Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH2:9]([O:11]CC)[CH3:10].C([Li])CCC.CN(C)C(=O)C>CCCCCC.C(OCC)(=O)C.O>[Br:8][C:4]1[N:3]=[C:2]([C:9](=[O:11])[CH3:10])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1cccc(Br)n1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
2,6-dibromopyridine (10.0 g, 42.2 mmol) was placed in a reaction flask. To ensure a nitrogen atmosphere in the reaction flask, the gas in the reaction flask was drawn out and the reaction flask was refilled with nitrogen gas in a rapid manner three times. To the reaction flask, 150 ml of anhydrous diethylether was added, and then 17.7 ml of an n-butyllithium solution (44.3 mmol, 2.5 M in n-hexane) was slowly added at −78° C. to obtain a mixture. In the meanwhile, the color of the mixture changed from transparent to yellowish-brown. The mixture in the reaction flask was kept at −78° C. and continuously stirred for 30 minutes. Then, N,N-dimethylacetamide (4.7 ml, 50.7 mmol) was slowly added to the mixture, and the mixture was kept at −78° C. for 3 hours for reaction. Thereafter, the temperature of the mixture was slowly raised to 20° C. At this moment, the color of the mixture in the reaction flask changed to cloudy gray. Deionized water was slowly added to the mixture to terminate the reaction in the reaction flask. The solvents in the mixture were drawn out of the reaction flask, and the residue in the reaction flask was washed several times with ethyl acetate and with a saturated sodium chloride solution to collect an organic layer, followed by dehydration of the organic layer using sodium sulfate (Na2SO4) to thereby obtain a crude product. The crude product was subjected to column chromatography (SiO2, ethyl acetate:n-hexane=1:20), followed by recrystallization in a mixed solvent having dichloromethane and n-hexane (dichloromethane:n-hexane=1:20) at 20° C., thereby obtaining white crystals (6.80 g, 81% yield).
Reaction SMILES: [C:1]1([C:7]2[N:18]3[C:10]([C:11]4[NH:12][CH:13]=[N:14][C:15]=4[N:16]([CH2:20][CH2:21][CH3:22])[C:17]3=[O:19])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:25](I)[CH2:26][CH3:27].[Cl-].[NH4+]>CN(C=O)C>[CH2:20]([N:16]1[C:15]2[N:14]=[CH:13][N:12]([CH2:25][CH2:26][CH3:27])[C:11]=2[C:10]2=[N:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:18]2[C:17]1=[O:19])[CH2:21][CH3:22]
Reactant: CCCI
Reactant: CCCn1c(=O)n2c(-c3ccccc3)nnc2c2[nH]cnc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCn1cnc2c1c1nnc(-c3ccccc3)n1c(=O)n2CCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After 500 mg (1.70 mmol) of Compound 30 obtained in Example 30 was dissolved in 5 ml of N,N'-dimethylformamide, 81.6 mg (2.04 mmol) of 60% sodium hydride was added to the solution at 0° C. 15 minutes after, 0.25 ml (2.51 mmol) of propyl iodide was added to the reaction solution at 0° C. The solution was stirred at room temperature for 30 minutes. After 20 ml of saturated ammonium chloride was added to the reaction solution at 0° C., the mixture was extracted 3 times with 30 ml of chloroform. The extracts were combined and washed with a saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was eva.oprated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: 2% methanol/chloroform) to afford 434 mg (yield, 76%) of Compound 35 as white needles.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25].Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:22][N:23]([CH3:28])[S:24](=[O:26])(=[O:25])[O:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=2[CH:3]=1
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)Oc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 0 °C

