Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:17]=[C:16]([CH:23]=[CH:22][CH:21]=1)[NH:15][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1)#[N:20]
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: N#Cc1cccc(N)c1
Product: Cc1cc(Nc2cccc(C#N)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and 3-aminobenzonitrile (57 mg, 0.486 mmol) similar to Example 11 and isolated as a pale white solid (107 mg, 76%). 1H NMR (DMSO-d6): 10.14 (s, 1H), 8.78-8.75 (m, 1H), 8.56 (s, 1H), 8.32 (d, J=7.8 Hz, 1H), 8.04-7.96 (m, 2H), 7.60-7.47 (m, 3H), 6.75 (s, 1H) 2.47 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:7][CH2:6][C@H:5]([CH:8]=[CH:9][C:10](=[CH2:12])[CH3:11])[CH:4]=[CH:3]1.[CH3:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[C:19]([CH:21]=1)[OH:20].O.O.C(O)(=O)C(O)=O>C1(C)C=CC=CC=1.C(OCC)C>[CH3:14][C:15]1[C:16]([CH:4]2[CH:5]([CH:8]=[CH:9][C:10](=[CH2:11])[CH3:12])[CH2:6][CH2:7][C:2]([CH3:1])=[CH:3]2)=[C:17]([OH:22])[CH:18]=[C:19]([OH:20])[CH:21]=1
Reactant: C=C(C)C=C[C@@H]1C=CC(C)(O)CC1
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: C=C(C)C=CC1CCC(C)=CC1c1c(C)cc(O)cc1O
Reaction time: 5 h
Yield: 140.7 %

Procedure:
(4R)-1-Methyl-4-isoprenylcyclohex-2-ene-1-ol (300 mg, 2 mmoles) was dissolved in toluene (20 ml) and 5-methylresorcinol (248 mg, 2 mmoles) was added in diethyl ether (5 ml). Oxalic acid dihydrate (252 mg, 2 mmoles) was added and the reaction mixture heated with stirring at 80° for 5 hours. The reaction mixture was allowed to cool and diluted with diethyl ether (30 ml). The ether solution was washed twice with aqueous sodium bicarbonate and dried over anhydrous magnesium sulphate. The solvents were evaporated under reduced pressure to give the crude product as a brown oil (800 mg). The product was purified using a silica column eluted with ethyl acetate:isohexane 1:9 going to ethyl acetate:isohexane 2:8.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][S:21]([CH:24]=[C:25]3[CH2:28][N:27]([CH:29]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)[C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[CH2:26]3)(=[O:23])=[O:22])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)=O>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([CH:29]([C:37]2[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=2)[N:27]2[CH2:26][C:25](=[CH:24][S:21]([CH2:20][C:16]3[CH:15]=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:19]=[CH:18][CH:17]=3)(=[O:22])=[O:23])[CH2:28]2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Solvent: O=CO
Product: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Yield: 66.6 %

Procedure:
A solution of 320 mg of 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester in 5 cm3 of formic acid is stirred for 5 hours at a temperature close to 20° C., and then for 1 hour at a temperature close to 45° C. The reaction medium is concentrated to dryness under reduced pressure (5 kPa) at a temperature close to 30° C., taken up in 20 cm3 of ethyl acetate and alkalinized with 10 cm3 of a saturated aqueous sodium bicarbonate solution. After separating after settling out, the organic phase is washed with three times 10 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. The residue obtained is purified by depositing, in solution in a minimum of dichloromethane, on silica gel deposited on a plate [(gel 0.5 mm thick, 5 plates of 20 20 cm, eluent: dichloromethane-methanol (80-20 by volume)]. The zone corresponding to the adsorbed desired product, located with UV rays, is scraped and the silica recovered is washed on sintered glass with a dichloromethane-methanol mixture (75-25 by volume). The filtrates are combined and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 30° C. 180 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine are thus obtained in the form of a white powder [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.77 (s, 3H), 3.05 (mt, 4H), 3.16 (mt, 4H), 3.81 (mt, 2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.79 (broad d, J=8Hz, 1H), 6.90 (dd, J=8 and 2.5 Hz, 1H), 6.98 (mt, 1H), from 7.20 to 7.40 (mt, 9H)].
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH3:11])=[C:6]([C:8](=[O:10])C)[CH:7]=1.BrC1C(C)=C(C(=O)C)C=CC=1[O:21]C.[O-]Cl.[Na+].[OH-].[K+].Cl>>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH3:11])=[C:6]([CH:7]=1)[C:8]([OH:10])=[O:21]
Reactant: COc1ccc(C(C)=O)c(C)c1Br
Reactant: COc1cc(C)c(C(C)=O)cc1Br
Agent: Cl
Agent: [K+]
Agent: [Na+]
Product: COc1cc(C)c(C(=O)O)cc1Br
Temperature: 25 °C

