Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:30](N(CC)C(C)C)(C)[CH3:31].BrCC>C1COCC1.ClCCl>[CH2:30]([N:12]1[CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:29])[F:27])=[CH:16][CH:15]=2)[CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:31]
Reactant: FC(F)(F)c1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCBr
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN1CCN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CC1c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
100 mg of 3-phenyl-1-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine were dissolved in THF, 2 equiv. of N,N-diisopropylethylamine were added followed by 2 equiv. of bromoethane. The reaction was stirred at 80° C. overnight. The reaction was diluted with dichloromethane and washed with 1N aqueous NaOH solution. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford 1-ethyl-2-phenyl-4-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine as the free base. Addition of 1 equiv. of 1M HCl in dioxane and drying in vacuo afforded the title compound as hydrochloride salt. Yield 35% ES MS m/z 425
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1C=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].CN(C)C=[O:14]>>[C@@H:1]12[O:9][CH2:6][C@@H:5]([O:8]1)[CH:4]=[CH:3][C@H:2]2[OH:14]
Reactant: CN(C)C=O
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Product: O[C@@H]1C=C[C@H]2CO[C@@H]1O2
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
10.5 g of 1,6-anhydro-3,4-dideoxy-2-O-(p-toluene)sulfonyl-β-D-threo-hex-3-enopyranose obtained in the above reaction, was dissolved in 100 ml of dried dimethylformamide, and 6 g of sodium benzoate was added thereto. The mixture was refluxed under heating for 30 minutes. The solvent was distilled off under reduced pressure, and 200 ml of water was added to the residue. The mixture was extracted with 300 ml of chloroform. The organic layer was washed once with 200 ml of a saturated sodium hydrogencarbonate aqueous solution and then washed twice with 200 ml of a saturated sodium chloride aqueous solution. Then, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the obtained syrup crude product was dissolved in 100 ml of dry methanol. Then, 2 ml of a methanol solution of sodium methoxide (28 wt %) was added thereto. The mixture was stirred for 25 minutes at room temperature. The reaction solution was neutralyzed with a 20% citric acid aqueous solution and then filtered through Celite® to remove the precipitate. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane=1:2) to obtain 1.1 g of the desired product (Compound No. 103). The NMR analytical data of this product are as follows.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32]>>[C:31]([C:33]1[CH:38]=[CH:37][C:36]([C:7]2[NH:6][C:5]([CH:9]=[O:10])=[C:4]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:3]=2[CH2:1][CH3:2])=[CH:35][CH:34]=1)#[N:32]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2ccc(C#N)cc2)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing of methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 4-cyanophenylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C22H19N2O3 (M+H): 359.1390. Found 359.1387
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[C:44]1(=[O:54])[NH:48][C:47](=[O:49])[C:46]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:45]12.[K].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl>[C:44]1(=[O:54])[N:48]([CH2:1][C:2]2[CH:3]=[C:4]([CH2:11][CH2:12][CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=2)[C:47](=[O:49])[C:46]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:45]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)C(CCc1cc(C)ccc1[N+](=O)[O-])C(=O)OCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(CCc1cc(CN2C(=O)c3ccccc3C2=O)ccc1[N+](=O)[O-])C(=O)OCC
Reaction time: 5 h
Yield: 17.6 %

Procedure:
A mixture of diethyl 2-(3-methyl-6-nitrophenyl)ethylmalonate (2.7 g, 8.35 mmol), N-bromosuccinimide (1.63 g, 9.19 mmol), and azobisisobutyronitrile (100 mg) in carbon tetrachloride (35 mL) was refluxed for 14 h, while 3×50 mg of AlBN were added every 3 h during the reaction. The insoluble material formed was removed by filtration and the filtrate was concentrated. The residue was dissolved in DMF (100 mL) and potassium phthalimide (1.3 g, 7.02 mmol) was added. The mixture was stirred for 5 h at 4°~50° C., poured into saturated sodium bicarbonate, and extracted with a 1:1 mixture of toluene and ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 4:1 hexane/ethyl acetate to give 580 mg of the title compound (15%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.Br[C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[N:22][CH:21]=[C:20]([CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH:19]=2>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[N:22][CH:21]=[C:20]([CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[CH:19]=3)=[CH:5][N:4]=1
Reactant: Brc1cnc2cc(CCN3CCCC3)cnc2c1
Reactant: COc1ncc(B(O)O)c(OC)n1
Product: COc1ncc(-c2cnc3cc(CCN4CCCC4)cnc3c2)c(OC)n1

