Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CN1CCN([C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][N:11]=2)CC1.Cl[C:18]1[C:23]([CH2:24][CH2:25]Cl)=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[N:21]=[C:20]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:19]=1>O1CCCC1>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([C:22]2[C:23]3[CH2:24][CH2:25][N:16]([C:14]4[CH:13]=[CH:12][N:11]=[C:10]([O:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:20])[CH:15]=4)[C:18]=3[N:19]=[C:20]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:21]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Reactant: CN1CCN(c2cc(N)ccn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccnc(OCCN(C)C)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 320.2 %

Procedure:
Sodium hydride (108 mg, 60% mineral oil dispersion, 2.72 mmol) was placed in a dried flask under a nitrogen atmosphere, followed by sequential addition of anhydrous tetrahydrofuran (10 ml) and 2-(4-methylpiperazin-1-yl)pyridin-4-ylamine (62 mg, 0.32 mmol) with a syringe. After the resulting mixture was stirred at room temperature for 2 hours, 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]morpholine (100 mg, 0.27 mmol) was added, followed by heating to reflux for 4 hours. The reaction mixture was cooled, which was subsequently added dropwise slowly onto ice water, followed by extraction twice with ethyl acetate (10 ml). The organic layer was washed with brine (10 ml), and dried over sodium sulfate, followed by distilling off under reduced pressure, to obtain a crude product as a red oil (206 mg).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][CH2:22][CH2:23][C:24]([O:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)=[O:25]>>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)=[O:25])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCC(OC(=O)CCN)CC1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Agent: Cl
Product: CN1CCC(OC(=O)CCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)CC1

Procedure:
The title compound was prepared from 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1-methylpiperidin-4-yl β-alaninate hydrochloride in a similar manner as described for Example 164. Mass Spectrum: [M+H]+ 450.12, [M−H]− 448.23.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:36])[CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](C3N(C)C=CN=3)[S:17][C:10]=12.FC1C=C(N)C=CC=1OC1C=CN=C2C=C([C:54]3[N:58]([CH3:59])[CH:57]=[N:56][CH:55]=3)SC=12>>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:36])[CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:54]3[N:58]([CH3:59])[CH:57]=[N:56][CH:55]=3)[S:17][C:10]=12
Reactant: Cn1cncc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccccc4)cc3F)c2s1
Product: Cn1cncc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccccc4)cc3F)c2s1
Yield: 5 %

Procedure:
Following the procedure described for compound 5b (example 2, step 6) but substituting amine 9 for compound 18, title compound 5e was obtained in 5% yield. MS (m/z): 502.0 (M+H).
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)CO.[C:38]([C@H:42]1[CH2:47][CH2:46][C@H:45]([O:48][C:49]2[C:50]([C:66]3[CH:67]=[N:68][CH:69]=[N:70][CH:71]=3)=[C:51]3[C:56](=[CH:57][CH:58]=2)[CH:55]=[C:54]([C@:59]2([CH3:65])[CH2:63][O:62]C(=O)[NH:60]2)[CH:53]=[CH:52]3)[CH2:44][CH2:43]1)([CH3:41])([CH3:40])[CH3:39]>>[NH2:60][C@@:59]([C:54]1[CH:53]=[CH:52][C:51]2[C:56](=[CH:57][CH:58]=[C:49]([O:48][C@H:45]3[CH2:44][CH2:43][C@H:42]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:47][CH2:46]3)[C:50]=2[C:66]2[CH:67]=[N:68][CH:69]=[N:70][CH:71]=2)[CH:55]=1)([CH3:65])[CH2:63][OH:62]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2cncnc2)CC1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2cncnc2)CC1

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(pyrimidin-5-yl)naphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol (Example 221) in 48% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(pyrimidin-5-yl)naphthalen-2-yl)-4-methyloxazolidin-2-one as starting material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([OH:16])=O)[CH2:7][CH2:6]2.[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1.C1(CC(O)=O)C2C(=CC=CC=2)CC1>>[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:14](=[O:16])[CH2:13][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: COc1ccc2c(c1)CCC(CC(=O)O)C2
Agent: O=C(O)CC1CCc2ccccc21
Product: COC(=O)[C@@H]1CCCN1C(=O)CC1CCc2cc(OC)ccc2C1
Yield: 79 %