Procedure:
Alternatively, 5-bromo-4-methoxy-2-methylbenzoic acid can be synthesized from 4′-hydroxy-2′-methylacetophenone as a starting material. Potassium carbonate (0.720 mg, 5.21 mmol) and methyl iodide (0.542 g, 3.82 mmol) were added to an acetone (10 mL) solution of 4′-hydroxy-2′-methylacetophenone (0.552 g, 3.47 mmol) and stirred at room temperature for 12 hours. Methyl iodide (0.24 g, 1.73 mmol) was further added, and the mixture was heated to reflux for two hours. After cooled to room temperature, the solvent was evaporated under reduced pressure. After chloroform was added to the residue, insolubles were filtered off and the filtrate was concentrated to obtain 4′-methoxy-2′-methylacetophenone (0.57 g). Then, oxone (0.79 g, 1.27 mmol) and NaBr (0.13 g, 1.27 mmol) were added to an acetone (4 mL) water (4 mL) solution of 4′-methoxy-2′-methylacetophenone (0.21 g, 1.27 mmol), and stirred at room temperature for one hour. After water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with water, a saturated sodium carbonate aqueous solution and brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure to obtain 4:1 mixture (0.28 g) of 5′-bromo-4′-methoxy-2′-methylacetophenone and 3′-bromo-4′-methoxy-2′-methylacetophenone. Then, 4:1 mixture (0.26 g) of 5′-bromo-4′-methoxy-2′-methylacetophenone and 3′-bromo-4′-methoxy-2′-methylacetophenone was added with 5% NaOCl solution (3 mL) and potassium hydroxide (0.92 g) and heated to reflux for 2.5 hours. After cooled to room temperature, the reaction mixture was made acidic with 2M HCl. After the mixture was extracted with ethyl acetate, the organic phase was washed with 1M HCl, brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was washed with methanol to obtain 5-bromo-4-methoxy-2-methylbenzoic acid (112 mg) as a colorless powder.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([O:21][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: ClCc1ccccn1
Agent: Cl
Product: Cc1c(C)c2c(c(C)c1OCc1ccccn1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 17 %

Procedure:
Using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and 2-chloromethylpyridine hydrochloride, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[CH:6][N:7]=1)#[N:2].C(N[C@H](C(O)=O)CS)(=O)C.C([O-])(=O)C.[NH4+].C([O:25][C:26](=[O:35])[C:27](=[CH:31][N:32](C)C)[C:28](=O)[CH3:29])C.CC([O-])(C)C.[K+].[OH-].[K+].Cl>CO.O>[CH3:29][C:28]1[C:27]([C:26]([OH:35])=[O:25])=[CH:31][N:32]=[C:1]([C:3]2[S:4][CH:5]=[CH:6][N:7]=2)[N:2]=1
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Reactant: N#Cc1nccs1
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CO
Solvent: O
Product: Cc1nc(-c2nccs2)ncc1C(=O)O
Temperature: 120 °C
Yield: 62.1 %

Procedure:
A solution of 2-cyanothiazole (1.55 g, 14.2 mmol) in MeOH (12 mL) is treated with N-acetylcysteine (234 mg, 1.42 mmol), ammonium acetate (1.5 g, 18.5 mmol) and heated in a microwave at 120° C. for 15 min. The mixture is then treated with 2-dimethylaminomethylene-3-oxo-butyric acid ethyl ester (3.2 g, 17.0 mmol) and KOt-Bu (2.2 g, 20 mmol), and heated in a microwave at 120° C. for an additional 15 min. The mixture is then treated with a solution of KOH (1.2 g, 20 mmol) in H2O (5 mL) and heated at reflux for 1 h. The mixture is neutralized with concentrated aqueous HCl. The precipitate is collected by filtration and dried to afford 4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (1.95 g, 62%). MS: 222 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 13.77 (s. OH, 1H), 9.18 (s, 1H), 8.13 (d, 1H), 8.07 (d, 1H), 2.81 (s, 3H).
Reaction SMILES: [C:1](=[O:5])([O:3][CH3:4])[NH2:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]([NH:2][C:1]([O:3][CH3:4])=[O:5])=[O:18])(=[O:14])=[O:15])=[CH:11][CH:12]=1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: COC(N)=O
Solvent: Cc1ccccc1
Product: COC(=O)NC(=O)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 95.3 %

