Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:3]=[CH:4][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10]=2[N:11]=1.[H-].[Na+].Br[CH2:19][C:20]([N:22]([CH2:29][CH:30]([NH2:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:21]>CN(C=O)C>[OH:1][CH:2]1[N:11]([CH2:19][C:20]([N:22]([CH2:29][CH:30]([NH2:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:21])[C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[N:3]1
Reactant: CCOC(=O)CN(CC(N)C(=O)OC(C)(C)C)C(=O)CBr
Reactant: Oc1ncc2c(n1)Nc1ccccc1S2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC(N)C(=O)OC(C)(C)C)C(=O)CN1C2=C(C=NC1O)Sc1ccccc1N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
2-Hydroxy-10-H-pyrimido[5,4-b][1,4]benzothiazin (653 mg, 3.0 mmol) was suspended in DMF (30 mL) and NaH (60% in mineral oil, 132 mg, 3.3 mmol) was added in one portion. After 15 minutes ethyl N-bromoacetyl-N-(2-Boc-aminoethyl)-glycinate (1.10 g, 3.3 mmol) was added. The mixture was stirred at room temperature for 2 hours, evaporated in vacuo, redissolved in dichloromethane (200 mL) and washed once with saturated aqueous NaHCO3 (100 mL) and once with saturated aqueous NaCl. The mixture was dried (MgSO4) and evaporated to dryness in vacuo. The crude material was purified on a silica gel column using methanol/dichloromethane (1:9, v/v) as the eluent to give 853 mg (57%) of the title compound.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:19][Mg]Cl.COC1C=C(C=CC=1)/C=C1\CCC2NC(C(OC)=O)=CC\1=2>[Pd]>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:19][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: COc1ccc(C[Mg]Cl)cc1OC
Agent: [Pd]
Agent: COC(=O)c1cc2c([nH]1)CC/C2=C\c1cccc(OC)c1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(OC)c(OC)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.50 g, 2.8 mmol) was reacted with 3,4-dimethoxy-benzylmagnesium chloride (0.25 M in THF, 28.0 mL, 7.0 mmol) according to General Procedure 3. The resulting exo-olefin ((E)-methyl 4-(3,4-dimethoxybenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) was then converted to the title compound by hydrogenation according to General Procedure 6 (with 5% Pd/C). The crude product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-50% EtOAc/heptane to afford the title compound: 0.050 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.06-2.18 (m, 1H) 2.50-2.68 (m, 3H) 2.68-2.81 (m, 2H) 3.20-3.35 (m, 1H) 3.74-3.94 (m, 9H) 6.36-6.46 (m, 1H) 6.69 (d, J=1.76 Hz, 1H) 6.74 (dd, J=8.10, 1.56 Hz, 1H) 6.82 (d, J=8.10 Hz, 1H) 8.80 (br. s, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.CN(C)[CH:24]=[O:25]>O1CCCC1.CCCCCC.C(O)(=O)C>[C:18]([C:17]1[CH:16]=[CH:15][C:14]([F:13])=[C:21]([CH:20]=1)[CH:24]=[O:25])#[N:19]
Reactant: N#Cc1ccc(F)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Product: N#Cc1ccc(F)c(C=O)c1
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
Diisopropylamine (2.80 ml, 19.8 mmol) was dissolved in tetrahydrofuran (20 ml). At −78° C., a hexane solution (1.60M, 11.4 ml, 18.2 mmol) of n-butyl lithium was added dropwise to the resulting solution. The reaction mixture was stirred at the same temperature for 30 minutes, followed by the dropwise addition of a tetrahydrofuran solution (20 ml) of 4-fluorobenzonitrile (2.00 g, 16.5 mmol). After stirring further at the same temperature for 30 minutes, N,N-dimethylformamide (1.7 ml, 21.5 mmol) was added dropwise to the reaction mixture. At the same temperature, the reaction mixture was stirred for 10 minutes. To the reaction mixture were added acetic acid and a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel chromatography. The fraction obtained from the n-hexane:ethyl acetate=10:2 eluate was concentrated under reduced pressure to give the title compound (1.83 g, 12.3 mmol, 74%) as a pale yellowish brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16](=S)[CH2:17][C:18](=O)[CH3:19])[C@H:13]([C:22]([O:24][CH3:25])=[O:23])[CH2:12]1)(=[O:10])=[O:9].Cl.[CH:27]1([NH:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:25][O:24][C:22]([C@@H:13]1[CH2:12][C@@H:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:9])[CH2:15][N:14]1[C:16]1[N:33]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[N:34]=[C:18]([CH3:19])[CH:17]=1)=[O:23]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Reactant: NNC1CCCCC1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1C1CCCCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-methyl 4-(2-chlorophenylsulfonyl)-1-(3-oxobutanethioyl)pyrrolidine-2-carboxylate (example 253c) was reacted with cyclohexylhydrazine hydrochloride (CAS Reg. No. 24214-73-1) to give the title compound as orange oil. MS (ESI): m/z=466.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][N:24](/[C:27](/[NH:36]C(=O)OC(C)(C)C)=[N:28]\C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:50][C:47]1[CH:48]=[CH:49][C:44]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27](=[NH:28])[NH2:36])[CH2:23][CH2:22]2)=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)N1CCC(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)N1CCC(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Reaction time: 0.5 h

