Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:36]=[C:35]([Cl:37])[C:9]([C:10]([NH:12][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:34])[C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])=[CH:20][CH:19]=2)[C:14]([OH:16])=[O:15])=[O:11])=[C:8]([Cl:38])[CH:7]=1.O=C1CCC(=O)N1[O:46][C:47](=O)[CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][NH:62][C:63](=[O:73])[CH2:64][CH2:65][N:66]1[C:70](=[O:71])[CH:69]=[CH:68][C:67]1=[O:72].CCN(C(C)C)C(C)C>>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=1[C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C@H:13]([NH:12][C:10](=[O:11])[C:9]2[C:8]([Cl:38])=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:47](=[O:46])[CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][NH:62][C:63](=[O:73])[CH2:64][CH2:65][N:66]3[C:70](=[O:71])[CH:69]=[CH:68][C:67]3=[O:72])=[CH:36][C:35]=2[Cl:37])[C:14]([OH:16])=[O:15])=[CH:23][CH:22]=1)=[O:34]
Reactant: NCCCOc1cc(Cl)c(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)c(Cl)c1
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCOCCOCCOCCOCCNC(=O)CCN1C(=O)C=CC1=O)NCCCOc1cc(Cl)c(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)c(Cl)c1

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-[4-(3-aminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid (214 mg, 0.3 mmol), 3-[2-[2-[2-[[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]-ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (154 mg, 0.3 mmol), and DIPEA (388 mg, 522 uL, 3.0 mmol), and after HPLC purification, resulted in a white solid (52 mg, 17%). ES(+)-HRMS m/e calcd. for C44H49Cl4N5O13 (M+Na)+ 1018.1973, obsd. 1018.1965.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:18][CH2:19][CH3:20].[BrH:21].N([O-])=O.[Na+]>O1CCOCC1.O.[Cu]Br>[Br:21][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:18][CH2:19][CH3:20]
Reactant: Br
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
2-(4-Amino-3-propylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (33.2 mmol, 10 g) was dissolved in dioxane (15 mL) and water (30 mL) was added. The suspension was heated to reflux then hydrobromic acid (48% weight in water, 149 mmol, 17 mL) was added drop wise via an addition funnel over a 20 minute period. The mixture was heated for a further 20 minutes before cooling to 0° C. A solution of sodium nitrite (33.2 mmol, 2.290 g) in water (30 mL) was added to the mixture over a 30 minute period and the mixture stirred at 0° C. for 30 minutes. A solution of copper (I) bromide (38.2 mmol, 5.48 g) in water (30 mL) and hydrobromic acid (48% weight in water, 149 mmol, 17 mL) was added drop wise to the mixture over a 20 minute period at 0° C. and the mixture was allowed to stir at 0° C. for 20 minutes. The mixture was warmed to 60° C. for 20 minutes then allowed to stir at room temperature overnight. The reaction mixture was extracted with diethyl ether (3×100 mL), the organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (eluting with 10% ethyl acetate/90% heptane) to afford the title compound (6.1 g). MS (ESI) m/z 365.5 [M−H]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O[CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.CCO.Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:13]=[CH:14][N:15]([CH2:18][CH2:19][NH2:20])[N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(-c2ccn[nH]2)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(-c2ccn(CCN)n2)ccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 14.6 %

Procedure:
5-(3-methoxy-4-nitrophenyl)-1H-pyrazole (0.555 g, 2.53 mmol), tert-butyl 2-hydroxyethylcarbamate (0.449 g, 2.79 mmol) and triphenylphosphine (0.863 g, 3.29 mmol) and THF (20 ml) were mixed. DIAD (0.997 ml, 5.06 mmol) was added. The mixture was stirred for 3 h. 10% EtOH/HCl (50 ml) was added. The mixture was stirred overnight. The solvent was removed by evaporation. Water (20 ml) was added to the residue. This mixture was washed with DCM (2×20 ml). 1 M NaOH was added until pH 14 was reached followed by extraction with DCM (3×20 ml). The organic layers were pooled and evaporated to dryness. Flash chromatography (gradient of DCM:MeOH) gave 97 mg of the title compound. 1H-NMR (400 MHz; CDCl3): δ 3.19-3.26 (m, 2H), 4.04 (s, 3H), 4.20-4.28 (m, 2H), 6.63 (m, 1H), 7.38-7.43 (m, 1H), 7.52 (m. 1H), 7.59 (m, 1H), 7.91-7.97 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.[CH3:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH2:45]Br)=[N:37]1>CN(C=O)C.C1(C)C=CC=CC=1>[CH:21]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:10](=[O:11])[CH2:9][N:8]1[C:2](=[O:1])[CH:3]([CH2:45][C:38]2[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:36]([CH3:35])[N:37]=2)[C:4](=[O:34])[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:6]2[CH:27]=[CH:26][CH:25]=[CH:24][C:7]1=2)([CH3:23])[CH3:22]
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: Cn1nc(CBr)c2ccccc21
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 22.8 %

