Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:19][N:20](C=O)C>[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[C:2]([C:19]#[N:20])[O:11][C:5]=2[CH:6]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(C=C(Br)Br)c(O)c1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: Cc1ccc2cc(C#N)oc2c1
Temperature: 80 °C

Procedure:
To a 500 mL 3-neck flask was added 2-(2,2-dibromovinyl)-5-methylphenol (17.7 g, 60.6 mmol), CuI (1.16 g, 6.06 mmol), Na2CO3 (12.85 g, 121 mmol) and DMF (120 mL). The reaction was heated to 80° C. for 6 hr. After 6 hr the r×n was cooled to RT and anhydrous K4Fe(CN)6 (4.47 g, 12.12 mmol), Pd(OAc)2 (2.04 g, 3.03 mmol) and PPh3 (0.32 g, 1.21 mmol) were added to the reaction and the reaction was flushed with nitrogen for 10 min. The reaction was then heated to 120° C. for 18 hr. After 18 hr the r×n was cooled to RT and diluted with EtOAc. The reaction mixture was filtered through a silica plug to remove solids and flushed with EtOAc. The collected filtrates were diluted with water and brine and extracted with EtOAc×2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified via silica gel FCC, 100% Heptane-20% EtOAc/80% Heptane to give a yellow solid, 6-methylbenzofuran-2-carbonitrile (5.1 g). 1H NMR (400 MHz, DMSO-d6) δ 2.47 (s, 3H), 7.27 (ddd, J=8.2, 1.4, 0.7 Hz, 1H), 7.57 (s, 1H), 7.71 (d, J=8.1 Hz, 1H), 8.05 (d, J=1.0 Hz, 1H).
Reaction SMILES: ClC1C(CC2C=CC(OCC)=CC=2)=CC([C@H]2[C@H](OCC3C=CC=CC=3)[C@@H](OCC3C=CC=CC=3)[C@H](OCC3C=CC=CC=3)[C@@H](COCC3C=CC=CC=3)O2)=C2C=1CCCO2.[CH2:61]([C:68]1[C:69]([Cl:119])=[C:70]([O:114][CH2:115][CH2:116][CH2:117]Cl)[C:71](Br)=[C:72]([C@H:74]2[C@H:79]([O:80][CH2:81][C:82]3[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=3)[C@@H:78]([O:88][CH2:89][C:90]3[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=3)[C@H:77]([O:96][CH2:97][C:98]3[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=3)[C@@H:76]([CH2:104][O:105][CH2:106][C:107]3[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=3)[O:75]2)[CH:73]=1)[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>>[CH2:61]([C:68]1[C:69]([Cl:119])=[C:70]2[C:71]([CH2:117][CH2:116][CH2:115][O:114]2)=[C:72]([C@H:74]2[C@H:79]([O:80][CH2:81][C:82]3[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=3)[C@@H:78]([O:88][CH2:89][C:90]3[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=3)[C@H:77]([O:96][CH2:97][C:98]3[CH:99]=[CH:100][CH:101]=[CH:102][CH:103]=3)[C@@H:76]([CH2:104][O:105][CH2:106][C:107]3[CH:112]=[CH:111][CH:110]=[CH:109][CH:108]=3)[O:75]2)[CH:73]=1)[C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1
Reactant: ClCCCOc1c(Cl)c(Cc2ccccc2)cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1Br
Agent: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)CCCO3)cc1
Product: Clc1c(Cc2ccccc2)cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c1OCCC2

Procedure:
Similar procedure with preparation of 30 proceeded except for using compound 173 to obtain the compound 174.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:33]=[CH:32][C:23]4[C:24]([C:28]([O:30]C)=[O:29])=[C:25]([CH3:27])[O:26][C:22]=4[CH:21]=3)[CH:11]=2)=[O:9])[CH2:4]1.O.[OH-].[Li+]>C1COCC1.CO.CO>[CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:33]=[CH:32][C:23]4[C:24]([C:28]([OH:30])=[O:29])=[C:25]([CH3:27])[O:26][C:22]=4[CH:21]=3)[CH:11]=2)=[O:9])[CH2:4]1
Reactant: COC(=O)c1c(C)oc2cc(Oc3ccnc4cc(C(=O)N5CCC(OC)C5)sc34)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)oc5c4)c3s2)C1
Yield: 78.3 %

