Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].C(O)C.[S:6]1[CH:10]=[C:9]([CH:11]=[CH:12][C:13]2[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=2)[C:8]2[CH:20]=[CH:21][CH:22]=[CH:23][C:7]1=2>O>[OH:19][CH2:18][C:16]1[S:17][C:13]([CH:12]=[CH:11][C:9]2[C:8]3[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=3[S:6][CH:10]=2)=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(C=Cc2csc3ccccc23)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1ccc(C=Cc2csc3ccccc23)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
A stirred, chilled (0° C.) suspension of sodium borohydride (0.50 g) and absolute ethanol (250 ml), under nitrogen, was treated in portions with 5-[2-(benzo[b]thiophen-3-yl)ethenyl]thiophene-2-carboxaldehyde (3.0 g). After stirring at room temperature overnight, the mixture was poured into water (250 ml). The organic phase was removed in vacuo, and the resulting aqueous phase was extracted with dichloromethane. The combined, dried over anhydrous magnesium sulfate, filtered organic phase was evaporated. The residue was purified by high performance liquid chromatography (silica gel, loaded and eluted first with dichloromethane, then with ethyl acetate). The appropriate fractions were combined and evaporated. The residue was recrystallized from toluene/hexane to yield 2.15 g (71%) of product, mp 68°-70° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:10])([F:9])[C:5](OC)=[O:6].[CH3:11][C:12]#[N:13]>C1COCC1>[F:3][C:4]([F:10])([F:9])[C:5](=[O:6])[CH2:11][C:12]#[N:13]
Reactant: CC#N
Reactant: COC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a suspension of NaH (2.88 g, 120 mmol) in THF (70 mL) at 80° C. was dropped a solution of methyl 2,2,2-trifluoroacetate (10.244 g, 80 mmol) in MeCN (5.377 g, 130 mmol) over 40 minutes. The mixture was heated at 70° C. for 2 hours and stirred at room temperature overnight. The reaction was quenched with water, acidified with 10% HCl solution to pH 1, and extracted with CH2Cl2. Extracts were dried over MgSO4, concentrated under reduced pressure, and dried under vacuum to afford 4,4,4-trifluoro-3-oxobutanenitrile as an oil (9.084 g, 83%). 1H NMR (300 MHz, CDCl3) δ 2.93 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28]CC4C=CC(Cl)=CC=4Cl)[C@@H:14]([O:15]CC4C=CC(Cl)=CC=4Cl)[C@@:12]3([CH:38]=[CH2:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.B(Cl)(Cl)Cl>ClCCl>[NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([OH:15])[C@@:12]3([CH:38]=[CH2:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C=C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(N)ncnc21
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: C=C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 34.8 %

Procedure:
To a solution of the compound from Step C (60 mg) in dichloromethane at −78° C. was added boron trichloride (1M in dichloromethane) dropwise. The mixture was stirred at −78° C. for 2.5 h, then at −30° C. to −20° C. for 3h. The reaction was quenched by addition of methanol/dichloromethane (1:1) and the resulting mixture stirred at −15° C. for 0.5 h, then neutralized with aqueous ammonia at 0° C. and stirred at room temperature for 15 min. The solid was filtered and washed with methanol/dichloromethane (1:1). The combined filtrate was evaporated and the residue purified by flash chromatography (SiO2, 10% methanol in EtOAc containing 0.1% triethylamine). The fractions containing the product were evaporated to give the title compound as a white solid (10 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][N:14]1[CH:18]=[C:17]([CH:19]=O)[C:16]([CH3:21])=[N:15]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][N:14]1[CH:18]=[C:17]([CH:19]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[C:16]([CH3:21])=[N:15]1
Reactant: O=C(O)CNC(=O)c1cccs1
Reactant: Cc1nn(C)cc1C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1nn(C)cc1C=C1N=C(c2cccs2)OC1=O
Temperature: 90 °C
Yield: 29.3 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 1,3-dimethyl-1H-pyrazol-4-carboxaldehyde (41 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 24 mg of the above-captioned compound.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])C.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[OH:28][CH2:27][C:26]([NH:25][C:4]([C:6]1[S:10][C:9]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])([CH3:30])[CH3:29]
Reactant: CC(C)(N)CO
Reactant: CCOC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)s1
Product: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NC(C)(C)CO)s1
Yield: 23 %

