Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].OS(O)(=O)=O.O>CC(O)=O>[C:1]([C:5]1[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[C:8]([OH:11])=[C:7]([C:12]([F:13])([F:14])[F:15])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc([N+](=O)[O-])c(O)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-tert-Butyl-2-trifluoromethyl-phenol (70 mg, 0.32 mmol) was dissolved in 3 mL AcOH/1.5 mL water and cooled to 0° C. HNO3 (1.5 mL) and catalytic H2SO4 were added and the reaction was allowed to warm to room temperature. Stirring was continued overnight, after which water was added and the compound was extracted into EtOAc. The organic layer was dried over MgSO4 and concentrated to yield 34 mg of final compound. Calculated mass=263. Observed mass=264
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH:3]1[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.CN(CCN(C)C)C.[Li]CCCC.Cl[P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30]>C1COCC1>[CH2:29]([O:28][P:27]([C:10]1[S:9][C:8]([CH:3]2[N:4]([CH3:7])[CH2:5][CH2:6][N:2]2[CH3:1])=[CH:12][CH:11]=1)(=[O:34])[O:31][CH2:32][CH3:33])[CH3:30]
Reactant: CN1CCN(C)C1c1cccs1
Reactant: CCOP(=O)(Cl)OCC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccc(C2N(C)CCN2C)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of 1,3-Dimethyl-2-thiophen-2-yl-imidazolidine (10 g, 60.17 mmol) in THF was added TMEDA (9.1 ml, 60.17 mmol), cooled to −78° C., then added 1.6 M nBuLi (47 ml, 75.21 mmol). After stirring at −78° C. for 30 min the mixture was warmed up to 0° C. in 1 hr and treated with diethyl chlorophosphonate (10.4 ml, 72.2 mmol). The reaction mixture was stirred at 0° C. for another 30 min. The reaction was then quenched by adding EtOAc and water. The EtOAc layer was separated and the water layer was further extracted with EOAc once. The combined EtOAc layers were dried over MgSO4, filtrated and concentrated to afford the crude product [5-(1,3-dimethyl-imidazolidin-2-yl)-thiophen-2-yl]-phosphonic acid diethyl ester (17 g). 1H NMR (300 MHz, DMSO-d6): δ 7.44 (m, 1H), 7.24 (m, 1H). 4.01 (m, 4H), 3.18 (m, 2H), 2.53 (m, 2H), 1.22 (m, 9H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH:18]4[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH:17]34)[N:13]([CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[C:12]=2[CH:36]=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[C:37]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH:18]4[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:23][CH:17]34)[N:13]([CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[C:12]=2[CH:36]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)=CCn1c(N2CCC3CN(C(=O)OC(C)(C)C)CC32)nc2ccc(N)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(N2CCC3CN(C(=O)OC(C)(C)C)CC32)nc2ccc(NC(=O)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
17 mg (0.05 mmol) of cesium carbonate were added to a solution of 43 mg (0.1 mmol) of tert butyl 1-[6-amino-1-(3-methylbut-2-enyl)-1H-benzimidazol-2-yl]hexahydropyrrolo-[3,4-b]pyrrole-5-carboxylate in 5 ml of dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. Subsequently, 12 μl (0.10 mmol) of benzoyl chloride were added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and purified by means of preparative HPLC (acetonitrile/water+0.5% trifluoroacetic acid, gradient: 20/80 to 100/0). 10 mg (20%) of the desired compound were obtained.
Reaction SMILES: C(OC([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N1C(C2C=CC=CC=2)=C2C(CCNC(C)C2)=N1)(C)C>>[CH:19]([N:13]1[C:12]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:11]2[C:15]([CH2:16][CH:17]([CH3:18])[NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:20])[CH3:21]
Reactant: OB(O)c1ccccc1
Reactant: CC1Cc2nn(C(C)C)c(OS(=O)(=O)C(F)(F)F)c2CCN1C(=O)OC(C)(C)C
Agent: CC1Cc2c(nn(C(C)C)c2-c2ccccc2)CCN1
Product: CC1Cc2nn(C(C)C)c(-c3ccccc3)c2CCN1
Yield: 64.3 %