Procedure:
To a stirred solution of methyl 6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-benzofuran-3-carboxylate 89d (540 mg, 1.16 mmole) in THF/MeOH/MeOH (6 ml, 1:1:1) was added lithium hydroxide monohydrate (54 mg, 1.29 mmole). When the ester disappeared by thin layer chromatography (tic), the organic solvents removed under reduced pressure, and the aqueous residue was neutralized with 2N HCl. The white solid which precipitated was collected by filtration and dried under vacuum to give the desired acid (411 mg, 83%). 1H NMR (DMSO-d6) δ 13.02 (1H, bs), 8.57 (1H,d, J=5.3 Hz), 8.05 (1H, s), 7.94 (1H, d, J=8.5 Hz), 7.68 (1H, s), 7.25 (1H, d, J=8.5 Hz), 6.75 (1H, d, J=5.5 Hz), 4.10–3.85 (3H, m), 3.65–3.45 (2H, m), 3.25 (3H, d, J=9.4 Hz), 2.74 (3H, s), 2.15–1.95 (2H,m).
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11](=[O:29])[NH:12][C@H:13]([C:17]1[NH:26][C:25](=[O:27])[C:24]2[C:19](=[CH:20][C:21]([Cl:28])=[CH:22][CH:23]=2)[N:18]=1)[CH:14]([CH3:16])[CH3:15])([CH3:9])([CH3:8])[CH3:7].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:6]([O:10][C:11](=[O:29])[NH:12][C@H:13]([C:17]1[N:26]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25](=[O:27])[C:24]2[C:19](=[CH:20][C:21]([Cl:28])=[CH:22][CH:23]=2)[N:18]=1)[CH:14]([CH3:16])[CH3:15])([CH3:8])([CH3:9])[CH3:7]
Reactant: BrCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer and nitrogen inlet, was charged with 50 mL of DMF, 3.50 g (10 mmol) of (S)-[1-(7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester (the compound of Formula 202 prepared, e.g., as described in Example 3.2), 1.34 mL of benzyl bromide (98%), and 3.04 g of potassium carbonate. The mixture was stirred at room temperature overnight. TLC (hexanes/ethyl acetate 7:3) indicated complete reaction. The mixture was transferred into a Erlenmeyer flask and mixed with 100 mL of water. To the stirring mixture was then added hexanes, 50 mL. The formed white solid was collected by filtration to afford the title compound of Formula 203 (S)-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester (also corresponding to Formula 107). The layers were separated and the organic was concentrated to dryness. The residue was chromatographed to afford an additional yield of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C:6]([CH3:11])([CH2:9][OH:10])[CH2:7][OH:8].C(O[CH:19](OCC)[CH2:20][Cl:21])C>>[Cl:21][CH2:20][CH:19]1[O:10][CH2:9][C:6]([O:5][CH2:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[CH3:1])([CH3:11])[CH2:7][O:8]1
Reactant: Cc1ccccc1COC(C)(CO)CO
Reactant: CCOC(CCl)OCC
Product: Cc1ccccc1COC1(C)COC(CCl)OC1

Procedure:
By the method of Example 39, 2-(2-methylbenzyloxy)-2-methyl-1,3-propanediol was reacted with chloroacetaldehyde diethyl acetal to yield a mixture which was separated by column chromatography. The t-isomer was a liquid b.p. 117° C/0.005 mm Hg; nD25 1.5175. The c-isomer was a solid, m.p. 57°-58° C.
Reaction SMILES: FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[C:39]2[CH:40]=[C:41]([N+:44]([O-:46])=[O:45])[CH:42]=[CH:43][C:38]=2[N:37](C)[C:36](=[O:48])[C:35]([CH3:50])([CH3:49])[N:34]=1>C(Cl)Cl.C(OCC)(=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[C:39]2[CH:40]=[C:41]([N+:44]([O-:46])=[O:45])[CH:42]=[CH:43][C:38]=2[NH:37][C:36](=[O:48])[C:35]([CH3:50])([CH3:49])[N:34]=1
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O

