Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24](O)=O)=[C:21](C)[N:22]=3)[CH2:14][C@@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([CH3:24])=[CH:21][N:22]=3)[CH2:14][C@@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@@H]2OC)nc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(c3ncc(C)s3)C[C@@H]2OC)nc1Cl
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 100.5 %

Procedure:
2-[(3S,4R)-4-{[(4-Chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-methyl-1,3-thiazole-5-carboxylic acid obtained by the method described in Example (56d) (15 mg, 0.035 mmol) was dissolved in THF (3 mL). 1 N hydrochloric acid (1 mL) was added, and the mixture was stirred at 60° C. for 40 minutes. A 1 N aqueous sodium hydroxide solution was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1, ethyl acetate) to obtain 13.5 mg of the title compound as a white solid (100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([CH2:15]C)[CH2:13]C)[C:6]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:5]2[Cl:24].[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30]([C:33]([C:35]2[N:39]([CH3:40])[CH:38]=[N:37][CH:36]=2)=[O:34])=[CH:29][CH:28]=1>>[Cl:24][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:33]([C:30]3[CH:31]=[N:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)([C:35]3[N:39]([CH3:40])[CH:38]=[N:37][CH:36]=3)[OH:34])[CH:3]=2)[N:8]=[C:7]([N:12]([CH3:15])[CH3:13])[C:6]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(C(=O)c2cncn2C)cn1
Reactant: CCN(CC)c1nc2ccc(Br)cc2c(Cl)c1Oc1ccccc1
Product: COc1ccc(C(O)(c2ccc3nc(N(C)C)c(Oc4ccccc4)c(Cl)c3c2)c2cncn2C)cn1

Procedure:
The title compound was prepared using 6-bromo-4-chloro-N,N-dimethyl-3-phenoxyquinolin-2-amine (Intermediate 5, step e) and (6-methoxypyridin-3-yl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 4, step d) according to the procedure of Example 3a. 1H NMR (400 MHz, MeOH-d4) δ 8.01 (d, J=2.02 Hz, 1H), 7.93 (d, J=2.02 Hz, 1H), 7.72-7.86 (m, 2H), 7.68 (dd, J=2.53, 8.59 Hz, 1H), 7.56 (dd, J=2.02, 9.09 Hz, 1H), 7.25-7.32 (m, J=7.07, 8.59 Hz, 2H), 7.01-7.07 (m, 1H), 6.81 (d, J=8.59 Hz, 1H), 6.72-6.78 (m, 2H), 6.37 (br. s., 1H), 3.91 (s, 3H), 3.51 (s, 3H), 3.11 (s, 6H); MS m/e 516.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH2:19][NH:20]C(=O)OC(C)(C)C)[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl>C(O)C>[NH2:20][CH2:19][C@@H:15]1[N:14]2[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:18][O:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Agent: Cl
Solvent: CCO
Product: NC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Temperature: 85 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
tert-Butyl [(11S)-6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]methylcarbamate (1.39 g, 3.77 mmol) was dissolved in 10 mL of ethanol and 3 mL of a 4.3 M solution of HCl in ethanol was added. The reaction mixture was heated to 85° C. After 1 hour, the reaction mixture was concentrated under reduced pressure. The resulting residue was treated with 40 mL of H2O and 20 mL of CHCl3. The layers were separated and the organic portion was discarded. The aqueous layer was then made basic by addition of 5 mL of concentrated NH4OH solution. The aqueous portion was then extracted with CHCl3 (15×20 mL). The combined organic extracts were concentrated under reduced pressure to give (11S)-11-(aminomethyl)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (778 mg) as a pumpkin colored solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([Si](C)(C)C)=[C:6]([F:12])[N:5]=[C:4]1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([F:12])[N:5]=[C:4]1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: CCn1c(-c2cccc3ccccc23)nc(F)c1[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1cc(F)nc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Crude 1-ethyl-4-fluoro-2-naphthalen-1-yl-5-trimethylsilanyl-1H-imidazole (5.49 g) is dissolved in THF (75 ml), and to the solution is added tetrabutylammonium fluoride hydrate (5.4 g, 20.6 mmol, 1.2 eq.). The resulting mixture is stirred at rt for 4 hr. The organic solvent is evaporated under reduced pressure, and the residue is dissolved in EtOAc (150 ml), washed with water and brine, and dried over Na2SO4. Concentration and purification through silica gel chromatography (hexanes/EtOAc, from 8:1 to 4:1) affords 1-ethyl-4-fluoro-2-naphthalen-1-yl-1H-imidazole. LCMS 241 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[CH2:8])[C:6]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[O:5][C:4]1=[O:14])[CH3:2].C(N(CC)CC)C.[I-].[K+].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[CH:32][CH2:33][CH2:34]Cl)=[CH:27][CH:26]=1>C(C(C)=O)C>[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)=[CH:32][CH2:33][CH2:34][N:11]2[CH2:12][CH2:13][C:6]3([O:5][C:4](=[O:14])[N:3]([CH2:1][CH3:2])[C:7]3=[CH2:8])[CH2:9][CH2:10]2)=[CH:29][CH:30]=1
Reactant: C=C1N(CC)C(=O)OC12CCNCC2
Reactant: Fc1ccc(C(=CCCCl)c2ccc(F)cc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: C=C1N(CC)C(=O)OC12CCN(CCC=C(c1ccc(F)cc1)c1ccc(F)cc1)CC2
Reaction time: 15 h
Yield: 68.7 %