Procedure:
To a stirring solution of 330 mg (0.73 mmol) of 2-(2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 10 mL DMF at 0° C. is added dropwise over 5 min 1.75 mL (0.87 mmol, 1.1 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 10 min, then a solution of 180 mg (1.18 mmol, 1.1 equiv) of 1-methyl-3-bromomethyl-1H-indazole in 3 mL DMF is added. The resulting solution is stirred 3 h at RT and then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 2/1 as eluent followed by further purification via silica gel MPLC using a Si60 column and hexane/EtOAc 1/1 as eluent followed by lyophilization in acetonitrile/H2O afforded 100 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.74 (d, 1H, J=8.3), 7.25-6.76 (m, 16H), 4.85 (m, 1H), 4.11 (s, br, 2H), 3.97 (dd, 1H, J=5.6, 7.8), 3.77 (s, 3H), 3.70 (s, 3H), 3.63 (dd, 1H, J=7.8, 15.9), 3.48 (dd, 1H, J=5.6, 15.9), 0.92 (d, 6H, J=6.8); low resolution MS (FAB)m/e 602 (MH+), 437. Anal. (C36H35N5O4) Calcd. C, 71.86; H, 5.86; N, 11.64; Found C, 71.69; H, 5.91; N, 11.56.
Reaction SMILES: Cl[C:2]1[C:19](Cl)=[CH:18][C:17]2[C:16](=[O:21])[C:15]3[C:6](=[C:7]([OH:25])[C:8]4[C:13]([C:14]=3[OH:22])=[CH:12][C:11](Cl)=[C:10](Cl)[CH:9]=4)[C:5](=[O:26])[C:4]=2[CH:3]=1.[C:27]1([SH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[C:27]1([S:33][C:2]2[C:19]([S:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:18][C:17]3[C:16](=[O:21])[C:15]4[C:6](=[C:7]([OH:25])[C:8]5[C:13]([C:14]=4[OH:22])=[CH:12][C:11]([S:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[C:10]([S:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:9]=5)[C:5](=[O:26])[C:4]=3[CH:3]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Sc1ccccc1
Reactant: O=C1c2cc(Cl)c(Cl)cc2C(=O)c2c1c(O)c1cc(Cl)c(Cl)cc1c2O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1c2cc(Sc3ccccc3)c(Sc3ccccc3)cc2C(=O)c2c1c(O)c1cc(Sc3ccccc3)c(Sc3ccccc3)cc1c2O