Procedure:
From 59 g (0.17 mol) of 5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details in paragraph (c) of Example 1, 5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 125°-127° (methylene chloride/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[CH:8][C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19].OO.C(=O)([O-])[O-:23].[Na+].[Na+]>C(O)C>[Cl:1][C:2]12[C:14]([Cl:15])([Cl:16])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]1[O:23][CH:8]1[C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19]
Reactant: O=C([O-])[O-]
Reactant: O=C1C=CC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: O=C1C2OC2C(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl

Procedure:
38 g. of 1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-1,4-methanonaphthalene-5,8-dione, prepared according to Example 1, were added slowly to a solution of 200 ml. of ethanol containing 20 ml. of 30% hydrogen peroxide and 13 g. of sodium carbonate at such a rate that the temperature was maintained at 40°-50° C. The yellow color of the dione disappeared quickly. The solution was then cooled to 10°--13° C. and a white precipitate formed. This solid was filtered and recrystallized from ethanol, m.p. 180°-181° C.
Reaction SMILES: C(O)C.[Na].[C:5](=[N:8][OH:9])([NH2:7])[CH3:6].[Br:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13](OC)=O>O>[Br:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]1[O:9][N:8]=[C:5]([CH3:6])[N:7]=1
Reactant: CC(N)=NO
Reactant: COC(=O)c1ccccc1Br
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Cc1noc(-c2ccccc2Br)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.5 %

Procedure:
To activated molecular sieves (2.0 g, 4 Å powdered) was added ethanol (20 ml) followed by sodium metal (0.435 g, 18.9 mmol), and the mixture heated at reflux for 15 min. After cooling to ambient temperature, acetamide oxime (1.4 g, 18.9 mmol) was added and the suspension stirred for 15 min. Methyl 2-bromobenzoate (1.32 ml, 9.5 mmol) was added and the mixture heated at reflux for 2 h. The reaction was poured into water and extracted with ethyl acetate. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated to give a white solid. The crude product was purified by crystallisation from ethyl acetatelisohexane to give 5-(2-bromophenyl)-3-methyl-[1,2,4]oxadiazole as a white solid (0.76 g): δH (400 MHz, CDCl3) 2.52 (3H, s), 7.45 (2H, m), 7.76 (1H, dd, J 7.8 and 1.2), 7.97 (1H, dd, J 7.8 and 1.2); m/z (ES+) 239:241 (1:1) (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]2[N:30]=[C:29](S(C3C=CC(C)=CC=3)(=O)=O)[S:28][N:27]=2)=[CH:20][CH:19]=1>C(#N)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:29]2[S:28][N:27]=[C:26]([CH2:25][CH2:24][C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)[N:30]=2)[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4]
Reactant: Cc1ccc(S(=O)(=O)c2nc(CCc3ccc(Cl)cc3)ns2)cc1
Reactant: Cc1cc(N)c(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(N)c(Cl)cc1Oc1nc(CCc2ccc(Cl)cc2)ns1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
1.45 g (9.24 mmol) of 2-chloro-4-hydroxy-5-methylaniline are introduced into 18 ml of acetonitrile, treated with 1.53 g (11.08 mmol) of potassium carbonate at ambient temperature and stirred at ambient temperature for 30 min. Subsequently, 3.50 g (9.24 mmol) of 3-[2-(4-chlorophenyl)ethyl]-5-[(4-methylphenyl]sulphonyl]-1,2,4-thiadiazole are added and the reaction mixture is stirred at 50° C. for 12 h. After cooling, the mixture is concentrated on a rotary evaporator, the residue is taken up in dichloromethane and the solution is extracted twice with water, dried over Na2SO4 and freed from the solvent under vacuum. 3.11 g of product are obtained (94.3% purity, 83.4% yield, log P (pH 2.3)=4.50).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].ClOC(C)(C)C.[CH3:15][S:16][CH2:17][C:18](=O)[CH3:19].C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[NH:4][C:18]([CH3:19])=[C:17]2[S:16][CH3:15]
Reactant: CSCC(C)=O
Reactant: Nc1ccccc1Cl
Agent: CC(C)(C)OCl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1c(C)[nH]c2c(Cl)cccc12
Temperature: -65 °C
Reaction time: 1 h

