Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1>[CH2:16]([O:15][C:13]([C:12]1[N:1]=[C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]2[CH:11]=1)=[O:14])[CH3:17]
Reactant: N#Cc1ccnc(N)c1
Reactant: CCOC(=O)C(=O)CBr
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2ccc(C#N)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 2-amino-4-cyanopyridine (4.00 g, 33.6 mmol) in THF (100 mL) add ethyl bromopyruvate (6.55 g, 33.6 mmol). Stir the mixture at rt overnight. A light yellow suspension forms. After filtration and washing with THF, dissolve the light yellow solid in EtOH (50 mL) and heat to reflux for 4 h. Concentrate in vacuo to afford the desired product 7-cyano-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester as a solid (6.21 g, 28.9 mmol).
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[O:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=3)=[N:3][CH:4]=[CH:5][N:6]=2)[CH2:9][CH2:10]1
Reactant: Nc1ccc(O)cc1
Reactant: Fc1nccnc1C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2nccnc2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottomed flask was added 2-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyrazine (1.1147 g, 6.12 mmol), 4-aminophenol (0.801 g, 7.34 mmol), and cesium carbonate (5.98 g, 18.35 mmol) in DMSO (20.39 mL) in DMSO at 110° C. to stir overnight. The reaction was allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with 50% sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% MeOH in DCM, to provide 4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)aniline. [M+H]=272.1.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([C:18](=[O:20])[NH2:19])[CH2:10][CH2:11][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[C:28]([O:32][C:33]([NH:35][C@H:36](C(O)=O)[CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([NH:35][C@H:36]([C:6]([NH:8][C@@H:9]([C:18](=[O:20])[NH2:19])[CH2:10][CH2:11][C:12]([O:14][CH:15]([CH3:16])[CH3:17])=[O:13])=[O:7])[CH2:37][O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CC(C)OC(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(N)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)CC[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(N)=O

Procedure:
Isopropyl t-butyloxycarbonyl-D-isoglutaminate (176 mg, 0.61 mmol) was treated with trifluoroacetic acid (1 ml) at room temperature for 20 minutes. Trifluoroacetic acid was evaporated and the residue was washed thoroughly with a mixture of diethyl ether-petroleum ether (1:1) and dried in a desiccator over sodium hydroxide pellets. The resulting trifluoroacetic acid salt was dissolved in acetonitrile (10 ml) together with triethylamine (0.19 ml). To this solution was added t-butyloxycarbonyl-O-benzyl-L-serine HOSuc ester (274 mg, 0.7 mmol), and the mixture was allowed to react for 15 hours at room temperature. The solvent was evaporated and the residue was dissolved in ethyl acetate (20 ml). The solution was washed successively with a 5% aqueous sodium bicarbonate solution, 1 N hydrochloric acid and water, dried over anhydrous sodium sulfate, and evaporated. The residue was crystallized by addition of petroleum ether and the resulting crystals were filtered to obtain isopropyl t-butyloxycarbonyl-O-benzyl-L-seryl-D-isoglutaminate (243 mg). Melting point, 98°-99° C. [α]D22 +2.0° (c 0.5, DMF). Rf2 =0.50; Rf3 =0.78.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:17][C:18]1([CH3:28])[CH2:27][N:21]2S(=O)(=O)O[CH2:24][C@H:20]2[CH2:19]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[C:7]=1[CH2:24][C@H:20]1[CH2:19][C:18]([CH3:28])([CH3:17])[CH2:27][NH:21]1
Reactant: Clc1cncc(Cl)c1
Reactant: CC1(C)C[C@@H]2COS(=O)(=O)N2C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CN[C@@H](Cc2c(Cl)cncc2Cl)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of 3,5-dichloropyridine (796 mg, 5.38 mmol) in THF (9.0 mL) at −78° C. was added lithium diisopropylamide (2.0 M heptane/THF/ethylbenzene, 3.41 mL, 6.82 mmol) dropwise. After stirring for 1 h at this temperature, a solution of (R)-5,5-dimethyltetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (686 mg, 3.59 mmol) in THF (9.0 mL) was added dropwise at −78° C. and the mixture was allowed to warm to room temperature over 3 h and then stirred at room temperature for 4 h. After evaporation of the solvent, the resulting beige foam was treated with hot (80° C.) 2 N HCl (8 mL) and EtOH (8 mL) overnight. The reaction mixture was concentrated under reduced pressure (rotary evaporator) and the mixture was treated with ice and basified with 5 N NaOH (8 mL) and extracted with EtOAc (2×75 mL). The organic extracts were dried, evaporated and purified by chromatography on an ISCO Combiflash™ RF (25 g Thomson SingleStep column, using a gradient of 0-10% MeOH in DCM) affording (R)-3,5-dichloro-4-((4,4-dimethylpyrrolidin-2-yl)methyl)pyridine (748 mg, 2.89 mmol, 80% yield) as an orange oil. MS (ESI) 259.1, 261.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[CH:22]2[O:24][CH2:23]2)=[CH:17][CH:16]=1>C1COCC1.C(OCC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[F:8])([CH:22]2[CH2:23][O:24]2)[OH:25])=[CH:17][CH:16]=1
Reactant: Fc1ccccc1Br
Reactant: O=C(c1ccc(Cl)cc1)C1CO1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)(c1ccccc1F)C1CO1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To a solution of 0.9 g of 2-bromofluorobenzene in 10 mL of THF and 20 mL of diethyl ether was added 3.2 mL of a 1.6M solution of n-butyllithium in hexanes at -78°. After the addition was complete, a solution of 0.9 g of 4'-chloro-2,3-epoxypropiophenone (J.T. Lumb, Tetrahedron Lett., 1970, 579) in 5 mL of ether was added, and the reaction mixture was allowed to warm to room temperature. After being quenched with 10 mL of saturated NH4Cl (aqueous), the mixture was separated, the organic phase was washed with brine, dried (MgSO4), filtered, concentrated, and triturated with hexanes to afford 1.0 g of the title compound, m.p. 120°-122°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][CH2:7][CH:8]([C:12](=[O:14])[CH3:13])[C:9](=[O:11])[CH3:10])[CH3:2].[C:16](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][CH2:7][C:8]([C:9](=[O:11])[CH3:10])([CH3:16])[C:12](=[O:14])[CH3:13])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCCC(C(C)=O)C(C)=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)CCCC(C)(C(C)=O)C(C)=O
Yield: 87.2 %

