Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:30][CH2:31]I>CN(C)C=O>[Cl:30][CH2:31][O:21][C:20](=[O:22])[C@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: ClCI
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCCl

Procedure:
The compound was prepared by the method of Example 7A from N-tert.butoxycarbonyl-tryptophan, triethylamine, and chloroiodomethane in dimethylformamide; reaction time 4 hours. M.p. 155°-157°C.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([OH:17])=O)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:42]1[CH:46]=[CH:45][N:44]=[C:43]1[NH:47][C:48]([C:50]1[C:58]2[NH:57][C:56]([NH2:59])=[N:55][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[O:49].C([O-])(O)=O.[Na+]>CN(C=O)C.CCN(C(C)C)C(C)C.O>[NH:44]1[CH:45]=[CH:46][N:42]=[C:43]1[NH:47][C:48]([C:50]1[C:58]2[N:57]=[C:56]([NH:59][C:15]([C:11]3[CH:10]=[C:9]([C:8]#[C:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:14]=[CH:13][N:12]=3)=[O:17])[NH:55][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[O:49]
Reactant: O=C(O)c1cc(C#Cc2ccccc2)ccn1
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cc(C#Cc2ccccc2)ccn1
Temperature: 25 °C
Yield: 43 %

Procedure:
0.05 (0.23 mmol) of the above synthesized 4-phenylethynyl-pyridine-2-carboxylic acid, 0.095 g (0.25 mmol) of HBTU in a mixture of 2.0 ml of DMF and 0.20 mL of DIEA was reacted with 0.05 g (0.20 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (Intermediate B) as described in general procedure A. The reaction mixture was cooled to r.t. 5.0 mL of water and 5.0 mL of saturated NaHCO3 was added, and the resulting solid was filtered. The solid was washed with water and ether, and dried to provide 0.04 g (43%) of 2-[(4-phenylethynyl-pyridine-2-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide. LCMS: 448 (M+1)+.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:27])([F:26])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[NH:21][C@H:20]2[CH3:25])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.Cl[CH2:29][C:30]1[C:35]([N:36]([CH2:39][C@H:40]2[CH2:45][CH2:44][C@H:43]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:42][CH2:41]2)[CH2:37][CH3:38])=[CH:34][CH:33]=[CH:32][N:31]=1.[NH4+].[Cl-]>CN(C=O)C.O>[F:27][C:8]([F:7])([F:26])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:29][C:30]3[C:35]([N:36]([CH2:39][C@H:40]4[CH2:45][CH2:44][C@H:43]([CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:42][CH2:41]4)[CH2:37][CH3:38])=[CH:34][CH:33]=[CH:32][N:31]=3)[C@H:20]2[CH3:25])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2cccnc2CCl)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2cccnc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Potassium t-butoxide (55.3 mg, 0.493 mmol) was added to a stirred solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (180.2 mg, 0.575 mmol) in dry DMF (5 mL) at room temperature under N2. The solution was stirred for 5 min at room temperature. A solution of ethyl (trans-4-{[[2-(chloromethyl)pyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate (145.0 mg, 0.411 mmol) in dry DMF (2 mL) was added via cannula and the reaction was stirred at room temperature for 3 h. Saturated aqueous NH4Cl (5 mL) and water (5 mL) were added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-50% EtOAc in hexanes gradient) to afford ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate. Rf=0.77 (50% EtOAc/hexanes). LCMS calc.=630.3; found=630.3 (M+1)+. 1H NMR (600 MHz, CDCl3): i 8.31 (dd, J=1.3, 4.6 Hz, 1 H); 7.85 (s, 1 H); 7.80 (s, 2 H); 7.43 (dd, J=1.3, 8.1 Hz, 1 H); 7.17 (dd, J=4.7, 8.1 Hz, 1 H); 5.78 (d, J=8.5 Hz, 1 H); 4.91 (d, J=16.7 Hz, 1 H); 4.45 (d, J=16-7 Hz, 1 H); 4.36-4.30 (m, 1 H); 4.06 (q, J=7.1 Hz, 2 H); 2.96-2.90 (m, 2 H); 2.82-2.74 (m, 2 H); 2.11 (d, J=6.8 Hz, 2 H); 1.80-1.75 (m, 2 H); 1.73-1.67 (m, 3 H); 1.30 (m, 1 H); 1.20 (t, J=7.1 Hz, 3 H); 0.96 (t, J=7.0 Hz, 3H); 0.93-0.77 (m, 4 H); 0.66 (d, J=6.7 Hz, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[CH2:22][CH2:21][N:20]3[C:13](=[CH:14][C:15]4[CH2:16][C:17]([CH3:24])([CH3:23])[CH2:18][C:19]=43)[C:12]2=[O:25])[C:3]=1[CH:4]=[O:5].C([OH:30])(C)(C)C.CC(=CC)C.[O-]Cl=O.[Na+]>O.ClCCl>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[CH2:22][CH2:21][N:20]3[C:13](=[CH:14][C:15]4[CH2:16][C:17]([CH3:23])([CH3:24])[CH2:18][C:19]=43)[C:12]2=[O:25])[C:3]=1[C:4]([OH:30])=[O:5]
Reactant: CC(C)(C)O
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1cc(F)cc(Br)c1C=O)C3=O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)Cc2cc3n(c2C1)CCN(c1cc(F)cc(Br)c1C(=O)O)C3=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a mixture of 2-bromo-6-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-fluorobenzaldehyde 128a (810 mg, 2.0 mmol), tert-butyl alcohol (50 mL), and dichloromethane (3 mL) was added 2-methyl-2-butene (22 mL, 262 mmol). An aqueous solution (20 mL) of NaClO2 (1.8 g, 20.0 mmol) and NaH2PO4 dihydrate (2.2 g, 14.0 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 1 h. It was then treated with water (30 mL) and extracted with ethyl acetate (4×90 mL). The combined organic extract was dried over MgSO4 and concentrated under reduced pressure to afford 129a (930 mg, 84%) as a yellow solid. MS-ESI: [M+H]+ 421.1
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[S:36](Cl)(=[O:38])=[O:37]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:36]([C:27]4[CH:28]=[CH:29][C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:26]=4)(=[O:38])=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc5ccccc5c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and naphthalene-2-sulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Cl.[CH:7]1([CH:13]2[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15][NH:14]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:7]1([CH:13]2[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15][N:14]2[C:2]([O:4][CH3:5])=[O:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)C1CCNC(C2CCCCC2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(C2CCCCC2)C1
Reaction time: 3 h
Yield: 129.5 %