Procedure:
1-(6-methoxy-1,2,3,4 tetrahydronaphthalen-2-ylacetyl)-L-proline methyl ester was prepared as an oily substance in the same manner as Reference Example 1, except that 6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and L-proline methyl ester were used instead of 2-indanylacetic acid and L-thioproline ethyl este respectively (yield: 79%).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:12].Br[CH:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17].[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[C:7]2=[O:12]
Reactant: CCCC(Br)CCC
Reactant: O=c1[nH]ccc2c(I)cccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCC(CCC)n1ccc2c(I)cccc2c1=O
Yield: 117.5 %

Procedure:
0.2 g of 5-iodo-2H-isoquinolin-1-one, 234 mg of 4-bromoheptane, 62 mg of finely ground potassium hydroxide, 79 mg of tetrabutylammonium bromide then 28 cm3 of toluene are stirred, under an inert atmosphere, for 6 h at the reflux of the solvent. The reaction mixture is filtered through sintered glass. The filtrate is concentrated using a rotary evaporator under reduced pressure (5 kPa). The 320 mg of brown oil obtained are purified by flash chromatography over silica (column: 35 g; particle size: 20-40 μm, spherical; eluent: 80% heptane/20% ethyl acetate). After concentrating the fractions under reduced pressure, 165 mg of 5-iodo-2-(1-propylbutyl)isoquinolin-1(2H)-one are obtained in the form of a yellow solid.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[C:6](Br)=[CH:5]1)[CH:2]=[CH2:3].[Li]CCCC.[F:20][C:21]([F:41])([F:40])[C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[N:28]=[CH:27]2)=[O:23]>C1COCC1.O.[Cl-].[Na+].O>[CH2:1]([N:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[C:6]([C:22]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[N:28]=[CH:27]3)([OH:23])[C:21]([F:40])([F:20])[F:41])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cc(Br)c2ncnc(Cl)c21
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 23.2 %

Procedure:
To a chilled (−78° C.) solution of 5-allyl-7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (570 mg, 2.1 mmol) in 10 mL of THF was added n-BuLi (2.5 M in THF, 1.5 mL, 2.5 mmol) dropwise. After 5 minutes, a chilled (−78° C.) solution of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (708 mg, 2.3 mmol) in 3 mL of THF was added in one portion. After 15 minutes, the mixture was diluted with water and warmed to room temperature, diluted with brine, and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using EtOAc-hexanes (15-60% gradient) to provide 245 mg (23%) of the title compound as a beige solid. MS m/z 502.23 (MH+).
Reaction SMILES: COC(=O)CC1C(=O)NC(CC2C=CC=CC=2)C(=O)N1.[CH:21]([NH:23][C@@H:24]1[C:29](=[O:30])[O:28][C:26](=[O:27])[CH2:25]1)=[O:22].[NH2:31][C@H:32]([C:40]([OH:42])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([OH:42])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30])[CH2:25][C:26](=[O:27])[OH:28])=[O:22]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=CN[C@H]1CC(=O)OC1=O
Agent: COC(=O)CC1NC(=O)C(Cc2ccccc2)NC1=O
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
5-benzyl-3,6-dioxo-2-piperazine acetic acid methyl ester can be prepared by condensating N-formyl-L-aspartic acid anhydride with L-phenylalanine to form N-formyl-α-L-aspartyl-L-phenylalanine, de-formylating and diesterifying the N-formyl-α-L-aspartyl-L-phenylalanine in methanol in the presence of an acid to produce α-L-aspartyl-L-phenylalanine dimethyl ester, and treating said diester, for example, in a mixed solvent of water and methanol under neutral or weakly alkaline conditions;
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[N:5][C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[N:3]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31].[OH-].[Li+].Cl>C1COCC1.O.O>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[N:5][C:6]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[N:3]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)CCCCCCN1c2nc(-c3ccccc3)c(-c3ccccc3)cc2CCC1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1CCc2cc(-c3ccccc3)c(-c3ccccc3)nc2N1CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Enantiomer 2 of Ethyl 7-(2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)heptanoate (37 mg, 0.081 mmol) was dissolved in THF/water (1 ml/2:1) and lithium hydroxide (9.70 mg, 0.405 mmol) was added. The mixture was stirred at room temperature for 4 days and then diluted with water (25 ml). The pH was adjusted to pH 5-6 using 1M HCl. The aqueous portion was extracted with EtOAc (2×20 ml) and the combined organics extracts were washed with brine, dried over MgSO4, filtered and evaporated to afford Enantiomer 1 of 7-(2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)heptanoic acid;
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl>O1CCOCC1.O.C(Cl)Cl>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 4-{[4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate in 1,4-dioxane (100 ml) was added 4M HCl in 1,4-dioxane (50 ml, 200 mmol) and 3 drops of distilled water. The reaction mixture was stirred overnight and then reduced to dryness in vacuo. The residue was dissolved in DCM (200 ml) and washed with 2M aq. NaOH (50 ml), twice. The organic layer was dried over dried magnesium sulphate, the insolubles removed by filtration, and filtrate reduced to dryness in vacuo to yield the title compound (6.60 g) as a pale yellow solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.S(N=[N+]=[N-])(C(F)(F)F)(=O)=O.Cl.N[CH:32]([CH2:37][S:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:33]([O:35][CH3:36])=[O:34]>O.CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:1]([CH:32]([CH2:37][S:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:33]([O:35][CH3:36])=[O:34])=[N+:2]=[N-:3]
Reactant: COC(=O)C(N)CSCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(CSCc1ccccc1)N=[N+]=[N-]
Yield: 75 %