Procedure:
The title compound was prepared by the method described in Example 156, using 2,4-dimethoxypyrimidin-5-ylboronic acid and the product from Example 153E in place of 2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and the product from Example 154. 1H NMR (CDCl3, 300 MHz) δ 1.55 (m, 2H), 1.65 (m, 2H), 2.50 (m, 4H), 2.60-2.65 (m, 4H), 3.80 (s, 3H), 3.85 (s, 3H), 8.35 (m, 1H), 8.70 (m, 1H), 8.85 (s, 1H), 8.90 (m, 1H), 9.20 (m, 1H). MS (ESI) [M+H]+ at 366.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][CH2:13][CH:14]([NH:41]C(=O)OCC1C=CC=CC=1)[C:15](=[O:40])[NH:16][CH:17]([C:26](=[O:39])[N:27]([CH2:31][CH:32](OCC)OCC)[CH:28]([CH3:30])[CH3:29])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=[O:11])=[O:10].[CH:52]([OH:54])=[O:53]>>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH:17]2[N:16]3[C:15](=[O:40])[CH:14]([NH:41][C:52](=[O:54])[O:53][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][N:12]([S:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])(=[O:11])=[O:10])[CH:32]3[CH2:31][N:27]([CH:28]([CH3:29])[CH3:30])[C:26]2=[O:39])=[CH:24][CH:23]=1
Reactant: O=CO
Reactant: CCOC(CN(C(=O)C(Cc1ccc(Cl)cc1)NC(=O)C(CNS(=O)(=O)c1ccc(Cl)cc1Cl)NC(=O)OCc1ccccc1)C(C)C)OCC
Product: CC(C)N1CC2N(C(=O)C(NC(=O)OCc3ccccc3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reaction time: 5 h

Procedure:
A solution of 218 mg of benzyl (2-(2,4-dichlorobenzenesulfonylamino)-1-{2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate in 3 ml of formic acid is stirred at room temperature for 12 h and then at 55° C. for 5 h. The reaction solution is concentrated under reduced pressure, and the residue is separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). The desired product is obtained with MW=692.10 (calculated monoisotopic); measured value (M+H)+: 693.05.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)=[C:12]([O:26][CH2:27][CH3:28])[CH:11]=2)=[CH:4][N:3]=1.CC([O-])(C)C.[K+].[CH3:35][O:36][CH2:37][CH2:38]Br>CN(C)C=O>[CH2:27]([O:26][C:12]1[CH:11]=[C:10]([CH2:9][C:5]2[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=2)[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:38][CH2:37][O:36][CH3:35])[CH:20]=1)[CH3:28]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1cccc(O)c1
Reactant: COCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1cccc(OCCOC)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4′-(2,4-Diamino-pyrimidin-5-ylmethyl)-2′,6′-diethoxy-biphenyl-3-ol (200 mg; 0.526 mmol) is suspended in dimethylformamide (5 ml; dried over a molecular sieve), and potassium tert-butylate (83 mg; 0.736 mmol) is added at room temperature. 2-Bromoethyl methyl ether (0.059 ml; 0.63 mmol) in dimethylformamide (5 ml; dried over a molecular sieve) is added in the course of 35 minutes to the solution formed. After stirring at room temperature for 12 hours, the reaction mixture is concentrated and the residue is stirred successively with water (twice) and diethyl ether, filtered off with suction and dried under a high vacuum.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]1[C:22](=[O:23])[NH:21][N:20]=[C:19]2[N:10]1[C:11]1[CH:12]=[C:13]3[N:26]([C:27]4([CH3:31])[CH2:30][NH:29][CH2:28]4)[CH2:25][CH2:24][C:14]3=[CH:15][C:16]=1[O:17][CH2:18]2.[O:32](C(OC(C)(C)C)=O)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=O.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:36]([O:35][C:33]([N:29]1[CH2:28][C:27]([CH3:31])([N:26]2[C:13]3[C:14](=[CH:15][C:16]4[O:17][CH2:18][C:19]5[N:10]([C:11]=4[CH:12]=3)[CH:9]([CH3:8])[C:22](=[O:23])[NH:21][N:20]=5)[CH2:24][CH2:25]2)[CH2:30]1)=[O:32])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC1C(=O)NN=C2COc3cc4c(cc3N21)N(C1(C)CNC1)CC4
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc4c(cc3N21)N(C1(C)CN(C(=O)OC(C)(C)C)C1)CC4
Yield: 50.7 %

