Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[OH:13].[CH3:14][C:15]1([CH3:25])[O:19][C@H:18]([CH2:20]/[CH:21]=[CH:22]/[CH2:23]O)[CH2:17][O:16]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:14][C:15]1([CH3:25])[O:19][C@H:18]([CH2:20][CH:21]=[CH:22][CH2:23][O:13][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:17][O:16]1
Reactant: COc1ccc2nccc(O)c2c1
Reactant: CC1(C)OC[C@@H](C/C=C/CO)O1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2nccc(OCC=CC[C@@H]3COC(C)(C)O3)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.9 %

Procedure:
A solution of 6-methoxy-quinolin-4-ol (0.54 g, 3 mmol) and (E)-4-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-but-2-en-1-ol (prepared according to J. Am. Chem. Soc. (2001), 123, 9525; 0.53 g, 3 mmol) in THF was treated with PPh3 (977 mg, 1.2 eq.) and dropwise with DIAD (0.77 mL, 1.2 eq.). The mixture was stirred at rt for 3 days, concentrated in vacuo and purified by FC (EA) to give the product as a yellowish oil (0.73 g, 72% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]2[CH2:22][C@@H:21]([C:23]3[CH:34]=[CH:33][C:26]4[O:27][C:28]([CH3:32])([CH3:31])[O:29][CH2:30][C:25]=4[CH:24]=3)[O:20][C:19]2=[O:35])=[CH:12][CH:11]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:31][C:28]1([CH3:32])[O:27][C:26]2[CH:33]=[CH:34][C:23]([C@H:21]3[O:20][C:19](=[O:35])[N:18]([CH2:17][CH2:16][C:13]4[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]5[CH:3]=[C:2]([NH:1][C:39](=[O:41])[CH3:40])[CH:38]=[CH:37][CH:36]=5)=[CH:15][CH:14]=4)[CH2:22]3)=[CH:24][C:25]=2[CH2:30][O:29]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(N)c5)cc4)C(=O)O3)ccc2O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cccc(COCCOc2ccc(CCN3C[C@@H](c4ccc5c(c4)COC(C)(C)O5)OC3=O)cc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (5R)-3-[2-(4-{2-[(3-aminobenzyl)oxy]ethoxy}phenyl)ethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one {Example 1 xii)} (100 mg), acetic anhydride (21 μL) and N,N-diisopropylethylamine (67 μL) in DCM (2 mL) was stirred at room temperature under nitrogen for 20 h. The solution was then diluted in DCM, washed with 2M HCl, NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to give the title compound (136 mg). LCMS RT=3.24 min.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11]C(=O)C)[CH:9]=2)[CH:4]=[C:3]1[C:15]1[CH:20]=[CH:19][C:18]([O:21]C(=O)C)=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH:4]=[C:3]1[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1
Reactant: CC(=O)Oc1ccc(-c2cc3ccc(OC(C)=O)cc3n2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(-c2ccc(O)cc2)cc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.3 grams of 1-methyl-2-(4-acetoxy-phenyl)-6-acetoxy-indole was dissolved in 20 cc of methanol, treated under nitrogen with 3 ml of 2N aqueous sodium hydroxide and stirred for 2 hours at room temperature. After acidification with 2N hydrochloric acid, the mixture was extracted by shaking with methylene chloride, dried and the solvent removed in a vacuum, the product was brought to crystallization with a little methylene chloride. Yield: 0.21 grams, M.P. 200°-204° C.
Reaction SMILES: N1C=CN=C1[C:6]([C:8]1[CH:9]=[CH:10][C:11]2[O:22][C:15]3[NH:16][C:17](=[S:21])[NH:18][C:19](=[O:20])[C:14]=3[CH2:13][C:12]=2[CH:23]=1)=[O:7].[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27].Cl>CN(C)C=O>[CH2:24]([NH:28][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[O:22][C:15]3[NH:16][C:17](=[S:21])[NH:18][C:19](=[O:20])[C:14]=3[CH2:13][C:12]=2[CH:23]=1)=[O:7])[CH2:25][CH2:26][CH3:27]
Reactant: O=C(c1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2)c1ncc[nH]1
Reactant: CCCCN