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (2.3 g, 0.01 mole), triethylamine (1.4 ml) and 4-dimethylaminopyridine (200 mg) in dimethylformamide (20 ml) was added dimethylsulfamoyl chloride (1.1 ml). The reaction mixture was heated on a steam bath for 18 hours, poured into ice water and excess hydrochloric acid, extracted into ethyl acetate, washed with water and dried over magnesium sulfate. The ethyl acetate was evaporated and the (2-sulfamoyl-6-benzothiazolyl) N,N-dimethylsulfamate purified by chromatography on a 2 mm preparative silica gel TLC plate developed with chloroform/methanol 9:1 (v/v) m.p.=162°-164° C.
Reaction SMILES: NC1C=C2C(=CC=1N)N=CC(C#N)=C2NC1C=C(OC)C=CC=1C.NC1C=C2C(C(NC3C=C(OC)C=CC=3C)=C(C#N)C=N2)=CC=1N(CCN1CCOCC1)C(N)=S.[NH2:60][C:61]1[CH:62]=[C:63]2[C:68](=[CH:69][C:70]=1[NH:71][C:72]([NH:74][CH2:75][CH2:76][N:77]1[CH2:82][CH2:81][O:80][CH2:79][CH2:78]1)=S)[N:67]=[CH:66][C:65]([C:83]#[N:84])=[C:64]2[NH:85][C:86]1[CH:91]=[C:90]([O:92][CH3:93])[CH:89]=[CH:88][C:87]=1[CH3:94].[S]>O1CCOCC1.C(O)C>[CH3:93][O:92][C:90]1[CH:89]=[CH:88][C:87]([CH3:94])=[C:86]([CH:91]=1)[NH:85][C:64]1[C:63]2[CH:62]=[C:61]3[N:60]=[C:72]([NH:74][CH2:75][CH2:76][N:77]4[CH2:82][CH2:81][O:80][CH2:79][CH2:78]4)[N:71]=[C:70]3[CH2:69][C:68]=2[N:67]=[CH:66][C:65]=1[C:83]#[N:84]
Reactant: COc1ccc(C)c(Nc2c(C#N)cnc3cc(NC(=S)NCCN4CCOCC4)c(N)cc23)c1
Agent: COc1ccc(C)c(Nc2c(C#N)cnc3cc(N)c(N(CCN4CCOCC4)C(N)=S)cc23)c1
Agent: COc1ccc(C)c(Nc2c(C#N)cnc3cc(N)c(N)cc23)c1
Agent: [S]
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(C)c(Nc2c(C#N)cnc3c2C=C2N=C(NCCN4CCOCC4)N=C2C3)c1
Temperature: 100 °C

Procedure:
A mixture of 0.1 g (0.3 mmol) of 6,7-diamino-4-(5-methoxy-2-methylanilino)-3-quinolinecarbonitrile and 0.11 g (0.62 mmol) of 2-(4-morpholino)ethylisothiocyanate in 0.3 mL of dioxane is heated at 100° C. for 2 hours under nitrogen. The mixture is cooled and solvent is evaporated to dryness to yield an oil consisting of N-[7-amino-3-cyano-4-(5-methoxy-2-methylanilino)-6-quinolinyl]-N-[2-(4-morpholinyl)-ethyl]thiourea and N-[6-amino-3-cyano-4-(5-methoxy-2-methylanilino)-7-quinolinyl]-N′-[2-(4-morpholinyl)ethyl]thiourea. The oil is dissolved in 3.0 mL of ethanol. To this is added 0.3 g of mercuric oxide and 20 mg of sulphur powder and the resulting mixture is heated at reflux temperature for 2 hours. The product mixture is filtered hot through diatomaceous earth, washed with methanol and solvent is evaporated to yield an oil. The oil is purified by silica gel chromatography, utilizing a gradient of methylene chloride/methanol (95:5 to 85:15) to yield 0.062 g of 8-(5-methoxy-2-methylanilino)-2-{[2-(4-morpholinyl)ethyl]amino}imidazo[4,5-g]quinoline-7-carbonitrile as a pink solid, mp 148–150° C. (shrinks at 140° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37].COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([C:2]2[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]3[CH2:15][NH:14][C:13](=[O:16])[CH2:12]3)[CH3:10])[C:5]3[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[N:19][C:4]=3[CH:3]=2)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(COCC[Si](C)(C)C)c12)[C@H]1CNC(=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cc3ncn(COCC[Si](C)(C)C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Temperature: 25 °C

Procedure:
Into the solution of (R)-4-((R)-1-(6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.12 (267 mg, 0.65 mmol) and 3,4-dimethoxyphenylboronic acid (142 mg, 0.78 mmol) in 2:1 DME:water (10 ml) was added cesium carbonate (3 equiv), and PEPPSI-IPr catalyst (0.1 equiv). Mixture was refluxed for 3 h, cooled to room temperature, poured into water and extracted with ethyl acetate (100 mL). Separated organic layer was washed with Brine (2×50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to yield residues which were purified by silica gel column chromatography to isolate (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.08.
Reaction SMILES: C[O-].[Na+].C([O:8][C:9]([CH:11]1[C:17]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])=[N:14][CH:13]=[CH:12]1)=O)CCC.C(OC(C1C2C=CC(Cl)=CC=2C(C2C=CC=CC=2F)=NCC=1)=O)CCC.Cl.[C:57]([NH2:60])(=[NH:59])[CH3:58]>C(O)C.O.CO>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]2[CH:11]3[C:9](=[O:8])[NH:60][C:57]([CH3:58])=[N:59][CH:12]3[CH2:13][N:14]=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:16]=2[CH:21]=1
Reactant: CCCCOC(=O)C1C=CN=C(c2ccccc2F)c2cc(Cl)ccc21
Reactant: CC(=N)N
Agent: CCCCOC(=O)C1=CCN=C(c2ccccc2F)c2cc(Cl)ccc21
Agent: C[O-]
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: O
Product: CC1=NC2CN=C(c3ccccc3F)c3cc(Cl)ccc3C2C(=O)N1

