Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][N:9]=[C:10]([C:15]3[CH:16]=[N:17][C:18]([CH:21]4[CH2:23][CH2:22]4)=[N:19][CH:20]=3)[CH:11]=2)[CH2:6]1)(C)(C)C.[Cl:24]C(OC(Cl)C)=O.[Cl-].[Ca+2].[Cl-]>C1(C)C=CC=CC=1>[ClH:24].[CH:21]1([C:18]2[N:19]=[CH:20][C:15]([C:10]3[CH:11]=[C:12]4[C:7](=[CH:8][N:9]=3)[CH2:6][NH:5][CH2:14][CH2:13]4)=[CH:16][N:17]=2)[CH2:23][CH2:22]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC(C)(C)N1CCc2cc(-c3cnc(C4CC4)nc3)ncc2C1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cl
Product: c1nc(C2CC2)ncc1-c1cc2c(cn1)CNCC2
Reaction time: 0.33 h
Yield: 106.6 %

Procedure:
A mixture of 2-tert-butyl-6-(2-cyclopropylpyrimidin-5-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine (0.12 g, 0.39 mmol), 1-chloroethyl chloroformate (1.0 mL, 5.8 mmol) and toluene (10 mL) was refluxed for 4 h under protection from moisture (calcium chloride tube). After concentration to dryness, the dark residue was taken up in MeOH (10 mL) and refluxed for 3 h more. Charcoal (1 g) was added and refluxing continued for 20 minutes. Then the mixture was filtered through Celite and the clear filtrate was concentrated to give the title compound (0.12 g) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>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>[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:18][CH2:19]2)=[CH:35][CH:34]=1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: NCc1ccc(B(O)O)cc1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN)cc4)cc23)CC1
Temperature: 160 °C
Yield: 30.9 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30.0 mg, 0.072 mmol), Cs2CO3 (95 mg, 0.290 mmol) and [4-(aminomethyl)phenyl boronic acid (55 mg, 0.290 mmol) in dioxane/H2O (1.5 mL/0.5 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh3)4 (7.5 mg, 0.0072 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 160° C. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine (10 mL), dried over MgSO4, filtered, concentrated, and purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (9.8 mg, 31%).
Reaction SMILES: [N+]([CH3:4])([O-])=O.[CH:5]1[CH:13]=[CH:12][C:11]2[C:7](=[N:8][O:9][N+:10]=2[O-:14])[CH:6]=1.CC1N=CN=C(C)C=1>O1CCCC1>[OH:9][N:8]1[C:7]2[CH:6]=[CH:5][CH:13]=[CH:12][C:11]=2[N+:10]([O-:14])=[CH:4]1
Reactant: [O-][n+]1onc2ccccc21
Reactant: C[N+](=O)[O-]
Agent: Cc1cc(C)ncn1
Solvent: C1CCOC1
Product: [O-][n+]1cn(O)c2ccccc21
Temperature: 25 °C

Procedure:
To a mixture containing nitromethane (7.4 g., 0.12 moles), benzofuroxan (13.6 g., 0.10 moles) and tetrahydrofuran (50 ml.) is slowly added dimethylpyrimidine (11.3 g.) dropwise. The heat of reaction causes the reaction temperature to rise sharply; therefore, an ice-bath is used to maintain a steady rate of reflux. Upon completion of addition, the resulting mixture is allowed to cool to room temperature whereupon the solid product which precipitates is filtered, washed with water, dried and recrystallized from a MeOH/NaOCH3 mixture which is subsequently acidified. The crystalline product has an M.P. 213° C. dec.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[C:11]2[C:12](=[O:23])[N:13]([CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][C:10]=2[NH:9][CH:8]=1.O.[OH-].[Na+].CN(C)[CH:29]=[O:30]>>[CH3:6][C:7]1[C:11]2[C:12](=[O:23])[N:13]([CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:15][C:10]=2[NH:9][C:8]=1[CH:29]=[O:30]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.37 %