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCNC(=O)c1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-(Imidazolylcarbonyl)-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione (1 g.) is suspended in dry dimethylformamide (60 ml.) and n-butylamine (1.1 g.) is added. The mixture is stirred at room temperature overnight then at 70° C. for 11/2 hours. The product is added to dilute HCl and the solid is collected, washed with water, ethanol and ether and dried to yield the desired 7-(n-butylaminocarbonyl)-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([CH2:20][CH2:21][CH2:22][OH:23])[N:9]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1.CN(C1C=CC=CN=1)C>C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([CH2:20][CH2:21][CH2:22][O:23][C:36](=[O:37])[NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH3:27])[CH:30]=2)[N:9]=1
Reactant: Cc1cccc(C=NNc2cc(N3CCOCC3)nc(CCCO)n2)c1
Reactant: COc1cccc(N=C=O)c1
Agent: CN(C)c1ccccn1
Solvent: CC#N
Product: COc1cccc(NC(=O)OCCCc2nc(NN=Cc3cccc(C)c3)cc(N3CCOCC3)n2)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
S5; 3-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yl}-propan-1-ol (355 mg, 1 mmol) was dissolved in acetonitrile (4 mL). To the mixture was added m-methoxyphenylisocyanate (149 mg., 1 mmol) and a catalytic amount of dimethylaminopyridine. The reaction was stirred at 60° C. for 16 hours. The reaction was then cooled to 4° C., and the precipitate was filtered, washed with acetonitrile (1 mL) and dried to give Compound 1, (3-methoxy-phenyl)-carbamic acid 3-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yl}-propyl ester.
Reaction SMILES: C[O:2][C:3](=[O:52])[C:4]1[CH:51]=[CH:50][C:7]([C:8]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([S:20]([C:23]4[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=4)(=[O:22])=[O:21])[CH:18]=3)[N:13]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:12]=2)=[O:9])=[CH:6][CH:5]=1.O1CCCC1.O.[OH-].[Li+]>O>[F:30][C:25]1[CH:24]=[C:23]([S:20]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:12]=[C:11]3[NH:10][C:8](=[O:9])[C:7]2[CH:50]=[CH:51][C:4]([C:3]([OH:52])=[O:2])=[CH:5][CH:6]=2)(=[O:22])=[O:21])[CH:28]=[C:27]([F:29])[CH:26]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-terephthalamic acid methyl ester (400 mg, 0.56 mmol), tetrahydrofuran (8 mL), water (4 mL) and lithium hydroxide hydrate (35 mg, 1.5 eq) was stirred at room temperature overnight. The solvents were evaporated to dryness. The residue was taken up with ethyl acetate, washed with 5% aqueous solution of potassium bisulfate, brine, dried over sodium sulfate and evaporated to dryness affording the crude title compound that was used as such for the next step without further purification.
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6](=O)[CH2:7][CH:8]([C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:13]([N+:28]([O-:30])=[O:29])[CH:12]=1)[CH3:9]>C(O)(=O)C>[CH3:9][CH:8]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:13]([N+:28]([O-:30])=[O:29])[CH:12]=2)=[N:3][NH:2][C:6](=[O:5])[CH2:7]1
Reactant: COC(=O)CC(C)C(=O)c1ccc(NC(=O)c2ccc(OC)cc2)c([N+](=O)[O-])c1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(C3=NNC(=O)CC3C)cc2[N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
20 ml of 80% hydrazine hydrate were added dropwise to 150 ml of glacial acetic acid while stirring and ice cooling. After cooling, 10.7 gm of 3-[3-nitro-4-(4-methoxybenzoylamino)-benzoyl]-butyric acid methyl ester were added and the mixture was refluxed for 40 minutes. After cooling, 250 ml of ice water were added, and the precipitate formed was suction filtered and washed with ice water.
Reaction SMILES: O.[OH-].[Li+].O.[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]1[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=1)[CH:10]=[C:9]2[C:25]([O:27]C)=[O:26].Cl>O1CCCC1>[C:25]([C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([F:5])[CH:7]=2)[N:11]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH:10]=1)([OH:27])=[O:26]
Reactant: COC(=O)c1cn(-c2ccnc3ccccc23)c2ccc(F)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccnc3ccccc23)c2ccc(F)cc12
Reaction time: 16 h