Procedure:
Methyl chloroformate (1.344 mL, 17.36 mmol) in DCM (50 mL) was added to a solution of methyl 2-cyclohexylpiperidine-4-carboxylate hydrochloride (3.50 g, 13.35 mmol) and DIPEA (1.88 mL, 10.76 mmol) in DCM (100 mL). The reaction solution was stirred for 3 h. 1.88 mL DIPEA and 1.345 mL methyl chloroformate was added and the reaction continued overnight (16 h). The organic phase was washed with satd NaHCO3. The phases were separated and the organic phase dried using a phase separator to give crude dimethyl 2-cyclohexylpiperidine-1,4-dicarboxylate (4.90 g). MS m/z 284 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3/[C:12](=[CH:19]\[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])/[C:11]([F:26])([F:25])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:29]1([C:35]2[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=2[C:37](O)=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OC(=O)C)C.[ClH:50]>C(Cl)(Cl)Cl>[ClH:50].[F:25][C:11]1([F:26])[CH2:10][CH2:9][N:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:28][CH:27]=2)=[O:7])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2/[C:12]/1=[CH:19]\[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23]
Reactant: CN(C)CC/C=C1\c2ccccc2N(C(=O)c2ccc(N)cc2)CCC1(F)F
Reactant: O=C(O)c1ccccc1-c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CN(C)CC/C=C1\c2ccccc2N(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)CCC1(F)F