Procedure:
(Z)-tert-butyl ((4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidin-1-yl)((tert-butoxycarbonyl)imino)methyl)carbamate was combined (154 mg, 0.21 mmol) with 30% TFA in CH2Cl2 (7 mL) at room temperature and the resulting mixture was stirred for 0.5 hr. The solvent was removed and the residue was triturated with diethyl ether. The white solid was collected and purified on a Gilson (20-90% CH3CN (0.1% TFA)/H2O) (0.1% TFA)) to yield 4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidine-1-carboximidamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Li]CCCC>>[C:16]1([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=3)[CH2:9][CH2:10]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: C=Cc1ccccc1
Agent: [Li]CCCC
Product: Cc1cccc(N2CCN(CCc3ccccc3)CC2)c1

Procedure:
According to GP, 2.22 mmol (=0.39 g) of 1-(3-methylphenyl)piperazine and 2.22 mmol (=0.23 g=0.25 ml) of styrene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetate gives the product 4-(2-phenyl-1-ethyl)-1-(3-tolyl)piperazine as a light-brown solid.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([N:14]2[C:18](=O)[C:17]([CH3:20])=[CH:16][S:15]2)[CH:10]=[CH:11][C:12]=1[Cl:13]>C(Cl)CCl>[CH3:20][C:17]1[CH2:16][S:15][N:14]([C:9]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=2)[CH:18]=1
Reactant: Cc1csn(-c2ccc(Cl)c(Cl)c2)c1=O
Solvent: ClCCCl
Solvent: O=S(=O)(Cl)Cl
Product: CC1=CN(c2ccc(Cl)c(Cl)c2)SC1
Reaction time: 8 h

Procedure:
Dithio-(3',4'-dichloro)-diisobutyranilide, 12.8 g. (0.0234 mole), was slurried in 250 ml. of ethylene dichloride, and a solution of 9.5 g. (0.0702 mole) of sulfuryl chloride in 25 ml. of ethylene dichloride was added dropwise at 25°-30° C. over one hour. The slurry was stirred overnight to insure completion of the reaction and then filtered to give 8.6 g. of gray 2-(3,4-dichlorophenyl)-4-methyl-3-isothiazolone, m.p. 160°-161° C. The product was crystallized from ethyl acetate to give a m.p. of 161°-163° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[CH2:11]2)=[CH:6][CH:5]=1.Cl[CH2:19][C:20](=O)[CH3:21]>CN(C)C=O>[CH3:21][C:20]1[C:13]2[C:12](=[O:17])[CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=3)[CH2:15][C:14]=2[O:16][CH:19]=1
Reactant: CC(=O)CCl
Reactant: O=C1CC(=O)CC(c2ccc(Br)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1ccc(Br)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
In dimethylformamide (10 ml) was suspended 60% sodium hydride (0.44 g, washed with hexane thrice), and to the suspension was added 5-(4-bromophenyl)cyclohexane-1,3-dione (2.6 g) and then was added chloroacetone (0.92 g), and the mixture was stirred at room temperature for 1 hour and then at 150° C. for 13 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from hexane to give colorless crystals of 3-methyl-6-(4-bromophenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.35 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:24][CH2:23][CH2:22][C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CCN)cc1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Solvent: O
Product: COc1ccc(CCNC(=O)C2(c3ccc(Cl)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (5.0 g, 25.3 mmol), 2-(4-methoxyphenyl)ethanamine (4.2 g, 28 mmol) and 4-N,N-Dimethylaminopyridin (3.3 g; 28 mmol) in methylenehloride (200 ml) was cooled to −10′C. N-ethyl-N′-(3-Dimethylaminopropyl)-carbodiimid hydrochloride (EDC, 5.3 g, 28 mmol) was added in several portions and the resulting mixture stirred overnight. The reaction mixture was poured into water and consecutively extracted with water, 2N NaOH and 1N HCl. Evaporation of the dried (NaSO4) extract yielded an oily residue that crystallized upon addition of n-heptan, which was used without further purification. Yield 7.0 g (21.2 mmol, 83%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[Br:12].F[C:15]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=1[CH:17]=[O:18]>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][C:15]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:16]=2[CH:17]=[O:18])[CH:8]=[CH:7][C:6]=1[Br:12]
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)Cc1cc(O)ccc1Br
Product: COC(=O)Cc1cc(Oc2ccc(C(F)(F)F)cc2C=O)ccc1Br

