Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9]CC)=[O:8])=[CH:5][N:6]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:12]1[CH:17]=[CH:16][C:15]([C:2]2[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)c1cnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cnc(-c2ccncc2)s1
Reaction time: 0.33 h

Procedure:
A mixture of ethyl 2-bromo-1,3-thiazole-5-carboxylate (0.095 mL, 0.64 mmol), pyridine-4-ylboronic acid (0.094 g, 0.76 mmol), tetrakis(triphenylphosphine)palladium(0) (0.007 g, 0.006 mmol), and potassium carbonate (0.263 g, 1.91 mmol) in 1,4-dioxane (10 mL) and water (0.5 mL) was subjected to MWI at 160° C. for 20 min. The reaction mixture was diluted with water and extracted with EtOAc. The organic solutions were combined, acidified and concentrated. The residue was dissolved in EtOAc and brine was added. The organic solution was separated, dried over Na2SO4, filtered and concentrated to give 2-pyridin-4-yl-1,3-thiazole-5-carboxylic acid which was used without further purification. LCMS: (FA) ES+ 207.
Reaction SMILES: C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[CH2:22]([O:29][C@H:30]1[C@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@H:33]([CH3:52])[O:32][C@@H:31]1[O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][OH:64])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)Cl.S(=O)(=O)(O)O>C(O)C>[CH2:22]([O:29][C@H:30]1[C@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@H:33]([CH3:52])[O:32][C@@H:31]1[O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH:63]=[O:64])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@@H]1O[C@H](OCCCCCCCCCCO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: ClCCl
Product: C[C@@H]1O[C@H](OCCCCCCCCCC=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
PDC oxidation of 10-(2,3,4-tri-O-benzyl-β-L-fucopyranosyloxy)-n-decanol. Under an atmosphere of nitrogen, pyridinium dichromate (550 mg, 1.424 mmol) was added to a dry methylene chloride solution (20 mL) of 10-(2,3,4-tri-O-benzyl-β-L-fucopyranosyloxy)-n-decanol (580 mg, 0.982 mmol). The resulting brown slurry was stirred at room temperature under nitrogen. TLC analysis (visualization by UV and char with 10% sulfuric acid in ethanol) of the reaction mixture indicated complete consumption of the starting material and the formation of a new compound after 18 h. The reaction mixture was treated with ether (10 mL), filtered through silica gel and Celite with an ether wash (25 mL) and concentrated to an off-white oil. Chromatographic purification (silica gel, 20% ethyl acetate in hexanes) afforded 410 mg (0.697 mmol, 71%) of 10-(2,3,4-tri-O-benzyl-β-L-fucopyranosyloxy)-n-decanal as a clear oil. Rf=0.50 (silica gel, 30% ethyl acetate in hexanes); 1H NMR (CDCl3, 300 MHz) δ: 9.76 (t, J=1.8 Hz, 1H), 7.35 (m, 15H), 5.02 (d, J=8.1 Hz, 1H), 4.98 (d, J=7.2 Hz, 1H), 4.81 (m, 2H), 4.76 (d, J=5.7 Hz, 1H), 4.72 (d, J=5.7 Hz, 1H); 3.34 (d, J=7.8 Hz, 1H), 3.97 (dt, J=9.6, 6.0 Hz, 2H), 3.84 (dd, J=9.6, 7.8 Hz, 1H), 3.65-3.40 (m, 3H), 2.41 (dt, J=7.2, 1.5 Hz, 2H), 1.65 9m, 4H), 1.31 (s, 10H), 1.21 (d, J=6.3 Hz, 3H); MS (FAB+): 611.2 ((M+Na)+, 8), 595.2 ((M+Li)+, 100), 567.2 (12), 505.2 (10), 441.1 (7), 401.1 (6).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[F:27][C:28]([F:40])([F:39])[C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:26][C:24]1[CH:23]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][N:20]([S:35]([C:32]2[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:39])[F:40])=[CH:34][CH:33]=2)(=[O:37])=[O:36])[CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCNCC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)c1
Reaction time: 18 h
Yield: 42.2 %

Procedure:
To a solution of compound 24 (0.099 g, 0.27 mmol) in CH2Cl2 (3 mL) was added 4-(trifluoromethyl)benzenesulfonyl chloride (0.093 g, 0.38 mmol) and triethylamine (0.039 g, 0.38 mmol). The reaction mixture was stirred for 18 hrs, whereupon the starting material was consumed (TLC, 1% MeOH in CH2Cl2). The reaction mixture was then concentrated in vacuo, redissolved in a minimal amount of CH2Cl2, and chromatographed over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white solid. The solid was triturated with diisopropyl ether/hexanes and vacuum filtered to afford compound 60 as a white powder. (0.065 g, 42.2% yield, 95.7% HPLC purity). 1H NMR (500 MHz, CDCl3): 8.23 (d, J=2 Hz, 1H), 7.86 (m, 4H), 7.67 (dd, J1=9 Hz, J2=2 Hz, 1H), 6.95 (s, 1H), 6.89 (d, J=9 Hz, 1H), 6.68 (s, 2H), 3.48 (m, 4H), 3.15 (m, 4H), 2.35 (s, 6H); MS (ESI, EI+): m/z=580 (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.S(=O)(=O)(O)[O-].[Na+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:25]([O:24][C:20](=[O:23])[CH:21]=[CH:22][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1)[CH3:26]
Reactant: C=CC(=O)OCC
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc([C@@H]2CCC[C@H]2NS(=O)(=O)C(C)C)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
(+,−) Trans propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (150 mg, 0.38 mmol, prepared in example 2) was dissolved in DMF (5.0 mL) and ethyl acrylate (103 uL, 0.95 mmol), triethylamine (186 uL, 1.3 mmol), palladium acetate (4 mg, 0.02 mmol), and triphenylphosphine (10 mg, 0.04 mmol) were added. The reaction was heated to 80° C. and stirred overnight under nitrogen. Allowed the reaction to cool and diluted with 75 mL of 10% aqueous sodium bisulfate and extracted into methylene chloride (2×50 mL). Dried the organics over sodium sulfate, filtered and concentrated in vacuo to a crude brown oil. The desired compound was purified by radial chromatography eluting with methylene chloride followed by the addition of 2% MeOH. The appropriate fractions were concentrated to provide 63 mg (45%) of a near-colorless oil of the title compound.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.OC1C=CC=C[N+]=1[O-].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][CH:27]=[C:26]2[O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43]([OH:45])=O)=[CH:38][CH:37]=1.[NH2:46][C:47]1[CH:51]=[CH:50][O:49][N:48]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:49]1[CH:50]=[CH:51][C:47]([NH:46][C:43](=[O:45])[CH2:42][C:39]2[CH:38]=[CH:37][C:36]([O:35][C:26]3[C:25]4[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([O:22][CH3:21])[CH:24]=4)[N:29]=[CH:28][CH:27]=3)=[CH:41][CH:40]=2)=[N:48]1
Reactant: Nc1ccon1
Reactant: COc1cc2nccc(Oc3ccc(CC(=O)O)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(CC(=O)Nc4ccon4)cc3)c2cc1OC
Temperature: 60 °C
Yield: 14.6 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.226 g) and 2-hydroxypyridine N-oxide (0.131 g) were added in turn to a stirred mixture of 2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]acetic acid (0.2 g), 3-aminoisoxazole (0.064 g), diisopropylethylamine (0.226 g) and DMF (3 ml) at ambient temperature. The resultant mixture was stirred and heated to 60° C. for 16 hours. The mixture was evaporated and the residue was purified by preparative HPLC using a Waters ‘Xterra’ reversed-phase column (5 microns silica, 30 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetoliitrile as eluent. There was thus obtained the title compound (0.035 g); 1H NMR: (DMSOd6) 3.76 (s, 2H), 3.92 (s, 3H), 3.95 (s, 3H), 6.47 (d, 1H), 6.93 (d, 1H), 7.23 (d, 2H), 7.4 (s, 1H), 7.46 (d, 2H), 7.49 (s, 1H), 8.49 (d, 1H), 8.80 (d, 1H), 11.33 (br s, 1H); Mass Spectrum: M+H+ 406.