Procedure:
Methyl carbamate (43.0 grams, 0.57 moles) was stirred in 500 milliliters of dry toluene. 4-chlorobenzenesulfonyl isocyanate (125 grams, 0.57 moles) was added dropwise. An exothermic reaction occurred. The reaction mixture was kept at 80° C. for 11/2hours. It was then cooled and the percipitate removed by filtration. The filtered material was washed with toluene and dried. There was obtained 159 grams of the title product, m.p. 174°-175° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:15]=O>C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH3:15])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: C=O
Reactant: Brc1ccc(CC2CCNCC2)cc1
Solvent: O=CO
Product: CN1CCC(Cc2ccc(Br)cc2)CC1
Temperature: 150 °C
Yield: 98.1 %

Procedure:
A mixture of 4-(4-bromobenzyl)-piperidine (290 mg, 1.14 mmol), formic acid (12 mL) and 37% aqueous formaldehyde (0.30 mL, 3.75 mmol) was divided into three portions. Each portion was heated at 150° C. for 5 minutes in a microwave reactor. The combined cold mixture was loaded onto a 5 g SCX-2 cartridge which was then washed with methanol (30 mL) then 2 N ammonia in methanol (50 mL). Concentration of the combined basic fractions in vacuo gave the title compound (300 mg, 98%) as a colourless oil. LCMS (Method B): RT=2.18 min, M+H+=268, 270.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)=[O:3].[C:15]([N:19]=[N:20][C:21]([C:27]#[N:28])([CH2:23][CH2:24][CH2:25][OH:26])[CH3:22])([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1>CCOCC>[C:15]([N:19]=[N:20][C:21]([C:27]#[N:28])([CH3:22])[CH2:23][CH2:24][CH2:25][O:26][C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)=[O:3])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)N=NC(C)(C#N)CCCO
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)OC2=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)N=NC(C)(C#N)CCCOC(=O)c1ccc2c(c1)C(=O)OC2=O
Reaction time: 0.25 h

Procedure:
To a solution of 2.1 g. (0.01 m) of 4-chloroformylphthalic anhydride in 25 ml ether in a 50 ml 4-neck round bottom flask equipped with a condenser containing a CaCl2 drying tube, a thermometer, a magnetic stirring bar and a dropping funnel was added a solution of 2.0 g. (0.01 m) 2-t-butylazo-2-cyano-5-hydroxypentane (from XIV) and 0.8 g. (0.01 m) pyridine in 10 ml ether. This solution was added dropwise with stirring over 15 minutes holding the temperature between 15° and 22° C with a water bath. The reaction was stirred an additional hour after the addition was completed and the pyridine hydrochloride filtered off. The ether filtrate was dried over anhydrous Na2SO4, filtered and evaporated to dryness leaving 3.1 g. (84%) of a viscous liquid. The infrared spectrum contained 3 carbonyl bands and no OH bands.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:10][CH2:11][C@@H:12]([CH2:16][N:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[N:19][C:18]2=[O:27])[C@H:13]([OH:15])[CH3:14])=[CH:5][CH:4]=1.N1[C-]=NN=N1.C([NH2+]C(C)C)(C)C.[CH:54]([N:57]([CH:71]([CH3:73])[CH3:72])[P:58](N(C(C)C)C(C)C)[O:59][CH2:60][CH2:61][C:62]#[N:63])([CH3:56])[CH3:55]>ClCCl>[CH:71]([N:57]([CH:54]([CH3:56])[CH3:55])[P:58]([O:59][CH2:60][CH2:61][C:62]#[N:63])[O:15][C@H:13]([CH3:14])[C@H:12]([CH2:16][N:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[N:19][C:18]1=[O:27])[CH2:11][O:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:73])[CH3:72]
Reactant: COc1ccc(C(OC[C@@H](Cn2ccc(NC(C)=O)nc2=O)[C@@H](C)O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Agent: CC(C)[NH2+]C(C)C
Agent: [c-]1nnn[nH]1
Solvent: ClCCl
Product: COc1ccc(C(OC[C@@H](Cn2ccc(NC(C)=O)nc2=O)[C@@H](C)OP(OCCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.5 %

