Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OCCCC)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:34]=[C:33](N)[CH:32]=[N:31][C:18]=3[N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]=3)[N:20]=2)=[CH:11][CH:10]=1>C1COCC1>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]3[CH:34]=[CH:33][CH:32]=[N:31][C:18]=3[N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[N:22]=3)[N:20]=2)=[CH:13][CH:14]=1
Reactant: Nc1cnc2c(c1)OC(c1ccc(F)cc1)=NN2c1cccc(C(F)(F)F)n1
Agent: CCCCON=O
Solvent: C1CCOC1
Product: Fc1ccc(C2=NN(c3cccc(C(F)(F)F)n3)c3ncccc3O2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 128.4 %

Procedure:
To a stirred solution of butyl nitrite (0.69 g, 6.66 mol) in THF (15 mL) at reflux under N2 was added a solution of the title compound of Step C (1.30 g, 3.33 mmol) in THF (15 mL) dropwise over 5 min. The dark brown solution was allowed to reflux 2 h. When TLC analysis was inconclusive, additional butyl nitrite (0.35 g, 3.33 mmol) was added. After 1 h, the solution was allowed to cool to room temperature and concentrated in vacuo to give a purple solid (1.6 g). Purification by flash chromatography eluting with 20-30% ethyl acetate/hexanes afforded the title compound of Step D, a compound of the invention, as a brown solid (0.45 g) melting at 67°-72° C. 1H NMR (CDCl3, 300 MHz) δ7.80-8.00 (m,5H), 7.46 (dd, 1H), 7.08-7.16 (m,3H), 6.88 (dd, 1H).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[C:16](I)=[CH:15][C:14]([S:18][CH3:19])=[CH:13][N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)#[CH:21].O>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:11]3=[N:12][CH:13]=[C:14]([S:18][CH3:19])[CH:15]=[C:16]3[CH:21]=[C:20]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1cnc(NS(=O)(=O)c2ccccc2)c(I)c1
Reactant: C#Cc1ccccn1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1cnc2c(c1)cc(-c1ccccn1)n2S(=O)(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A suspension of the compound obtained in Example 5 (1) (100 mg), 2-ethynylpyridine (30.4 mg), bis(triphenylphosphine) palladium(II) dichloride (17.3 mg) and cuprous iodide (4.7 mg) in triethylamine (2.5 ml) was stirred in a sealed tube at 100° C. for 1 hour. After completion of the reaction, the reaction suspension was poured into water, extracted with methylene chloride, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) to obtain 71.9 mg of the desired product as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[C:12]1([CH:18]([NH2:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CN1C(=O)CCC1>CO.O>[CH3:11][C:8]1[N:6]2[N:7]=[C:2]([NH:20][CH:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:19])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: CC(N)c1ccccc1
Reactant: Cc1nnc2ccc(Cl)nn12
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1nnc2ccc(NC(C)c3ccccc3)nn12
Temperature: 150 °C
Reaction time: 0.75 h