Procedure:
N,N-dimethylformamide (1.5 ml) was added slowly with phosphorus oxychloride (115 μl, 3.2 mmol) under an argon atmosphere while maintaining the temperature at 0° C. Upon completion of the addition, the mixture was stirred for 15 minutes at room temperature, and cooled down to 0˜5° C. in an ice-water bath. A mixture of 3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (719 mg, 2.91 mmol) in 3 ml of N,N-dimethylformamide was added dropwise to the above solution. Upon completion of the addition, the mixture was stirred for 2 hours at 0° C., added with cold water (20 ml) and stirred for another 5 minutes. The resulting mixture was adjusted to pH 12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (30 ml×3). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with triethylamine:methanol:dichloromethane (1:20:500) as eluents to give 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (411 mg, 51.37%) as a brown oil which was used as such.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].[CH2:29]([C:31]1[N:35]=[C:34]([CH2:36][N:37]2[C:42]3[CH:43]=[C:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[S:45][C:41]=3[C:40](=[O:52])[N:39]([CH:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[C:38]2=[O:59])[O:33][N:32]=1)[CH3:30].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:56]4[CH2:57][CH2:58][CH:53]([N:39]5[C:40](=[O:52])[C:41]6[S:45][C:44]([C:46]7[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=7)=[CH:43][C:42]=6[N:37]([CH2:36][C:34]6[O:33][N:32]=[C:31]([CH2:29][CH3:30])[N:35]=6)[C:38]5=[O:59])[CH2:54][CH2:55]4)=[O:21])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(CC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (99.4 mg; compound C10), 1-(3-Ethyl-[1,2,4]oxadiazol-5-ylmethyl)-6-phenyl-3-piperidin-4-yl-1H-thieno[3,2-d]pyrimidine-2,4-dione (109 mg; compound B52) and HOBT (38 mg) in DCM (2.5 ml) is added EDCI (48.9 mg). The mixture is stirred for 2.5 h at RT. EtOAc (25 ml) is added and the mixture is extracted with 1 M aqueous hydrochloride solution (5 ml) (three times). The combined aqueous phases are washed with EtOAc (15 ml) and subsequently the combined organic phases are washed with water (5 ml) (three times) and afterwards with saturated solution of sodium bicarbonate (10 ml) (three times). The organic phase is dried over magnesium sulfate, concentrated in vacuo and the resulting residue is purified by flash column chromatography [amino phase silica gel, eluation gradient: EtOAc/cyclohexane=0/100 to 20/80 (v/v)] to give the title compound as a solid.
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH2:17][CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13].[N+](=[CH2:21])=[N-]>>[CH3:21][O:13][C:12](=[O:14])[CH2:11][CH2:10][C:9](=[O:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([OH:1])[CH2:16][CH2:17][CH3:18]
Reactant: C=[N+]=[N-]
Reactant: CCCC(O)CCCCCCC(=O)CCC(=O)O
Product: CCCC(O)CCCCCCC(=O)CCC(=O)OC

Procedure:
In order to determine the stereochemistry at the 11-position, 1 was hydrolyzed first with base and then with acid to yield 11-hydroxy-4-oxo-tetradecanoic acid (8). The long chain fatty acid (8) was reacted with excess diazomethane to furnish 11-hydroxy-4-oxo-tetradecanoic acid methyl ester (9). Compound 9 was converted to the two Mosher esters 10 and 11 with (R)- and (S)-methoxyphenylacetic acid (MPA), using the EDCI/DMAP coupling conditions. (Seco, J. M.; Quinoa, E.; Riguera, R., Tetrahedron: Asymmetry 2001, 12, 2915-2925.) The resulting 11-MPA esters 10 and 11 were subjected to NMR analysis. The chemical shift differences ΔδRS were significant (Scheme 1), which made it possible to conclude that 1 had the (S)-configuration at C-11. The sugars were determined as D-glucose and D-fucose by hydrolysis and determination of the sign of rotation of the isolated carbohydrates. This conclusion was supported by MM2 calculations, which indicated that only the diastereomer with both D-sugars would give the relatively strong ROESY correlations between H-11 and H—F-1 and between H—F-2 and H-G-1 that were exhibited in the spectrum of 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[N:8][N:9]([C:11]2[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([CH3:23])=[CH:13][C:12]=2[F:24])[CH:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[F:33][C:34]([O:38][C:39]([F:42])([F:41])[F:40])=[C:35]([F:37])[F:36].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:35]([F:37])([F:36])[CH:34]([F:33])[O:38][C:39]([F:42])([F:41])[F:40])=[N:8][N:9]([C:11]2[CH:16]=[C:15]([S:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([CH3:23])=[CH:13][C:12]=2[F:24])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2cc(SCC(F)(F)F)c(C)cc2F)nc1O
Reactant: FC(F)=C(F)OC(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2cc(SCC(F)(F)F)c(C)cc2F)nc1OC(F)(F)C(F)OC(F)(F)F