Reaction SMILES: O[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.O=P(Cl)(Cl)[Cl:19]>>[CH2:15]([O:14][C:12]([C:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:19])[C:3]=2[NH:10][C:9]=1[CH3:11])=[O:13])[CH3:16]
Reactant: CCOC(=O)c1c(C)[nH]c2c(O)ncnc12
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12

Procedure:
A reaction flask, equipped with a mechanic stirrer, a reflux condenser and a nitrogen bubbler is charged with POCl3 (1200 mL). Ethyl 4-hydroxy-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate from example A3 (207.19 g; 1.00 mol) is added in several portions. The carefully stirred suspension is heated to gentle reflux for five hours.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3](=[O:13])[C@@H:4]([CH3:12])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:15][C:16]([F:37])([F:36])[C:17]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:18]=1[CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([CH:26]=O)[CH2:22][CH2:21]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:37][C:16]([F:15])([F:36])[C:17]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:18]=1[CH2:19][N:20]1[CH2:25][CH2:24][CH:23](/[CH:26]=[C:10]2/[C:6]([NH:5][C@@H:4]([C:3]([N:2]([CH3:1])[CH3:14])=[O:13])[CH3:12])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:22][CH2:21]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: C[C@@H](NC1=NC(=O)SC1)C(=O)N(C)C
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C[C@@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a solution of N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-D-alaninamide (1.02 g) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.93 g) in 2-propanol (10 mL) was added piperidinium acetate (826 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (1.30 g)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[C:61]([Cl:62])=[CH:60][CH:59]=[CH:58][C:57]=2[Cl:63])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[C:57]([Cl:63])=[CH:58][CH:59]=[CH:60][C:61]=2[Cl:62])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2c(Cl)cccc2Cl)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2c(Cl)cccc2Cl)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 106 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(2,6-dichloro-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 2 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was crystallized from diethylether, leading to 123 mg white solid (85%). MS (ISP) 479.5 (M+H)+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[C@@H:27]2[C@@H:23]([O:24][C:25](=[O:28])[CH2:26]2)[CH2:22][C@@H:21]1[F:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[Si:1]([O:18][CH2:19][C@@H:20]1[C@@H:27]2[C@@H:23]([O:24][CH:25]([OH:28])[CH2:26]2)[CH2:22][C@@H:21]1[F:29])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@@H]1F)(c1ccccc1)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC[C@@H]1[C@H]2CC(O)O[C@H]2C[C@@H]1F)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a stirring solution consisting of (3aR,4S,5S,6aS)-4-((tert-butyldiphenylsilyloxy)methyl)-5-fluorohexahydro-2H-cyclopenta[b]furan-2-one (prepared in Step A, 26.6 g, 64.6 mmol) in anhydrous THF (1 L) cooled to −78° C. was added DIBAL-H (1 M solution in THF; 200 mL) dropwise. The reaction mixture was stirred at −78° C. and reaction progress was monitored by TLC. After 2 hours, the reaction mixture was quenched by the addition of 2:1 THF-water at −78° C. and the reaction mixture was allowed to warm to room temperature with stirring until precipitated aluminum salts settled out of solution. The aluminum salts were removed by filtration through a sintered glass fritted filter funnel and the filtrate was evaporated to dryness to afford the title intermediate (26 g) The crude intermediate was carried on with no further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[ClH:19].Cl.[NH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([NH2:31])=[NH:30])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C>CN(C)C=O>[ClH:19].[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29](=[NH:30])[NH2:31])[CH2:25][CH2:24]1)[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N=C(N)N1CCC(CN)CC1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCC1CCN(C(=N)N)CC1)C1CCCCC1