Procedure:
0.63 g (15 mmol) of lithium hydroxide monohydrate and 75 cm3 of water are added at a temperature in the region of 20° C. to 1.6 g (5 mmol) of 5-fluoro-3-methoxycarbonyl-1-(quinol-4-yl)-1H-indole dissolved in 75 cm3 of tetrahydrofuran. After stirring at the reflux point of the solvent for 16 hours, the reaction mixture is concentrated under reduced pressure (2.7 kPa) to give a residue which is taken up with 15 cm3 of N hydrochloric acid. After filtering off and drying the solid residue at atmospheric pressure at a temperature in the region of 60° C., 1.44 g of 3-carboxy-5-fluoro-1-(quinol-4-yl)-1H-indole are obtained in the form of a yellow solid melting at approximately 148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=1)[C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)=[O:6]
Reactant: NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1c(F)cccc1Cl
Product: O=C(NCC(c1ccc(F)cc1)c1ccc(C(F)(F)F)nc1)c1c(F)cccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-6-fluorobenzoic acid and 2-(4-fluorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound LCMS (MH+): m/z=441.0, tR (minutes, Method G)=2.86. [α]D20=+17.1 (c=4.44 mg/mL,CHCl3)
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:13]2)[C:8]([C:22]2[N:23]=[C:24]3[C:30]([C:31]#[N:32])=[CH:29][N:28](COCC[Si](C)(C)C)[C:25]3=[N:26][CH:27]=2)=[CH:7][N:6]=1)(=O)=O.O1CCOCC1.[CH3:47][NH:48][CH3:49].CS(C)(=O)=O>>[CH3:47][N:48]([CH3:49])[C:5]1[N:10]=[C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([S:18]([CH3:21])(=[O:19])=[O:20])[CH2:13]2)[C:8]([C:22]2[N:23]=[C:24]3[C:30]([C:31]#[N:32])=[CH:29][NH:28][C:25]3=[N:26][CH:27]=2)=[CH:7][N:6]=1
Reactant: CNC
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CN(C)c1ncc(-c2cnc3[nH]cc(C#N)c3n2)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1

Procedure:
In a dioxane 2-[2-methanesulfonyl-4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-pyrimidin-5-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonitrile derived from step 2 above, dimethylamine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to Scheme 1, step 5 to give 2-[2-dimethylamino-4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-pyrimidin-5-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carbonitrile. MS: (ES+): 442.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2)[CH3:2].C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:20][CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cccc2cccnc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1cccc2cccnc12
Temperature: 100 °C
Yield: 77.5 %

Procedure:
A solution of (12) (3.0 g, 19.1 mmol) in carbon tetrachloride (30 mL) was added NBS (5.10 g, 28.6 mmol), and benzoyl peroxide (0.12 g, 0.48 mmol). The mixture was heated at 100° C. for 3 hours. The reaction was cooled to room temperature. The mixture was filtered through filter paper, and washed with ethyl acetate. The filtrate was adsorbed into silica gel. The mixture was purified by chromatography on silica gel with 5 to 15% ethyl acetate in hexane to give 8-(1-bromoethyl)quinoline (13) (3.5 g, 14.8 mmol, 78% yield).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:12][C:11]([C:13]3[O:14][C:15]4[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:16]=4[N:17]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.C(=O)([O-])[O-].[Ca+2].[C:31](Cl)(Cl)=[S:32]>O1CCCC1.C(Cl)(Cl)Cl.[Pt]=O>[N:22]([C:19]1[CH:20]=[CH:21][C:15]2[O:14][C:13]([C:11]3[S:12][C:8]([CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)=[N:17][C:16]=2[CH:18]=1)=[C:31]=[S:32]
Reactant: S=C(Cl)Cl
Reactant: O=[N+]([O-])c1ccc2oc(-c3ccc(CN4CCOCC4)s3)nc2c1
Agent: O=[Pt]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: S=C=Nc1ccc2oc(-c3ccc(CN4CCOCC4)s3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.3 %