Procedure:
5.5 g of 5-acetyl-6-oxo-heptanoic acid ethyl ester, 5.7 g of potassium carbonate, 15 g of iodo-methane, and 15 ml of acetone were refluxed for 18 hours. After cooling, petroleum ether was added, and the solid was filtered off and washed with acetone and petroleum ether. Fractional distillation and re-distillation yielded 5.11 g of 5-acetyl-5-methyl-6-oxo-heptanoic acid ethyl ester (boiling point: 151° C./20 mbar; purity: 82%; colorless).
Reaction SMILES: [Br-].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[P+](C)(C1C=CC=CC=1)C1C=CC=CC=1.[C:32]1(CC(Cl)=O)[CH:37]=CC=C[CH:33]=1>>[C:15]1([CH2:16][C:17]2[O:2][C:3]3[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=3[CH:12]=2)[CH:14]=[CH:13][CH:37]=[CH:32][CH:33]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1-c1cc([N+](=O)[O-])ccc1O
Agent: [Br-]
Product: O=[N+]([O-])c1ccc2oc(Cc3ccccc3)cc2c1
Yield: 58.5 %

Procedure:
40 g (81 mmol) of (2-hydroxy-5-nitrophenyl)-methyltriphenylphosphonium bromide and 21.4 g (162 mmol) of phenylacetyl chloride are treated under the conditions described in step 1 of Example 1. 12 g of product are obtained. Melting point: 100° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[CH2:23]([O:25][C:26]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:31]=[C:30]([O:32][CH2:2][C:3]2[CH:22]=[CH:21][CH:20]=[C:5]([O:6][CH2:7][C:8]3[N:9]=[C:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:11][C:12]=3[CH3:13])[CH:4]=2)[CH:29]=[CH:28][C:27]=1[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH3:24]
Reactant: CCOC(=O)CCc1ccc(O)cc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)cc1OCC
Temperature: 90 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.78 g), ethyl 3-(2-ethoxy-4-hydroxyphenyl)propionate (0.50 g), anhydrous potassium carbonate (0.29 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 3-[2-ethoxy-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate as a colorless oil (0.94 g, 87%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[CH3:14].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:12])=[CH:7][C:6]=1[CH3:14]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCC(F)F)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)F
Yield: 82 %

