Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1)#[CH:2].C([Li])CCC.C1(C#C[Li])CCCCC=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C1COCC1.CCCCCC.[Cl-].[Cl-].[Zn+2].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.C(OCC)(=O)C>[Cl:23][CH2:24][C:25](=[O:26])[C:2]#[C:1][C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1
Reactant: C#CC1=CCCCC1
Reactant: O=C(Cl)CCl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C#CC1=CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(C#CC1=CCCCC1)CCl
Temperature: 0 °C
Yield: 66.4 %

Procedure:
Anhydrous ZnCl2 (5.0 g, 37 mmol) was dissolved in TBF (25 mL) and the solution cooled to 0° C. in an ice bath. In another flask 1-ethynylcyclohexene (4.3 mL, 36.3 mmol) was dissolved in THF (25 mL), cooled to 0° C. in an ice bath, and treated with n-butyllithium (15.7 mL of a 2.2M solution in hexane, 34.5 mmol). After 20 minutes the cyclohexenylethynyllithium solution was added via cannula to the ZnCl2 solution. After an additional 20 minutes Pd(PPh3)4 (620 mg, 0.54 mmol) was added to the alkynylzinc solution. The resulting yellow solution was treated with chloroacetyl chloride (4.2 mL, 55 mmol) dropwise over 10 minutes. After 2 h at 0° C. the reaction mixture was quenched by the addition of saturated aqueous NH4Cl(500 mL), and diluted with ethyl acetate. The aqueous phase was extracted with ethyl acetate (3.times.200 ml) and the combined organic layers were washed with water (200 ml), brine (200 ml), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to afford a dark brown oil that was purified by column chromatography eluting with hexane, then 99:1 hexane:ethyl acetate to afford 1-chloro-4-(1-cyclohexen-1-yl)-3-buty-n-2-one (4.4 g, 67% yield) as an orange oil. 1H NMR (CDCl3, 300 MHz) Δ6.56 (m, 1H), 4.23 (s, 2H), 2.19 (m, 4H), 1.68-1.62 (m, 4H). MS (EI ionization) 182 (35Cl M+), 184 (37Cl M+). The material was carried on to the next step without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)C>[CH2:1]([NH:8][C:9]1[N:10]=[CH:11][C:12]([CH2:13][NH2:14])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(NCc2ccccc2)nc1
Agent: [Pd]
Solvent: CCO
Product: NCc1ccc(NCc2ccccc2)nc1
Yield: 45.5 %

Procedure:
Stir 6-benzylamino-nicotinonitrile (680 mg, 3.3 mmol) and 10% Pd/C (Degussa type E101) vigorously in absolute ethanol (80 mL) under hydrogen at 25 psi for 1 h. Filter the solution through Celite® and concentrate in vacuo. Purify by chromatography on silica gel eluting sequentially with 2M ammonia in methanol/dichloromethane (4:96, 9:91) to give the title compound as a white solid (320 mg, 45%). MS (ES+) m/z: 214 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:11]=[C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[O:9][N:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[CH:11]=[C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)[O:9][N:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2cc(Cn3cc(N)cn3)on2)OCCO1
Product: CC(=O)c1cc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)on1

Procedure:
Following general procedure B followed by T, starting from 1-[3-(2-methyl-[1,3]dioxolan-2-yl)-isoxazol-5-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.97 min; [M+H]+=378.36.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15]>>[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:14]=1[NH:15][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[N:4][C:5]=1[OH:11]
Reactant: O=C(O)c1cc(Cl)cnc1O
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Product: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Cl)cnc1O
Yield: 42.9 %