Procedure:
Following a method described by Aubé and coworkers [S. K. Ramanathan, J. Keeler, H.-L. Lee, D. S. Reddy, G. Lushington, J. Aubé, Org. Lett. 2005, 7, 1059-1062], a solution of NaN3 (0.88 g, 13.7 mmol) in H2O (2.5 mL) was cooled to 0° C. and CH2Cl2 (4 mL) was added. Whilst the mixture was stirring vigorously, Tf2O (CF3SO2OSO2CF3, 0.47 mL, 2.26 mmol) was added dropwise. The resulting solution was stirred for an additional 2 h. The mixture was then placed in a separating funnel, and the organic layer was removed. The aqueous phase was extracted further with CH2Cl2 (2×3 mL). The organic layers were combined, washed with saturated Na2CO3, dried over Na2SO4(s), and filtered. The resulting solution of TfN3 was added dropwise to a solution of methyl 2-amino-3-(benzylsulfanyl)propanoate hydrochloride salt (0.37 g, 1.40 mmol) and DMAP (0.75 g, 6.16 mmol) in CH2Cl2 (5 mL). The resulting solution was stirred overnight under Ar(g). The mixture was concentrated under reduced pressure and purified by silica gel flash chromatography, eluting with CH2Cl2, to give azide 2e as an oil (0.26 g, 1.05 mmol, 75% yield).
Reaction SMILES: [NH2:1]/[C:2](=[N:30]\[S:31]([C:34]1[C:35]([CH3:47])=[C:36]([CH3:46])[C:37]2[O:41][C:40]([CH3:43])([CH3:42])[CH2:39][C:38]=2[C:44]=1[CH3:45])(=[O:33])=[O:32])/[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([NH:16][S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])[C:8](=[O:15])[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.Cl[C:58]([O:60][CH2:61][CH3:62])=[O:59]>C(Cl)(Cl)Cl>[CH2:61]([O:60][C:58]([N:12]1[CH2:11][CH2:10][N:9]([C:8](=[O:15])[C@@H:7]([NH:16][S:17]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)(=[O:19])=[O:18])[CH2:6][CH2:5][CH2:4][NH:3]/[C:2](/[NH2:1])=[N:30]/[S:31]([C:34]2[C:35]([CH3:47])=[C:36]([CH3:46])[C:37]3[O:41][C:40]([CH3:43])([CH3:42])[CH2:39][C:38]=3[C:44]=2[CH3:45])(=[O:33])=[O:32])[CH2:14][CH2:13]1)=[O:59])[CH3:62]
Reactant: CCOC(=O)Cl
Reactant: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCNCC2)c(C)c2c1OC(C)(C)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCCN/C(N)=N/S(=O)(=O)c2c(C)c(C)c3c(c2C)CC(C)(C)O3)NS(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of compound D (8.0 g, 11.1 mmol) in CHCl3 (50 ml) was added DIEA (4.1 mL, 23.3 mmol) at room temperature and stirred for 15 min. The mixture was cooled to ˜5° C., ethyl chloroformate (1.06 mL, 11.1 mmol) was added drop wise. After stirring at room temperature overnight (˜18 h), solvent removed in vacuo. The residue was dissolved in MeOH (˜25 ml) and Et2O (˜500 mL) was added. The precipitated crude product was filtered off, washed with Et2O and dried under vacuo to afford compound E (8.5 g, 11.1 mmol). LC-MS [M+H] 757.6 (C36H48N6O8S2+H, calc: 757.9). Compound E was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:7]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]#[N:12])=[N:8][C:4]=2[CH:3]=1.[NH2:23][OH:24]>CCO>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:7]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]([NH:23][OH:24])=[NH:12])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)n1c(-c2ccccc2C#N)nc2cc(Br)ccc21
Reactant: NO
Solvent: CCO
Product: CC(C)(C)n1c(-c2ccccc2C(=N)NO)nc2cc(Br)ccc21
Temperature: 80 °C
Yield: 81 %