Procedure:
6-Chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine (200 mg, 1.186 mmol; commercially available or prepared according to patent WO2006/039325A2), rac-1-phenylethanamine (575 mg, 4.75 mmol; commercially available from Aldrich) and anhydrous NMP (1 mL) were charged into a microwave tube equipped with a magnetic stirbar (light brown solution). After the vessel was sealed, the mixture was heated at 150° C. for 15 min, followed by an extra 45 min using microwave irradiation. The reaction was then diluted with MeOH/H2O (19:1), filtered, purified by reverse phase chromatography and lyophilized to give the rac-3-methyl-N-(1-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (Compound 1) as a white solid (42 mg; 14% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.84 (d, J=9.8 Hz, 1H), 7.81 (d, J=7.1 Hz, 1H), 7.42 (d, J=7.8 Hz, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 6.80 (d, J=9.8 Hz, 1H), 4.92 (dd, J=7.0, 7.0 Hz, 1H), 2.42 (s, 3H), 1.49 (d, J=6.9 Hz, 3H). LRMS [M+H]+: 254 m/z.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[C:25]([CH:30]([CH3:32])[CH3:31])[CH:24]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:29][C:26]1[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][C:25]=1[CH:30]([CH3:32])[CH3:31]
Reactant: Cc1ccc(S)c(C(C)C)c1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1ccc(SC2=C(O)CC(c3ccccc3)(c3ccccc3)OC2=O)c(C(C)C)c1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 2.1 mmol of 4-methyl-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 185°-186° C.). 1H NMR (DMSO-d6) δ 1.17 (d, J=10 Hz, 6 H), 2.15 (s, 3 H), 3.17 (m, 1 H), 3.76 (bs, 2 H), 5.56 (d, 1 H), 6.29 (d, 1 H), 6.94 (s, 1 H), 7.32 -7.47 (m, 10 H).
Reaction SMILES: [F:1][C:2]1[C:16]([F:17])=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])=[C:4]([O:18]C)[CH:3]=1.[Cl-].[Li+]>CN(C=O)C>[F:1][C:2]1[C:16]([F:17])=[CH:15][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([OH:18])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1OCC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(O)COc1cc(F)c(F)cc1O
Temperature: 150 °C

Procedure:
A mixture of the product from step (ii) (0.75 g) and lithium chloride (0.345 g) in DMF (20 ml) was heated at 150° C. for 6 h, cooled and partitioned between ethylacetate/2M hydrochloric acid. The organics were dried and evaporated under reduced pressure, yield 0.7 g.
Reaction SMILES: C([O:3][C:4]([CH:6]([CH3:17])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])=[O:5])C>[OH-].[Na+].CO>[C:4]([CH:6]([CH3:17])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 6 h

Procedure:
1-(2-Ethoxycarbonylpropanoyl)-L-proline (4.1 g.) is dissolved in a mixture of N sodium hydroxide (51 ml.) and methanol (51 ml.). The solution is kept at room temperature for 6 hours and then concentrated to half volume in vacuo. Ion exchange resin (Dowex 50) (50 ml.) is added and the suspension applied to a column of 150 ml. of the same resin. The fractions containing the desired material (carboxyl reagent positive) are pooled and freeze dried to obtain to obtain 1-(2-carboxypropanoyl)-L-proline, yield 1.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O-:11])=[O:10].O.[C@:22]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[C:9]([O:11][CH3:22])=[O:10]
Reactant: O=C([O-])C(c1ccccc1Cl)N1CCc2sccc2C1
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: -2.5 °C
Reaction time: 0.17 h

Procedure:
2 g (0.0173 mole) Methyl (2-chlorophenyl(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate (where ee was 95%) was dissolved in 10 ml acetone and the reaction mixture was stirred for 10 min, followed by reflux. To the reaction mixture, 1.49 g (1S)-(+)-camphor-10-sulfonic acid hydrate in 0.8 mL water was added followed by 1 mL acetone. Then whole reaction mixture was refluxed for 1 hrs and cooled gradually. This was later stirred overnight at room temperature. The clear solution was cooled further at 0 to −5° C., wherein precipitate was obtained. The salt formed was added to ethyl acetate and water, which was later basified with NaHCO3, the organic layer was washed with water, concentrated under reduced pressure, to give free base 0.386 g with chiral purity=99.85% (+)-isomer (ee=99.7%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:29])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].Br[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][OH:21])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:29][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cn(CCO[Si](C)(C)C(C)(C)C)nn3)cc2[C@H](N)C[C@@H]1C
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3cn(CCO)nn3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,4R)-1-acetyl-6-[1-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see intermediate 44) (100 mg, 0.233 mmol) and 2-bromo pyridine (110 mg, 0.698 mmol) in toluene (2.5 mL) were successively added sodium tert-butoxide (224 mg, 2.328 mmol), tris(dibenzylideneacetone)dipalladium(0) (213 mg, 0.233 mmol) and 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (DavePhos) (183 mg, 0.466 mmol). The resulting mixture was stirred at 100° C. for 2 h then cooled to room temperature and filtered through Celite. The insoluble material was washed with 5% MeOH in DCM and the combined filtrate and washings were concentrated in vacuo. The residue was dissolved in a 1:1 MeOH/DMSO mixture and purified via MDAP (modifier: formic acid). The appropriate fractions were combined and concentrated using a blow down apparatus (45° C.) to give 2-{4-[(2S,4R)-1-acetyl-2-methyl-4-(2-pyridinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-1,2,3-triazol-1-yl}ethanol as a colourless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[N+:31]([O-])=O)[CH2:20][CH2:19]3)=[O:17])=[CH:10][CH:9]=2)[CH2:4]1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>[Pd].C(O)(=O)C>[CH3:1][N:2]([CH3:34])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[NH:31][C:35](=[O:37])[CH3:36])[CH2:20][CH2:19]3)=[O:17])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2ccc(CNC(=O)C3CCN(c4ccc(Cl)cc4[N+](=O)[O-])CC3)cc2)C1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Cl)ccc1N1CCC(C(=O)NCc2ccc(N3CCC(N(C)C)C3)cc2)CC1
Reaction time: 1 h