Procedure:
As described for example 127, 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-thiazole-5-carboxylic acid ethyl ester (95 mg, 0.28 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of isopropylamine, to the title compound (25 mg, 23%) which was obtained as a colourless gum after purification by chromatography (silica, 0 to 3% methanol in dichloromethane). MS: m/e=388.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12](=[CH:18][CH:19]2[CH2:23][CH2:22][C:21]3([O:28][CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][O:24]3)[CH2:20]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8][CH:9]1[CH2:11][CH2:10]1.[OH:31]OS([O-])=O.[K+].C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>CO.C1COCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:12](=[CH:18][CH:19]2[CH2:23][CH2:22][C:21]3([O:24][CH2:25][C:26]([CH3:29])([CH3:30])[CH2:27][O:28]3)[CH2:20]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH:9]1[CH2:11][CH2:10]1)=[O:31]
Reactant: O=S([O-])OO
Reactant: CCOC(=O)C(=CC1CCC2(C1)OCC(C)(C)CO2)c1ccc(SC2CC2)c(Br)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(=CC1CCC2(C1)OCC(C)(C)CO2)c1ccc(S(=O)C2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
Ethyl 2-[3-bromo-4-(cyclopropylsulfanyl)phenyl]-3-(8,8-dimethyl-6,10-dioxaspiro[4.5]dec-2-yl)acrylate (1.63 g, (E)/(Z)-mixture) was dissolved in methanol (16.3 mL)-THF (16.3 mL) mixed solvent, followed by ice-cooling. To this solution was added a solution of Oxone (registered trademark, 2.43 g) in water (16.3 mL), followed by warming to room temperature and stirring for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added thereto, and further added a 1 M aqueous sodium sulfite solution and ethyl acetate. The organic layer was separated and the aqueous layer was then extracted with ethyl acetate. The organic layer was further washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain ethyl 2-[3-bromo-4-(cyclopropylsulfinyl)phenyl]-3-(8,8-dimethyl-6,10-dioxaspiro[4.5]dec-2-yl)acrylate (1.64 g) as an (E)/(Z)-mixture of olefin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](C1C3C(=CC=CC=3)C=CC=1)([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.C=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C=CN=C4C=CC=CC=34)N(CC2)C1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(C)(C(=O)O)c3cccc4ccccc34)ccc2c1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Solvent: CO
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Reaction time: 2 h

Procedure:
A mixture of 2.3 g. of 6-methoxy-2-naphthyl-α-naphthyl-α-methylacetic acid, 2.9 g. of cinchonidine, and 50 ml. of methanol is stirred for two hours; the mixture is then allowed to stand until crystallization is complete. The crystals are filtered off and washed with methanol. The crystals are recrystallized from methanol, filtered, washed, and dried. The pure crystals are added to 60 ml. of 0.2N hydrochloric acid. The resulting mixture is stirred for two hours and then extracted with diethyl ether. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, and evaporated to yield one of the optical isomers of 6-methoxy-2-naphthyl-α-methylacetic acid. The filtrates from the above filtrations are acidified with aqueous dilute hydrochloric acid and the product is isolated by diethyl ether extractions to give the other optical isomer of 6-methoxy-2-naphthyl-α-methylacetic acid.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]3[N:16]([CH2:19][CH2:20][C:21]#[N:22])[N:17]=[CH:18][C:10]=13)[CH2:2]2.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:13]2[N:12]=[C:11]3[N:16]([CH2:19][CH2:20][C:21]#[N:22])[N:17]=[CH:18][C:10]3=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:14]=2)=[CH:26][CH:25]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: N#CCCn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#CCCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Temperature: 25 °C

Procedure:
3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propanenitrile (1.75 mmol) was dissolved in toluene (32 mL) and ethanol (19 mL). 4-Aminophenylboronic acid, pinacol ester (858 mg, 3.9 mmol) was added followed by the addition of a 2M aqueous solution of Na2CO3 (7.1 mL). The mixture was degassed by bubbling a stream of nitrogen through the solution and tetrakis(triphenylphosphine)palladium (53 mg) was added. The mixture was heated under reflux for 4 h, cooled to room temperature and concentrated. The mixture was dissolved in ethyl acetate and washed with brine. The organic phase was dried over MgSO4, filtered and concentrated. The crude product was applied to a silica gel column and eluted with ethyl acetate in hexanes (30-100%) to give 547 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[CH:4][NH:3]1.Cl>[OH-].[Na+]>[O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][NH:3]1
Reactant: CCOC(=O)c1cnc[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cnc[nH]c1=O
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 89.3 %