Procedure:
To a suspension of 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-benzonitrile (765 mg, 2.16 mmol) in EtOH (15 mL) is added hydroxylamine 50% aqueous solution (2.85 mL, 43.19 mmol) at room temperature. The solution is heated to 80° C. for 2 hours. The reaction mixture is cooled to room temperature and the ethanol removed in vacuo. Water (30 mL) is added to the reaction mixture and the resultant precipitate is filtered and washed with 10% EtOAc/heptane (10 mL) to afford 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-N-hydroxy-benzamidine (716 mg, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH:14]=[C:13]2[C:7]([CH2:8][N+:9]([O-])=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:11]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=32)=[CH:6]1)=[O:4].[C:28]([O:31]C(=O)C)(=[O:30])[CH3:29]>>[CH3:1][O:2][C:3]([N:5]1[CH:14]=[C:13]2[C:7]([CH:8]([O:31][C:28](=[O:30])[CH3:29])[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:11]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:12]=32)=[CH:6]1)=[O:4]
Reactant: COC(=O)n1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=[N+]([O-])C2
Reactant: CC(=O)OC(C)=O
Product: COC(=O)n1cc2c(c1)C(OC(C)=O)N=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Reaction time: 5 h

Procedure:
A mixture of 7.6 g (19 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-carboxylic acid methyl ester 5-oxide and 200 ml of acetic anhydride was stirred at 70° for 12 hr and at 105° for 5 hr. The acetic anhydride solution was concentrated at reduced pressure. The residue was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give an oil. Purification by column chromatography (50 g, neutral alumina; 5% ether in methylene chloride, eluent) gave a tan solid, mp 175°-177°. Recrystallization from ether gave an off-white solid, mp 177°-178°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[S:9][CH2:8][CH2:7][N:6]3C(=O)[C:11](=[O:14])[C:12]([CH:13]=1)=[C:5]23.[OH-:16].[Na+].OO.Cl>O>[Br:1][C:2]1[CH:3]=[C:4]2[S:9][CH2:8][CH2:7][NH:6][C:5]2=[C:12]([C:11]([OH:14])=[O:16])[CH:13]=1
Reactant: [OH-]
Reactant: O=C1C(=O)N2CCSc3cc(Br)cc1c32
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Br)cc2c1NCCS2
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a suspension of 8-bromo-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzothiazine-5,6-dione (4.6 g) in water (50 ml) was added 2N sodium hydroxide solution (30 ml) and dissolved. To the solution was added 30% hydrogen peroxide solution (4 ml) at 15° C. After stirring for 30 minutes, the mixture was brought to slightly acidic by the addition of concentrated hydrochloric acid. The resulting crystals were collected by filtration, washed with water and dried to give the title compound (4.1 g, 92.3%) which was recrystallized from ethanol as pale yellow needles, mp 205°-206° C. (decompd.).
Reaction SMILES: [CH3:1][C:2]1([CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:6](=[O:7])[NH:5][NH:4][C:3]1=[O:8].ClOC(C)(C)C.[C:24]([O:30][CH3:31])(=[O:29])[CH:25]=[CH:26][CH:27]=[CH2:28]>O1CCOCC1>[CH3:1][C:2]1([CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:6](=[O:7])[N:5]2[CH2:28][CH:27]=[CH:26][CH:25]([C:24]([O:30][CH3:31])=[O:29])[N:4]2[C:3]1=[O:8]
Reactant: CC1(CCOC2CCCCO2)C(=O)NNC1=O
Reactant: C=CC=CC(=O)OC
Agent: CC(C)(C)OCl
Solvent: C1COCCO1
Product: COC(=O)C1C=CCN2C(=O)C(C)(CCOC3CCCCO3)C(=O)N12
Temperature: 25 °C
Yield: 29.5 %