Procedure:
The title compound was prepared using (S)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (10.1 g, 39.28 mmol), 4-aminomethyl-piperidine-1-carboxamidine dihydrochloride (9.0 g, 39.28 mmol) , HATU (14.9 g, 39.28 mmol), and collidine (15.6 ml, 117.8 mmol) in dimethylformamide as described in example 223 a).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)#[N:4].Cl[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[CH2:24]2)=[CH:18][N+:17]=1[O-].Cl.P(Cl)(Cl)Cl>CN(C)C=O.C(OCC)(=O)C>[OH:14][C:9]1[NH:10][C:11]2[C:7]([C:8]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([CH3:29])[CH2:24]3)=[CH:18][N:17]=1)=[CH:6][C:5]([C:3]#[N:4])=[CH:13][CH:12]=2
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: CC1CCCN(Cc2ccc(Cl)[n+]([O-])c2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Product: CC1CCCN(Cc2ccc(-c3c(O)[nH]c4ccc(C#N)cc34)nc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.1 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 45 mg, 1.12 mmol) in N,N-dimethylformamide (1 mL) was added 5-cyanooxindole (133 mg, 0.84 mmol), and the mixture was stirred at ambient temperature for 10 min. To the obtained brownish solution was added a solution of 2-chloro-5-[(3-methylpiperidin-1-yl)methyl]pyridine 1-oxide (0.56 mmol) in N,N-dimethylformamide (1.5 mL). The reaction mixture was heated at 130° C. for 30 min, and was then allowed to cool. To the residue was added 2 M HCl(aq) and the obtained suspension was washed with ethyl acetate. The aqueous layer was neutalized with 45% NaOH(aq) and alkalized to saturation with NaHCO3 (s), and extracted two times with ethyl acetate. The extracts were combined, dried (MgSO4) and the solvent was removed in vacuo affording 84 mg of the crude product. The material was dissolved in ethyl acetate (10 mL), and to the solution was added phosphorus trichloride (0.2 mL, 2.24 mmol). The obtained orange suspension was heated at reflux for 1 h and was then allowed to cool. The precipitate was filtered, washed with ethyl acetate, and dried in vacuo affording 70 mg of an orange residue. The material was was purified by preparative HPLC (column: Xterra, C8, 7 μm, 19×300 mm; eluent: 0.1 M NH4OAc buffer/acetonitrile, 8:2 to 4:6) affording 15 mg (8% yield) of the title compund as an orange solid: 1H NMR (aceton-d6, 400 MHz) δ 9.86 (br s, 1 H), 8.11 (s, 1 H), 7.91 (dd, J=9, 2 Hz, 1 H), 7.84 (d, J=9 Hz, 1 H), 7.82 (d, J=1 Hz, 1 H), 7.26 (dd, J=8, 2 Hz, 1 H), 7.11 (d, J=8 Hz, 1 H), 3.44 (s, 2 H), 2.00-1.50 (m, 6 H), 0.95-0.81 (m, 4 H); MS (ES) m/z 347 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[C:15]([CH:18]=1)[CH:16]=O.Cl.[CH3:29][NH:30][CH3:31].C(N(CC)CC)C.C([BH3-])#N.[Na+]>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[C:15]([CH:18]=1)[CH2:16][N:30]([CH3:31])[CH3:29]
Reactant: CNC
Reactant: O=Cc1cc(/C=C/c2ccc(F)cc2F)ccc1S(=O)(=O)c1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)Cc1cc(/C=C/c2ccc(F)cc2F)ccc1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-[(E)-2-(2,4-difluorophenyl)vinyl]-2-(phenylsulfonyl)benzaldehyde (prepared from Example 58 according to the method of Example 50 Step 1, 100 mg, 0.26 mmol), dimethylamine hydrochloride (50 mg, 0.62 mmol), titanium(IV) isopropoxide (0.2 mL, 0.62 mmol) and triethylamine (0.1 mL, 0.62 mmol) in ethanol (2 mL) was stirred at room temperature overnight. Sodium cyanoborohydride (35 mg, 0.56 mmol) was added and the reaction stirred for a further 3 hours. The solvent was removed in vacuo and the residue partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 0–3% methanol/dichloromethane, to give the title compound as a white solid. δH (360 MHz, d6 DMSO): 8.12 (1H, d, J=8.2 Hz), 7.93–7.81 (5H, m), 7.68–7.56 (3H, m), 7.38 (2H, s), 7.33–7.27 (1H, m), 7.14 (1H, td, J=2.4, 8.5 Hz), 3.57 (2H, s), 1.88 (6H, s). m/z (ES+) 414 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH2:21][CH2:22][C:23]#[N:24].O1CCOCC1>C(O)(C)(C)C>[Cl:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[C:23]([NH2:24])[C:22]([CH2:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH3:11])=[CH:4]2