Procedure:
In one portion 14.0 mL of a 4.34M methanol solution of sodium methoxide was added to a solution of 14.0 g (37.7 mmol) of a mixture of 8-chloro-1-(2-fluorophenyl)-5H-2-benzazepine-5-carboxylic acid butyl ester and 8-chloro-1-(2-fluorophenyl)-3H-2-benzazepine-5-carboxylic acid butyl ester and 7.0 g (74 mmol) of acetamidine hydrochloride in 250 mL of ethanol. The mixture was refluxed for 17 hr, cooled and poured into 1 L of water. The resulting precipitate was collected by filtration and washed with ether to yield an off-white solid, mp 150°-165°.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:16])[O:4][N:3]=1.[CH2:17]([Li])CCC.CCCCCC.CI>O1CCCC1>[CH2:16]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[C:6]=1[C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:17]
Reactant: Cc1noc(C)c1-c1cc2ccccc2[nH]1
Reactant: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1onc(C)c1-c1cc2ccccc2[nH]1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A solution of 5 g (0.024 mole) of 2-(3,5-dimethyl-4-isoxazolyl)-indole in 100 ml of dry tetrahydrofuran is cooled to -60° and treated by dropwise addition with 32.4 ml of 1.6 M n-butyllithium in hexane (0.052 mole) maintaining temperature at -60° C. The resulting mixture is then stirred at -60° C. for 30 min. and then treated by dropwise addition of 4.01 g (0.028 mole) of methyl iodide in 10 ml dry tetrahydrofuran. The resulting mixture is stirred at -60° for 4 hours and quenched by the addition of 6 ml saturated ammonium chloride solution. The mixture is then warmed to room temperature and treated with 50 ml of water and extracted with methylene chloride. The organic layers are dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting oil is then purified by filtration through silica gel to give 2-(5-ethyl-3-methyl-4-isoxazolyl)-indole as a viscous oil.
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([OH:10])=[O:9].[CH2:11](I)[CH3:12]>CS(C)=O>[CH2:11]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([OH:10])=[O:9])[CH3:12]
Reactant: O=C(O)c1ccc[nH]1
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCn1cccc1C(=O)O
Reaction time: 8 h
Yield: 78.3 %

