Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:55]1[CH2:60][CH2:59][CH:58]([C:61]2[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[NH:63][CH:62]=2)[CH2:57][CH2:56]1>CN(C=O)C>[NH:63]1[C:64]2[C:69](=[CH:68][CH:67]=[CH:66][CH:65]=2)[C:61]([CH:58]2[CH2:59][CH2:60][N:55]([C:6]([C:5]3[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=3)[C:1]#[N:2])=[O:8])[CH2:56][CH2:57]2)=[CH:62]1
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cccc(C(=O)N2CCC(c3c[nH]c4ccccc34)CC2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-Cyano-benzoic acid (0.09 g, 0.6 mmol) is dissolved in 3 ml of DMF, then HBTU (0.28 g, 0.75 mmol), HOBt (0.10 g, 0.75 mmol) and DIPEA (0.26 g, 2.0 mmol) are added. The mixture is stirred at RT for 20 min before adding the 3-piperidin-4-yl-1H-indole (0.09 g, 0.6 mmol). The reaction was stirred at RT for 3 hours, monitored with LC/MS. The organic solvent is removed under the reduced pressure and the residue is purified by a silica gel flash column using heptane and ethyl acetate as the elutes.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:4]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[N:27]=[C:28]=[O:29].CO>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[NH:27][C:28](=[O:29])[N:2]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH:4]=1)[CH3:1]
Reactant: Cc1ccc([N+](=O)[O-])cc1N=C=O
Reactant: CNc1cc(NC(=O)OC(C)(C)C)ncn1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])cc1NC(=O)N(C)c1cc(NC(=O)OC(C)(C)C)ncn1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A solution of tert-butyl (6-Methylamino-pyrimidin-4-yl)-carbamate (240 mg, 1.07 mmol, 1.0 eq.), commercially available 2-methyl-5-nitrophenylisocyanate (210 mg, 1.18 mmol, 1.1 eq.), and DMAP (26 mg, 0.21 mmol, 0.2 eq.) in toluene (10 ml) is stirred at 80° C. for 24 h. After cooling to room temperature methanol (10 ml) is added and the suspension formed is stirred for 10 min at 50° C. The precipitate is filtered off and washed with methanol (2×10 ml). After drying in vacuo an extremely insoluble colorless powder is obtained: HPLC: tR=8.09 min (purity: 85%, gradient A), ESI-MS: 403.5 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17](Cl)=[O:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.[NH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([NH:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(Cl)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reaction time: 14 h
Yield: 60 %

Procedure:
To a solution of 7-((3-chlorobenzyl)oxy)quinoline-3-carbonyl chloride in THF (1.5 mL) was added tert-butyl (2-aminoethyl)carbamate (38 mg, 0.23 mmol) and triethylamine (0.044 mL, 0.32 mmol). The reaction was stirred for 14 h. The crude reaction was loaded directly onto a column and purification (FCC, SiO2, 0-5%, MeOH/DCM) afforded the title compound as a white solid (44 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 9.31-9.20 (m, 1H), 8.61-8.51 (m, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.68-7.60 (m, 1H), 7.49 (s, 2H), 7.40-7.29 (m, 4H), 5.20 (s, 2H), 5.09-4.92 (m, 1H), 3.68-3.59 (m, 2H), 3.50-3.43 (m, 2H), 1.44 (s, 9H). [M+H]=456.3
Reaction SMILES: [Na].CN(C)C([S:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:9][CH:8]=1)=O.O.Cl>CO>[SH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[O:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=1
Reactant: COC(=O)CCC(=O)c1ccc(SC(=O)N(C)C)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)CCC(=O)c1ccc(S)cc1
Temperature: 25 °C