Procedure:
Palladium on carbon (10%; 10 mg) was added to a solution of 1-(4-chloro-2-nitro-phenyl)piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]methylamide (50 mg) in glacial acetic acid (5 ml). The solution was stirred under a hydrogen atmosphere (1 bar), and acetic anhydride (14 μl) was added. After one hour, further acetic anhydride (6 μl) were added and the mixture was stirred for 15 minutes. The suspension was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (7N in methanol)). This resulted in the product with the molecular weight of 498.07 (C27H36CIN5O2); MS (ESI): 498 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:25][CH2:24][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][CH3:23])[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:26])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[K+].[K+].Br[C:57]1[C:66]([F:67])=[C:65]2[C:60]([CH:61]=[CH:62][CH:63]=[N:64]2)=[CH:59][CH:58]=1>O1CCOCC1.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:22]([N:17]1[CH2:16][C:15]2([CH2:24][CH2:25][N:12]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:57]4[C:66]([F:67])=[C:65]5[C:60]([CH:61]=[CH:62][CH:63]=[N:64]5)=[CH:59][CH:58]=4)=[CH:3][C:4]=3[F:26])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]2)[O:20][CH2:19][C:18]1=[O:21])[CH3:23]
Reactant: Fc1c(Br)ccc2cccnc12
Reactant: CCN1CC2(CCN(C(C(N)=O)c3ccc(Br)cc3F)CC2)OCC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN1CC2(CCN(C(C(N)=O)c3ccc(-c4ccc5cccnc5c4F)cc3F)CC2)OCC1=O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A 20 mL reaction vial equipped with a stirbar was charged with 2-(4-bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (0.150 g, 0.350 mmol), bis(pinacolato)diboron (0.205 g, 0.806 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.020 g, 0.025 mmol), and potassium acetate (0.076 g, 0.770 mmol). The solids were diluted with 1,4-dioxane (3.12 mL) and the reaction mixture was warmed to 90° C. with stirring overnight. The reaction mixture was then treated with PdCl2(dppf)-CH2Cl2 adduct (0.020 g, 0.025 mmol), 2M aq potassium carbonate (0.385 mL, 0.770 mmol), and 7-bromo-8-fluoroquinoline (0.091 g, 0.403 mmol), and the resulting reaction mixture was stirred at 90° C. for 1 h. The mixture was then diluted with 20 mL dichloromethane and filtered through a stacked pad of sodium sulfate over celite. The filtrate was concentrated to a residue, which was purified by silica gel flash chromatography (0.5-10% methanol:ethyl acetate). Fractions containing the desired material were pooled and concentrated to a hard lacquer and the product was resolved by chiral preparative HPLC (Chromegachiral CC4, 100% methanol) to afford the title compound in >99% ee as an off white solid (42 mg, 0.081 mmol, 23% yield). MS(ES)+ m/e 495.4 [M+H]+. αD=+40 deg (c=0.06, methanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[CH3:15][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO.O1CCCC1.ClCCl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([O:13][CH3:15])=[O:12])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(N)cc1
Reaction time: 22 h