Procedure:
50 g (116.8 mmol) of 2,3,8,9-tetrachloro-6,11-dihydroxynaphthacene-5,12-dione, 77.22 g (700.8 mmol) of thiophenol, 129.15 g (934 mmol) of potassium carbonate and 400 ml of dimethyl sulfoxide (DMSO) are stirred for 1 day at 100° C. The mixture is poured into a dilute aqueous solution of HCl and stirred. The red crude product is isolated by filtration, washed with water, dried at 140° C. under vacuum, then extracted three times by boiling with cyclohexanone and dried once more. Yield: 80.11 g (95%); melting point >260° C. MS: 722 (M+ ; base peak).
Reaction SMILES: Cl[CH2:2][C:3]1[N+:12]([O-:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:25][CH2:24][O:23][C:8]=3[CH:9]=2)[N:4]=1.[CH3:26][NH:27][CH3:28]>C1COCC1>[CH3:26][N:27]([CH2:2][C:3]1[N+:12]([O-:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:25][CH2:24][O:23][C:8]=3[CH:9]=2)[N:4]=1)[CH3:28]
Reactant: CNC
Reactant: [O-][n+]1c(CCl)nc2cc3c(cc2c1-c1ccc2c(c1)OCO2)OCO3
Solvent: C1CCOC1
Product: CN(C)Cc1nc2cc3c(cc2c(-c2ccc4c(c2)OCO4)[n+]1[O-])OCO3
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline-3-oxide (200 mg, 0.55 mmol), in THF (6 mL), was added dimethylamine (2M in THF 2 mL, 4 mmol). The mixture as stirred at 65° C. for 2 h. After cooling, the solvent was evaporated and the residue was purified by column chromatography on silica gel (hexane:acetone 4:1); mp 205-210° C. 1H NMR (CDCl3) 7.41 (s, 1H), 6.90-7.06 (m, 4H), 6.78 (s, 1H) 6.11 (s, 2H), 6.08 (s, 2H), 4.05 (s, 2H), 2.52 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]=2[CH:16]=1.CN(C)[C:19]1[O:20][C:21](=[O:29])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:24]=1>C(O)(=O)C>[O:20]=[C:19]1[NH:24][C:23]([C:25]([F:26])([F:27])[F:28])=[CH:22][C:21](=[O:29])[N:1]1[C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]=2[CH:16]=1
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Reactant: CCOC(=O)Cc1nsc2ccc(N)cc12
Solvent: CC(=O)O
Product: CCOC(=O)Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12

Procedure:
A mixture of ethyl 5-amino-1,2-benzisothiazole-3-acetate (0.748 g, 3.16 mmol) and 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (0.660 g, 3.17 mmol) in acetic acid is refluxed for three hours, concentrated in vacuo, and diluted with saturated sodium hydrogen carbonate solution. The resultant mixture is extracted with methylene chloride. The combined organic extracts are washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a tan solid which is identified by NMR spectral analysis.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH3:30][C:31](O)([CH:33]=[CH2:34])[CH3:32]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([O:9][C:31]([CH3:32])([CH3:30])[CH:33]=[CH2:34])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: C=CC(C)(C)O
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(C)(C)OC(=O)C#C[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Using the procedure of Step A of Example 15, 2 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[2-carboxy-ethynyl]-cyclopropane-carboxylate, 3 ml of 2-methyl-3-buten-2-ol and 150 mg of 4-dimethylamino-pyridine were admixed at 0° C. with 1.06 g of dicyclohexycarbodiimide in 3 ml of methylene chloride and the mixture was stirred at room temperature for 16 hours. The mixture was evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 9-1 cyclohexane-ethyl acetate mixture yielded 700 mg of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[2-(1,1-dimethylallyloxycarbonyl)-ethynyl]-cyclopropane-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[C:6]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=[N:7]2.C(O[CH:29](OCC)[N:30]([CH3:32])[CH3:31])C>O>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:6]2[C:5]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[N:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[N:1]=[CH:29][N:30]([CH3:32])[CH3:31])[N:7]=2)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2nc3cccc(N)c3nc2N2CCN(C)CC2)CC1
Reactant: CCOC(OCC)N(C)C
Solvent: O
Product: CN(C)C=Nc1cccc2nc(N3CCN(C)CC3)c(N3CCN(C)CC3)nc12
Temperature: 135 °C
Reaction time: 2 h

Procedure:
A 2.4 g. portion of 5-amino-2,3-bis(4-methyl-1-piperazinyl)quinoxaline prepared as in Example 3 is combined with 23.0 g. of dimethylformamide diethylacetal in a reaction flask. The suspension is heated in an oil bath at 135° C. with magnetic stirring. The solid is dissolved within four minutes and refluxing is continued for two hours. The reaction solution is cooled and stripped of solvent by water pump evacuation. The residual yellow solid is recrystallized by boiling in 200 ml. of hexane, after filtering to remove a small amount of insoluble material. The recrystallized material is collected by filtration and dried in vacuo over phosphorous pentoxide at 78° C. The above filtrate is set aside and the dried material is again recrystallized from 200 ml. of hexane in exactly the same manner as above, collected and dried to give 0.35 g. of orange solid. A yellowish-brown insoluble material removed by filtering the hot hexane prior to cooling is set aside. The final hexane cold filtrate and the initial hexane cold filtrate previously set aside are combined and the hexane is removed by water pump evacuation. The insoluble residue set aside previously is added to the combined filtrate residue and this is recrystallized from 70 ml. of hot acetonitrile by cooling at -10° C. The solid formed is collected by filtration, washed with cold acetonitrile and dried in vacuo over phosphorous pentoxide at 78° C. to give 1.6 g. of additional orange solid. The combined yield of the product of the example is 1.9 g., m.p. 183°-186° C.
Reaction SMILES: Br[CH2:2][CH:3]([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13]>CN(C)C=O>[CH3:4][CH:3]([CH3:5])[CH2:2][O:21][C:18]1[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)COc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C