Procedure:
Using 690 mg of (E)-1-(4-aminobenzoyl)-5-(3-dimethylaminopropylidene)-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepine and 430 mg of o-phenylbenzoic acid, 520 mg of free base was synthesized in the same manner as described in Reference Example 8. Next, 340 mg of the free base was dissolved in chloroform, the resulting solution was mixed with 4N hydrochloric acid ethyl acetate solution, and the solvent was evaporated. Then, the resulting residue was mixed with hexane to obtain 111 mg of (E)-4'-[[4,4-difluoro-5-(3-dimethylaminopropylidene)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl]-2-phenylbenzanilide hydrochloride in the form of colorless amorphous solid.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)=[CH:4][N:3]=[CH:2]1.[CH2:15]([C:22]1([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O.C(N(CC)CC)C>[CH2:15]([C:22]1([OH:28])[CH2:27][CH2:26][N:25]([C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5]2[O:1][CH:2]=[N:3][CH:4]=2)=[O:10])[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccccc1-c1cnco1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1-c1cnco1)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.7 %

Procedure:
A suspension of 2-(1,3-oxazol-5-yl)benzoic acid (0.30 g), 4-benzyl-4-hydroxypiperidine (0.36 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.46 g), 1-hydroxybenzotriazole (0.40 g) and triethylamine (0.40 g) in DMF (3 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (0.28 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][C@@H:3]2[CH2:7][CH2:8][CH2:9][C@@H:2]12.Br[C:11]1[N:28]([CH2:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]2)[C:14]2[C:15]([C:21]3[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=3)=[N:16][C:17]([C:19]#[N:20])=[CH:18][C:13]=2[N:12]=1.[F-].[K+].CCN(C(C)C)C(C)C>CCOC(C)=O.CS(C)=O>[Cl:27][C:25]1[CH:26]=[C:21]([C:15]2[C:14]3[N:28]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:11]([N:1]4[CH2:6][CH2:5][NH:4][C@@H:3]5[CH2:7][CH2:8][CH2:9][C@@H:2]45)=[N:12][C:13]=3[CH:18]=[C:17]([C:19]#[N:20])[N:16]=2)[CH:22]=[N:23][CH:24]=1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: C1C[C@H]2NCCN[C@@H]2C1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CC[C@H](Cn2c(N3CCN[C@@H]4CCC[C@H]43)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C

Procedure:
To a microwave vial was added (4aR,7aR)-octahydro-1H-cyclopenta[b]pyrazine (Preparative Example 5.2,295 mg, 2.338 mmol), 2-bromo-4-(5-chloropyridin-3-yl)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, 800 mg, 1.799 mmol), potassium fluoride (209 mg, 3.60 mmol), DMSO (8 ml), and DIEA (0.942 ml, 5.40 mmol). The reaction vial was capped and heated to 100° C. overnight. The mixture was then cooled to room temperature and diluted with EtOAc. The solution was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give crude 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(4aR,7aR)-octahydro-1H-cyclopenta[b]pyrazin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C27H32ClN7 [M+H]+ 490. found 490.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:27][NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])=[O:30].C(=O)(O)[O-].[Na+].CCOC(C)=O>COCCOC.O.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>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:35]2[CH:34]=[CH:33][C:32]([S:29]([NH:28][CH3:27])(=[O:30])=[O:31])=[CH:37][CH:36]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CNS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3cnn(C(C)C)c3c2)cc1
Temperature: 140 °C
Yield: 55 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (100 mg, 0.24 mmol), {4-[(methylamino)sulfonyl]phenyl}boronic acid (77 mg, 0.36 mmol) in DME/water (3 mL:1 mL). PdCl2(dppf)-CH2Cl2 (9.8 mg, 0.012 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (60.4 mg, 0.72 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 140° C. for 30 min. EtOAc was added and the solution was filtered thru Celite and evaporated. DCM/MeOH (1:1) was added, it was pre-absorbed on silica gel and purified by SiO2 chromatography (eluent: gradient 100% DCM to 90:10:1 DCM/MeOH/NH4OH). Fractions were evaporated. EtOAc was added along with some hexanes, it was sonicated and the solids that precipitated were filtered, washed with DCM and dried to afford the title compound (67 mg, 54%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 9.87 (br. s., 1H) 8.62 (t, J=4.80 Hz, 1H) 8.37 (s, 1H) 8.07 (s, 1H) 7.82-7.86 (m, 3H) 7.35 (s, 1H) 7.32 (s, 1H) 5.89 (s, 1H) 5.15 (quin, J=6.63 Hz, 1H) 4.39 (d, J=4.80 Hz, 2H) 3.04 (s, 3H) 2.22 (s, 3H) 2.12 (s, 3H) 1.51 (s, 3H) 1.49 (s, 3H). MS (ES) [M+H]+ 507.9.
Reaction SMILES: [S:1]1[C:5]2[S:6](=[O:11])(=[O:10])[CH2:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:12]([NH2:15])(=[O:14])=[O:13].C(O)C>[Pd].CO>[S:1]1[C:5]2[S:6](=[O:10])(=[O:11])[CH2:7][CH2:8][CH2:9][C:4]=2[CH:3]=[C:2]1[S:12]([NH2:15])(=[O:13])=[O:14]
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CC=C2
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CCC2
Reaction time: 0.25 h
Yield: 75.8 %