Procedure:
Sodium (280 mg, 12.18 mmoles) was dissolved in anhydrous methanol (50 ml). To the resulting solution was added the compound of Example 75, Step D (5.0 g). The mixture was stirred at room temperature for twelve hours and poured into a mixture of water (30 ml) and concentrated HCl (7 ml). The resulting yellow solid was collected by filtration, washed with water and dried to afford the title compound, m.p. 83°-84°.
Reaction SMILES: [S:1]([O:6]C)([O:4][CH3:5])(=[O:3])=[O:2].[O:8]=[C:9]([O:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[CH2:10][CH2:11][CH2:12][C:13]1[C:26]2[C:27]3=[C:28]4[C:23](=[CH:24][CH:25]=2)[CH:22]=[CH:21][CH:20]=[C:19]4[CH:18]=[CH:17][C:16]3=[CH:15][CH:14]=1>CC(C)=O>[CH3:5][O:4][S:1]([O-:6])(=[O:3])=[O:2].[CH3:5][N+:32]1([CH2:31][CH2:30][O:29][C:9](=[O:8])[CH2:10][CH2:11][CH2:12][C:13]2[C:26]3[C:27]4=[C:28]5[C:23](=[CH:24][CH:25]=3)[CH:22]=[CH:21][CH:20]=[C:19]5[CH:18]=[CH:17][C:16]4=[CH:15][CH:14]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: COS(=O)(=O)OC
Reactant: O=C(CCCc1ccc2ccc3cccc4ccc1c2c34)OCCN1CCOCC1
Solvent: CC(C)=O
Product: COS(=O)(=O)[O-]
Product: C[N+]1(CCOC(=O)CCCc2ccc3ccc4cccc5ccc2c3c45)CCOCC1
Temperature: 50 °C

Procedure:
Dimethyl sulfate (6 mls; 0.063M) is added dropwise to a solution of 4-[2-[1-oxo-4-(1-pyrenyl)butoxy]ethyl]morpholine (2.64 grams; 0.006M) in dry acetone (50 mls) at 0° C., and the resulting reaction mixture is then heated at 50° C. for 1.5 hours. The reaction mixture is cooled to ambient temperature and filtered to recover a precipitate of the desired compound which weighs 2.28 grams, after drying in a vacuum oven, and melts at 115°-117° C.
Reaction SMILES: [SiH4].[NH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11].[CH2:16]([Cl:19])[CH:17]=[CH2:18]>CO.[Cu]>[ClH:19].[CH2:18]([N:5]([CH2:4][CH2:3][NH2:2])[CH2:6][CH2:7][CH2:8][Si:9]([O:14][CH3:15])([O:10][CH3:11])[O:12][CH3:13])[CH:17]=[CH2:16]
Reactant: C=CCCl
Reactant: CO[Si](CCCNCCN)(OC)OC
Agent: [Cu]
Agent: [SiH4]
Solvent: CO
Product: C=CCN(CCN)CCC[Si](OC)(OC)OC
Product: Cl

