethyl acetate, and water were added for partition. The organic layer was washed with a saturated saline solution, and the resultant was dried over anhydrous sodium sulfate, and then filtered. The solvent was evaporated, the resultant residue was dissolved in dichloromethane, and the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate=19:1-3:1). The target fraction was concentrated under vacuum to obtain the title compound (2.59 g, 94%).
Reaction SMILES: ClC1C=CC(C2N(CC(O)C(F)(F)F)C(=O)N(CC3C=CC(C(O)=O)=CC=3)N=2)=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[N:42]([CH2:43][CH:44]([OH:49])[C:45]([F:48])([F:47])[F:46])[C:41](=[O:50])[N:40]([CH2:51][C:52]3[CH:53]=[C:54]([CH:59]=[CH:60][CH:61]=3)[C:55]([O:57]C)=[O:56])[N:39]=2)=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]2[N:42]([CH2:43][CH:44]([OH:49])[C:45]([F:47])([F:46])[F:48])[C:41](=[O:50])[N:40]([CH2:51][C:52]3[CH:53]=[C:54]([CH:59]=[CH:60][CH:61]=3)[C:55]([OH:57])=[O:56])[N:39]=2)=[CH:36][CH:37]=1
Reactant: COC(=O)c1cccc(Cn2nc(-c3ccc(Cl)cc3)n(CC(O)C(F)(F)F)c2=O)c1
Agent: O=C(O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(CC(O)C(F)(F)F)c2=O)cc1
Product: O=C(O)c1cccc(Cn2nc(-c3ccc(Cl)cc3)n(CC(O)C(F)(F)F)c2=O)c1

Procedure:
In the same way as for the compound from Example 28A, 265 mg (0.58 mmol) of the compound from Example 25A were reacted. This gave 250 mg (97% of theory) of the target compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][CH2:14][C:9]21[CH2:13]CC[CH2:10]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1(C(N)(C)CN)C[CH2:21]1.CC(C)(O)C#N>>[CH2:1]([N:8]1[CH2:17][C:16]([CH:18]2[CH2:21][CH2:20]2)([CH3:19])[NH:15][CH2:14][C:9]1([CH3:10])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(N)(CN)C1CC1
Reactant: CC1(C)CN(Cc2ccccc2)C2(CCCC2)CN1
Agent: CC(C)(O)C#N
Product: CC1(C2CC2)CN(Cc2ccccc2)C(C)(C)CN1

Procedure:
1-Benzyl-5-cyclopropyl-2,2,5-trimethyl-piperazine was synthesized in analogy to 6-benzyl-8,8-dimethyl-6,9-diaza-spiro[4.5]decane starting from 2-cyclopropyl-propane-1,2-diamine and acetone cyanohydrin.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]([CH3:16])[C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[CH:9]=2)[C:4](=O)[CH2:3]1.C([O-])(=O)C.[Na+].Cl.[NH2:27][OH:28]>C(O)C.O>[OH:28]/[N:27]=[C:4]1\[CH2:3][C:2]([CH3:20])([CH3:1])[C:10]2[C:5]\1=[CH:6][CH:7]=[C:8]([C:11]1[N:15]([CH3:16])[C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[CH:9]=2
Reactant: NO
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)CC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)C/C2=N\O
Temperature: 25 °C
Yield: 55.1 %

Procedure:
To a stirred mixture of 5-(3,3-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (0.07 g, 0.26 mmol) in ethanol (1.6 mL)/water (0.4 mL) was added sodium acetate (0.03 g, 0.34 mmol) and hydroxylamine hydrochloride (0.02 g, 0.32 mmol). The resulting mixture was heated to reflux for 5 hours. The solution was allowed to cool to room temperature, diluted with water, and filtered to give 5-[(1E)-1-(hydroxyimino)-3,3-dimethyl-2,3-dihydro-1H-inden-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile as a white solid (0.04 g, 55%). MS (ES) m/z 280.1. HRMS: calcd for C17H17N3O+H+, 280.14444; found (ESI, [M+H]+), 280.145.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25][OH:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].O[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[CH2:25][O:26][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2CO)CC1
Reactant: Oc1ccncc1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2COc2ccncc2)CC1

Procedure:
The title compound was prepared in analogy to example 162 using (1R,2R,4S)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-hydroxymethyl-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 155) and 4-hydroxypyridine. Colorless oil (22%). MS (EI): 478.1 (M+H)+.