Reactant: Nc1ccc(Cl)cc1C=O
Reactant: COc1cccc(OC)c1CCC#N
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: COc1cccc(OC)c1Cc1cc2cc(Cl)ccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-chlorobenzaldehyde and 3-(2,6-dimethoxyphenyl)propionitrile. Instead of dioxane, tert-butanol was used from [sic; as]1 the solvent. 1TN: “aus” (from) appears to be a typo for “als” (as).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1C=[CH:32][C:6]([CH2:7][N:8]2[CH2:15][CH2:14][C:11]3([CH2:13][CH2:12]3)[CH2:10][CH:9]2[C:16]([NH:18][C:19]2([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)[CH2:21][CH2:20]2)=[O:17])=[CH:5][CH:4]=1.ClCC1C=[N:40]C(C(F)(F)F)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[F:35][C:2]([F:1])([F:34])[C:3]1[N:40]=[CH:32][C:6]([CH2:7][N:8]2[CH2:15][CH2:14][C:11]3([CH2:13][CH2:12]3)[CH2:10][CH:9]2[C:16]([NH:18][C:19]2([C:22]3[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[CH2:20][CH2:21]2)=[O:17])=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3Cc3ccc(C(F)(F)F)cc3)CC4)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3Cc3ccc(C(F)(F)F)nc3)CC4)CC2)cc1
Yield: 93.8 %

Procedure:
The title compound (D124) (47 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate (D90) (50 mg) and 3-chloromethyl-6-(trifluoromethyl)piridine (38 mg). (Cs2CO3: 1.3 eq; reaction time: 18 hrs; RT)
Reaction SMILES: CS[C:3](=[C:6]([C:12]([O:14]CC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:4][CH3:5].[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[NH:27])=[CH:21][CH:20]=1.[K+].[Br-]>>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[N:25]([C:22]3[CH:23]=[CH:24][C:19]([S:18][CH3:17])=[CH:20][CH:21]=3)[C:12](=[O:14])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:3]([S:4][CH3:5])[N:27]=2)=[CH:33][CH:32]=1
Reactant: CSc1ccc(NC(=N)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)C(C(=O)OCC)=C(SC)SC
Agent: [Br-]
Agent: [K+]
Product: CCOC(=O)c1c(SC)nc(-c2ccc(F)cc2)n(-c2ccc(SC)cc2)c1=O
Yield: 2.9 %

Procedure:
The title compound was prepared from diethyl [bis(methylthio)methylene]malonate (5.3 g, 20 mmol) and N-(4-methythiophenyl)-4-(fluoro)benzenecarboximidamide (5.2 g, 20 mmol) (prepared according to the procedure described in preparation 2) by following the procedure described in example 41 (0.25 g, yield 2.9%, mp 166-169° C., purity 96.84% by HPLC). 1H-NMR (CDCl3):δ 1.36-1.4 (t, 3H), 2.45 (s, 3H), 2.55 (s, 3H), 4.38-4.43 (q, 2H), 6.91-6.96 (m, 2H), 7.01-7.03 (d, 2H), 7.16-7.18 (d, 2H), 7.33-7.37 (m, 2H). IR (KBr) cm−1: 3447, 3069, 2989, 2900, 1733, 1666. MS m/z:431.2.0(M+).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:8][O:7][N:6]=1)[NH2:4].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])N>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:8][O:7][N:6]=2)=[N:2][OH:1])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)NCCCNc1nonc1C(N)=NO
Product: CS(=O)(=O)NCCCNc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Yield: 10 %

Procedure:
The title compound was prepared according to the procedure of Example 4, step E, using N′-hydroxy-4-({3-[(methylsulfonyl)amino]propyl} amino)-1,2,5-oxadiazole-3-carboximidamide [made according to Example 4, steps A through D] and 3-chloro-4-fluoroaniline [Aldrich, product #228583] as the starting materials in 10% yield. LCMS for C13H17ClFN6O4S (M+H)+: m/z=407.1. 1H NMR (400 MHz, CD3OD): δ 7.06 (t, J=8.9 Hz, 1H), 6.98 (m, 1H), 6.80 (m, 1H), 3.73 (m, 2H), 3.28 (m, 2H), 2.94 (s, 3H), 1.28 (m, 2H).