Procedure:
The title compound (102 mg) was prepared as in Example 263 using 260 mg of 2-isopropyl-7-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (as outlined in Example 308 replacing cyclopentyl hydrazine with isopropyl hydrazine) and 101 mg of phenylboronic acid. The reaction sequence also yielded 2-isopropyl-5-methyl-3-phenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. MS (ESI): exact mass calculated for C17H23N3, 269.19; found, m/z 270.5 [M+H]+. 1H NMR (600 MHz, CD3OD): 7.58-7.52 (m, 3H), 7.36-7.35 (m, 2H), 4.43 (m, 1H), 3.65-3.57 (m, 1H), 3.51-3.48 (m, 1H), 3.23-3.11 (m, 3H), 2.87-2.82 (m, 2H), 2.76-2.73 (m, 1H), 1.48 (d, J=6.4 Hz, 3H), 1.43-1.40 (m, 6H).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19](=[O:21])[CH3:20]>CC(C)=O>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][CH2:18][C:19](=[O:21])[CH3:20])=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: CC(=O)CCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 82.1 %

Procedure:
Into acetone (300 ml) were suspended 41.7 g (0.3 mol) of p-nitrophenol and 41.4 g (0.3 mol) of anhydrous potassium carbonate. Under stirring and reflux, 27.7 g (0.3 mol) of chloroacetone were added dropwise therein over five hours. After the resulting mixture was reacted for two hours as it was, it was cooled down, and the reaction liquid was dispersed into ice water (500 ml). After the extract obtained by extraction therefrom with ethyl acetate (500 ml) was washed with water and dried, the solvent was distilled off under reduced pressure. The thus-obtained light-yellow crystalline residue was recrystallized from ethyl acetate/n-hexane, whereby 48.1 g of the title compound were obtained. (Yield: 82.2%)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8](O)=[O:9].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:24][C:25]1[C:33]([NH2:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28]>CN(C=O)C.N1C=CC=CC=1>[NH2:24][C:25]1[C:26]([C:27](=[O:28])[NH2:29])=[CH:30][CH:31]=[CH:32][C:33]=1[NH:34][C:8]([C:7]1[CH:6]=[C:5]([Cl:11])[N:4]=[N:3][C:2]=1[Cl:1])=[O:9]
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: NC(=O)c1cccc(N)c1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: NC(=O)c1cccc(NC(=O)c2cc(Cl)nnc2Cl)c1N
Temperature: 50 °C