Procedure:
A mixture containing 7.8 g of 3-ethyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 8.5 ml of anhydrous triethylamine, 80 ml of anhydrous methyl ethyl ketone, 3.0 g of potassium iodide and 16.7 g of 4,4-bis(4-fluorophenyl)-3-butenyl chloride is refluxed under nitrogen while stirring for 15 hours, then the solvent is distilled off under reduced pressure. After adding benzene and water to the residue, the benzene layer is washed with water to neutral, dried over anhydrous magnesium sulfate, filtered through an aluminum oxide bed and evaporated under reduced pressure. After recrystallizing the residue from ethanol, the title product is obtained in 68.7% yield, m.p.: 138°-139° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[O:9]=C(CCC([O-])=O)C([O-])=O>>[OH:9][C@@H:6]1[CH2:7][CH2:8][NH:1][C@@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C([O-])CCC(=O)C(=O)[O-]
Product: O=C(O)[C@H]1NCC[C@H]1O
Reaction time: 0.5 h

Procedure:
The enzyme reaction by use of purified L-proline-3-hydroxylase obtained in Example 5 was carried out. The reaction mixture was composed of 200 mM TES buffer (pH 7.0), 20 mM L-proline, 20 mM 2-ketoglutarate, 5 mM L-ascorbic acids 1 mM, ferrous sulfate, and 106 U of purified enzyme preparation, the total volume being 100 μl. The reaction was carried out at 35° C. for 30 minutes. As a result of the reaction, 18 mM (2.4 g/l) of cis-3-hydroxy-L-proline was produced in the reaction mixture.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[C:8]1([CH:15]=[CH:14][CH:13]=[C:11]([OH:12])[CH:10]=1)[OH:9].B(F)(F)F.CCOCC.C([O-])(=O)C.[Na+]>>[OH:9][C:8]1[CH:10]=[C:11]([OH:12])[CH:13]=[CH:14][C:15]=1[C:1](=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CC(=O)O
Reactant: Oc1cccc(O)c1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)CC(=O)c1ccc(O)cc1O
Temperature: 90 °C
Reaction time: 8 h
Yield: 111.2 %

Procedure:
Add isovaleric acid (5.10 g, 50 mmol, 5.5 mL) in one portion to a mixture of resorcinol (5.00 g, 45.4 mmol) in boron trifluoride etherate (38.67 g, 272.5 mmol, 34.5 mL) at room temperature under Argon gas. Heat the reaction mixture at 90° C. for 1.5 hr. Cool the reaction to room temperature and pour it into a 20% aqueous sodium acetate solution and stir overnight. Extract the aqueous mixture with ethyl acetate (3×). Combine the organic layers, wash with saturated aqueous sodium bicarbonate solution and brine sequentially. Dry the organic phase over sodium sulfate, filter and concentrate under reduced pressure to provide the product as a brownish oil (9.80 g; 50.5 mmol, 111% yield). MS (m/z): 195 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:25])[CH:7]([N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:19]([F:22])([F:21])[F:20])[CH:10]1[C:23]#[N:24])[CH3:8])(C)(C)C.[H][H].[ClH:28]>[Pd].CO>[ClH:28].[NH2:24][CH2:23][CH:10]1[C:11]2[C:16](=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:14]=[CH:13][CH:12]=2)[C:17](=[O:18])[N:9]1[CH:7]([CH3:8])[C:6]([OH:25])=[O:5]
Reactant: [H][H]
Reactant: CC(C(=O)OC(C)(C)C)N1C(=O)c2c(cccc2C(F)(F)F)C1C#N
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C(=O)O)N1C(=O)c2c(cccc2C(F)(F)F)C1CN
Reaction time: 4 h