Procedure:
To a stirred, partial solution of 4-(4-amino-phenyl)-4-oxo-butyric acid (6.96 g, 0.0360 mol) in toluene (240 mL) and methanol (240 mL) at room temperature under nitrogen was added dropwise over 30 minutes a 2.0 M solution of trimethylsilyldiazomethane in hexanes (18 mL, 0.036 mol), and the mixture was stirred for 22 hours. Additional 2.0 M solution of trimethylsilyldiazomethane in hexanes (12 mL, 0.024 mol) was added dropwise, and the mixture was stirred overnight. Additional 2.0 M solution of trimethylsilyldiazomethane in hexanes (19 mL, 0.038 mol) was added dropwise, and the mixture was stirred overnight. After a total of 3 days, the mixture was rotary evaporated, and the residue was suspended in tetrahydrofuran (200 mL) and dichloromethane (100 mL). The mixture was washed with 0.1 M aqueous sodium hydroxide, water, brine, and dried (Na2SO4). The solution was rotary evaporated to give a solid, which was crystallized from chloroform to give 5.13 g of 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester as a tan solid; mp 160-162° C.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[CH2:9]([CH:11]([CH2:17][CH3:18])[C:12](OCC)=[O:13])[CH3:10].Cl>C1COCC1>[CH2:9]([CH:11]([CH2:17][CH3:18])[C:12](=[O:13])[CH2:7][C:6]#[N:8])[CH3:10]
Reactant: CCOC(=O)C(CC)CC
Reactant: CC#N
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)C(=O)CC#N
Temperature: -45 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of n-butyllithium (56.6 ml, 1.6M solution in hexane, 90.6 mmol) in THF (60 ml) was added a solution of acetonitrile (3.71 g, 4.73 ml, 90.5 mmol) in THF (12 ml) slowly at a temperature between −78° C. and −70° C. Then a solution of ethyl 2-ethylbutanoate (6.52 g, 7.5 ml, 45.2 mmol) in THF (17 ml) was added and the reaction mixture was stirred for 1 h at −78° C. and for 1.5 h at −45° C. Then cold 2M HCl was added carefully to adjust the pH to 7. The mixture was extracted with DCM and the combined extracts were dried with MgSO4 and evaporated. The crude material was purified by chromatography (silica gel, heptane/EtOAc 9:1) to afford the title compound (6.29 g, 100%) as light yellow oil. MS (ESI): 138.3 (M−H)−.
Reaction SMILES: BrC1C=C(F)C=CC=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].NC1C(C(OC)=O)=C2C(C3CC3CO2)=CC=1.[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1S(Cl)(=O)=O>>[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:10])=[O:11]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCC1CC21
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: COC(=O)c1c(N)ccc2c1OCC1CC21
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 41, starting from methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42) and 2-fluorobenzenesulfonyl chloride.
Reaction SMILES: [CH:1]1([C:4]2[C:8]([C:9]([OH:11])=O)=[CH:7][O:6][N:5]=2)[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C)C=O.ClCCl>[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:9]([C:8]2[C:4]([CH:1]3[CH2:2][CH2:3]3)=[N:5][O:6][CH:7]=2)=[O:11])[CH:17]=1
Reactant: Nc1cccnc1
Reactant: O=C(O)c1conc1C1CC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(Nc1cccnc1)c1conc1C1CC1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
400 mg (2.6 mmol) of 3-cyclopropyl-isoxazole-4-carboxylic acid were suspended in 10 mL of toluene and one drop of dimethylformamide was added to the mixture. 0.24 mL of thionylchloride (3.3 mmol) were added at room temperature and the reaction mixture was stirred at 65° C. for two hours. After removal of the solvent, toluene was added and the evaporation was repeated. The obtained residue was then dissolved in 5 mL of dichloromethane and the solution was added dropwise to a solution containing 246 mg pyridin-3-ylamine (2.6 mmol) and 0.45 ml triethyl amine (3.3 mmol) in 5 ml dichloromethane. The mixture was stirred at room temperature for 16 h and the solvent was removed under vacuum. The residue was purified by flash column chromatography (silica, gradient elution cyclohexane→ethyl acetate→methanol) and the solvent was removed under vacuum to give 436 mg (69%, 95% purity) of the title compound as a brown solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:28][C:29]([NH:31][CH3:32])=[O:30]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:28][C:29]([NH:31][CH3:32])=[O:30])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CNC(=O)CCl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CNC(=O)CN1CCn2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2-chloro-N-methylacetamide, to give the desired product in a yield of 68%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].F.C(F)([F:18])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([F:18])=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(F)F
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: F
Product: O=C(F)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 24 °C
Reaction time: 96 h