Procedure:
3,6-Dichloropyridazine-4-carboxylic acid (1.15 g, 5.96 mmol) and 1,1′-carbonyldiimidazole (CDI (0.97 g) in DMF (25 ml) were stirred at room temperature for 2 h. A solution of 2,3-diaminobenzamide (1.30 g, 5.96 mmol) in pyridine (25 ml) was added and the solution heated at 50° C. for 4 h. The cooled solution was concentrated and partitioned between ethyl acetate (EtOAc) and water, the organic layer separated, dried, filtered and concentrated to give the product.
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[C:14](=[O:18])[CH2:15][CH2:16][CH:17]=1)(=[O:6])[CH3:5]>CO.C(O)(=O)C>[C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[C:14](=[O:18])[CH2:15][CH2:16][CH:17]1[C:1]#[N:2])(=[O:6])[CH3:5]
Reactant: CC(=O)OCCCCCC1=CCCC1=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)OCCCCCC1C(=O)CCC1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
98 g [1.5 mols] of potassium cyanide were suspended in 600 ml of methanol, and 105 g [0.5 mol] of 2-(5-acetoxypentyl)- cyclopent-2-ene-1-one, dissolved in 45 ml of acetic acid, were added dropwise within 2.5 hours. After 20 hours, agitation at room temperature, the suspension was dropped into ice-water with agitation, extracted thrice with diethyl ether, the ether phases were united, washed with water, dried over sodium sulfate and concentrated. The oily residue was stirred for 5 hours at room temperature in 200 ml of pyridine and 30 ml of acetic anhydride, the solvent was then distilled off under reduced pressure and the residue was distilled in a bulb tube. 102 g having a boiling point of 180° C. at 0.4 mm Hg were obtained; IR spectrum: 2220 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.Cl.Cl.Cl.[NH:19]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)[CH2:20]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:19]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)[CH2:20]1)=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: c1cnc(C2CCNC2)cn1
Agent: Cl
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(c2cnccn2)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 2-pyrrolidin-3-yl-pyrazine trihydrochloride (15.5 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (7.0 mg). Calcd for C18H15ClN4O2: 354.0884, found 354.0885.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[C:14](=[O:22])[N:13]([CH3:23])[CH2:12][C:11]=12)=[O:6])[C:2]#[CH:3].I[N:25]1C(=O)[CH2:28][CH2:27][C:26]1=O.C(N)CC>C(O)(=O)C>[F:21][C:19]1[CH:18]=[CH:17][C:16]2[N:10]3[CH:9]=[N:8][C:7]([C:5]4[O:6][C:2]([CH2:3][NH:25][CH2:26][CH2:27][CH3:28])=[CH:1][N:4]=4)=[C:11]3[CH2:12][N:13]([CH3:23])[C:14](=[O:22])[C:15]=2[CH:20]=1
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Solvent: CCCN
Product: CCCNCc1cnc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)o1
Temperature: 25 °C
Reaction time: 90 h
Yield: 9.9 %

Procedure:
A solution of 10 g (0.032 mol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid prop-2-ynylamide in 200 ml of acetic acid was treated with 10.8 g (0.048 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 90 hrs. the dark suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The dark residue was dissolved in 200 ml of THF, treated with 23 ml (0.278 mol) of propylamine and stirred at room temperature for 5 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated and the orange crystalline product was chromatographed twice; firstly over basic Alox (grade III) with ethyl acetate/methanol 4:1 as the eluent, then over silica gel with dichloromethane/methanol 9:1 as the eluent. There were obtained 1.17 g (10%) of 8-fluoro-5-methyl-3-(5-propylaminomethyl-oxazol-2-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as yellowish crystals; m.p. 134°-136°.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:28])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
4-Ethoxycarbonylpiperidine (1.572 g, 10.0 mmol) was dissolved in tetrahydrofuran (50 ml); triethylamine (2.79 ml, 20.0 mmol) and benzyl chlorocarbonate (1.71 ml, 12.0 mmol) were added dropwise while cooled with an ice water bath; and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and the saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:hexane=1:3) to yield the title compound (2.315 g, 7.95 mmol, 79.5%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5].O=[C:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:1]=[C:17]([CH3:24])[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(C)CCc1cccc(N)c1C#N
Product: CCOC(=O)c1c(C)nc2cccc(CCC(C)(C)C)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(3,3-dimethylbutyl)benzonitrile (Example 21b) and ethyl 3-oxobutanoate as a white solid (95%). 1H NR (400 MHz, DMSO-d6) δ 0.93 (s, 9H), 1.32 (t, J=7.2 Hz, 3H), 1.42-1.46 (m, 1H), 2.55 (s, 3H), 3.11-3.15 (m, 2H), 4.33 (q, J=7.2 Hz, 2H), 7.12 (s, 2H), 7.19-7.21 (m, 1H), 7.46-7.52 (m, 2H). MS 315 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.[CH:9](=[O:11])[CH3:10].S(=O)(=O)(O)O>O.C(OO)(C)(C)C>[C:9]([C:2]1[CH:3]=[C:4]([C:7]#[N:8])[CH:5]=[CH:6][N:1]=1)(=[O:11])[CH3:10]
Reactant: N#Cc1ccncc1
Reactant: CC=O
Agent: CC(C)(C)OO
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1cc(C#N)ccn1