Procedure:
A stirring degassed solution of 2-(1-cyano-3-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid tert-butyl ester (390 mg, 1.1 mmol) and 10% palladium on carbon (20 mg) in methanol (10 mL) and conc. hydrocloric acid (1 mL) was added 80 psi of hydrogen. The reaction was stirred for 4 h and then filtered. The filtrated was conc. in vacuo to a white solid. The solid was dissolved in water and lypholized to give 352 mg of the desired product as a white solid. MS (ESI) 303 (M−Cl).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:20])=[N:8][C:9]=2[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:2][CH2:3]1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1ccc(C2CC2)c(OCc2ccccn2)n1
Product: CNC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(OCc2ccccn2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(pyridin-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 189 b) and (2S)-2-amino-N,3,3-trimethyl-butanamide (CAN 89226-12-0) as starting materials, MS (EI): m/e=397.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][NH:21][CH3:22])[CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:36](Cl)(=[O:38])[CH3:37].C(=O)([O-])O.[Na+]>ClCCl>[C:36]([N:21]([CH2:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][N:17]=1)[C:13]([NH:12][C:10]1[S:11][C:7]2[C:6]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:23])[CH3:22])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CNCc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(CN(C)C(C)=O)c3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-methylaminomethyl-isonicotinamide (207 mg, 0.5 mmol) is dissolved in dichloromethane (10 ml) and treated with pyridine (0.07 ml, 0.85 mmol) and acetyl chloride (0.05 ml, 0.7 mmol) and stirred for 16 h at ambient temperature. Saturated aqueous sodium hydrogen carbonate (10 ml) is added, the layers are separated and the aqueous phase extracted twice with each 10 ml dichloromethane. The combined organic phases are dried with magnesium sulfate and evaporated. Recrystallization from ethyl acetate afforded the title compound as light-yellow solid (80% yield), mp 228-230° C. MS: m/e=456 (M+H+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11])([CH3:3])[CH3:2].O=P(Cl)(Cl)Cl.CN([CH:20]=[O:21])C>>[CH:20]([C:8]1[CH:7]=[CH:6][C:5]([O:10][CH3:11])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1)=[O:21]
Reactant: CN(C)C=O
Reactant: COc1ccccc1C(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C=O)cc1C(C)C
Temperature: 85 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
To a stirred solution of 2-isopropylanisole (859 g, 5.85 mol) and POCl3 (2690 g, 17.5 mol) at 80° C. under N2, was slowly added DMF (1584 mL, 20.46 mol) at a rate such that the temperature remained between 80-90° C. After stirring for 16 hr at 85° C., the dark solution was poured cautiously onto 7 Kg of ice. (Quench required 1.5 hr due to violent exotherm) The mixture was extracted twice with EtOAc (total volume 16 L). The combined EtOAc layers were washed once with aq. NaHCO3 and then with brine. Upon concentration, 881 g of 4-formyl-2-isopropylanisole was obtained.
Reaction SMILES: [C:1]([CH:4]1[CH2:13][CH2:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[N:17]=[C:7]3[C:6]=2[CH2:5]1)([OH:3])=O.[CH3:25][NH:26][CH3:27].O>CN(C=O)C>[CH3:25][N:26]([CH3:27])[C:1]([CH:4]1[CH2:13][CH2:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[N:17]=[C:7]3[C:6]=2[CH2:5]1)=[O:3]
Reactant: O=C(O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Reactant: CNC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture containing 9-Carboxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (150 mg) and 1,1-carbonyldiimadazole (120 mg) in DMF (5 mL) was heated to 60° C. for 15 min after which time the reaction was cooled and 2 mL of dimethylamine added. The reaction was allowed to stand at room temperature for 1 hour. To the mixture was then added 10 mL of H2O and the resultant product was collected and dried to yield 9-(N,N-Dimethylcarbamyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (Compound 18), m.p.>325° C.
Reaction SMILES: [CH:1]([O:4]C(C)C)(C)[CH3:2].[C:8]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)(=[O:11])[CH:9]=[CH2:10].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:8]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:1](=[O:4])[CH3:2])=[CH:18][CH:19]=1)(=[O:11])[CH:9]=[CH2:10]
Reactant: C=CC(=O)OCc1ccc(O)cc1
Reactant: CC(C)OC(C)C
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=CC(=O)OCc1ccc(OC(C)=O)cc1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
1400 g of isopropyl ether, 100 g of 4-hydroxybenzyl acrylate and 53 g of pyridine were charged into a separable flask of the same type as used in Reference Example 3, and the flask inside gas was replaced with a nitrogen gas over 30 minutes, while ice cooling the flask. Then, 125 g of acetic anhydride was dropwise added thereto at 3° C. over 2 hours, and stirring was continued at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed with 0.5N hydrochloric acid and then with water. By distilling off isopropyl ether from the reaction mixture, 113 g of 4-acetoxybenzyl acrylate of the following chemical formula was obtained (yield:91%): ##STR2##
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH:24]=[CH:23][N:22]=[N:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[CH:24]=[CH:23][N:22]=[N:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: c1c[nH]nn1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1ccnn1