Procedure:
To a solution of 1-methyl-10-(3-methyl-azetidin-3-yl)-3,5,9,10-tetrahydro-8H-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-2-one 2,2,2-trifluoroacetate (Example #158, 0.65 g, crude, 1.985 mmol) in DCM (15 mL) was added TEA (0.603 g, 5.96 mmol), DMAP (0.024 g, 0.199 mmol) and BOC2O (0.867 g, 3.97 mmol). The resultant mixture was stirred at ambient temperature for 3 h. Water (2×10 mL) was added and the reaction mixture was extracted with EtOAc (2×40 mL). The combined organic phase was washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was dried in vacuo and the residue was purified by column chromatography on silica gel (eluting with 10%-50% EtOAc in petroleum ether) to give racemic 3-methyl-3-(1-methyl-2-oxo-1,2,3,5,8,9-hexahydro-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-10-yl)-azetidine-1-carboxylic acid tert-butyl ester (0.43 g, 1.006 mmol). LC/MS (Table 1, Method 25) Rt=0.823 min; MS m/z: 428 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:25])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[Cl:25][C:6]1[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(C2CCOC2)cc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: Nc1nc(Cl)cc(C2CCOC2)n1
Temperature: 110 °C
Yield: 41.1 %

Procedure:
A suspension of 2-amino-6-(tetrahydro-furan-3-yl)-3H-pyrimidin-4-one (1.5 g, 8.28 mmol), tetraethyl ammonium chloride (2.7 g 16.3 mmol) and dimethylaniline (1.4 mL, 11.1 mmol) in acetonitrile (15 mL) was treated with phosphorous oxychloride (2.4 mL, 26.2 mmol) and heated at 110° C. for 20 min. The resulting solution was cooled to rt and concentrated to minimum volume and pipetted onto ice chips. The aqueous portion was extracted with EtOAc (3×50 mL). The combined organic layers were basified with satd. aq. NaHCO3 solution to pH ˜7. The organic portion was separated, dried, and concentrated. The crude material was chromatographed (MeOH/CH2Cl2) to yield 680 mg (42%) of product as a light orange foam. 1H NMR (CDCl3): 6.59 (s, 1H), 5.16 (br s, 2H), 4.00-4.10 (m, 2H), 3.85-3.91 (m, 2H), 3.28-3.35 (m, 1H), 2.25-2.34 (m, 1H), 2.08-2.18 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].[C:17]([O:21][C:22]([N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH:14]([S:11]([C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:25]1[N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH:28]=[CH:27][CH:26]=1)(=[O:13])=[O:12])([CH3:16])[CH3:15]
Reactant: CC(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1Br
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1-c1cccn1C(=O)OC(C)(C)C
Temperature: 95 °C
Yield: 96 %