Procedure:
Ethyl 3,4-dihydro-4-oxopyrimidine-5-carboxylate (K R Huffman, F C Schaefer and G A Peters, J. Org. Chem. (1962) 27, 551-8) (1.68 g) was dissolved in 1N NaOH (23 ml) and heated at 60° C. overnight. After cooling in ice, the solution was acidified to pH2 with 2N HCl, stirred 5 mins and the solid filtered off and dried under vacuum to give title compound (1.25 g).
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:26])[CH2:9][CH2:10][C@@H:11]3[C@@:16]4([CH3:25])[CH2:17][CH2:18][C@H:19]([O:21]C(C)=O)[CH2:20][C:15]4=[CH:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].BrN1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl>[OH:21][C@H:19]1[CH2:18][CH2:17][C@@:16]2([CH3:25])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:11]2[CH2:10][CH2:9][C@@:8]2([CH3:26])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:2](=[O:3])[CH3:1])[CH2:20]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Pregnenolone acetate (15.0 g) was dissolved in 100 ml of carbon tetrachloride, and after addition of 8.95 g of N-bromosuccinimide and 8 g of a finely powdered sodium bicarbonate, the mixture was refluxed for 30 minutes. After cooling, the reaction mixture was washed with water and dried, followed by the distilling off of the solvent under vacuum. The yellow solid residue was dissolved in 100 ml of xylene and after addition of 4.5 ml of collidine, the solution was refluxed on an oil bath for 1 hour. After cooling, ethyl acetate was added to the solution and the mixture was successively washed with water, dilute hydrochloric acid, water and an aqueous solution of sodium bicarbonate. The washed solution was dried and the solvent was distilled off under vacuum. The residue was dissolved in 100 ml of methanol under heating. After cooling, 4 g of potassium hydroxide was added to the solution, which was then stirred for 4 hours at room temperature. The resulting white precipitate was filtered off. After washing with methanol, the filtrate was freed of the solvent by vacuum distillation, whereby 6.46 g of a crude product of the desired 5,7-diene compound was obtained.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[CH2:9]([NH:16][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1ccc(I)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(NCc2ccccc2)cc1
Yield: 78.7 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), benzylamine (131 μl, 1.20 mmol), 4-iodobenzonitrile (229 mg, 1.00 mmol), ethylene glycol (111 μl, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=5/1, Rf=0.4) afforded 4-(N-benzyl)aminobenzonitrile (164 mg, 79% isolated yield) as light yellow solid. Spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158–1174.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=1)[CH2:10][N:11]1[CH2:15][CH:14]2[CH2:16][N:17](C(OCC3C=CC=CC=3)=O)[CH2:18][CH:13]2[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:29][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:10][N:11]2[CH2:12][CH:13]3[CH:14]([CH2:16][NH:17][CH2:18]3)[CH2:15]2)=[CH:36][CH:35]=1)#[N:38]
Reactant: CC(C)(C)OC(=O)N[C@H](COc1ccc(C#N)cc1)CN1CC2CN(C(=O)OCc3ccccc3)CC2C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](COc1ccc(C#N)cc1)CN1CC2CNCC2C1
Yield: 63.7 %

Procedure:
Benzyl 5-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-cyanophenoxy)-propyl]hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3.6 g, 6.9 mmol; from step (i) above) was dissolved in ethanol (300 mL of 95%) and hydrogenated over 5% Pd/C (w/w). The reaction was stopped when the theoretical amount of H2 (173 mL) was consumed. The mixture was filtered (through Celite®) and then evaporated. Purification by chromatography on silica (DCM, 5% MeOH eluant) gave 1.7 g (63.6%) of the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])(C(C)(C)C)(C)C.O>C(O)(=O)C>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19]
Reactant: CCOP(=O)(CCCCO[Si](C)(C)C(C)(C)C)OCC
Solvent: CC(=O)O
Solvent: O
Product: CCOP(=O)(CCCCO)OCC
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 90.6 %