Procedure:
Using general procedure 4 and purification method E with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.15 g, 0.57 mmol) and 1,2,3-triazole (0.037 mL, 0.63 mmol) gives the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([S:19]([O-:21])=[O:20])[CH:13]=[CH:12]2.[Na+].Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:30]([OH:32])[CH3:31].N>CS(C)=O.[Cu]I>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([S:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:30]([OH:32])[CH3:31])(=[O:21])=[O:20])[CH:13]=[CH:12]2
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3F)ccc2c1
Reactant: C[C@H](O)c1ccccc1Br
Agent: [Cu]I
Agent: N
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@H](O)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3F)ccc2c1
Temperature: 110 °C
Yield: 26.5 %

Procedure:
Sodium 6-(2,4-difluorophenyl)naphthalene-2-sulfinate (Step 3, 486 mg, 1.49 mmol), (1S)-1-(2-bromophenyl)ethanol (260 mg, 1.29 mmol) and copper(I) iodide (1.23 g, 6.46 mmol) were combined in dimethylsulfoxide (10 mL) and degassed. The reaction was heated to 110° C. for 2 hours. The cooled reaction mixture was poured into conc. ammonia solution and extracted with diethyl ether (x4). The combined organic layers were washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 5% then 10% diethyl ether/dichloromethane, followed by trituration with isohexane. A second column, eluting with 60% diethyl ether/isohexane, followed by trituration with isohexane, gave the title compound (145 mg). 1H NMR (500 MHz, CDCl3) δ 8.56 (1H, s), 8.17 (1H, d, J=7.9 Hz), 8.06-7.98 (3H, m), 7.79-7.76 (3H, m), 7.66 (1H, t, J=7.5 Hz), 7.54-7.48 (2H, m), 7.03-6.95 (2H, m), 5.65 (1H, q, J=6.2 Hz), 2.51 (1H, s), 1.35 (3H, d, J=6.3 Hz); m/z (ES+) 407 [(M-OH)+].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[CH2:12][NH:11][CH2:10]3)[CH2:3][CH2:2]1.[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22](O)=[O:23])([CH3:18])[CH3:17]>>[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22]([N:11]1[CH2:10][C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:8]=2)[CH2:12]1)=[O:23])([CH3:18])[CH3:17]
Reactant: CC(C)Oc1ccc(S(=O)(=O)CC[Si](C)(C)C)cc1C(=O)O
Reactant: c1cc2c(cc1C1CCOCC1)CNC2
Product: CC(C)Oc1ccc(S(=O)(=O)CC[Si](C)(C)C)cc1C(=O)N1Cc2ccc(C3CCOCC3)cc2C1

Procedure:
In analogy to the procedure described for the synthesis of example 1, step 2, the title compound was prepared from 5-(tetrahydro-pyran-4-yl)-2,3-dihydro-1H-isoindole (CAS: 905274-50-2) and 2-isopropoxy-5-(2-trimethylsilanyl-ethanesulfonyl)-benzoic acid. MS (m/e): 529.3 [M]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH:15]([OH:17])[CH:14]=[CH:13]3)[N:9]=[C:10](I)[C:3]=12.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[NH:35][C:36](=[O:48])[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][C:38]=1[F:47].O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH:15]([OH:17])[CH:14]=[CH:13]3)[N:9]=[C:10]([C:24]3[CH:23]=[CH:22][C:21]([NH:35][C:36](=[O:48])[C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:39][C:38]=4[F:47])=[C:20]([O:19][CH3:18])[CH:25]=3)[C:3]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: Nc1ncnc2c1c(I)nn2C1C=CC(O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn(C3C=CC(O)C3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Yield: 97.1 %