Procedure:
A solution of 6H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (3.05 g, 0.011 m) is absolute ethanol (130 ml) and methanol (20 ml) was hydrogenated on a Parr apparatus at 40 psi with 5% palladium on carbon catalyst (250 mg) at ambient temperature. After 15 minutes, 10% palladium on carbon catalyst (350 mg) was added, followed by an identical addition after 30 minutes. After 16 hours, the catalyst was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in absolute ethanol (100 ml) and methanol (50 ml) and hydrogenated at 50 psi with 10% palladium on carbon catalyst (500 mg) for 16 hours. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. The solid residue was chromatographed on silica gel, eluting with 10% methanol-chloroform to give 2.33 g (76%) of product.
Reaction SMILES: [C:1]([C:3]([CH2:12][CH2:13][O:14][CH3:15])([CH2:8][CH2:9][O:10][CH3:11])[C:4]([O:6]C)=[O:5])#[N:2].[OH-].[Na+].CCCCCC.COC(C)(C)C>O1CCCC1>[C:1]([C:3]([CH2:8][CH2:9][O:10][CH3:11])([CH2:12][CH2:13][O:14][CH3:15])[C:4]([OH:6])=[O:5])#[N:2]
Reactant: COCCC(C#N)(CCOC)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COCCC(C#N)(CCOC)C(=O)O
Reaction time: 7 h

Procedure:
To a solution of methyl 2-cyano-4-methoxy-2-(2-methoxyethyl)butanoate (1.13 g) synthesized according to the method described in European Journal of Organic Chemistry, 2005, vol. 20, pp. 4313-4321 in tetrahydrofuran (10 mL), 1.0 mol/L aqueous sodium hydroxide (20 mL) was added at room temperature, and the mixture was stirred at the same temperature for 7 hours. To the reaction mixture, hexane and tert-butyl methyl ether were added. The aqueous layer was separated, and ethyl acetate and 1.0 mol/L aqueous hydrochloric acid were added. The organic layer was separated, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 2-cyano-4-methoxy-2-(2-methoxyethyl)butyric acid (G19, 957 mg).
Reaction SMILES: [O:1]([CH:8]([P:17](=[O:24])([O:21]CC)[O:18]CC)[P:9](=[O:16])([O:13]CC)[O:10]CC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl>[O:1]([CH:8]([P:17](=[O:18])([OH:21])[OH:24])[P:9](=[O:10])([OH:13])[OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(OCC)C(Oc1ccccc1)P(=O)(OCC)OCC
Agent: Cl
Product: O=P(O)(O)C(Oc1ccccc1)P(=O)(O)O

Procedure:
A mixture of tetraethyl (phenoxymethylene)-bisphosphonate (20 g) and 6N hydrochloric acid (150 ml) was refluxed overnight and the resulting solution was evaporated to dryness in vacuo. Residual hydrochloric acid was removed by repeated evaporation with absolute ethanol. The residue was taken up in acetone (7 ml) and ether (200 ml) was added. The crystalline product was filtered, washed with ether and dried in vacuo.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[N+:7]([C:10]([N+:32]([O-:34])=[O:33])([N+:29]([O-:31])=[O:30])[CH2:11][CH2:12][C:13]([NH:15][NH:16][C:17](=[O:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=O)([O-:9])=[O:8]>ClC(Cl)C>[N+:32]([C:10]([N+:7]([O-:9])=[O:8])([N+:29]([O-:31])=[O:30])[CH2:11][CH2:12][C:13]1[O:28][C:17]([C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[N:16][N:15]=1)([O-:34])=[O:33]
Reactant: O=C(CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])NNC(=O)C(F)(F)C(F)(F)C(F)(F)F
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])C(CCc1nnc(C(F)(F)C(F)(F)C(F)(F)F)o1)([N+](=O)[O-])[N+](=O)[O-]
Yield: 66.9 %