Procedure:
A solution of ferrous sulfate heptahydrate (496 g) in water (1080 ml) and tert-butylhydroperoxide (173 ml) were simultaneously added to a solution of 4-pyridinecarbonitrile (30 g), acetaldehyde (97.6 ml) and sulfuric acid (15.4 ml) in water (90 ml) at 0° C. with stirring. After stirring at the same temperature for one hour, the resulting precipitate was collected by filtration and washed with water to give 2-acetyl-4-pyridinecarbonitrile (22.5 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=O)[CH2:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:6][C:5]=2[NH:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:9]1[CH2:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:6][C:5]2[NH:4][CH:3]=[C:2]([CH3:1])[C:10]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1ccccc1C1CC(=O)c2c(C)c[nH]c2C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C)c[nH]c2C1
Yield: 4.1 %

Procedure:
A mixture of 3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindol-4-one (0.70 g), aminoguanidine hydrochloride (0.34 g), concentrated hydrochloric acid (0.44 ml), water (0.44 ml) and ethanol (50 ml) was refluxed for 12 hours. Under reduced pressure, the solvent was evaporated. To the residue was added sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/MeOH/Et3N). The resulting oil was dissolved in ethanol, and to the solution was added 1N hydrochloric acid. The solvent was evaporated, and the residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-3-methyl-6-(2-methylphenyl)-4,5,6,7-tetrahydroindole hydrochloride (Compound 6) (0.04 g) as colorless crystals.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH3:20])[CH:8]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][N:40]=[C:39](S(C)(=O)=O)[N:38]=2)=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:1]([N:5]([CH2:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH3:20])[CH:8]=1)[C:39]1[N:38]=[C:37]([C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)[CH:42]=[CH:41][N:40]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)c1nccc(-c2ccc(Cl)cc2)n1
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1nccc(-c2ccc(Cl)cc2)n1
Temperature: 100 °C
Yield: 23.2 %

Procedure:
To a mixture of the ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (686 mg, 2.46 mmol) and N,N-diisopropylethylamine (285 μL, 1.64 mmol) was added 4-(4-chlorophenyl)-2-(methylsulfonyl)pyrimidine (439 mg, 1.64 mmol) and the resultant mixture heated at 100° C. for 16 h in a reactivial. The cooled reaction mixture were then treated with N,N-diisopropylethylamine (285 μL, 1.64 mmol) and heated for a further 16 h at 100° C. in the reactivial. The cooled reaction mixtures were diluted with CH2Cl2 (30 mL), washed with water (20 mL), the aqueous extracted with CH2Cl2 (30 mL), the CH2Cl2 extracts combined and the solvent removed in vacuo. Purification by Biotage™ chromatography (silica, 90 g) eluted with 10:1 cyclohexane:EtOAc gave the title compound as a colourless gum (178 mg).
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC(OC)=CC=3)C=2N=1)(C)(C)C.[C:29]([C:33]1[N:34]=[C:35](Cl)[C:36]2[N:41]=[N:40][N:39]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[C:37]=2[N:38]=1)([CH3:32])([CH3:31])[CH3:30].Cl.[F:53][C:54]1([F:59])[CH2:58][CH2:57][NH:56][CH2:55]1>>[C:29]([C:33]1[N:34]=[C:35]([N:56]2[CH2:57][CH2:58][C:54]([F:59])([F:53])[CH2:55]2)[C:36]2[N:41]=[N:40][N:39]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[C:37]=2[N:38]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: FC1(F)CCNC1
Reactant: COc1ccc(Cn2nnc3c(Cl)nc(C(C)(C)C)nc32)cc1
Agent: COc1ccc(Cn2nnc3c(N4CCOCC4)nc(C(C)(C)C)nc32)cc1
Agent: Cl
Product: COc1ccc(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)cc1

Procedure:
In analogy to the procedure described for the synthesis of 4-(5-tert-butyl-3-(4-methoxy benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)morpholine (example 58, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo [4,5-d]pyrimidine and 3,3-difluoropyrrolidine hydrochloride and isolated as white solid (271 mg, 83%). MS(m/e): 403.4 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([OH:24])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31]([O:33][C:34](=[O:39])[C:35](Br)([CH3:37])[CH3:36])[CH3:32]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][C:35]([C:34]([O:33][CH2:31][CH3:32])=[O:39])([CH3:37])[CH3:36])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1ccc(C2CCCN(C(=O)OCc3ccccc3)C2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cc(C2CCCN(C(=O)OCc3ccccc3)C2)ccc1C
Temperature: 60 °C
Reaction time: 18 h
Yield: 49.8 %