Procedure:
To a stirred solution of 22 (1.0 g, 1.79 mmol) in 25 ml of anhydrous dichloromethane was added diisopropylammonium tetrazolide (0.35 g) followed by 0.8 g (2.66 mmol) of 2-cyanoethyl N,N,N′,N′-tetraisopropylphosphordiamidite. After being stirred at room temperature for 20 hrs the reaction was concentrated, and the residue portioned between ethyl acetate and saturated NaHCO3. The organic phase was washed with saturated NaCl, dried over Na2SO4 and concentrated in vacuo. The crude phosphoramidite was precipitated twice by re-dissolving in small (˜10 ml) amount of ethyl acetate, diluting with hexane (100 ml), allowing precipitate as an oil and decanting the liquid. Drying in vacuo afforded 1.2 g (88%) of 23 as an amorphous white solid. 31P NMR (DMSO-d6): δ 148.03, 147.19.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:9]2([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH3:21])[CH2:15][C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CNC
Reactant: O=CC1(c2cccc(C(F)(F)F)c2)CCCCC1
Product: CN(C)CC1(c2cccc(C(F)(F)F)c2)CCCCC1
Yield: 51.9 %

Procedure:
The title compound was prepared from 1-(3-(trifluoromethyl)phenyl)cyclohexane-carbaldehyde (128 mg, 0.50 mmol) and dimethylamine (2.0 M in THF, 2.5 ml, 5.0 mmol) according to General Procedure H2.The crude product was purified by silica gel column chromatography (MeOH/CH2Cl2, MeOH from 0% to 15%) to give N,N-dimethyl-1-(1-(3-(trifluoromethyl)phenyl)cyclohexyl)methanamine (74 mg, 52%) as a clear oil. 1H NMR (CDCl3): δ 1.29-1.38 (m 3H), 1.48-1.57 (m, 3H), 1.63-1.70 (m, 2H), 1.97 (s, 6H), 2.11-2.15 (m, 2H), 2.34 (s, 2H), 7.41-7.43 (m, 2H), 7.56-7.59 (m, 1H), 7.63 (s, 1H). 13C NMR (CDCl3) δ 22.4, 26.7, 34.3, 43.9, 48.6, 72.7, 122.4, 124.3, 128.6, 126.0, 131.1, 147.6, 150.8.ESI MS m/z 286.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:6]2[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3]1.[OH-].[K+].O.Cl>CCO>[CH3:1][C:2]1([CH3:22])[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:6]2[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3]1
Reactant: CCOC(=O)c1cnn2c1NC(c1ccccc1)CC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CC(c2ccccc2)Nc2c(C(=O)O)cnn21
Temperature: 90 °C
Reaction time: 12 h
Yield: 83.1 %

Procedure:
A mixture of 1(0.73 g) obtained in Example 1009, KOH (0.41 g), H2O(20 ml) and EtOH (20 mL) was stirred at 90° C. for 12 h, acidified with 1N HCl, and extracted with AcOEt. The extract was washed with brine, dreid over MgSO4, and concentrated in vacuo to give 0.55 g (83% yield) of the title compound as colorless prisms ([α]D20° C.=−85.33, in CHCl3, C=0.46). mp 205-206° C., 1H NMR (CDCl3, 300 MHz): 1.59 (3H, s), 1.66 (3H, s), 2.05-2.15 (2H, m), 4.64 (1H, dd, J=9.6, 5.4 Hz), 6.04 (1H, s), 7.30-7.41 (5H, m), 7.73 (1H, s)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([C:13](OCC)=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+].[OH-].[Na+]>O1CCCC1.C(O)C>[NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][OH:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cc(-c2cccnc2N)on1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ncccc1-c1cc(CO)no1
Temperature: 20 °C
Reaction time: 21 h
Yield: 82.8 %