Procedure:
The title compound is prepared in 82% yield (1.22 g, colorless oil) from 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanone (0.99 g, 4.61 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C1COCC1.CC(O)C>[CH:9]1([NH:8][C:6]2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][N:3]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)=[CH:22][CH:23]=3)[N:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1NC1CCCC1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CN1CCN(c2ccc(Nc3ncc([N+](=O)[O-])c(NC4CCCC4)n3)cc2)CC1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
To a solution of 0.97 g (4 mmol) of 2-chloro-4-(cyclopentylamino)-5-nitropyrimidine in 50 mL THF at −78° C. is added a solution of 0.91 g (4.8 mmol) of 1-(4-aminophenyl)-4-methylpiperazine in 50 mL of 2-propanol, and the resulting mixture is allowed to warm slowly to room temperature. After acidification with acetic acid, the solvents were removed under vacuum, and the residue is dissolved in water. After being washed with EtOAc, the aqueous solution is basified with aqueous ammonia, and the product is extracted into EtOAc and dried, to give 1.15 g (77%) of the title compound: mp (MeOH) 204–206° C.
Reaction SMILES: [C:1]([O:7][C@@H:8]1[C@@H:13]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:12]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@@H:11]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:10][C@H:9]1[O:36][C:37]1[C:45]2[C:40](=[N:41][CH:42]=[CH:43][C:44]=2[CH2:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:50][CH:49]=2)[NH:39][N:38]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:61][N:62]([CH3:66])[CH2:63][CH2:64]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:61][N:62]([CH3:66])[CH2:63][CH2:64][N:39]1[C:40]2=[N:41][CH:42]=[CH:43][C:44]([CH2:46][CH2:47][C:48]3[CH:49]=[CH:50][C:51]([O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:52][CH:53]=3)=[C:45]2[C:37]([O:36][C@@H:9]2[O:10][C@H:11]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:34])[CH3:32])[C@@H:12]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:13]([O:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])[C@H:8]2[O:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[N:38]1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OC(=O)C(C)(C)C)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: CN(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCn1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c2c(CCc3ccc(OC(=O)C(C)(C)C)cc3)ccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo-[3,4-b]pyridine (75 mg) in tetrahydrofuran (0.5 mL) were added 2-dimethylaminoethanol (9 mg), triphenylphosphine (26 mg) and diethyl azodicarboxylate (40% toluene solution, 0.059 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=15/1) to give 1-(2-dimethylaminoethyl)-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (79 mg). This material was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.04 mL), and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol =5/1−1/1) to give the title compound (16 mg).
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC.O>C1(C)C=CC=CC=1>[CH2:2]([O:3][CH2:4][C@H:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)CO
Temperature: 25 °C
Yield: 82.3 %

Procedure:
11 grams of (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol, 20 grams of powdered potassium hydroxide and 27.96 grams of hexadecyl bromide were stirred in 150 ml toluene and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 40 ml. The reaction mixture was cooled to room temperature, 100 ml water was added, and the reaction mixture was extracted thrice with 75 ml dichloromethane. The combined organic phase was washed with 50 ml water and the solvent was removed under reduced pressure. The residue was dissolved in 200 ml of a mixture of 90:10:5 (volume/volume) methanol:water:concentrated hydrochloric acid, and the resulting solution was refluxed for 2 hours. After cooling to room temperature, 100 ml of water was added. The product was extracted thrice with 100 ml dichloromethane, washed consecutively with 100 ml water, 100 ml saturated aqueous solution of sodium carbonate and again with 100 ml water. The solvent was then removed under reduced pressure, and the product was crystallized from hexane (200 ml) to give 21.69 grams pure (S)-1-hexadecyl-glycerol, which was dried in a desiccator under reduced pressure. The yield was 82%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:22]=[C:23]([NH2:25])[S:24][CH:2]=3)=[C:6]([CH3:21])[CH:7]=2)=[CH:14][CH:15]=1)[CH3:20]
Reactant: NC(N)=S
Reactant: CCc1ccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Solvent: CCO
Product: CCc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 87.5 %