Procedure:
To a solution of 3-(3-hydroxy-4-methyl-phenyl)-piperidine-1-carboxylic acid benzyl ester (2.02 g, 6.21 mmol) in 15 mL dimethylformamide was added cesium carbonate (4.05 g, 12.42 mmol) and ethyl-2-bromoisobutyrate (3.64 mL, 24.83 mmol). The mixture was heated to 60° C. under N2 with stirring for 18 h and cooled to ambient temperature. The resultant brown suspension was diluted with 300 mL water and extracted with diethyl ether (2×200 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 20% ethyl acetate/hexanes to yield 1.36 g (50%) of the desired 3-[3-(1-ethoxycarbonyl-1-methyl-ethoxy)-4-methyl-phenyl]-piperidine-1-carboxylic acid benzyl ester as a clear oil.
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.O.[OH-].[Li+].[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27]([CH:39]=O)[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]>COC(C)(C)C.O>[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27](/[CH:39]=[CH:7]/[C:8](=[O:16])[C:9]([F:14])([F:15])[CH2:10][CH2:11][CH2:12][CH3:13])[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of dimethyl(3,3-difluoro-2-oxoheptyl)phosphonate (1) (50.50 g, 195.6 mmol) in t-butyl methyl ether (750 ml), lithium hydroxide monohydrate (7.94 g, 189 mmol) was added and the mixture was stirred for one hour at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyl-oxy)cyclopentyl]heptanate (2) (52.00 g, 130.5 mmol) in t-butyl methyl ether (150 ml) and water (27 ml) were added thereto, and the mixture was heat refluxed for approximately 49 hours (internal temperature: approximately 53° C.). After cooling to room temperature, water (300 ml) was added and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (200 ml). The organic layers were combined, washed twice with saturated aqueous sodium chloride (300 ml), and dried with anhydrous magnesium sulfate (50 g). After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 1805 g; ethyl acetate:hexane=1:4). The fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300: 580 g; ethyl acetate:hexane=1:4), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (62.38 g; 117.6 mmol; yield: 90.1%) as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2](N)[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[OH:13]N1C2C=CC=CC=2N=N1.C(O)(=O)[C@@H](C1C=CC=CC=1)O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][CH2:4][CH2:3][C:2](=[O:13])[CH3:1])[CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CC(N)CCCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)CCCc1cccnc1
Temperature: -5 °C
Reaction time: 18 h
Yield: 173 %

Procedure:
To a cooled (-5° C.) solution of 32 g of the above enriched amine, 33 g of 1-hydroxybenzotriazole and 31.22 g of (R)-mandelic acid in 350 mL of dimethylformamide, was added a solution of 44.26 g of 1,3-dicyclohexylcarbodiimide in 150 mL of dimethylformamide and the mixture was stirred at -5° C. for 18 hours. After the precipitated dicyclohexylurea was removed by filtration, the filtrate was evaporated and the residue dispersed in 300 mL of cold 2N sodium hydroxide. The resulting solids were removed by filtration, washed with dilute sodium hydroxide solution and with water and then dissolved in 500 mL of 2N hydrochloric acid. The acidic solution was extracted with dichloromethane (3×150 mL) to remove neutral impurities, then was basified with 10N sodium hydroxide and extracted with dichloromethane (6×300 mL). The dried extracts were evaporated to give 55 g of residual solid. Crystallization of the product from ethanol gave 25.6 g of [R-(R*,R)]-alpha-hydroxy-N-[1-methyl-4-(3-pyridinyl)butyl]benzeneacetamide, mp 141°-143° C. An additional 1.3 g of product, mp 141°-143° C., was obtained from the mother liquors.