Procedure:
Example 1 was repeated except that the copper foil was pretreated with a silane solution prepared as follows. 6.66 grams of N-2-aminoethyl-3-aminopropyltrimethoxysilane (a product of Petrarch Systems Inc.) in 886 g of methanol were charged in a reaction vessel with 2.29 grams of allyl chloride to produce 3-(N-allyl-2-aminoethylamino)-propyltrimethoxysilane hydrochloride. A 1% solution of this silane in methanol was prepared as described in Example 12 and the copper foil dipped for 30 minutes. The copper foil and lamination were performed as described in Example 12 at a psi of 1100. The prepregs (2-ply) had a 62.45% polymer uptake and were formed into 6"×6" 2-ply laminates.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:14]3[CH3:17])=[C:10]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2].[C:35](Cl)(=[O:39])[CH:36]([CH3:38])[CH3:37].CCN(CC)CC>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH2:23][CH2:24]4)[N:14]3[CH3:17])=[C:10]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(=O)C(C)C)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.5 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-8-piperidin-4-ylmethyl-9H-purine (230 mg, 0.50 mmol), isobutyryl chloride (59 mg, 0.55 mmol) and NEt3 (140 μL, 1.00 mmol) in DCM (10 mL) was allowed to stir at r.t. for 5 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-5%) then further purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 40-98%) affording 851 as a white solid (57 mg, 21%). LCMS (method I): RT 3.69 min, [M+H]+ 531.4. 1H NMR (DMSO, 400 MHz): δ 8.01-8.00 (1 H, m), 7.63-7.62 (1 H, m), 7.27-7.23 (2 H, m), 4.40 (1 H, d, J=13.34 Hz), 4.25 (4 H, brd s), 3.94 (1 H, d, J=13.78 Hz), 3.77-3.74 (7 H, m), 3.26 (2 H, q, J=7.45 Hz), 3.01 (1 H, t, J=13.02 Hz), 2.87-2.85 (3 H, m), 2.50-2.50 (1 H, m), 2.12-2.08 (1 H, m), 1.77-1.73 (2 H, m), 1.33 (3 H, t, J=7.44 Hz), 1.29-1.07 (2 H, m), 1.00-0.98 (6 H, m)
Reaction SMILES: C([C:4]1C(CO)=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:6]([CH:28]([CH3:30])[CH3:29])[N:5]=1)(C)C.C([O:34][CH2:35][CH3:36])(=O)C.[CH3:37][CH2:38][CH2:39]CCC>>[CH:38]([CH:36]1[C:35]([OH:34])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:6]([CH:28]([CH3:29])[CH3:30])[N:5]1[CH3:4])([CH3:39])[CH3:37]
Reactant: Cc1ccc(/C=C/c2c(C(C)C)nc(C(C)C)c(CO)c2-c2ccc(F)cc2)cc1
Reactant: CCOC(C)=O
Reactant: CCCCCC
Product: Cc1ccc(CCC2=C(C(C)C)N(C)C(C(C)C)C(O)=C2c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from 2,6diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5-[2(E)-(4-methylphenyl)ethenyl]pyridine (Example 42 ) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.17 (m, 4 H), 7.02 (d, J=7.7 Hz, 2 H), 6.75 (d, J=7.7 Hz, 2 H), 4.36 (d, J=4 Hz, 2 H), 3.43 (sept, J=6.6 Hz, 1 H), 3.34 (sept, J=6.6 Hz, 1 H), 2.55 (m, 4 H), 2.29 (s, 3 H), 1.34 (d, J=6.6 Hz, 6 H), 1.33 (d, J=6.6 Hz, 6 H), 1.20 (m, 1 H). FAB-MS: calculated for (C27H32FNO) 405, found 406 (M+H). Anal. Calcd for C27H32FNO: C, 79.96; H, 7.95; N, 3.45. Found: C, 79.40; H, 7.84; N, 3.44. mp 121-123° C. Rf=0.3 (20% ethyl acetate/hexane). vl)propyllpyridine
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH2:10]1[CH2:14]OC[CH2:11]1>C(OCC)C.[Ti]>[C:2]1([C@@H:1]([OH:8])[CH2:14][CH:10]=[CH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C1CCOC1
Agent: [Ti]
Solvent: O
Solvent: CCOCC
Product: C=CC[C@H](O)c1ccccc1
Temperature: -74 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of 1.25 mmol of the titanium compound of Example 2b in 60 ml of diethyl ether is cooled to -74° C., and 0.1 ml (1.0 mmol) of freshly distilled benzaldehyde is added. The slightly yellow, clear solution is stirred for a further 2 hours at -74° C. and 5 ml of a 5N H2O/THF solution are added and the mixture is warmed to RT, stirred for a further hour at this temperature, filtered with suction and concentrated on a rotary evaporator. The crude product (0.80 g of a clear colourless oil) is flash-chromatographed (60 g of silica gel, 35 cm long, cross-section 2 cm, 5 ml/fraction, 0.4 bar, 10:1 toluene/ethanol). 0.098 g of product is obtained. Yield: 66%, ee: 93%.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[I-:11].[Na+]>CC(=O)CC.C(OCC)(=O)C>[I:11][CH2:2][C:3](=[O:10])[N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: [I-]
Reactant: O=C(CCl)N1CCOCC1
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: O=C(CI)N1CCOCC1
Yield: 86.1 %

Procedure:
Dissolve 1-chloro-2-oxo-2-(morpholin-4-yl)ethane (7.0 g, 42.8 mmol) and sodium iodide (8.0 g, 53.4 mmol) in 2-butanone (150 mL) and reflux for 3 hours under nitrogen. Dilute with ethyl acetate (200 mL), filter, concentrate under reduced pressure and chromatograph on flash silica using neat ethyl acetate to obtain 9.4 g (86%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.S(Cl)(Cl)=O.[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH2:17].[OH-].[Na+]>O1CCCC1.C(N(CC)CC)C>[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH:17][C:4]([C:1]1([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:5]
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: Nc1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(O)C1(C(=O)Nc2ccc(F)cc2F)CC1
Temperature: 25 °C
Yield: 63 %