Procedure:
Prepared according to the procedure described in Example 9, Step 2, using the following starting materials: (2-bromo-5-hydroxy-phenyl)-acetic acid methyl ester and 2-fluoro-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][SH:5].[F:10][C:11]1[CH:16]=[C:15](F)[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=1[N:21]1[C:29](=[O:30])[C:24]2=[CH:25][CH2:26][CH2:27][CH2:28][N:23]2[C:22]1=[O:31].Cl>C(OCC)(=O)C.O1CCOCC1>[CH2:8]([O:7][C:3]([CH2:4][S:5][C:15]1[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]([N:21]2[C:29](=[O:30])[C:24]3=[CH:25][CH2:26][CH2:27][CH2:28][N:23]3[C:22]2=[O:31])=[C:11]([F:10])[CH:16]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)CS
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc([N+](=O)[O-])c(F)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CSc1cc(F)c(N2C(=O)C3=CCCCN3C2=O)cc1[N+](=O)[O-]
Yield: 29.8 %

Procedure:
Sodium hydride (1.20 g, 0.03 mol) was put in to a flask, to which 1,4-dioxane (100 mL) and ethyl thioglycolate (1.83 mL, 0.017 mol) was added with stirring under cooling in an ice-water bath after replacing the inside of flask throughly with argon gas, and the mixture was stirred for 15 minutes at the ambient temperature. Then, 2-(2,4-difluoro-5-nitrophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (4.7 g, 0.015 mol) was added to the mixture at the same temperature. The reaction mixture was wormed up to room temperature and stirred for 24 hours. 1N Hydrochloric acid (100 mL) and ethyl acetate (100 mL) were added to the resulting mixture and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 mL×2 times). The organic layer combined was washed with a saturated sodium bicarbonate (100 mL) and a saturated sodium chloride solution (100 mL), and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/1) to obtain a white solid of 2-(4-ethoxycarbonylmethylthio-2-fluoro-5-nitrophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (1.83 g, yield:29.8%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[N:14]=3)[S:10][C:9]=2[CH:31]=1)=[O:4].C1COCC1.[OH-].[Li+].[ClH:39]>CO.O>[ClH:39].[ClH:39].[ClH:39].[CH3:19][C:18]1[C:13]([C:11]2[S:10][C:9]3[CH:31]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=3[CH:12]=2)=[N:14][C:15]([NH:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)=[N:16][CH:17]=1
Reactant: COC(=O)c1ccc2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3C)sc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cnc(NCCCN2CCN(C)CC2)nc1-c1cc2ccc(C(=O)O)cc2s1
Temperature: 70 °C
Yield: 97 %