Procedure:
Diethyl 4-(tert-butyldimethylsilyloxy)butylphosphonate (1.7 g, 5.25 mmol) was dissolved in 80% acetic acid (5 ml) and the resulting solution was stirred at 70° C. for 20 min. The reaction mixture was then allowed to cool and water (2 ml) was added. The resulting mixture was washed with hexane (3×5 ml) and chloroform (5×5 ml). The combined chloroform phase was washed with sat. aq. NaHCO3 (2×10 ml), water (1×10 ml) and the solvents were evaporated under vacuum. The residue was chromatographed on silica gel (eluted with chloroform: ethanol 96:4) to give the title compound as a colorless oil (1 g, 91%). 1H NMR:δH ((CD3)2SO), 1.22 (6H, t, J=7Hz, (OCH2CH3)2), 1.47 (4H, br.s, CH2CH2), 1.68 (2H, m, CH2P), 3.38 (2H, br.s, HOCH 2), 3.96 (4H, m, (OCH2CH3)2), 4.43 (1H, br.s, HOCH2, D2O exchangeable).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[C:8](C)[CH:9]=1)=[O:4]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(C)c(OCCn2ccnc2)s1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCCn2ccnc2)s1

Procedure:
5-[2-(1-Imidazolyl)-1-ethoxy]-4-methyl-thiophene-2-carboxylic acid methyl ester (formula I: R=4-methyl, R1 =CH3) melting point (toluene) 102°-105° C. (44%).
Reaction SMILES: [N+](C1C=CSC=1C1C=CC(Cl)=CC=1)([O-])=O.[N+:16]([C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)([O-])=O>>[NH2:16][C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1
Reactant: O=[N+]([O-])c1ccsc1-c1cccc(Cl)c1
Agent: O=[N+]([O-])c1ccsc1-c1ccc(Cl)cc1
Product: Nc1ccsc1-c1cccc(Cl)c1
Yield: 71 %

Procedure:
The same procedures as described in Example 3 were carried out except that 3-nitro-2-(4-chlorophenyl)thiophene was replaced by 3-nitro-2-(3-chlorophenyl)thiophene. The yield was 71%. 1 H-NMR(CDCl3, δ value):3.84(2H, brs), 6.65(1H, d, J=5.1), 7.14(1H, d, J=5.1), 7.21(1H, dd, J=1.5, 8.8), 7.35(1H, dt, J=1.5, 8.8), 7.41(1H, dd, J=1.5, 8.8), 7.51-7.53(1H, m)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:17][C:13]=1[C:14](O)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:14]([C:13]3[CH:17]=[CH:18][C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][C:12]=3[O:11][CH3:10])[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1N
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2ccc(F)cc2[nH]1

Procedure:
Prepared analogously to Example 14 from 4-fluoro-1,2-phenylenediamine and 2-methoxy-4-methanesulfonylamino-benzoic acid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][N:18](CO)[C:15]3=[N:16][CH:17]=2)[CH:7]=1)[C:3]([OH:5])=O.[CH3:31][NH:32][CH2:33][C:34]#[N:35].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:34]([CH2:33][N:32]([CH3:31])[C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][NH:18][C:15]3=[N:16][CH:17]=2)[CH:7]=1)#[N:35]
Reactant: COc1ccccc1-c1nn(CO)c2ncc(-c3cccc(C(O)C(=O)O)c3)cc12
Reactant: CNCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(O)C(=O)N(C)CC#N)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
A mixture of hydroxy-{3-[1-hydroxymethyl-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid (0.1 g, 0.25 mmol), methylaminoacetonitrile (20 μl, 0.27 mmol), diisopropylethylamine (DIEA, 87 μl, 0.48 mmol), N,N,N′,N′,-Tetramethyl-O-(7-azabenotriazol-1-yl)uronium hexafluorophosphate (HATU, 101 mg, 0.27 mmol) in DMF (3 ml) was stirred at room temperature overnight. The reaction mixture was dissolved in 10 ml ethyl acetate and subsequently extracted with 1N HCl, saturated NaHCO3, brine, dried with Na2SO4, concentrated to dryness. The crude was purified by silica gel chromatography. The resulting material was dissolved in 3 ml of methanol, aqueous NaOH was added (1 ml, 2 N in H2O) and the mixture stirred overnight at room temperature. The solvent was removed under reduced pressure and the crude was neutralized with 500 μl of 1N HCl and purified by mass-triggered reverse phase HPLC to afford N-cyanomethyl-2-hydroxy-2-{3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-5-yl]-phenyl}-N-methyl-acetamide as a yellow powder (56 mg, 53% yield). 1H NMR (500 MHz, DMSO-d6) δ 3.02 (s, 3H), 3.87 (s, 3H), 4.14 (s, 2H), 5.55 (s, 1H), 7.10 (m, 1H), 7.23 (d, 1H), 7.40 (d, 1H), 7.45-7.52 (m, 2H), 7.66 (d, 1H), 7.72 (m, 2H), 8.32 (s, 1H), 8.33 (s, 1H). MS: m/z 427.5 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]2[N:26]=[C:25]([NH:27][C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:31]=[CH:32][CH:33]=3)[C:24]([F:42])=[CH:23][N:22]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][O:18][CH3:19])C1C=CC=CC=1>[Pd].C(O)C>[F:42][C:24]1[C:25]([NH:27][C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH:31]=[CH:32][CH:33]=2)=[N:26][C:21]([NH:20][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:9]([OH:8])[CH:10]=2)=[N:22][CH:23]=1
Reactant: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)OC(C)(C)C)c3)n2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)OC(C)(C)C)c3)n2)cc1O
Temperature: 25 °C
Reaction time: 50 h
Yield: 81.3 %