Procedure:
1.20 g of ethyl-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole-4-carboxylate was dissolved in 40 mL of N,N-dimethylformamide, 25 g of triethylamine was added, and stirring was carried out at 50° C. for 3 hours while trifluoromethyl trifluorovinyl ether was blown. To this solution, ethyl acetate was added, followed by washing with a saturated aqueous solution of citric acid, and then the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.73 g of ethyl-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole-4-carboxylate (1H-NMR (CDCL3/TMS δ (ppm) value) δ: 1.36 (3H, t), 2.51 (3H, s), 3.41 (2H, q), 4.34 (2H, q), 6.21 (1H, dt), 7.16 (1H, d), 7.97 (1H, d), 8.38 (1H, d)).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].O[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1.[OH-:17].[Na+:18]>>[C:1]([O:5][C:10]1[CH:9]=[CH:8][CH:16]=[CH:15][C:11]=1[C:12]([O-:14])=[O:13])(=[O:17])[C:2]([CH3:4])=[CH2:3].[Na+:18]
Reactant: C=C(C)C(=O)Cl
Reactant: [OH-]
Reactant: O=C(O)c1ccc(O)cc1
Agent: [Na+]
Product: C=C(C)C(=O)Oc1ccccc1C(=O)[O-]
Yield: 50 %

Procedure:
Methacryloyl chloride was reacted with p-hydroxy benzoic acid that had been neutralised with NaOH solution to give sodium methacryloyl-oxy-benzoate in about 50% yield. Treatment with hydrochloric acid gave methacryloyl-oxy-benzoic acid which was purified by re-crystallisation from glacial acetic acid, ethanol and acetone respectively. The acid was polymerised at 90° C. in dimethyl formamide solution in a sealed degassed ampoule using benzoyl peroxide as initiator. This gave PMBA which was separated from residual monomer by dissolving the latter in diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@@H:27]([CH3:39])[CH2:26]1.[NH2:40][C@@H:41]1[CH2:46][CH2:45][C@@H:44]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C@H:43]([CH3:55])[CH2:42]1.C(N(CC)CC)C>CS(C)=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5]([NH:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@@H:27]([CH3:39])[CH2:26]2)=[N:6][CH:7]=1.[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5]([NH:40][C@@H:41]2[CH2:46][CH2:45][C@@H:44]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:52])([CH3:51])[CH3:53])[C@H:43]([CH3:55])[CH2:42]2)=[N:6][CH:7]=1
Reactant: C[C@H]1C[C@@H](N)CC[C@@H]1NC(=O)OC(C)(C)C
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Reactant: C[C@@H]1C[C@H](N)CC[C@H]1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@@H]1C[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC[C@H]1NC(=O)OC(C)(C)C
Product: C[C@H]1C[C@@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC[C@@H]1NC(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
A mixture of Intermediate B (preparation of intermediate B is described in the intermediate session which is in front of the Examples) (25 mg, 0.075 mmol), tert-butyl (1S,2S,4S)-4-amino-2-methylcyclohexylcarbamate/tert-butyl(1R,2R,4R)-4-amino-2-methylcyclohexylcarbamate (25.8 mg, 0.113 mmol), triethylamine (28 μl, 0.201 mmol) in DMSO (0.25 mL) was heated at 100° C. for 3 days. The mixture was allowed to cool to ambient temperature and diluted with EtOAc (20 mL) and saturated aqueous NaHCO3 solution (10 mL). The separated aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered off and concentrated in vacuo providing crude tert-butyl (1S,2S,4S)-4-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)-2-methylcyclohexylcarbamate/tert-butyl (1R,2R,4R)-4-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)-2-methylcyclohexylcarbamate, which was directly used in the next step without further purification.
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[CH3:8][C:9]([NH:12][C:13]1[O:14][C:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1)([CH3:11])[CH3:10].CI>>[CH3:11][C:9]([N:12]([CH3:4])[C:13]1[O:14][C:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:16]([C:18]([F:20])([F:21])[F:19])[N:17]=1)([CH3:8])[CH3:10]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1oc(NC(C)(C)C)nc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CCOC(=O)c1oc(N(C)C(C)(C)C)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 50% oil dispersion of sodium hydride (0.38 g; 7.9 mmol) was washed three times with petroleum ether under a nitrogen atmosphere. The oil-free sodium hydride was suspended in 15 mol anhydrous tetrahydrofuran in a reaction vessel cooled in an ice bath. Then, with the sodium hydride suspension at 0° C. and stirred, there was added dropwise 25 ml anhydrous tetrahydrofuran containing 2.0 g (7.15 mmol) of ethyl 2-[(1,1-dimethylethyl)amino]-4-trifluoromethyl-5-oxazolecarboxylate (as prepared in Example 6. The reaction mixture was stirred for 1/2 hour at 0° C. and then 15 ml of anhydrous tetrahydrofuran containing 2.54 g (20 mmol) of methyl iodide was added dropwise to the mixture. The reaction mixture was stirred at room temperature for 3 hours. An additional 0.2 g (4 mmol) of 50% oil dispersion of sodium hydride (washed as before) was added and the mixture was stirred at room temperature for one hour. The reaction mixture was heated at reflux for 45 minutes, then stirred overnight at ambient temperature. The mixture was partitioned between ethyl ether and 5% hydrochloric acid solution. The organic phase was dried with sodium sulfate and concentrated under reduced pressure to yield 2.1 g of a reddish-brown product which was subjected to Kugelrohr distillation (100°-120° C. @ 2.5 mm Hg) to yield 1.7 g of a brown oil. This brown oil was dissolved in methylene chloride, washed with 10% sodium bisulfite, and concentrated under reduced pressure to yield 1.3 g of a colorless oil which was subjected to Kugelrohr distillation (100° C. @ 4 mm Hg) to yield 1.25 g of a pale yellow oil identified in Table I.
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[O:3][Si:4]([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])([O:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][CH2:6]CCl.[CH3:21][NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[CH3:31]C(=O)CC>>[CH3:18][Si:15]([CH3:16])([CH3:17])[O:14][Si:4]([O:9][Si:10]([CH3:13])([CH3:12])[CH3:11])([O:3][Si:2]([CH3:20])([CH3:19])[CH3:1])[CH2:5][CH2:6][CH:23]([NH:22][CH3:21])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: C[Si](C)(C)O[Si](CCCCl)(O[Si](C)(C)C)O[Si](C)(C)C
Reactant: CCCCCCCCNC
Reactant: CCC(C)=O
Product: CCCCCCCCC(CC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C)NC
Reaction time: 18 h