Procedure:
Under nitrogen, a suspension of 50 g (0.9 mol) of pulverized KOH in 440 ml of anhydrous DMSO was treated with 20 g (0.18 mol) of pyrrole-2-carboxylic acid (Aldrich); this mixture was cooled in ice and treated with 28 ml (0.36 mol of ethyl iodide. The reaction was allowed to warm to ambient temperatures and stir overnight prior to concentration in vacuo. The residue was dissolved in 125 ml of water and the pH adjusted to 4 with aqueous HCl. The product was extracted with methylene chloride, dried (MgSO4), and concentrated in vacuo to give 19.6 g (78%) of colorless material: mp 77°-78° C.; NMR (DMSO-d6) δ 1.23(t, J=7 Hz, 3H), 4.29(q, J=7 Hz, 2H), 6.06(dd, J=3 and 1 Hz, 1H), 7.10 (t, J=2 Hz, 1H).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[CH2:17][S:16][C@@H:11]2[C@H:12]([NH2:15])[C:13](=[O:14])[N:10]2[C:9]=1[C:18]([OH:20])=[O:19].C(#N)C.[CH2:24]([O:31][C:32](=[O:54])[CH:33]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:34](OC1C(Cl)=C(Cl)C(Cl)=C(Cl)C=1Cl)=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([O:31][C:32]([CH:33]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:34]([NH:15][CH:12]1[C:13](=[O:14])[N:10]2[C:9]([C:18]([OH:20])=[O:19])=[C:8]([CH3:7])[CH2:17][S:16][C@H:11]12)=[O:35])=[O:54])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(OCc1ccccc1)C(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)OCc3ccccc3)c3ccccc3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
1.8 ml. of pyridine are added to a suspension of 2.17 g. (0.01 mole) of 7-ADCA in 40 ml. of acetonitrile and 2 ml. of water. The obtained solution is cooled to 0° C., 5.6 g. (0.01 mole) of phenylmalonic acid pentachlorophenylester benzylester are added, and the mixture is stirred for 4 hours. The acetontrile is evaporated, the residue is taken up in 50 ml. of ethyl acetate, and the ethyl acetate solution is admixed with saturated sodium bi-carbonate solution. The aqueous phase is washed with ethyl acetate, thereafter it is covered with 50 ml. of ethyl acetate, and acidified to pH=2 with 2 n aqueous hydrochloric acid. The ethyl acetate phase is separated, dried, and evaporated. 3.5 g. (75%) of 7-(α-benzyloxycarbonyl-phenylacetamido)-3-methyl-ceph-3-em-4-carboxylic acid are obtained with a purity degree of 95% (determined by titrimetry).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][C:22]([OH:26])([CH3:25])[CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[CH:34][C:33]=1[N:47]1[N:56]=[CH:55][C:54]2[C:49](=[C:50]([F:61])[CH:51]=[C:52]([C:57]([CH3:60])([CH3:59])[CH3:58])[CH:53]=2)[C:48]1=[O:62])(=[O:29])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[C:57]([C:52]1[CH:53]=[C:54]2[C:49](=[C:50]([F:61])[CH:51]=1)[C:48](=[O:62])[N:47]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([C:17]([N:19]5[CH2:24][CH2:23][C:22]([OH:26])([CH3:25])[CH2:21][CH2:20]5)=[O:18])=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:32]=1[CH2:31][O:30][C:27](=[O:29])[CH3:28])[N:56]=[CH:55]2)([CH3:58])([CH3:59])[CH3:60]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cn1nc(Cl)cc(Nc2ccc(C(=O)N3CCC(C)(O)CC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCC(C)(O)CC4)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 125 °C

Procedure:
To a 10 mL microwave vial was added 6-chloro-4-(5-(4-hydroxy-4-methylpiperidine-1-carbonyl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (33 mg, 87.3 μmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (56.1 mg, 114 μmol) and Cs2CO3 (99.6 mg, 306 μmol) in dioxane (5 ml) and water (0.5 ml). The yellow suspension was purged with argon and PdCl2(DPPF) (7.13 mg, 8.73 μmol) was added. The vial was capped and heated in the microwave at 125° C. for 30 min. The reaction was cooled to 25° C. and diluted with DCM. Na2SO4 was added and the mixture was filtered through celite. The filter cake was washed with DCM until clear and the yellow filtrate was conc. in vacuo to afford the title compound as a brown solid in quantitative yield. (M−H)+=708 m/e.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[CH:14]4[C:18]([CH3:20])([CH3:19])[C:11]([CH3:21])([CH2:12][CH2:13]4)[C:10]=3[N:9]2[CH3:22])[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.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]>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[C@@H:14]4[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]4)[C:10]=3[N:9]2[CH3:22])[CH:3]=1
Reactant: Cn1c2c(c(=O)n1-c1cccc(I)c1)C1CCC2(C)C1(C)C
Reactant: OB(O)c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: Cn1c2c(c(=O)n1-c1cccc(-c3ccccc3Cl)c1)[C@H]1CC[C@]2(C)C1(C)C
Yield: 29.3 %

Procedure:
A mixture of 2-(3-iodo-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Example 23; 80 mg, 0.2 mmol), 2-chloro-phenyl-boronic acid (46 mg, 0.29 mmol), potassium carbonate (66 mg, 0.47 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 0.014 mmol) in dimethoxyethane (4 mL) was sealed under argon and heated at 80 degrees overnight and then at 90 degrees over the weekend. The reaction mixture was diluted with dichloromethane, filtered through a cotton plug and frit, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an RS-12 column, eluting with 0-75% ethyl acetate/hexanes to give (4S,7R)-2-(2′-chloro-biphenyl-3-yl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (23 mg, 30%) as a light brown solid and unreacted starting material (37 mg, 46%). ES(+)-MS (M+H) 393.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[C:16]([Br:21])[CH:17]=[C:18]([F:20])[CH:19]=1.CI>O1CCCC1.C(OCC)(=O)C.O.CCCCCC>[Br:21][C:16]1[CH:15]=[C:14]([F:13])[C:19]([CH3:1])=[C:18]([F:20])[CH:17]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(F)cc(Br)cc1F
Reaction time: 1 h