Procedure:
Using the procedure described in J. Amer. Chem. Soc., 1974, 96 (17) 5495 , 2-chloroaniline (1.27 g, 10 mmole) was dissolved in dichloromethane (35 ml) and cooled to −65° C. To this solution was added dropwise with vigorous stirring, t-butyl hypochlorite (1.08 g, 10 mmole) in dichloromethane (5 ml). After 10 minutes 1-methylsulfanyl-propan-2-one (1.04 g, 10 mmole) dissolved in dichloromethane (5 ml) was added. The mixture was stirred at −65° C. for 1 h more. At this point triethylamine (1.01 g, 10 mmole) dissolved in dichloromethane (5 ml) was added. Upon completion of the addition, the reaction mixture was allowed to reach ambient temperature. Water was added and the layers were separated, the organic layer was dried over magnesium sulfate, filtered and the solvent evaporated to dryness. The residue was purified by column chromatography on silica gel using a mixture of hexane-ethyl acetate (95:5) to elute 7-chloro-2-methyl-3-methylsulfanyl-1H-indole (1.94 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:12]=2)=[N:6][CH:7]=1.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[N:6][CH:7]=1
Reactant: Fc1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)nc1
Agent: Cl
Solvent: C1CCOC1
Product: Fc1ccc(-c2c[nH]cn2)nc1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
To a solution of 4-(5-Fluoro-2-pyridyl)-1-trityl-1H-imidazole (0.23 g, 0.56 mmol) in tetrahydrofuran (4 ml) added hydrochloric acid (2.4 ml, 2N aqueous). The resulting reaction mixture was heated at reflux for 45 min. The reaction mixture was cooled to room temperature and concentrated in-vacuo. The isolated residue was triturated with diethyl ether to yield 4-(5-Fluoro-2-pyridyl)imidazole (0.06 g) as the hydrochloride salt.
Reaction SMILES: I[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.[NH:34]1[CH:38]=[N:37][CH:36]=[N:35]1.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:32][Si:3]([CH3:33])([CH2:2][N:34]1[CH:38]=[N:37][CH:36]=[N:35]1)[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12
Reactant: c1nc[nH]n1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)Cn1cncn1
Yield: 79 %

Procedure:
A solution of Compound 4 (60 mg), 1,2,4-triazole (22 mg) and NaHCO3 (26 mg) in dry N,N-dimethylformamide (1 mL) was heated at 70° C. for 5 hours under argon. The N,N-dimethylformamide was removed from the reaction mixture under vacuum and the residue was directly eluted on a silica gel column using 4% ethanol in dichloromethane to obtain the required product in 79% yield (43 mg).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:25](O)=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.[C:37]([NH2:41])([CH3:40])([CH3:39])[CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:25](=[O:26])[NH:41][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:16]=1)([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
N-Boc-O-Benzyl-tyrosine (20.0 g, 53.9 mmol) was dissolved in DMF (270 mL) and treated with diisopropylethylamine (19 mL, 108 mmol), tert-butylamine (5.7 mL. 53.9 mmol), and HBTU (13.9 g, 53.9 mmol). The reaction was stirred for 15 minutes and then diluted with EtOAc (1 L), washed with saturated bicarbonate solution (2×1 L) and brine (1 L), dried over Na2SO4 and concentrated to give 22.1 g (92%) of (S)-[2-(4-Benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]/[N:9]=[C:10](\[C:17]#[C:18][Si](C)(C)C)/[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:18]=[CH:17][C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N/N=C(\C#C[Si](C)(C)C)CCCC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc(CCCC(=O)O)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a stirred solution of 77.0 g, (236 mmol) of (5Z)-5-[(tert-butoxycarbonyl)hydrazono]-7-(trimethylsilyl)hept-6-ynoic acid from step B above in 500 mL of THF was added 350 mL (350 mmol) of a 1.0 M solution of tetrabutylammonium fluoride in THF over 30 min. The resulting mixture was stirred at ambient temperature for 48 h and then evaporated to dryness in vacuo. The residue was diluted with 1 L of a 5% aqueous acetic acid solution and the aqueous phase extracted with ethyl acetate (3×350 mL). The combined organic layers were washed with water (2×100 mL), and brine (150 mL), dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was purified by silica gel chromatography eluting with 3% acetic acid and 35% ethyl acetate in hexanes mixture to afford the title compound as yellow oil (60 g, quantitative yield). LC-MS: m/z (ES) 255 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18]O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:18][CH2:17][N:16]([CH3:20])[CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CN(C)CCO
Reactant: COc1cc2c(Cl)ncnc2cc1O
Product: COc1cc2c(Cl)ncnc2cc1OCCN(C)C