Procedure:
To 186.3 grams (0.5 moles) of the tris-trimethylsiloxy-3-chloropropylsilane in 250 gm. of 2-butanone is added 71.5 grams (0.5 moles) of methyloctylamine. The mixture is heated in an autoclave under 200 psi. nitrogen to 130° C. for 18 hours. The 2-butonone is removed from the product by distillation and the residue is added to two liters of hexane. An excess of trimethylamine (anhydrous gas) is added and the mixture is allowed to stir for 16 hours. Filtration to remove the trimethylamine hydrochloride salt, and short path distillation of the filtrate yields tris-trimethylsiloxy-3-octylmethylaminopropylsilane.
Reaction SMILES: CS[C:3]1[N:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[S:5][N:4]=1.Cl[C:14]1C=C(C=CC=1)C(OO)=O.[S:24]([O-:27])(O)=[O:25].[Na+]>C(Cl)(Cl)Cl>[CH3:14][S:24]([C:3]1[N:7]=[C:6]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[S:5][N:4]=1)(=[O:27])=[O:25]
Reactant: CSc1nsc(C2CCCC2)n1
Reactant: O=S([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1nsc(C2CCCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
710 mg of 3-methylthio-5-cyclopentyl-1,2,4-thiadiazole was dissolved in 15 ml of chloroform, 1.89 g of 3-chloroperoxybenzoic acid (content>65%) was added thereto, and the reaction mixture was stirred for 30 minutes under ice-cooling and for 3.5 hours at room temperature. Then, the reaction mixture was added to saturated sodium hydrogensulfite aqueous solution, and separated. The organic layer was washed with sodium hydrogencarbonate aqueous solution, dried over anhydrous sodium sulfate, concentrated to give 804 mg of 3-methylsulfonyl-5-cyclopentyl-1,2,4-thiadiazole.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:45])[NH2:44])[CH:39]=2)[CH:34]=1)(=O)=O.C(OCC)C>N1C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([O:12][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:44])[NH2:45])[CH:39]=3)[CH:34]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: O=C(O)CCCC1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: N=C(N)c1ccc2cc(OC(=O)CCCC3CCCCC3)ccc2c1
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
To a solution of 3.0 g of 4-cyclohexylbutyric acid in 50 ml of anhydrous pyridine, while being cooled in ice and stirred, was added 4.4 g of DCC. After 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture, and the mixture was stirred for 24 hours at room temeprature. The precipitate which was formed upon addition of ethyl ether was collected by filtration, admixed with dimethylformamide. Ethyl ether was added to the filtrate, and the precipitate was collected by filtration. On recrystallization from a dimethylformamide ethyl ether mixture there were obtained 3.2 g of a white powder of 6-amidino-2-naphthyl 4-cyclohexylbutyrate methanesulfonate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[C:9]([N:13]=[CH:14][CH3:15])([CH3:12])([CH3:11])[CH3:10].[ClH:16]>O1CCCC1.C([Li])CCC.C(OCC)(=O)C>[ClH:16].[ClH:16].[C:9]([NH:13][CH:14]([CH3:15])[CH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC=NC(C)(C)C
Reactant: Cc1ccc(O)cn1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(Cc1ccc(O)cn1)NC(C)(C)C