Procedure:
Using 5-chloro-2-hydroxynicotinic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 24 gave the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[C:9](=[O:14])[S:10]2)=[O:6])[CH:2]=[CH2:3].[CH3:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.Cl>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][C@@H:11]([SH:10])[CH2:13][C@H:8]1[C:9]([N:19]1[CH2:20][CH2:21][CH:16]([CH3:15])[CH2:17][CH2:18]1)=[O:14])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H]2C[C@H]1C(=O)S2
Reactant: CC1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1C(=O)N1CCC(C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (1S,4S)-5-allyloxycarbonyl-2-thia-5-azabicyclo[2.2.1]heptan-3-one (38.5 mg) in tetrahydrofuran (1 ml) was added 4-methylpiperidine (19.7 mg). The mixture was stirred for 4 hours at room temperature. After the reaction was over, 1N-hydrochloric acid (0.036 ml) was added thereto, and the mixture was diluted with ethyl acetate (2 ml) and dried above magnesium sulfate. Distillation of the solvent, followed by purifying the residue by silica gel chromatography, gave oily 1-[(2S,4S) -1-allyloxycarbonyl-4-mercapto-2-pyrrolidinecarbonyl]-4-methylpiperidine.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]#[N:22].S(=O)(=O)(O)[OH:24]>>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[CH2:20][C:21]([NH2:22])=[O:24]
Reactant: O=S(=O)(O)O
Reactant: N#CCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Product: NC(=O)Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Temperature: 0 °C
Yield: 99 %

Procedure:
5g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetonitrile and 10 ml of 96 % sulfuric acid are stirred for 4 hours at room temperature. The batch is added to 50 g of ice, the precipitate is separated by vacuum filtering and washed with water. 5-Chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-acetamide is obtained with a 99 % yield; F 192°-193°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:14])[CH2:12][OH:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C>[Si:20]([O:13][CH2:12][CH:11]([OH:14])[C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1ccc(C(O)CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C(O)CO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 6 h

Procedure:
(4-tert-butylphenyl) ethane 1,2 diol (0.5 g, 2.57 mmol) is dissolved in DMF in a 25 ml round bottom flask and to this were added imidazole (0.210 g, 3.09 mmol) and tert-butyldimethylsilyl chloride (0.46 g, 3.09 mmol). The mixture is stirred for 6 hours after which it is extracted in dichloromethane and the organic layer washed with water and dried. Purification by flash chromatography (silica gel; ethyl acetate/hexanes) affords the above mentioned product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH3:16])[CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O[NH:32][C:33](=[NH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH3:16])[C@@H:10]([C:11]1[O:13][N:40]=[C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:32]=1)[OH:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N=C(NO)c1ccccc1
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC(NC(=O)OC(C)(C)C)[C@H](O)c1nc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (500 mg, 2.14 mmol) was combined with EDC (600 mg, 3.14 mmol), HOBt (600 mg, 3.92 mmol), and N-hydroxy-benzamidine (292 mg, 2.14 mmol). Dichloromethane (10 mL) was added and then 4-methylmorpholine (1 mL). The reaction mixture was stirred at ambient temperature for 16 h. After dilution with ethyl acetate (200 mL), the solution was washed with water (30 mL), saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in pyridine (10 mL) and heated at 80° C. for 15 h. The pyridine was evaporated under vacuum and the residue was purified by flash chromatography on silica gel (eluent: ethyl acetate) to yield (290 mg, 0.83 mmol) of (S)-2-tert-butoxycarbonylamino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol. (S)-2-tert-Butoxycarbonylamino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol (145 mg, 0.41 mmol) was dissolved in CH2Cl2 (4 mL) and TFA (4 mL) was added. After stirring for 1 h, the reaction mixture was evaporated to dryness to yield (S)-2-amino-1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:14][CH:13]=1)=[CH:7][C:8]([O:10][CH3:11])=[O:9]>CO.[Pd]>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:14][CH:13]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C=C(c1ccc(OC2CCCCO2)cc1)c1ncco1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC(c1ccc(OC2CCCCO2)cc1)c1ncco1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of compound 10.3 (2.55mmol) and Pd—C (440 mg) in MeOH was stirred under hydrogen at room temperature for 30 minutes. The Pd—C was removed by filtration through silica gel with EtOAc as eluant. After concentration, the residue was chromatographed (silica gel, 1:1 EtOAc/hexane) to afford compound 10.4. MS ESI (pos.) m/e 332.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[C:4]([O:24][CH3:25])[CH:3]=1.[C:26]([O:30][C:31](SC1N=C(C)C=C(C)N=1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[C:26]([O:30][C:31]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)=[C:4]([O:24][CH3:25])[CH:3]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1cc(N)ccc1OCCCN1CCN(c2ccccc2)CC1
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)n1
Solvent: C1CCOC1
Product: COc1cc(NC(=O)OC(C)(C)C)ccc1OCCCN1CCN(c2ccccc2)CC1
Yield: 101.3 %