Procedure:
2-{5-Methyl-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-6-carboxylic acid methyl ester (1.31 g, 2.98 mmol) is dissolved in methanol (30 mL), THF (30 mL) and water (10 mL) and lithium hydroxide solution (4.6 mL of 2.0 M solution) is added. The solution is heated at 70° C. for 4.5 hours and 5 N HCl (9 mL) is added in one portion while still heating the solution. The solution is cooled to room temperature and the resulting solid is filtered and washed with methanol. The solid is dried at 60° C. in a vacuum oven for 4 hours to give the title compound (1.43 g, 97% yield). ES+(m/z) 426 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([O:19]CCCC)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[OH-].[Na+].C(OCC)C.CCCCCC>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][CH:27]([CH3:28])[CH3:29])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2OCC(C)C)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCN(Cc1cc(Br)ccc1OCC(C)C)c1ccc(C(=O)O)nn1
Yield: 73 %

Procedure:
Butyl 6-[N-(5-bromo-2-(2-methylpropoxy)benzyl)-N-ethylamino]pyridazine-3-carboxylate (reference example 10) (0.22 g 0.47 mmol) in THF (3 ml) and methanol (3 ml) was treated with a 1N solution of aqueous sodium hydroxide (3 ml) and left at ambient temperature for 1.5 hours (after which time TLC (1:1 diethyl ether/hexane) indicated that none of the ester remained). The reaction mixture was evaporated to low bulk, taken up in a little water and acidified with acetic acid to produce a gum. The gum did not solidify so it was extracted with ethyl acetate (×2) and the combined extracts washed with brine, dried .paren open-st.MgSO4 .paren close-st.- and evaporated to give a gum. The gum was evaporated from toluene and dichloromethane to give the title compound as a foam (140 mg 73%).
Reaction SMILES: [NH:1]([C@@H:8]([CH2:24][O:25]C(C)(C)C)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[ClH:36]>C(OCC)(=O)C.CCCCCC>[ClH:36].[ClH:36].[NH:1]([C@@H:8]([CH2:24][OH:25])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC[C@H](Nc1ccccc1)C(=O)Nc1ccc(-c2ccncc2)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(-c2ccncc2)cc1)[C@H](CO)Nc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of (2S)-2-anilino-3-tert-butoxy-N-[4-(4-pyridinyl)phenyl]propanamide (70 mg) in ethyl acetate (0.42 mL) was added 4N hydrogen chloride-ethyl acetate (1.8 mL) and the mixture was stirred at ambient temperature for 5 hours. The resulting mixture was diluted with n-hexane (2.5 mL) and the solid was collected by filtration and washed with n-hexane (2.5 mL) to give (2S)-2-anilino-3-hydroxy-N-[4-(4-pyridinyl)phenyl]propanamide dihydrochloride (72 mg) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[N:4][C:3]=1[CH3:10].[CH:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[OH:20][CH:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:10][C:3]1[C:2]([CH3:1])=[N:7][C:6]([CH3:8])=[C:5]([CH3:9])[N:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1nc(C)c(C)nc1C
Product: COc1ccc(C(O)Cc2nc(C)c(C)nc2C)cc1
Yield: 52.1 %

Procedure:
The reaction of 13.6 grams (0.1 mole) of tetramethylpyrazine with 13.6 grams (0.1 mole) of p-anisaldehyde was conducted in the manner described in Example II. Crystallization of the recovered crude product from ether yielded 14.2 grams (52%) of white crystals, m.p. 97°-98° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:28]=[C:27]([CH3:29])[C:18]([O:19][CH2:20][CH2:21]OS(C)(=O)=O)=[C:17]([CH2:30][CH3:31])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:32])[N:5]=1)[CH3:2].[NH3:35]>CO>[NH2:35][CH2:21][CH2:20][O:19][C:18]1[C:27]([CH3:29])=[CH:28][C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[C:6]([CH3:32])[N:5]=[C:4]([N:3]([CH2:33][CH3:34])[CH2:1][CH3:2])[N:9]=3)[O:14][N:13]=2)=[CH:16][C:17]=1[CH2:30][CH3:31]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OCCOS(C)(=O)=O
Reactant: N
Solvent: CO
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OCCN
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A solution of methanesulfonic acid 2-{4-[5-(2-diethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-ethyl ester (850 mg, 1.74 mmol), derived from Example 102, in 7M NH3 in MeOH (20 mL) is stirred at 60° C. for 18 h. Volatiles are then evaporated and the residue is purified by CC (eluting with EA/MeOH 10:1) to give (4-{-3-[4-(2-amino-ethoxy)-3-ethyl-5-methyl-phenyl]-[1,2,4]oxadiazol-5-yl}-6-methyl-pyrimidin-2-yl)-diethyl-amine as a yellow solid (700 mg); LC-MS: tR=0.92 min; [M+H]+=410.95.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:57])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C:40]([O:42]CC3C=CC=CC=3)=[O:41])=[O:34])[N:28]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[CH:51]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:57])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C:40]([OH:42])=[O:41])=[O:34])[N:28]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[CH:51]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)n(-c3cccc(F)c3)n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)O)n(-c3cccc(F)c3)n2)CC1
Reaction time: 24 h