Procedure:
Phosphorus pentachloride (1.2 g, 0.0057 mole) and N-(4,4,4-trinitrobutyryl)-N'-(perfluorobutyryl)hydrazine (0.8 g, 0.0018 mole) in 10mL of dichloroethane was held at reflux temperature for 4 hours. Removal of volatiles 9ave an oil which was washed with water and then chromatographed on Silica gel 40 (CH2Cl2 as eluent) to give 0.5 g (66%) of 2-(3,3,3-trinitropropyl)-5-(perfluoropropyl)-1,3,4-oxadiazole, mp 43°-45° C.; 1H NMR (acetone): 3.84 (m, 2H), 4.23 (m, 2H). Anal. Calcd for C8H4F7N5O7 : C, 23.14; H, 0.97; F, 32.04; N, 16.87. Found: C, 23.07; H, 1.00; F, 31.80; N, 16.95.
Reaction SMILES: [CH:1]([NH:3][C:4]1[NH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][C:5]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.B.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][NH:3][C:4]1[NH:8][C:7]([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[N:6][C:5]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=CNc1[nH]c(-c2ccc(F)cc2)nc1-c1ccccc1
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CNc1[nH]c(-c2ccc(F)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.7 %

Procedure:
To a solution of 5-formylamino-2-(4-fluorophenyl)-4-phenylimidazole (1.06 g) in tetrahydrofuran (15 ml) was added dropwise 10M borane.dimethylsulfide complex (1.90 ml), and the mixture was stirred under argon atmosphere at room temperature for 2.5 hours. To the reaction mixture was slowly added 10% hydrochloric acid, and the mixture was refluxed for one hour. After cooling, the mixture was neutralized by adding a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flush column chromatography (solvent: hexane:ethyl acetate=5:1) to obtain 5-methylamino-2-(4-fluorophenyl)-4-phenylimidazole (702 mg) as colorless powder. 88 mg of the product was treated with hydrogen chloride-methanol solution to obtain the hydrochloride salt (84 mg) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[N:15]=[C:16]([CH:20]=C)[C:17]=2[O:18][CH3:19])[C:4]2[C:9]([C:10]=1[Cl:11])=[CH:8][CH:7]=[CH:6][CH:5]=2.[O:24]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:1][C:2]1[N:3]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[N:15]=[C:16]([CH:20]=[O:24])[C:17]=2[O:18][CH3:19])[C:4]2[C:9]([C:10]=1[Cl:11])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=[O+][O-]
Reactant: C=Cc1nn(C)c(=O)c(-n2c(Cl)c(Cl)c3ccccc32)c1OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1c(C=O)nn(C)c(=O)c1-n1c(Cl)c(Cl)c2ccccc21
Temperature: -78 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A 3-necked flask is charged with 4-(2,3-dichloroindol-1-yl)-5-methoxy-2-methyl-6-vinyl-pyridazin-3-one (418 mg, 1.19 mmol) and dichlormethane (10 mL). The flask was fitted with a thermometer, an inlet tube and an outlet tube connected to two Dreschel bottles, the latter of which contained a 10% aq. KI solution. The inlet tube was connected to the ozone generator (turned off). The airflow was turned on to give a steady bubbling through the reaction flask and out through the KI solution. The flask was cooled to −78° C. and once at this temperature, the ozone generator was turned on and bubbled for 10 min. The KI solution became darker over the course of the reaction. The ozone generator was turned off and the reaction purged with air for 2 min. It was then disconnected from the inlet and outlet tubes and triphenylphosphine (939 mg, 3.58 mmol) was added. The reaction was allowed to stir and gradually warm to RT over 1 h, then stirred at RT for a further 3 h and left to stand overnight. The resulting reaction mixture was concentrated onto silica and the purified by chromatography (combiflash, 0 to 50% EtOAc/ihexane) to give the desired product 5-(2,3-dichloroindol-1-yl)-4-methoxy-1-methyl-6-oxo-pyridazine-3-carb aldehyde (262 mg, 0.744 mmol, 63%) as a yellow solid.