Procedure:
A mixture of 1 g of 1-[3-(4-amino-2-methoxyphenoxy)-n-propyl]-4-phenyl-piperazine, 1.06 g of 2-(t-butoxycarbonylthio)-4,6-dimethylpyrimidine and 15 ml of anhydrous tetrahydrofuran is refluxed for 65 hours. After the reaction, the mixture is evaporated under reduced pressure to remove tetrahydrofuran. Methylene chloride is added to the residue, and the mixture is washed with an aqueous 10% sodium hydroxide solution and water, successively. Said mixture is dried and then evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel chromatography (Solvent; 1.5% methanol/chloroform), and then recrystallized from a mixture of benzene and n-hexane. 1.31 g of 1-[3-(4-t-butoxycarbonylamino-2-methoxyphenoxy)-n-propyl]-4-phenyl-piperazine are thereby obtained as colorless needles. Yield: 85%
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=2)[C:16]([O:18]C)=[O:17])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.O>[CH:1]1([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=2)[C:16]([OH:18])=[O:17])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(C(=O)NCCC2CCCC2)ccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)NCCC2CCCC2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To methyl 5-((2-cyclopentylethyl)carbamoyl)-2-methylbenzoate (1.2 g, 4.3 mmol) dissolved in THF (15 mL) was added a solution of LiOH, monohydrate (0.27 g, 6.4 mmol) in water (15 mL). The reaction mixture was stirred at RT for 18 h. THF was removed, the residue was extracted with ether (5 mL) and the layers were separated. To the aqueous layer was added 2N HCl until pH 4-5 (a lot of precipitate formed). The solid was collected by filtration, washed with water, dried to give 5-((2-cyclopentylethyl)carbamoyl)-2-methylbenzoic acid as a white solid. MS (ESI, pos. ion) m/z: 276.2 (M+1).
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].C1COCC1.[Si:10]([O:17][CH2:18][CH:19]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:20]#[N:21])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[OH-].[Na+]>CCOCC.C(Cl)Cl>[Si:10]([O:17][CH2:18][CH:19]([C:20]1([NH2:21])[CH2:2][CH2:1]1)[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)([C:13]([CH3:15])([CH3:16])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC[Mg+]
Reactant: CC(C)(C)[Si](C)(C)OCC(C#N)c1ccc(Cl)cc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCC(c1ccc(Cl)cc1)C1(N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
TBS-Cl (2.29 g, 15.2 mmol) in dry DMF (12 mL) was added to a solution of 2-(4-chlorophenyl)-3-hydroxypropanenitrile (2.30 g, 12.7 mmol) and imidazole (3.45 g, 50.7 mmol) in DMF (20 mL) at 0° C. under nitrogen. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was partitioned between ether and water. The organic layer was washed with brine, dried and concentrated. The residue was purified by column (hexanes:EtOAc, 30:1) to give 3-(tert-butyldimethylsilyloxy)-2-(4-chlorophenyl)propanenitrile (3.40 g, 91%) as a colorless oil. A solution of EtMgBr in THF (3.0 M, 7.0 mL, 21 mmol) was added dropwise at room temperature to a stirred solution of this 3-(tert-butyldimethylsilyloxy)-2-(4-chlorophenyl)propanenitrile (3.1 g, 10 mmol) and Ti(i-PrO)4 (3.4 mL, 11 mmol) in Et2O (60 mL). After the mixture was stirred at room temperature for 1 hour, BF3OEt (2.7 mL, 21 mmol) was added at once. The mixture was stirred for an additional 1 hour. A solution of 10% NaOH (10 mL) was added, followed by DCM (300 mL). The resulting precipitate was filtered and washed with DCM. The combined filtrates were dried and concentrated. The residue was purified by column chromatography (30:1 DCM:MeOH) to give 1-(2-(tert-butyldimethylsilyloxy)-1-(4-chlorophenyl)ethyl)cyclopropanamine (2.3 g, 67%) as a colorless oil. LCMS: 326.1 [M+H+] (APCI+); Rf: 3.04 min.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:14][CH2:15][CH2:16][CH2:17][O:18]C2CCCCO2)=[C:9]1[CH3:25])(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C(O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[C:9]1[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCC1CCCC(CCCCOC2CCCCO2)=C1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCO
Product: CC(=O)OCCC[C@H]1CCCC(CCCCO)=C1C
Temperature: 50 °C
Yield: 78 %