Procedure:
To a solution of 2.24 g 4-((S)-2-{[5-[2-((S)-2-Benzyloxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-(3-fluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 25 ml ethyl acetate were added under argon 0.5 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 24 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was used in the subsequent reaction. Yield: 1.80 g colorless foam.
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:19])[CH2:15][CH2:16][CH:17]=[O:18].[C:22]([O:25][CH2:26][C:27]([CH2:29][Si](C)(C)C)=[CH2:28])(=[O:24])[CH3:23].ClCCl>C(N(CC)CC)C>[C:22]([O:25][CH2:26][C:27]([CH2:29][CH:17]([OH:18])[CH2:16][CH2:15][C@H:14]([C@@H:8]1[C@:9]2([CH3:13])[CH:5]([CH:4]([O:3][Si:2]([CH3:1])([CH3:20])[CH3:21])[CH2:12][CH2:11][CH2:10]2)[CH2:6][CH2:7]1)[CH3:19])=[CH2:28])(=[O:24])[CH3:23]
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Reactant: C[C@H](CCC=O)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(COC(C)=O)CC(O)CC[C@@H](C)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Temperature: -78 °C
Yield: 57 %

Procedure:
A 1.72 g amount of the compound (4-7), (4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-pentanal and 1.10 g of 2-(trimethylsilyl-methyl)-2-propenyl acetate were taken in a 200 ml eggplant-shaped flask, then 30 ml of dichloromethane was added and the solution stirred at -78° C. To this was added 0.86 ml of BF·Et2 0, then the solution stirred at -78° C. for 1 hour. Further, 3 ml of triethylamine was added to stop the reaction, then the solvent was distilled off under reduced pressure. The obtained residue was purified by a silica gel column (IR-60, 150 g, hexane/ethyl acetate=50/1 to 9/1) to obtain the desired product (4-8), (7R)-2-acetoxymethyl-7-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-octen-4-ol in an amount of 1.32 g (yield 57%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:7]([CH:8]=[O:9])=[CH:6][NH:5][N:4]=1.CC(C)([O-])C.[K+].Br[CH2:19][C:20]([NH:22][C:23]1[S:27][C:26]2[CH2:28][CH2:29][CH2:30][CH2:31][C:25]=2[C:24]=1[C:32]([NH:34][CH3:35])=[O:33])=[O:21].[NH4+].[Cl-]>C1COCC1>[CH:8]([C:7]1[C:3]([C:2]([F:1])([F:10])[F:11])=[N:4][N:5]([CH2:19][C:20]([NH:22][C:23]2[S:27][C:26]3[CH2:28][CH2:29][CH2:30][CH2:31][C:25]=3[C:24]=2[C:32]([NH:34][CH3:35])=[O:33])=[O:21])[CH:6]=1)=[O:9]
Reactant: O=Cc1c[nH]nc1C(F)(F)F
Reactant: CNC(=O)c1c(NC(=O)CBr)sc2c1CCCC2
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)c1c(NC(=O)Cn2cc(C=O)c(C(F)(F)F)n2)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
3-(Trifluoromethyl)pyrazole-4-carbaldehyde (332 mg, 2.02 mmol) was dissolved in THF (10 mL). Potassium tert-butoxide (454 mg, 4.05 mmol) was added, followed by 2-(2-bromoacetamido)-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (670 mg, 2.02 mmol). The reaction mixture was stirred at RT overnight. Aqueous NH4Cl (10 mL) was added and the reaction mixture extracted with DCM (3×10 mL). The combined DCM layers were washed with sodium bicarbonate solution (5×10 mL). The aqueous was separated using hydrophobic filter paper and the solvent removed in vacuo to give the desired product as a brown foam (0.73 g, 1.76 mmol, 87%).