Procedure:
To a solution of 2-[5-(4-morpholinylmethyl)-2-thienyl]-5-nitrobenzoxazole (1.75 g, 0.005 mole) in 50 ml of tetrahydrofuran, 0.2 g of platinum oxide is added. The mixture is hydrogenated at 50 psi over a period of 3 hours. The catalyst is removed by filtration and the solvent is evaporated under vacuum yielding an oil. The oil is dissolved in 25 ml of chloroform and added slowly to the following mixture at 10°C: water 25 ml; calcium carbonate 1.2 g, 0.012 mole; thiophosgene 0.6 g, 0.005 mole; and chloroform 25 ml. The reaction mixture is then stirred overnight at room temperature. The chloroform layer is separated, dried over anhydrous magnesium sulfate and evaporated under vacuum yielding a solid. Crystallization from petroleum ether yields 0.380 g of the title compound, melting point 135°-138°C.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3([OH:25])[CH2:22][C@@H:21]([CH3:23])[O:20][C@@H:19]([CH3:24])[CH2:18]3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([C:17]3([OH:25])[CH2:22][C@@H:21]([CH3:23])[O:20][C@@H:19]([CH3:24])[CH2:18]3)=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: [H][H]
Reactant: C[C@@H]1CC(O)(c2ccc3c(c2)CN(Cc2ccccc2)C3)C[C@H](C)O1
Product: C[C@@H]1CC(O)(c2ccc3c(c2)CNC3)C[C@H](C)O1

Procedure:
Prepared in analogy to Example A62(c) from (2S,6R)-4-(2-benzyl-2,3-dihydro-1H-isoindol-5-yl)-2,6-dimethyl-tetrahydro-pyran-4-ol and hydrogen. Brown oil. MS (m/e): 248.3 ([M+H]+, 100%).
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[N:10]1([C:8](=[O:9])[CH2:7][N:1]2[CH2:2][CH2:3][N:4]([C:17]3[CH:18]=[CH:19][C:20]4[N:21]([C:23]([C:26]([F:27])([F:29])[F:28])=[N:24][N:25]=4)[N:22]=3)[CH2:5][CH2:6]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: O=C(CN1CCNCC1)N1CCCCC1
Product: O=C(CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1)N1CCCCC1

Procedure:
A mixture of 2-piperazin-1-yl-1-piperidin-1-ylethanone and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 1-piperidin-1-yl-2-[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]ethanone.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([CH:10]=[O:11])=[CH:8][NH:9][C:4]2=[CH:3][CH:2]=1.[H-].[Na+].[C:14]1([C:20]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH:28](Br)[CH3:29])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C>C1COCC1.ClCCl>[C:14]1([C:20]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][N:9]2[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]([CH:10]=[O:11])=[CH:8]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(Br)OCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1cn(CCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc12