Procedure:
(B)(a) 1.21 g (5 mmol) of 4-methyl-4-[2-(tetrahydro-2-pyranyloxy)ethyl]pyrazolidine-3,5-dione were suspended in 20 ml of dry dioxan and the suspension was stirred at room temperature under a stream of nitrogen. A solution of 0.543 g (5 mmol) of tert.butyl hypochlorite in 5 ml of dry dioxan was added over a period of 15 minutes. The resulting blue solution was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in 10 ml of dry dioxan and the solution was added portionwise to a stirred solution of 0.616 g (5.5 mmol) of methyl penta-2,4-dienoate in 20 ml of dry dioxan. The blue color was allowed to fade between additions. When the addition was complete and no blue color persisted, the solution was stirred at room temperature for 1 hour. The resulting solution was evaporated in vacuo and the residue was chromatographed on silica gel. Elution with diethyl ether gave 0.52 g (29%) of methyl 2,3,5,8-tetrahydro-2-methyl-1,3-dioxo-2-[2-(tetrahydro-2-pyranyloxy)ethyl]-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate having a melting point of 127.5°-128.5° C. (from diethyl ether).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[N:9]=[N:10][CH:11]=[C:12]([O:14]C3N(C)N=C(C(F)(F)F)C=3)[CH:13]=2)=[CH:5][C:4]([C:25]([F:28])([F:27])[F:26])=[N:3]1.[OH-].[Na+].O.Cl>CS(C)=O>[CH3:1][N:2]1[C:6]([O:7][C:8]2[N:9]=[N:10][CH:11]=[C:12]([OH:14])[CH:13]=2)=[CH:5][C:4]([C:25]([F:28])([F:26])[F:27])=[N:3]1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cn1nc(C(F)(F)F)cc1Oc1cc(O)cnn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
3,5-Bis[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (Compound No. 11, 3.0 g, 0.0073 mole) and 2.5N NaOH (14.7 mL, 0.0367 mole) were stirred in dimethylsulfoxide (45 mL) at room temperature under N2 for 15 minutes. The mixture was then heated to 80° C. for 5 minutes. The mixture was cooled to room temperature and allowed to stir for 1 h. The mixture was then poured into water and made acidic with 12N HCl. The mixture was extracted 3×200 mL with ethyl acetate and the organic layer was dried (MgSO4), filtered and evaporated in vacuo. The residue was triturated with a minimum amount of ethyl acetate and filtered to collect the product. The mother liquor was condensed and this process was repeated two more times. 6-[[1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]-4-pyridazinol (1.35 g, 71% yield) was obtained as a white solid.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH:6](CS([O-])(=O)=O)[CH2:5][O:4]2)[CH2:2]1.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:26]=[CH:27][C:28]([N:31]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:32]([C:34]4([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]4)=[O:33])=[N:29][CH:30]=3)=[CH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:2]1[C:3]2([CH2:7][CH:6]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([C:18]([O:24][C:25]5[CH:26]=[CH:27][C:28]([N:31]([C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)[C:32]([C:34]6([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]6)=[O:33])=[N:29][CH:30]=5)=[CH:19][CH:20]=[N:21]4)=[CH:16][CH:15]=3)[CH2:5][O:4]2)[CH2:1]1
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(O)ccc34)cn2)CC1
Reactant: O=S(=O)([O-])CC1COC2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(OC5COC6(CC6)C5)ccc34)cn2)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 19.9 %

Procedure:
To a mixture of (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (168 mg, 0.877 mmol) and N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide (300 mg, 0.682 mmol) in 5 mL of N,N-dimethylacetamide was added cesium carbonate (893 mg, 2.74 mmol). After stirring at room temperature for 36 hrs, then the reaction mixture was warmed up to 40° C. for 8 hrs. The reaction mixture was concentrated in vacuo and the residue was chromatographed with a silica gel column (2:1 (v/v) EtOAc/n-hexane) to afford the title compound as a white solid (73 mg, 20%).