Procedure:
98.66 g (0.72 mol) of 1-bromo-2-methylpropane, 74.63 g (0.54 mol) of potassium carbonate and 250 ml of dimethylformamide are added to 50 g (0.36 mol) of 4-nitrophenol. The mixture is heated to 100° C. for 4 hours and then evaporated to dryness. The residue is taken up with 500 ml of 1N sodium hydroxide solution, and 200 ml of ether are added. The organic phase is recovered and washed successively three times with 100 ml of 1N sodium hydroxide, then three times with 200 ml of water and finally with 100 ml of saturated sodium chloride solution. It is dried over magnesium sulphate and evaporated to dryness.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12]([NH:15][CH:16]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH2:17][CH2:18][CH3:19])=[N:13][CH:14]=2)=[CH:5][CH:4]=1.CO.[OH-].[Na+]>C1COCC1>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12]([NH:15][CH:16]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH2:17][CH2:18][CH3:19])=[N:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CCCC(Nc1cnc(-c2ccc(C(F)(F)F)cc2)cn1)c1ccc(C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(Nc1cnc(-c2ccc(C(F)(F)F)cc2)cn1)c1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
Part B: A round bottom flask was charged with (±)-ethyl 4-(1-((5-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)amino)butyl)benzoate (3.96 g, 8.93 mmol), MeOH (70 mL) and THF (70 mL). NaOH aq. 1M (44.6 mL) was then added in one portion and reaction stirred at room temperature for 1 hour and at 50° C. for 2 hours. Reaction mixture was cooled down to room temperature and organic solvents removed under reduced pressure. Water added to dissolve the crude solid and pH adjusted to ca. 4.5 with HCl (aq. 1N). The yellow solid formed was then recovered by filtration with a buchner funnel and dried under high vacuum to provide (±)-4-(1-((5-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)amino)butyl)benzoic acid as a yellow solid (3.23 g, 87.1%). MS (M+1): 416.3.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:21]1[N:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:21]3[N:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)(=[O:28])=[O:29])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(Cl)nc2)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(OC3CCN(c4ccc(C(F)(F)F)cc4)CC3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a stirred solution of 1-(4-(trifluoromethyl)phenyl)piperidin-4-ol (1.4 g, 5.71 mmol) in dimethylormamide (10 mL) at room temperature was added sodium hydride slowly (0.5 g, 60%, 12.4 mmol). After effervescence subsided, tert-butyl 4-(6-chloropyridine-3-sulfonamido)piperidine-1-carboxylate (1.03 g, 4.75 mmol) was added slowly. The mixture was stirred at room temperature overnight and then poured into ice-water. The residue was purified by flash chromatography (silica gel, 2% methanol in methylene chloride) to afford the title compound as a yellow solid (2.75 g, 99%). 1H-NMR (CDCl3, 300 MHz): δ 8.64 (s, 1H), 7.97 (dd, 1H), 7.47 (d, 2H), 6.98 (d, 2H), 6.79 (d, 1H), 5.37 (m, 1H), 4.91 (d, 1H), 3.93 (m, 2H), 3.63 (m, 2H), 3.29 (m, 2H), 2.861 (m, 2H), 1.97 (m, 2H), 1.78 (m, 2H), 1.43 (s, 9H), 1.41 (m, 2H); LCMS: MS (m/z): 585 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].C1COCC1.[H-].[Na+].[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:21](=[O:22])[C:20]([F:27])([F:26])[F:19])[C:10]#[N:11]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(C(=O)C(F)(F)F)c1ccc(Cl)cc1Cl
Temperature: 90 °C