Procedure:
A mixture of 2-bromo-1-(4-(4-ethylphenoxy)-2,6-dimethylphenyl)ethanone (7.70 g, 2212 mmol) and thiourea (1.69 g, 22.2 mmol) in 95% EtOH (31.7 mL) was heated at reflux for 180 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-(4-ethylphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (6.30 g) as yellow solids in 88% yield: 1H NMR (500 MHz, CDCl3) δ 7.18 (d, J=7.5 Hz, 2 H), 6.95 (d, J=8.5, 2 H), 6.71 (s, 2 H), 6.29 (s, 1H), 5.45 (bs, 2 H), 2.64 (q, J=7.5 Hz, 2 H), 2.14 (s, 6 H), 1.25 (t, J=8.0 Hz, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[F:10].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][S:12]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:10])[CH:4]=1)(=[O:14])=[O:13]
Reactant: OCc1ccc(Br)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A cooled (0° C.) solution of (4-bromo-3-fluorophenyl)methanol (Intermediate 9; 299 mg; 1.46 mmol) and methanesulfonyl chloride (147 μL; 1.90 mmol) in DCM (3 mL) was treated slowly with a solution of triethylamine (305 μL; 2.19 mmol) in DCM (1.5 mL). The reaction mixture was allowed to warm to RT and stirred for 45 minutes before being quenched by addition of water. The organic phase was washed with HCl (0.1N in water) and brine, dried over MgSO4, filtered and concentrated to dryness affording a residue, which was purified by flash column chromatography, eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound as a colourless liquid.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:9]1[C:10]2([CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]2)[CH2:11][NH:8]1
Reactant: CC(=O)N1CCC2(CC1)CN(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC2(CC1)CNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester (70 mg, 0.309 mmol) in DCM (3 mL) were added acetyl chloride (32 μL, 0.450 mmol) and triethylamine (54 μL, 0.526 mmol). The resulting mixture was stirred at RT for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, and washed with MeOH then eluted with 2 M NH3 in MeOH to give 7-acetyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester. To a solution of 7-acetyl-2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester in DCM (3 mL) was added TFA (1 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as a colourless oil (41 mg, 79%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Li+].CS(O[CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)(=O)=O>CN(C=O)C>[N:1]([CH:14]1[CH2:15][CH2:10][CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(N=[N+]=[N-])C1
Temperature: 60 °C

Procedure:
Lithium azide (1.35 g, 27.6 mmol) was added to a solution of 3-methanesulfonyloxy-N-t-butoxycarbonylpiperidine (1.54 g, 5.51 mmol) in DMF (20 ml) and the resulting mixture heated at 60° C. for 48 h. Removal of the solvent in vacuo and chromatographic purification (3:1 hexane/ethyl acetate) of the residue afforded the title compound. 1H NMR (CDCl3) d 1.46 (s, 9 H), 1.75 (m, 2 H), 1.96 (m, 2 H), 3.13 (br s, 1 H), 3.46 (m, 2 H), 3.57 (m, 2 H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11][C:12]#[N:13]>[Ni].C(O)C>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]2[C:5]=1[CH2:11][CH2:12][NH:13][C:3]2=[O:2]
Reactant: COC(=O)c1cccc(F)c1CC#N
Agent: [Ni]
Solvent: CCO
Product: O=C1NCCc2c(F)cccc21
Reaction time: 15 h

Procedure:
Ethanol and Raney nickel (Aldrich) were added to 2-cyanomethyl-3-fluoro-benzoic acid methyl ester (3.3 g, 17 mmol) to carry out catalytic reduction under ordinary pressure at 50° C. for 7 hours and then at room temperature for 15 hours. Raney nickel was removed from the reaction solution by filtration, the solvent was removed by evaporation under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 2.1 g (13 mmol, 74% in yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[F:19])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:21].[CH3:23][S:24]([CH:27]=[CH2:28])(=[O:26])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[F:19])=[CH:8][CH:9]=2)[N:4]([CH2:28][CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])[C:3]1=[O:21]
Reactant: CC1(C)C(=O)Nc2cc(NC(=O)c3ccncc3F)ccc21
Reactant: C=CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(CCS(C)(=O)=O)c2cc(NC(=O)c3ccncc3F)ccc21

Procedure:
To a solution of N-(3,3-dimethyl-2-oxoindolin-6-yl)-3-fluoroisonicotinamide (example 72, 100 mg, 334 μmol) in DMF (1.67 ml) under an argon atmosphere was added methylsulfonylethene (35.5 mg, 31.6 μl, 334 μmol) and cesium carbonate (109 mg, 334 μmol). After 3 hours at room temperature the reaction mixture was poured into water and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (with 10% ammonia) as eluent followed by preparative HPLC. The title compound was obtained as off-white solid (60 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:15]=[C:16]([C:22]([CH3:24])=O)[C:17]([O:19]CC)=[O:18])C>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:22]([CH3:24])=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=[N:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Product: Cc1c(C(=O)O)cnn1-c1ccc([N+](=O)[O-])cc1

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 1 using 4-nitrophenylhydrazine and ethyl 2-ethoxymethyleneacetoacetate, the title compound was obtained, melting point: 202° C.