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-7-hydroxy-6-methoxy-quinazoline and 2-Dimethylamino-ethanol. LC/ESI-MS: m/z=282 [M+H].
Reaction SMILES: [F:1][C:2]1[C:3]([NH:30][CH:31]2[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]2)=[C:4]([CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl>[F:1][C:2]1[C:3]([NH:30][CH:31]2[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]2)=[C:4]([CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3cc(F)c(NC4CCC(O)CC4)c(C(=O)N(C)C)c3)cc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cc(F)c(NC4CCC(=O)CC4)c(C(=O)N(C)C)c3)cc12
Reaction time: 8 h
Yield: 69.7 %

Procedure:
3-Fluoro-2-(4-hydroxy-cyclohexylamino)-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide (167 mg, 0.33 mmol) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (212 mg, 0.5 mmol; Dess-Martin periodinane) were dissolved in 5 mL dichloromethane and stirred overnight. The reaction was quenched with a saturated sodium bicarbonate solution, applied to a Varian Chemelut cartridge and eluted with ethyl acetate. Purification by flash silica gel chromatography using a gradient of ethyl acetate and hexanes afforded 3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-2-(4-oxo-cyclohexylamino)-benzamide as a white solid (113 mg, 0.23 mmol, 68%). 1H NMR (500 MHz, DMSO-d6) δ 13.78 (s, 1H), 8.82 (s, 1H), 8.30 (s, 1H), 7.63 (m, 2H), 7.45 (m, 1H), 7.34 (s, 1H), 7.20 (d, J=10 Hz, 1H), 7.08 (t, J=8 Hz, 1H), 4.80 (d, J=9 Hz, 1H), 3.82 (s, 3H), 3.71 (m, 1H), 3.01 (bs, 3H), 2.92 (bs, 3H), 2.37 (m, 2H), 2.24 (m, 2H), 2.05 (m, 2H), 1.69 (m, 2H). MS: m/z 502.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: NCCCCO
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCCCO)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-aminobutan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.53 (m, 2H) 1.53-1.64 (m, 2H) 2.44 (s, 3H) 3.27-3.33 (m, 2H) 3.44 (br. s., 2H) 4.43 (br. s., 1H) 7.67 (d, J=8.08 Hz, 1H) 7.74 (s, 1H) 7.78 (br. s., 1H) 8.07-8.27 (m, 1H) 8.41 (d, J=6.57 Hz, 2H) 8.70 (t, J=5.43 Hz, 1H) 8.85-8.97 (m, 1H) 12.82-13.57 (m, 1H). MS m/z [M+H]+ 392.2
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>>[N:14]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: N#Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: c1c[nH]cn1
Product: N#Cc1ccc(-n2ccnc2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 4-chloro-3-(trifluoromethyl)-benzonitrile (Lancaster Synthesis, GmbH) and imidazole (Fluka, Buchs, Switzerland), with a reaction temperature of 110° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[C:8](O)=[N:9][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:11][CH:12]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:8]1[C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][N:11]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:9]=1
Reactant: CCOC(=O)Cc1cnc(C(C)(C)C)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1cnc(C(C)(C)C)nc1Cl

Procedure:
Phosphorus oxychloride (30 cm3) was added portionwise to 5-ethoxycarbonylmethyl-4hydroxy-2-(2-methylprop-2-yl)-pyrimidine (15.0 g). An exothermic reaction occurred and the resultant mixture was poured onto ice. After neutralisation with sodium carbonate the mixture was extracted with ethyl acetate and the extracts washed with water and dried over anhydrous magnesium sulphate. Removal of the solvent by evaporation under reduced pressure yielded 4-chloro-5-ethoxycarbonylmethyl-2-(2-methylprop-2-yl)pyrimidine (11.35 g, oil, solidified on standing, m.p. 42°-44° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[O:16]([CH2:23][CH2:24]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:24][CH2:23][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: BrCCOc1ccccc1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(CCOc3ccccc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=318.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-phenoxyethyl bromide.