Procedure:
To a mixture of 1C (3.0 g, 9.7 mmol), 1-(tert-butoxycarbonyl)-1H-pyrrol-2-ylboronic acid (2.5 g, 11.7 mmol, prepared according to the procedure in Synthesis, 1991, 613-615.) and sodium carbonate (19.5 mL, 2M, 38.9 mmol) in 1,2-dimethoxyethane (100 mL, flushed and degassed (3×) with nitrogen) was added Pd(PPh3)4 (2.2 g, 1.9 mmol) under nitrogen. The reaction was heated to 95° C. for 3 h. The catalyst was filtered over Celite® and washed with ethyl acetate. The organic layer was washed with water, brine and then dried over sodium sulfate. The solvent was removed and the crude residue was purified by flash column chromatography to give 3.68 g of 1D (96% yield). 1H NMR (400 MHz, Methanol-d4) δ ppm 1.01 (d, J=6.85 Hz, 3H) 1.15 (d, J=6.85 Hz, 3H) 1.20 (d, J=7.83 Hz, 9H) 3.00 (m, 1H) 6.29 (m, 2H) 7.41 (dd, J=3.18, 1.71 Hz, 1H) 8.20 (d, J=2.20 Hz, 1H) 8.25 (d, J=8.56 Hz, 1H), 8.41 (dd, J=8.68 Hz, 2.32 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]N2C3C=C(Cl)C=CC=3N=N2)=O)=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.[CH3:25][C:26]1[C:30]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[C:29]([NH2:36])[S:28][N:27]=1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:12]([NH:36][C:29]2[S:28][N:27]=[C:26]([CH3:25])[C:30]=2[N:31]2[CH2:32][CH2:33][CH2:34][CH2:35]2)=[O:14])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)On1nnc2ccc(Cl)cc21
Reactant: Cc1nsc(N)c1N1CCCC1
Solvent: c1ccncc1
Product: Cc1nsc(NC(=O)c2c(N)nn3cc(F)cnc23)c1N1CCCC1
Temperature: 105 °C

Procedure:
A mixture of (6-chlorobenzotriazol-1-yl) 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate (140.4 mg, 0.4038 mmol), 3-methyl-4-(pyrrolidin-1-yl)isothiazol-5-amine (37 mg, 0.2019 mmol) (synthesized according to preparation 13) in pyridine (3 mL) was heated at 105° C. for 24 h. The mixture was concentrated in vacuo and the residue was purified by fractionlynx. The clean fractions were combined and freeze dried to yield 2-amino-6-fluoro-N-(3-methyl-4-(pyrrolidin-1-yl)isothiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a pale yellow solid. (25 mg, 26%). MS (ES+) 362.1.
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]([CH3:22])[C:18]([O:20]C)=[O:19])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].Cl>C(O)C.O>[CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]([CH3:22])[C:18]([OH:20])=[O:19])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C(C)c1ccc(C2CCCCC2)c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(C2CCCCC2)c2ccccc12
Yield: 82.6 %