Procedure:
A mixture of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-cyclopenten-1-ol (0.12 g, 0.35 mmol), N1-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-fluoro-4-trifluoromethylbenzamide (0.23 g, 0.53 mmol), tetrakis(triphenyl-phosphine)palladium(0) (0.02 g, 0.02 mmol) and sodium carbonate monohydrate (0.11 g, 0.88 mmol) was heated in a mixture of ethylene glycol dimethyl ether (6 mL) and water (3 mL) at 85° C. for 6 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC to yield N1-{4-[4-amino-1-(4-hydroxy-2-cyclopentenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-trifluoromethylbenzamide (0.18 g, 0.34 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.89 (dd, 1H), 8.31(d, 1H), 8.26 (s, 1H), 8.00 (t, 1H), 7.88 (d, 1H), 7.75 (d, 1H), 7.32 (s, 1H), 7.29 (d, 1H), 6.90 (br, 2H), 6.09 (d, 1H), 5.93 (d, 1H), 5.76 (m, 1H), 5.31 (m, 1H), 4.74 (m, 1H), 3.94 (s, 3H), 2.84 (m, 1H), 2.02 (m, 1H); RP-HPLC (Hitachi HPLC, Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 8.50 min. MS: MH+ 529.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[C:12](=O)([O-])[O-].[K+].[K+].IC>CC(=O)CC>[CH3:12][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:9])([F:10])[F:11]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: COc1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A stirred solution of 2-hydroxybenzotrifluoride (23.0 g, 142 mmol) in 2-butanone (107 mL) was treated with potassium carbonate (25.51 g, 185 mmol) and iodomethane (13.3 mL, 213 mmol). The mixture was heated at reflux overnight under argon until the thin-layer chromatography showed a completed reaction. The mixture was cooled to room temperature and filtered through diatomaceous earth. The filtered solid was washed with acetone and the filtrate concentrated carefully in vacuo without heating. The resulting crude liquid was purified by vacuum distillation to yield the title compound (21.79 g, 0.124 mol, 87%) as a colorless liquid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:7][C:8]1[C:9]([C:16](O)=[O:17])=[N:10][C:11]([OH:15])=[N:12][C:13]=1[OH:14])[CH3:6]>CCO>[CH2:1]([O:3][C:16]([C:9]1[C:8]([O:7][CH2:5][CH3:6])=[C:13]([OH:14])[N:12]=[C:11]([OH:15])[N:10]=1)=[O:17])[CH3:2]
Reactant: CCOc1c(O)nc(O)nc1C(=O)O
Reactant: CC(=O)Cl
Solvent: CCO
Product: CCOC(=O)c1nc(O)nc(O)c1OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
Acetyl chloride (100 ml, 36 eq.) was added dropwise to absolute EtOH (780 ml) at 0° C. After stirring the resulting solution for 20 min at r.t., 5-ethoxy-2,6-dihydroxy-pyrimidine-4-carboxylic acid (7.76 g, 1 eq.) was added in one portion and the mixture was refluxed overnight. The volatiles were evaporated in vacuo to give 5-ethoxy-2,6-dihydroxy-pyrimidine-4-carboxylic acid ethyl ester as an off-white solid (8.85 g, 100%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([C:12]#[N:13])=[C:10]([Cl:14])[CH:9]=[C:8](Cl)[N:7]=1)(=[O:3])[CH3:2].[C:16]1([C@H:22]([NH:24][C:25]([NH2:27])=[O:26])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(N(CC)CC)C>C1COCC1>[C:1]([O:4][CH2:5][C:6]1[C:11]([C:12]#[N:13])=[C:10]([Cl:14])[CH:9]=[C:8]([NH:27][C:25]([NH:24][C@@H:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:23])=[O:26])[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc(Cl)cc(Cl)c1C#N
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc(Cl)c1C#N
Temperature: 50 °C

Procedure:
A mixture of (4,6-dichloro-3-cyanopyridin-2-yl)methyl acetate (366.3 mg, 1.495 mmol), (R)-1-(1-phenylethyl)urea (443 mg, 2.70 mmol) and Xantphos G2 precatalyst (130 mg, 0.146 mmol) in THF (2 ml) was sealed, sparged with argon, charged with triethylamine (0.73 ml, 5.24 mmol) and heated to 50° C. for 17 hr. The mixture was filtered through celite, eluted with EtOAc, concentrated in vacuo and purified via flash chromatography (25-100% Et2O/Hex) to provide (R)-(4-chloro-3-cyano-6-(3-(1-phenylethyl)ureido)pyridin-2-yl)methyl acetate. MS ESI calc'd. For C18H18ClN4O3 [M+H]+ 373. found 373.