Procedure:
To 1.01 g of indole-3-carboxyaldehyde (6.95 mmol) dissolved in 250 mL THF is added 0.28 g of sodium hydride (11 mmol). After heating the reaction to reflux for 3 hours under nitrogen, 5.0 g of 2-(2-triphenylmethoxyethoxy)ethoxy-1-bromo-ethane (11 mmol) is added. The reaction is allowed to reflux for an additional 16 hours, monitoring by TLC (9:1-ethyl acetate:dichloromethane on alumina). Upon complete consumption of the indole-3-carboxyaldehyde, the reaction is quenched via addition of 25 mL MeOH and the solvent is removed via evaporation. The residue is resuspended in 250 mL dichloromethane and washed 3×200 mL saturated NH4CO3, followed by drying over anhydrous Na2SO4. The crude product is purified via column chromatography over alumina, eluting in dichloromethane with an ethyl acetate gradient.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1[CH:24]=[CH:23][C:11]2[N:12]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:13](=O)[CH2:14][CH2:15][CH2:16][C:10]=2[CH:9]=1.[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][N:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C:10]2[CH:9]=[C:8]([NH2:7])[CH:24]=[CH:23][C:11]1=2
Reactant: CN(C)CCN1C(=O)CCCc2cc(N)ccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(C)CCN1CCCCc2cc(N)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A suspension of 1 M LiAlH4 in THF (1.82 mL, 1.82 mmol) was cooled to 0° C. then treated with 7-amino-1-(2-(dimethylamino)ethyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (225 mg, 0.91 mmol) (see experimental procedure for the synthesis of Example 25) in 10 mL THF dropwise. The suspension was stirred at room temperature overnight. After this time, the mixture was cooled to 0° C. and treated with 1 mL 1N NaOH dropwise with rapid stirring. After stirring for 20 minutes, the suspension was treated with Na2SO4. The suspension was filtered and the solid was rinsed with 50 mL 10% 2M NH3 in MeOH/CH2Cl2. The filtrate was concentrated and the dark residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2 to give a dark viscous oil (75 mg, 35.4%). 1H-NMR (CDCl3) δ 6.80-6.78 (m, 1H), 6.52-6.48 (m, 2H), 3.40 (brs, 2H), 3.21-3.17 (m, 2H), 2.87-2.83 (m, 2H), 2.70-2.66 (m, 2H), 2.47-2.43 (m, 2H), 2.27 (s, 6H), 1.72-1.64 (m, 2H), 1.59-1.55 (m, 2H). MS (EI): 234.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([OH:13])=O)[C:7](=[O:21])[CH:6]=1.[N:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[NH2:33].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C.Cl>ClCCl.C(OCC)(=O)C.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([NH:33][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][N:27]=2)=[O:13])[C:7](=[O:21])[CH:6]=1
Reactant: Nc1cnccn1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2c(F)cccc2Cl)=CC1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Nc1cnccn1)[C@H](CC1CCCCC1)N1CC(Oc2c(F)cccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.7 %

Procedure:
A solution of (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (prepared as in Example 67, 200 mg, 0.52 mmol) in dichloromethane (5 mL) was treated with pyrazin-2-ylamine (65 mg, 0.68 mmol), bromotripyrrolidinophosphonium hexafluorophosphate (503 mg, 1.1 mmol) and N,N-diisopropylethylamine (110 mg, 0.85 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 0% to 100% ethyl acetate/hexanes) to give a waxy material. This material was dissolved in dichloromethane (2 mL). The clear solution was treated with hydrogen chloride in diethyl ether (1M, 4 mL) and solvents were evaporated. The residue was triturated with diethyl ether and filtered to afford (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-pyrazin-2-yl-propionamide hydrochloride (28 mg, 33%) as a orange solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.77-1.37 (m, 6H) 1.43-1.95 (m, 7H) 4.29 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 5.00 (s, 1H) 5.02-5.12 (m, 1H) 7.36-7.57 (m, 3H) 8.38 (d, J=2.4 Hz, 1H) 8.40-8.47 (m, 1H) 9.27 (d, J=1.2 Hz, 1H) 11.20 (s, 1H). HR-ES-MS m/z calculated for C23H24ClFN4O3 459.1594, observed 459.1593 [M+H]+.
Reaction SMILES: O=[C:2]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=[C:3]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].P(Cl)(Cl)([Cl:25])=O>CN(C)C=O>[Cl:25][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1cc(C(=O)OCC)c(=O)[nH]c1C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)OCC)c(C(=O)OCC)nc1Cl
Yield: 47 %

Procedure:
A solution of triethyl 1,6-dihydro-6-oxo-2,3,5-pyridine-tricarboxylate (39.7 g) in 300 mL of phosphorous oxychloride and 0.5 mL dimethylformamide is stirred at 100° C. for four hours and 15 minutes. After cooling, the excess phosphorous oxychloride is removed under vacuum. The residue is taken up in 200 mL methylene chloride and the solution poured into 500 mL of ice water and the layers are separated. The aqueous layer, made basic with concentrated ammonium hydroxide and ice, is extracted with 150 mL methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate, filtered and concentrated under vacuum, and the resulting crude product is chromatographed on silica using 5:1 hexanes:ethyl acetate and then 4:1 hexanes:ethyl acetate as eluants affording 26.5 g (47%) of the title product as an oil.