Procedure:
4.44 g (0.015 mole) of methyl 2(4-cyclohexyl-1-naphthyl)-propionate were solubilized in 50 ml of ethyl alcohol and 50 ml of water under heating. 2.8 g of KOH in 50 ml of water were then added and the mixture was heated with reflux for 10 hours. The conventional treatment followed by an acidification with diluted HCl and a recrystallization from a mixture of ethyl alcohol/water gave 3.5 g of 2-(4-cyclohexyl-1-naphthyl)propionic acid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:32]1[CH2:33][CH2:34][C@@H:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[CH:9]=[C:10]([O:14][CH3:15])[C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[C@H:30]([OH:35])[CH2:31]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(C)=O)C[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f38) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])[CH:4]([CH3:6])[CH3:5]>C(O)C>[CH3:5][CH:4]([CH3:6])[CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:7]
Reactant: CC(C)C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Sodium borohydride (6.5 g, 0.17 mol) was added in portions over a 2 h period to a solution of isobutyrophenone (50 g, 0.34 mol) in ethanol (150 mL) under nitrogen. The reaction mixture was stirred at room temperature for 2 h. Ethanol was removed under reduced pressure. The reaction mixture was added to water (100 mL) and extracted with methylene chloride (3×100 mL). The organic extract was collected, dried (anhy. MgSO4), and concentrated to give 2-methyl-1-phenyl-1-propanol (48 g, 94% yield): bp 62° C. at 0.1 mm; 1H NMR (CDC13) 0.75 (d, J=7, 3 H), 0.96 (d, J=7, 3 H), 1.98 (m, 1 H), 2.90 (bs, 1 H), 4.25 (d, J=7, 1 H), and 7.31 (s, 5 H).
Reaction SMILES: C([O:5]O)(C)(C)C.C(CC(C)(C)C)(C)C.[CH2:15]([OH:27])/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.O.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:18]([C@@H:17]1[O:5][C@H:16]1[CH2:15][OH:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CC(C)(C)OO
Reactant: CCCCCCCCC/C=C/CO
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CC(C)CC(C)(C)C
Solvent: O
Product: CCCCCCCCC[C@@H]1O[C@H]1CO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 1.00 g of 4a powdered molecular sieves in 50 ml of dry CH2Cl2 was cooled to 0° C. under argon. To the cooled suspension was added 308 mg (1.09 mmole) of Ti(OiPr)4 and 356 mg (1.52 mmole) of L(+)diisopropyl tartrate via syringe. The mixture was stirred for 15 min and cooled to -20° C. A solution of tert-butyhydroperoxide in isooctane (3.8 M, 4.30 ml, 16.4 mmole) was added slowly to the mixture and the catalyst was allowed to "age" for 30 min at -20° C. A solution of 2.00 g (10.9 mmole) of E-2-dodecen-1-ol in 10 ml of CH2Cl2 was dried over 3A molecular sieves for 15 ml before being added to the mixture slowly, with stirring, at -20°. The solution was then placed in the freezer (-30° C.) and allowed to stand for 24 H. The mixture was warmed to 0° C. and poured into a solution of 1.00 g of citric acid and 3.50 g of FeSO4 in 15 ml H2O. The organic layer was separated and the acqueous layer washed twice with 20 ml of CH2Cl2. The CH2Cl2 layers were combined, dried over MgSO4, filtered and evaporated to yield a sticky white solid. Recrystallization from Et2O:petroleum ether afforded 1.98 g of white solid, mp 62-4° C. 1H NMR δ 3.92 (ddd, 1, J=2.5, 6, 12 Hz), 3.63 (ddd, 1, J=4, 7, 12 Hz), 2.95 (m, 2), 1.69 (dd, 1, J=7, 6 Hz), 1.6-1.2 (m, 16), 0.88 (t, 3, J=6 Hz). Mass Spectra: M-31(--CH2OH)(0.4)169, M(100)55.1.
Reaction SMILES: [CH:1]([C:3]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH2:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1)=[O:2].[OH-].[Na+]>C(O)C.O>[CH:1]([C:3]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH2:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)=[O:2]
Reactant: CCOC(=O)c1ccc(COc2cccc(O)c2C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=Cc1c(O)cccc1OCc1ccc(C(=O)O)cc1

Procedure:
Ethyl 4-(2-formyl-3-hydroxyphenoxymethyl)benzoate (0.6 g. 0.002 M) was suspended in 95% ethanol (5 ml) and 1 N sodium hydroxide solution (5 ml) and stirred at room temperature (2.5 hr). The yellow solution was diluted with water, extracted with ethyl acetate, and acidified with concentrated hydrochloric acid. The precipitated solid was filtered off, washed well with water, and recrystallised from 95% ethanol to give 4-(2-formyl-3-hydroxyphenoxymethyl) benzoic acid, m.p. 239°-240° C. (Found: C. 65.99; H, 4.29. C15H12O5 requires C, 66.17; H, 4.44%).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([N:10]([CH3:34])[C:11]([C:13]1[N:17]2[CH2:18][CH2:19][C:20]3[C:25]([C:16]2=[C:15]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[CH:14]=1)=[CH:24][C:23]([NH2:26])=[C:22]([O:27][CH3:28])[CH:21]=3)=[O:12])([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C>ClCCl>[C:6]([N:10]([CH3:34])[C:11]([C:13]1[N:17]2[CH2:18][CH2:19][CH:20]3[CH:25]([C:16]2=[C:15]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[CH:14]=1)[CH:24]=[C:23]([NH:26][C:3](=[O:4])[CH2:2][Br:1])[C:22]([O:27][CH3:28])=[CH:21]3)=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: COc1cc2c(cc1N)-c1c(-c3cccs3)cc(C(=O)N(C)C(C)(C)C)n1CC2
Reactant: O=C(Br)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC1=CC2CCn3c(C(=O)N(C)C(C)(C)C)cc(-c4cccs4)c3C2C=C1NC(=O)CBr

Procedure:
Bromoacetyl bromide (0.137 ml) was added to a stirred solution of the product of example 95 (500 mg) and DIPEA (0.425 ml) in dichloromethane (20 ml) over a period of 6 h. The reaction mixture was concentrated in vacuo.