Procedure:
1,1-Cyclopropanedicarboxylic acid (2.5 g) was dissolved in tetrahydrofuran (25 ml) under a nitrogen atmosphere, and triethylamine (2.68 ml) was added dropwise thereto while stirring in an ice water bath. After stirring at the same temperature for 30 min, thionyl chloride (1.4 ml) was added dropwise while stirring in an ice water bath. After stirring at the same temperature for 30 min, a solution of 2,4-difluoroaniline (2.15 ml) in tetrahydrofuran (15 ml) was added while stirring in an ice water bath, and the reaction mixture was allowed to gradually warm up to room temperature and stirred overnight. After addition of a 2N aqueous solution of sodium hydroxide (75 ml) to the reaction mixture, tetrahydrofuran was removed under reduced pressure. To the resultant solution was added tert-butyl methyl ether (25 ml), followed by stirring. The organic layer and the aqueous layer were separated. The aqueous layer was cooled in an ice water bath, 5N hydrochloric acid (30 ml) was added and stirred. The precipitated solid was collected by filtration, and washed with water. Drying under aeration and hot-air drying at 60° C. for 8 hr provided the titled compound as white powder (2.918 g, 63%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.C(N(CC)CC)C.O1CCCC1.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[OH:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C#C[Si](C)(C)C)cc(C(C)(C)C)c1O

Procedure:
Following General Procedure D and using 4-bromo-2,6-di-t-butyl-phenol (1.43 g, 5 mmol), triethyl amine (15 mL), anhydrous tetrahydrofuran (15 mL), copper(I)iodide (0.06 g, 0.31 mmol), trimethylsilyl acetylene (4.9 g, 50 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.18 g, 0.26 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using hexane as eluent, the title compound was obtained (1.35 g, 90%).
Reaction SMILES: [CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:32]1[C:35]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:34][N:33]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>>[CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([N:38]5[CH2:39][CH2:40][C:35]6([CH2:34][N:33]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[CH2:32]6)[CH2:36][CH2:37]5)=[O:23])=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCC5(CC4)CN(C(=O)OC(C)(C)C)C5)cn3)nc2n1C1CCCCCC1
Yield: 18.4 %

Procedure:
Following general amide formation method 1, 6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (80 mg, 0.19 mmol, 1.0 eq) was combined with tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (47.1 mg, 0.208 mmol, 1.1 eq) to afford tert-butyl 7-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate as a white solid (22 mg, 0.035 mmol) in 18.4% yield. 1H NMR (400 MHz, chloroform-d) δ ppm 8.67 (s, 1H) 8.60 (d, J=8.59 Hz, 1H) 8.31 (d, J=2.02 Hz, 1H) 8.16-8.28 (m, 1H) 7.74 (dd, J=8.59, 2.53 Hz, 1H) 6.39 (s, 1H) 5.23 (s, 1H) 4.38-4.51 (m, 1H) 3.63 (s, 4H) 3.52 (br s, 2H) 3.10 (s, 6H) 2.48-2.66 (m, 2H) 1.86-2.03 (m, 2H) 1.56-1.85 (m, 9H) 1.42-1.56 (m, 4H) 1.38 (s, 9H). MS (m/z, MH+): 631.7
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][S:6][C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.S(=O)(=O)(O)[OH:17]>>[CH3:5][S:6]([C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:1]([O-:4])=[O:2])[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:17]
Reactant: CSc1nc2ccccc2s1
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])O
Product: CS(=O)c1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
At a temperature of 0° to 15° C, a mixture of 17.6 grams of fuming nitric acid and 35 grams of concentrated sulfuric acid was added dropwise while stirring to a solution of 18.1 grams (0.1 mole) of 2-methylmercaptobenzthiazole in 70 ml of concentrated sulfuric acid. The mixture was heated to 30°-35° C and stirred for a further 3 hours at this temperature. The reaction mixture was then poured onto 200 grams of ice, the 2-methylsulfinyl-6-nitrobenzthiazole was filtered off, washed until neutral and dried. 17.5 Grams of crude product were obtained (72.4 %).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:15]([OH:17])=O)=[N:6][O:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.O/[N:42]=[C:43](/[C:45]1[CH:62]=[CH:61][C:48]([CH2:49][N:50]2[CH2:53][CH:52]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:51]2)=[CH:47][CH:46]=1)\[NH2:44]>C(#N)C>[CH:1]1([C:4]2[C:5]([C:15]3[O:17][N:44]=[C:43]([C:45]4[CH:46]=[CH:47][C:48]([CH2:49][N:50]5[CH2:51][CH:52]([C:54]([O:56][C:57]([CH3:58])([CH3:60])[CH3:59])=[O:55])[CH2:53]5)=[CH:61][CH:62]=4)[N:42]=3)=[N:6][O:7][C:8]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1noc(-c2ccccc2)c1C1CC1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccc5)c4C4CC4)n3)cc2)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 4-cyclopropyl-5-phenylisoxazole-3-carboxylic acid (22 mg, 0.096 mmol), HOBt (26.5 mg, 0.173 mmol), and diisopropylethylamine (0.067 mL, 0.384 mmol) in acetonitrile (1 mL) was added EDC (43.2 mg, 0.226 mmol) and (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 29.3 mg, 0.096 mmol). The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give tert-butyl 1-(4-(5-(4-cyclopropyl-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5](I)=[CH:4][N:3]=1.[F:11][C@H:12]1[CH2:14][C@H:13]1[C:15]([NH:17][C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23](B1OC(C)(C)C(C)(C)O1)[CH:22]=2)=[O:16]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:23]2[CH:22]=[C:21]3[C:26]([CH:27]=[C:18]([NH:17][C:15]([C@@H:13]4[CH2:14][C@@H:12]4[F:11])=[O:16])[N:19]=[CH:20]3)=[CH:25][CH:24]=2)=[C:6]([CH3:9])[C:7]=1[F:8]
Reactant: Cc1c(I)cnc(Cl)c1F
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)[C@@H]4C[C@@H]4F)ncc3c2)OC1(C)C
Product: Cc1c(-c2ccc3cc(NC(=O)[C@@H]4C[C@@H]4F)ncc3c2)cnc(Cl)c1F