Procedure:
To a solution of 2.04 g of diisopropylamine in 30 ml of tetrahydrofuran is dropwise added 9.19 ml of 1.6 M n-hexane solution of n-butyllithium at -20°C. At the same temperature, the resulting mixture is stirred for one hour and then cooled to -70° C., at which temperature a solution of 3 g of 3,5-difluorobromobenzene in 10 ml of tetrahydrofuran is dropwise added thereto over 30 minutes. The temperature of the resulting reaction mixture is elevated to -40° C. and then lowered again to -70° C., at which temperature 0.97 ml of methyl iodide is then added thereto. The temperature of the resulting mixture is elevated to room temperature, and 80 ml of water and 80 ml of ethyl acetate are then added thereto, after which the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluent:hexane:ethyl acetate=10:1], to obtain 1.98 g of colorless, oily 4-bromo-2,6-difluorotoluene.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([OH:28])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.N1CCOCC1>C1COCC1.CN(C=O)C>[OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:23])([CH3:24])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)=[O:28])[CH:3]=1
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)O)c4[C@]3(C)CC[C@@H]12
Reactant: CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)N5CCOCC5)c4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.6 %

Procedure:
A mixture of (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3-carboxylic acid (65) (0.06 g, 0.2 mmol), HATU (0.15 g, 0.40 mmol), N-methylmorpholine (0.04 mL, 0.6 mmol) and morpholine (0.1 mL, 1 mmol) in THF (4.0 mL) and DMF (1.0 mL) was stirred at room temperature for 18 h. The THF was evaporated under reduced pressure, the residue was quenched with water and the resulting solid was collected by filtration. The crude product was purified by flash column chromatography on silica gel (Hexanes/EtOAc, 3:1) to give (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-3-[(morpholin-4-yl)carbonyl]-8λ6-thiatetracyclo-[8.8.0.02,7.011,16]octadeca-2,4,6-triene-8,8-dione (88) (0.05 g, 45%) as a tan solid. 1H NMR (DMSO-d6): δ 8.49 (s, 1H), 7.14 (s, 1H), 6.75 (s, 1H), 3.72-3.14 (m, 10H), 2.44 (m, 1H), 2.00 (d, 1H), 1.83 (d, 1H), 1.70-1.32 (m, 8H), 1.28-1.22 (m, 1H), 1.12 (m, 1H), 0.96 (m, 1H), 0.89 (s, 3H), 0.86 (m, 3H), 0.82 (m, 1H), 0.79 (s, 3H). MS m/z 476 (C26H37NO6S+H+).
Reaction SMILES: [BH4-].[Na+].C1(S(O)(=O)=O)C=CC=CC=1.[O:13]=[C:14]([N:28]1[CH2:33][CH2:32][N:31]2[C:34]([C:37]([F:40])([F:39])[F:38])=[N:35][N:36]=[C:30]2[CH2:29]1)[CH:15]=[C:16]([NH2:27])[CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26].N>C1COCC1.O.CC(O)C>[O:13]=[C:14]([N:28]1[CH2:33][CH2:32][N:31]2[C:34]([C:37]([F:40])([F:39])[F:38])=[N:35][N:36]=[C:30]2[CH2:29]1)[CH2:15][CH:16]([NH2:27])[CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: N
Agent: O=S(=O)(O)c1ccccc1
Agent: [BH4-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: -10 °C
Reaction time: 5 h

Procedure:
In a 250 mL round bottom flask dry THF (56 mL) was taken. It was cooled to −10° C. and NaBH4 (1.4 g) was added. After that benzenesulfonic acid (14.6 g) dissolved in THF (20 mL) was added dropwise at −10 to 5° C. over a period of 30-60 min. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (5.0 g) was mixed in a solvent mixture of THF (12.5 mL) and IPA (5.5 mL) and added into the reaction mixture, keeping the temperature between −10 to 5. It was stirred for 5 h at −10 to 0° C. Reaction mixture was poured into cold water. It was basified by adding aq. ammonia solution. Product was extracted in ethyl acetate. The organic layer was collected. It was washed with water and dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-5.5 g; % Y-95.6%; % Purity by HPLC-62.5%).