Procedure:
4-Chloro-3-(trifluoromethyl)phenyl carbamic fluoride was prepared in situ by the reaction of 221 parts of 4-chloro-3-(trifluoromethyl)isocyanatobenzene and 450 parts of hydrogen fluoride added over a period of 15-20 minutes at about 4° C. The reaction mixture was then sealed in a polytetrafluoroethylene reactor, heated to about 24° C. and maintained thereat, with agitation, for about 96 hours. The reactor was then opened to atmospheric pressure and most of the hydrogen fluoride and carbonyl fluoride gases removed. Analysis of the remaining organic product by gas chromatographic techniques, using n-heptadecane as an internal standard indicated a yield of 77 parts of 4-chloro-3-(trifluoromethyl)benzenamine.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].B(F)(F)F.[Cl:16][CH2:17][C:18]([CH3:22])(O)[CH:19]=[CH2:20]>ClC1C=CC=CC=1.CCCCCC.C(OCC)C>[Cl:16][CH2:17][C:18]([CH3:22])=[CH:19][CH2:20][C:8]1[C:2]([CH3:1])=[C:3]([OH:11])[C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[OH:7]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCl
Agent: FB(F)F
Solvent: CCCCCC
Solvent: CCOCC
Solvent: Clc1ccccc1
Product: CC(=CCc1c(C)c(O)c(C)c(C)c1O)CCl
Reaction time: 0.5 h
Yield: 44 %

Procedure:
Trimethylhydroquinone (2.00 g, 14 mol) was suspended at room temperature in a mixture of chlorobenzene (10 ml) and hexane (5 ml). Boron trifluoride diethyl ether complex (3.60 ml of a 48 percent strength solution of boron trifluoride in diethyl ether, 1.95 g of boron trifluoride, 28 mmol) was then added in the course of 15 min. 1-Chloro-2-methylbut-3-en-2-ol (2.42 g, 20 mmol) was then added dropwise in the course of 15 min. After 30 min.,, the reaction mixture was filtered, and the filtrate was washed with chlorobenzene (10 mol) and dried at 40° C./20 mbar for 8 hours. 2.24 g (62.9 percent) of 2-(1-chloro-2-methylbut-2-en-4-yl)-1,4-dihydroxy-3,5,6-trimethylbenzene were obtained. The melting point of the product was 118° to 122° C. (decomposition). Other data regarding the product was:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=O)=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:7]([O:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][NH2:28])=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(N)=O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.5 %

Procedure:
To a room temperature mixture of 3.64 g of lithium aluminum hydride in 300 ml of dry tetrahydrofuran is added a hot solution of 15.98 g of product from Example 98 in 150 ml of tetrahydrofuran. The reaction is stirred at room temperature for 20 hours, refluxed for 8 hours and stirred at room temperature for 50 hours. The reaction is treated with saturated sodium sulfate, filtered and concentrated to give 14.77 g of the desired product as colorless crystals.