Procedure:
In a 100 mL Autoclave, Pd—C (0.035 g) and ethanol were charged. tert-butyl (3-((2-((3-(benzyloxy)-4-(2-methoxyethoxy)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)carbamate (0.35 g) was added to the above reaction mixture, and the autoclave was flushed with nitrogen. Hydrogen pressure (140 psi) was applied and reaction mixture was stirred at room temperature for 50 hr. After completion, the reaction mixture was filtered using Celite and the filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure at 40° C. to give 0.240 g of tert-butyl (3-((5-fluoro-2-((3-hydroxy-4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)carbamate. 1H NMR: DMSO-d6 (400 MHz): 1.475 (s, 9H), 3.316 (s, 3H), 3.618-3.641 (t, 2H, J=4.4), 4.028-4.050 (t, 2H, J=4.4), 6.732-6.753 (d, 1H, J=8.4), 7.075-7.097 (m, 2H), 7.141-7.208 (m, 2H), 7.476-7.495 (d, 1H, J=7.6), 7.851 (s, 1H), 8.036-8.045 (d, 1H, J=3.6), 8.784-8.796 (d, 2H, J=4.8), 9.260-9.301 (d, 2H, J=16.4).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:34]2[CH2:46][CH2:45][N:37]3[C:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=4[CH:44]=[C:36]3[C:35]2=[O:47])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:31]=[C:22]3[CH2:23][N:24]([CH:27]4[CH2:30][O:29][CH2:28]4)[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:32])[N:14]([CH3:33])[CH:13]=1)(=O)C.[OH-].[Li+]>>[OH:4][CH2:5][C:6]1[C:7]([N:34]2[CH2:46][CH2:45][N:37]3[C:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=4[CH:44]=[C:36]3[C:35]2=[O:47])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:31]=[C:22]3[CH2:23][N:24]([CH:27]4[CH2:28][O:29][CH2:30]4)[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:32])[N:14]([CH3:33])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C3COC3)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Yield: 62.7 %

Procedure:
Following the procedures as described in Example 123, 125j (200 mg 0.31 mmol) was hydrolyzed by lithium hydroxide to give 125 as a white solid (116 mg, 62%). LCMS: [M+H]+ 597. 1H NMR (500 MHz, CDCl3) δ 8.48 (d, J=5.0, 1H), 7.95 (d, J=2.0, 1H), 7.69 (d, J=2.0, 1H), 7.43 (s, 1H), 7.34 (d, J=5.5, 1H), 6.89 (s, 1H), 5.73 (s, 1H), 5.02 (t, J=6.5, 1H), 4.75 (t, J=6.5, 2H), 4.67 (t, J=6.5, 2H), 4.61-4.63 (m, 1H), 4.50 (s, 1H), 4.31-4.35 (m, 1H), 4.10-4.16 (m, 4H), 3.86-3.88 (m, 1H), 3.74-3.79 (m, 1H), 3.70 (s, 3H), 3.56 (d, J=4.5, 2H), 2.82 (t, J=4.5, 2H), 2.50-2.62 (m, 4H), 1.88-1.92 (m, 2H), 1.78-1.82 (m, 2H)