Procedure:
To a solution of 7.3 g (20.7 mmole) of [R-(R*,S*)]-3-[4-[(tetrahydro-2H-pyran-2yl)oxy]butyl]-2-methyl-2-cyclohexene-1-propanol acetate in 68 ml of absolute ethanol was added 530 mg (2.1 mmole) of pyridinium p-toluenesulfonate and the homogeneous solution heated at 50° C. for 4 hours. The cooled reaction mixture was poured into 280 ml of water and extracted with 3×350 ml of ether. The combined organic extracts were washed with NaHCO3, brine, dried over MgSO4, filtered and concentrated. The crude product was chromatographed on a silica gel column (5:1, hexane/EtOAc) to give 4.3 g (78%) of (R)-3-[3-(acetyloxy)propyl]-2-methyl-1-cyclohexene-1-butanol as an oil.
Reaction SMILES: [NH2:1][C@H:2]([CH2:26][F:27])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[C:18]([CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)[OH:4].C(N(CC)CC)C.[F:35][CH:36]([F:42])[C:37](OCC)=[O:38]>CO>[F:35][CH:36]([F:42])[C:37]([NH:1][C@H:2]([CH2:26][F:27])[C@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[C:18]([CH2:20][NH:21][S:22]([CH3:25])(=[O:23])=[O:24])[N:19]=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)=[O:38]
Reactant: CS(=O)(=O)NCc1cn2ccc(-c3ccc([C@@H](O)[C@H](N)CF)cc3)cc2n1
Reactant: CCOC(=O)C(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCc1cn2ccc(-c3ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc3)cc2n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution N-{7-[4-((1R,2S)-2-Amino-3-fluoro-1-hydroxy-propyl)-phenyl]imidazo[1,2-a]pyridin-2-ylmethyl}-methane sulfonamide (88 mg, crude) in methanol (1 mL) is added triethyl amine (0.05 mL, 0.346 mmol) followed by addition of ethyl difluoroacetate (0.02 mL, 0.208 mmol) at 0° C. then stirred at room temperature for 20 h. The reaction mixture is concentrated and purified by flash column chromatography eluting in 2.1% MeOH in CH2Cl2 followed by re-purification by preparative TLC to afford 5 mg and which is re-crystallized in
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH2:11])=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:13][C:14](=O)[CH2:15][C:16]([O:18][CH3:19])=[O:17]>>[CH2:1]([NH:8][C:9]1[S:10][CH:13]=[C:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)NCc1ccccc1
Reactant: COC(=O)CC(=O)CCl
Product: COC(=O)Cc1csc(NCc2ccccc2)n1
Yield: 105.1 %

Procedure:
1.87 g of N-benzylthiourea and 1.82 g of methyl 4-chloroacetoacetate were subjected to a cyclization reaction to obtain 3.10 g of methyl (2-benzylaminothiazol-4-yl)acetate.
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:12][CH2:21][C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccnc1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Product: c1ccc(Oc2ccc(NCc3cccnc3)cc2)cc1