Procedure:
Slurry 2,4-dichlorophenylacetonitrile (I) (5.0 g, 26.9 mmol, 186.04 g/mol) in ethyl trifluoroacetate (6.4 mL, 7.6 g, 142.08 g/mol) and add 20 mL anhydrous THF. Portionwise at ambient temperature add NaH (1.88 g, 47.1 mmol, 60% in mineral oil) over 5 minutes. Heat reaction to reflux (90° C. bath temperature) overnight. Evaporate to thick red-brown oil and partition between Et2O (100 mL) and H2O (60 mL). Separate layers and extract H2O with Et2O (2×75 mL). Acidify the aqueous layer with 1.0 N HCl to pH 1 (becomes cloudy white suspension) and extract aqueous layer with CH2Cl2 (3×100 mL). Dry pooled CH2Cl2 layers over Na2SO4, filter and concentrate to yellow oil (7.5 g, 26.5 mmol). Use without further purification. LCMS=281.9 (MH+); 279.8 (M−)
Reaction SMILES: [C:1]1(=[N:10]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:12]1([N:18]2[C:22]3([CH2:27][CH2:26]N[CH2:24][CH2:23]3)[C:21](=O)[NH:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH:1]1([N:10]2[CH2:26][CH2:27][C:22]3([N:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:19][NH:20][CH2:21]3)[CH2:23][CH2:24]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: ON=C1CCc2ccccc21
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Product: c1ccc(N2CNCC23CCN(C2CCc4ccccc42)CC3)cc1

Procedure:
The title compound, m.p.>250° C. and MS: m/e=348.4 (M+H+) was prepared in accordance with the general method of example 11 from 2,3-dihydro-1H-inden-1-one oxime and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
Reaction SMILES: [C:1]([N:9]1[CH2:26][CH2:25][C:13]2[N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[C:12]=2[CH2:11][CH2:10]1)[C:17](=[O:24])[CH2:16][CH2:15]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[C:1]([N:9]1[CH2:26][CH2:25][CH:13]2[N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[CH:12]2[CH2:11][CH2:10]1)[CH:17]([OH:24])[CH2:16][CH2:15]3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCn2c3c(c4cccc1c42)CCN(C(=O)c1ccccc1)CC3
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(c1ccccc1)N1CCC2c3cccc4c3N(CCC4O)C2CC1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
A solution of 10-benzoyl-5,6,9,10,11,12-hexahydro-4H,8H-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-4-one (1.46 g, 4.24 mmol) in ethanol (40 mL) was cooled to 0° C. under N2. Added sodium borohydride (0.32 g, 8.46 mmol) and allowed to warm slowly to room temperature. Concentrated under reduced pressure to approximately 10 mL, diluted with H2O, and extracted with CH2Cl2. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography with EtOAc/heptanes (2:1) to give 1.24 g (84%) of the title compound as a yellow foam. 1H NMR (CDCl3) δ 7.42, 7.33, 7.12-7.02, 5.10, 4.13, 4.02, 3.68, 3.21, 2.92, 2.38, 2.23, 1.80; IR (drift) 1627, 1614, 1475, 1466, 1457, 1448, 1429, 1372, 1360, 1329, 1292, 1268, 785, 747, 706 cm−1; MS (ESI) 369.1 (M++Na).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:22]=[C:9]2[N:10]=[C:11]([NH:15][CH2:16][CH:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:25]=1[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:25]=1[CH2:26][N:18]1[CH2:19][CH2:20][CH2:21][CH:17]1[CH2:16][NH:15][C:11]1[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:22]=[C:9]2[N:10]=1
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: Nc1nc(NCC2CCCN2)nc2nc(-c3ccco3)nn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1nc(NCC2CCCN2Cc2c(Cl)cccc2Cl)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Furan-2-yl-N5-pyrrolidin-2-ylmethyl-[1,2,4]-triazolo[1,5-a][1,3,5]triazine-5,7-diamine (0.15 mmol) was dissolved in 4 mL of CH2Cl2 along with 2 eq. of 2,6-dichlorobenzaldehyde and 25 mL of glacial acetic acid. The reaction mixture was stirred at room temperature for 30 minutes and sodium triacetoxyborohydride (4 eq.) was added in a single portion. The resulting reaction mixture was then stirred at room temperature for 18 hours. It was then concentrated under a stream of N2 and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 6.95-7.0 (m, 3H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 2.2-3.2 (m, 8H). MS: m/z: 460[M+H]+.