Procedure:
The title compound was prepared following a procedure similar to that described for Example 12, using 2-chloro-3-fluoro-5-iodo-4-methyl-pyridine and (1S,2S)-2-fluoro-N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)cyclopropanecarboxamide, and was carried forward without purification; 0.407 g (98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:20][CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:5]([CH:8]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:10]=1)[CH:6]=[O:7].[C:29]([O:33][C:34]([N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[C:37]1[C:45]1[CH:50]=[C:49](Cl)[N:48]=[N:47][C:46]=1[O:52][CH3:53])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[C:37]1[C:45]1[CH:50]=[C:49]([C:9]2[CH:10]=[C:3]([O:2][CH3:1])[C:4]([O:20][CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])=[C:5]([CH:6]=[O:7])[CH:8]=2)[N:48]=[N:47][C:46]=1[O:52][CH3:53])=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(C=O)c1OCOCC[Si](C)(C)C
Reactant: COc1nnc(Cl)cc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Product: COc1cc(-c2cc(-c3cc4ccccc4n3C(=O)OC(C)(C)C)c(OC)nn2)cc(C=O)c1OCOCC[Si](C)(C)C

Procedure:
400 mg of 3-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-(2-trimethylsilanyl-ethoxymethoxy)-benzaldehyde and 353 mg of 2-(6-Chloro-3-methoxy-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester is reacted analogously to the procedure described in Example 126(a). Yield 377 mg. LC-MS (ES+) 606 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[C:7]1\[CH2:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:10][CH2:11][CH:12]\1[OH:13].[C:33]([OH:36])(=[O:35])[CH3:34]>ClCCl>[C:33]([OH:36])(=[O:35])[CH3:34].[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[C:7]1\[CH2:8][NH:9][CH2:10][CH2:11][CH:12]\1[OH:13]
Reactant: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccco1
Solvent: ClCCl
Solvent: CC(=O)O
Product: OC1CCNC/C1=C\c1ccco1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of (E)-3-[(furan-2-yl)methylidene]-1-(triphenylmethyl)piperidin-4-ol (3.70 g) in dichloromethane (75 ml) was added acetic acid (10 ml) under ice-cooling, and the resulting mixture was stirred at 60° C. for 3 hours. After stirring, acetic acid (10 ml) was added to the reaction mixture, and the resulting mixture was furthermore stirred at 60° C. for 1.5 hours. The reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of methanol and dichloromethane (1:19 to 1:9) as the eluent to afford the title compound (2.81 g, yield: quantitative) as a pale brown solid.