Procedure:
To a suspension of ethyl 5-(2-aminopyridin-3-yl)isoxazol-3-carboxylate (381 mg, 1.63 mmol) in tetrahydrofuran (3.8 mL) and ethanol (3.8 mL) was added sodium borohydride (201 mg, 4.89 mmol) at 0° C. under a nitrogen atmosphere, which was stirred at 0° C. for one hour and at 20° C. for 21 hours. Under an ice water bath cooling, to the reaction mixture was added 2N hydrochloric acid (2.46 mL, 4.89 mmol) dropwise, which was stirred at 0° C. for 10 minutes and at room temperature for 30 minutes. Under the ice water bath cooling, after an aqueous solution of 5% sodium bicarbonate was added dropwise to adjust basic, the solution was extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure. The residue was suspended in tetrahydrofuran (1.4 mL), to the reaction mixture was added sodium borohydride (67 mg, 1.63 mmol) at 0° C., which was washed thereto down with methanol (1.4 mL). After stirring at room temperature for one hour, the solution was stirred at 60° C. for five hours. Under an ice water bath cooling, to the reaction mixture was added 1N hydrochloric acid (1.63 mL, 1.63 mmol) dropwise, which was stirred at 0° C. for 10 minutes and at room temperature for 30 minutes. Under the ice water bath cooling, after adding 1N aqueous sodium hydroxide dropwise to adjust basic, the solution was extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure to obtain the title compound (258 mg) as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][NH:7][C:6]2=[N:10][CH:11]=[CH:12][C:5]=12.Cl[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH2:16]([O:15][CH2:14][N:10]1[C:6]2[N:7]=[CH:8][N:9]=[C:4]([Cl:3])[C:5]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ncnc2c1ccn2COCc1ccccc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a oven dried 250 mL three-neck round bottom flask equipped with a stir bar, thermocouple, septa and nitrogen inlet was charged sodium hydride (NaH, 60 wt %, 1.56 g, 0.0391 mol, 1.2 equiv) and anhydrous tetrahydrofuran (THF, 25.0 mL, 0.308 mol) and the resulting mixture was chilled to 0-5° C. To a 100 ml oven dried round bottom flask was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 5.00 g, 0.0326 mol) and anhydrous tetrahydrofuran (50 mL, 0.616 mol), and the resulting slurry was added portion wise via large bore canula over 20 minutes to the sodium hydride (NaH) suspension in THF. The cooling bath was removed after the addition is complete and the reaction mixture was stirred at room temperature for 1 hour. The slurry becomes green in color after it is warmed to 16.5° C. The mixture was cooled to 0-5° C. before neat benzyl chloromethyl ether (5.28 mL, 0.0342 mol, 1.05 equiv) was charged over 13 minutes via syringe. The cold bath was removed and the reaction mixture was warmed to room temperature gradually and stirred at room temperature for 20 h. The reaction mixture was quenched with 20% aqueous brine (50 mL) and diluted with ethyl acetate (100 mL) when the reaction was deemed complete. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrate under reduced pressure. The residue was then purified by flash chromatography (SiO2, 10% to 15% ethyl acetate/hexane gradient elution) to afford 7-[(benzyloxy)methyl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3e, 6.31 g, 8.92 g theoretical, 70.7%) as a green oil. For 3e: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.69 (s, 1H), 7.90 (d, 1H, J=3.7 Hz), 7.26 (m 5H), 6.71 (d, 1H, J=3.7 Hz), 5.75 (s 2H), 4.51 (s, 2H); C14H12ClN3O (MW, 273.72), LCMS (EI) m/e 274/276 (M++H).
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][C:10]([C:12]1[O:13][C:14]([CH3:33])=[C:15]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][N:26]=3)=[CH:21][CH:20]=2)[CH:16]=1)=[O:11].[ClH:34]>O1CCCC1>[ClH:34].[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][CH2:17][C:15]3[CH:16]=[C:12]([C:10]([OH:11])=[O:9])[O:13][C:14]=3[CH3:33])=[CH:24][CH:23]=2)=[N:26][CH:27]=1
Reactant: COC(=O)c1cc(CNc2ccc(-c3ccc(OC)cn3)cc2)c(C)o1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(NCc3cc(C(=O)O)oc3C)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-{[4-(5-methoxy-pyridin-2-yl)-phenylamino]-methyl}-5-methyl-furan-2-carboxylic acid methyl ester trifluoroacetic acid salt (165) (38 mg, 0.082 mmoles) in tetrahydrofuran (4 ml) was treated with potassium trimethylsilanoate (63 mg, 0.049 mmoles) and the mixture stirred at room temperature for 16 hours. The mixture was evaporated to dryness and pumped under high vacuum to remove silanol volatiles. The residue was purified by HPLC to afford a residue, which was dissolved in 1M aqueous hydrochloric acid. The solution was evaporated to give compound 166 as a solid (30 mg). LC/MS System A; Rt=2.22 mins, m/z (ES+)=339 (M+H for C19H18N2O4) and m/z (ES−)=337 (M−H for C26H25N3O5S).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][C:15]=1[CH2:24]O>C(Cl)Cl>[Cl:3][CH2:24][C:15]1[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:14]=1[C:7]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=1[F:5]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CCl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (available from Aldrich) (4.46 g, 37.5 mmol) was added to a solution or 66.63A in DCM (6 mL). The reaction mixture was stirred at room temperature for 2 hours and then at 50° C. for 3 hours. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:9 EtOAc/hexane) and gave 66.69A (386 mg) as a colorless oil.