Procedure:
To the suspension of 9.8 g of 2-methyl-5-pyridinol in 200 ml of tetrahydrofuran, 135 ml of 1.6 molar n-butyllithium are added during 30 minutes while stirring under nitrogen at -20°. After 3 hours 10 g of t-butyliminoethane are added during 30 minutes at said temperature and the resulting mixture is processed as described in Example 4, except that the final solution is acidified with hydrogen chloride in ethyl acetate, to yield the 2-(2-t-butylaminopropyl)-5-pyridinol dihydrochloride melting at 218°-220°.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]([NH:14][CH2:15][C:16]([F:25])([F:24])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[C:7]=1[F:26])C.CO.[Li+].[OH-].Cl>O.C1COCC1>[C:12]([C:11]1[C:6]([CH2:5][C:4]([OH:27])=[O:3])=[C:7]([F:26])[C:8]([NH:14][CH2:15][C:16]([F:25])([F:24])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)=[CH:9][CH:10]=1)#[N:13]
Reactant: CCOC(=O)Cc1c(C#N)ccc(NCC(F)(F)c2ccc(C)cn2)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(C(F)(F)CNc2ccc(C#N)c(CC(=O)O)c2F)nc1
Reaction time: 1.5 h

Procedure:
{6-Cyano-3-[2,2-difluoro-2-(5-methyl-pyridin-2-yl)-ethylamino]-2-fluoro-phenyl}-acetic acid ethyl ester (968 mg, 2.57 mmol), prepared as described in the previous step, was dissolved into MeOH:THF:H2O (51 mL, 1:2:1) and treated with LiOH (92 mg, 3.85 mmol, 1.5×). After 1.5 h, the reaction was neutralized with 428 μL, 12N HCl and concentrated in vacuo. The crude material was diluted with toluene and concentrated (3×25 mL) to afford the saponification product {6-cyano-3-[2,2-difluoro-2-(5-methyl-pyridin-2-yl)-ethylamino]-2-fluoro-phenyl}-acetic acid. {6-cyano-3-[2,2-difluoro-2-(5-methyl-pyridin-2-yl)-ethylamino]-2-fluoro-phenyl}-acetic acid, HCl salt of [N,N′-di(tert-butoxycarbonyl)]-2-aminoethoxyguanidine (1.8 g, 5.13 mmol, 2×) (prepared as described in Example 1d), and BOP (1.8 g, 4.16 mmol, 1.6×) were dissolved into CH3CN/CH2Cl2 (12 mL, 1:1) and cooled to 0° C. DIEA (2.7 mL, 15.6 mmol, 6×) was added dropwise and the reaction continued for 12 h, allowing the ice bath to warm to rt. The reaction was partitioned between EtOAc (50 mL) and H2O (50 mL), the organic phase dried over Na2SO4, and concentrated to afford the crude product as a white amorphous solid. Purification via flash chromatography (20% EtOAc/CH2Cl2) afforded the product as a white solid (832 mg, 1.28 mmol, 50% yield). 1H NMR (300 Hz, CDCl3) δ 9.14 (s, 1H), 8.49 (s, 1H), 7.61, m, 2H), 6.75 (t, J=8.2 Hz, 1H), 4.13 (m, 4H), 3.83 (s, 2H), 3.61 (m, 2H), 2.41 (s, 3H), 1.51 (s, 9H), 1.47 (s, 9H); LC/MS (m/z) [M+1]+ 650.3 (calculated for C30H39F3N7O6, 650.7).