Procedure:
Using the method of Example 343 using 4-phenoxyaniline (Aldrich) and 3-pyridinecarboxaldehyde (Aldrich) and purifying via preparative HPLC eluting with 95:5 to 60:40 DCM/ethyl acetate gave N-(4-phenoxypheny)pyridin-3-ylmethylamine. Anal Calcd for C18H16N2O: C, 78.24; H, 5.84; N, 10.14. Found: C, 78.19; H, 5.67; N, 10.03. 1H NMR (400 MHz, DMSO) 4.00 (1H, bt), 4.35 (2H, d, J=5.1 Hz), 6.62 (2H, m), 6.89-6.93 (4H, m), 6.99-7.03 (1H, m), 7.25-7.30 (3H, m), 7.71 (1H, m), 8.54 (1H, dd, J=1.8, 4.8 Hz), 8.64 (1H, d, J=1.8 Hz) MS found 277.0 [M+H]+
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][CH2:21][C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)[CH3:2].[CH3:23][C:24]([CH2:30][CH2:31][CH2:32][CH:33]([CH3:45])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:25][CH2:26]CCO.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[CH2:21][O:22][CH:5]1[O:4][CH2:1][CH2:2][CH2:26][CH:25]=[C:24]([CH3:23])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:45])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])(=[O:10])[CH3:9]
Reactant: CC(=CCCCO)CCCC(C)CCCC(C)CCCC(C)C
Reactant: CC(=O)O[C@@H]1OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)COC(OCCCC=C(C)CCCC(C)CCCC(C)CCCC(C)C)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.7 %

Procedure:
Under a nitrogen atmosphere, 80.0 g (0.251 mol) of β-xylose tetraacetate and 106 g (0.327 mol) of 5,9,13,17-tetramethyloctadec-4-en-1-ol was dissolved in dry acetonitrile (0.30 L), and stirred for 30 min. After the solution was cooled to 0° C., 38 mL (0.30 mol) of boron trifluoride diethyl etherate complex was added. The reaction mixture was allowed to warm up to room temperature while being stirred overnight before addition of 70 mL (0.50 mol) of triethylamine at 0° C. The resulting solution was diluted with ethyl acetate, and washed with water, 3M hydrochloric acid (twice), saturated sodium bicarbonate aqueous solution (twice), and saturated brine, successively, and dried over magnesium sulfate. After filtration, the filtrate was concentrated to obtain 161.95 g of the title compound as a crude product. A part of the crude product was purified by silica gel column chromatography (hexane/ethyl acetate 85:15). The results of NMR analysis of the resulting compound are as shown below.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]3[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]3)[N:12]=2)=[CH:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>CO>[CH3:24][C:22]1([CH3:25])[CH2:23][CH:18]([NH:17][C:13]2[N:12]=[C:11]([C:8]3[S:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=3)[CH:16]=[CH:15][N:14]=2)[CH2:19][C:20]([CH3:27])([CH3:26])[NH:21]1
Reactant: CCOC(=O)c1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CC(Nc2nccc(-c3ccc(C(=O)O)s3)n2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-[2-(2,2,6,6-Tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-thiophene-2-carboxylic acid ethyl ester (4.90 g, 12.6 mmol) were dissolved in methanol (50 ml). After addition of sodium hydroxide (31 ml of a 40% solution) the mixture was stirred at room temperature overnight. The reaction mixture was acidified using 1N HCl and the product was collected by filtration (4.50 g, 12.5 mmol).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[CH:36]=[CH:37][C:38]([C:40]([F:41])([F:43])[F:42])=[CH:39][C:32]=3[F:31])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Fc1cc(C(F)(F)F)ccc1CBr
Product: Cc1nc2c(ccn2Cc2ccc(C(F)(F)F)cc2F)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-fluoro-4-(trifluoromethyl)benzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.49-7.41 (m, 1 H), 7.39-7.28 (m, 3 H), 7.25-7.18 (m, 1 H), 7.14-7.10 (m, 1 H), 6.93 (dd, J=3.9, 8.4 Hz, 1 H), 6.29 (dd, J=3.5, 12.1 Hz, 1 H), 5.70-5.62 (m, 1 H), 5.62-5.52 (m, 2 H), 4.33-4.25 (m, 2 H), 2.96-2.77 (m, 2 H), 2.73 (s, 3 H), 2.16-2.03 (m, 2 H), 1.01-0.92 (s, 9 H); LC/MS (m/z) ES+=571 (M+1).