Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:6][C:7]=1[NH2:8].[CH:21](OCC)(OCC)OCC>C(#N)C.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[F:17][C:15]([F:18])([F:16])[C:11]1[CH:10]=[C:9]([C:5]2[N:4]=[C:3]([C:19]#[N:20])[C:2]3[N:1]=[CH:21][NH:8][C:7]=3[CH:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N)c1N
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc2[nH]cnc12
Yield: 93.6 %

Procedure:
3,4-Diamino-6-(3-trifluoromethyl-phenyl)-pyridine-2-carbonitrile (120 mg, 0.43 mmol) was suspended in acetonitrile (5 ml) and the vessel was purged with nitrogen. Ytterbium triflate (5 mg, 0.009 mmol) and triethyl orthoformate (214 μl, 1.29 mmol) were added and the resulting orange suspension was heated at reflux for 1 hour. Reaction mixture was concentrated in vacuo to give the title compound as a yellow solid (116 mg). 1H NMR (MeOD): δ 8.55 (s, 1H), 8.35-8.41 (m, 3H), 7.71-7.76 (m, 2H). MS m/z 288.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.I[CH:16]([CH3:18])[CH3:17].[H-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][N:8]([CH:16]([CH3:18])[CH3:17])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2[nH]ccc12
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.7 %

Procedure:
To a stirred solution of methyl 6-bromo-1H-indole-4-carboxylate (100 g, 393.7 mmol) in DMF (800 mL) was added 2-iodopropane (160 g, 944.8 mmol) followed by portionwise addition of sodium hydride (20.4 g, 511.8 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 h. Diluted the reaction mixture with cold water and extracted with ethylacetate (200 mL×4), finally organic layer was washed with cold water, brine solution dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude, which was purified by column chromatography using silica gel (60-120 mesh) with 5% EtOAC: pet ether as an eluent to afford methyl 6-bromo-1-isopropyl-1H-indole-4-carboxylate (65 g, 55.7%) as a solid. 1H NMR (CDCl3, 400 MHz) δ 1.53 (d, 6H, J=6.4 Hz), 3.973 (s, 3H), 4.598-4.664 (m, 1H), 7.111 (d, 1H, J=2.4 Hz), 7.338 (d, 1H, J=2.8 Hz), 7.711 (s, 1H), 7.987 (s, 1H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:45])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:28]2[CH:33]=[CH:32][C:31]([O:34][Si](C(C)C)(C(C)C)C(C)C)=[CH:30][CH:29]=2)=[C:19](\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)/[CH2:20][CH3:21])=[CH:14][CH:13]=1.C(N(CC)CC)C.C1(C)C=CC([S:59](Cl)(=O)=O)=CC=1.[F:64][C:65]([F:75])([C:71]([F:74])([F:73])[F:72])[CH2:66][CH2:67][CH2:68]CS>ClCCl>[OH:34][C:31]1[CH:30]=[CH:29][C:28](/[C:18](/[C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:59][CH2:68][CH2:67][CH2:66][C:65]([F:75])([F:64])[C:71]([F:74])([F:73])[F:72])=[O:45])=[CH:17][CH:16]=2)=[C:19](/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)\[CH2:20][CH3:21])=[CH:33][CH:32]=1
Reactant: CC/C(=C(/c1ccc(OCC(=O)NCCCCCCO)cc1)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: FC(F)(F)C(F)(F)CCCCS
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCC(=O)NCCCCCCSCCCC(F)(F)C(F)(F)F)cc1)c1ccccc1

Procedure:
(E)-N-(6-hydroxyhexyl)-2-(4-(2-phenyl-1-(4-(triisopropylsilyloxy)phenyl)but-1-enyl)phenoxy)acetamide from reaction 3 is dissolved in dichloromethane. To this solution are added triethyl amine and p-toluenesulfonyl chloride in that order. The solution is stirred until the reaction is complete (TLC). 5,5,6,6,6-pentafluorohexanethiol is then added and the mixture stirred until the reaction is complete (TLC). When the reaction is complete, the mixture is washed with dilute hydrochloric acid, dilute sodium bicarbonate and water. The organic layer is the dried over sodium sulfate or other suitable desiccant. The dried suspension is then filtered and concentrated under reduced pressure to afford (Z)-2-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-enyl)phenoxy)-N-(6-(4,4,5,5,5-pentafluoropentylthio)hexyl)acetamide among other products.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O=[C:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1.[CH2:19](OCC)C>>[CH2:17]([O:16][C:14]([CH:11]1[CH2:12][CH2:13][C:8](=[CH2:19])[CH2:9][CH2:10]1)=[O:15])[CH3:18]
Reactant: CCOCC
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C=C1CCC(C(=O)OCC)CC1

Procedure:
4-Methylenecyclohexanecarboxylic acid ethyl ester is prepared from the Wittig reaction on ethyl 4-oxocyclohexanecarboxylate using Method 3. This ester is reduced to compound III-5 according to the following procedure: To a solution of lithium aluminum hydride (4.0 equiv) in diethyl ether (1.0 M with respect to hydride) is added ethyl 4-oxocyclohexanecarboxylate in diethyl ether (2.0 M with respect to ester). The reaction is heated to reflux for 2 h after which it is cooled in an ice bath and quenched with by subsequent additions of isopropanol, 50% NaOH in water, and water. The mixture is then filtered and the filter cake is washed with excess diethyl ether. The filtrate is then washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to provide a clear oil that is used without further purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16](CC=C)[C:15]([Cl:23])=[N:14][C:13]=2[N:12]([CH2:24][CH2:25][CH2:26][CH3:27])[C:11]1=[O:28])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].[C:35]1([C:41]2[NH:45][N:44]=[N:43][N:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N1CCOCC1>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.CO.CN(C=O)C>[CH2:24]([N:12]1[C:13]2[N:14]=[C:15]([Cl:23])[NH:16][C:17]=2[C:18](=[O:19])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:43]2[N:44]=[N:45][C:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:42]2)[C:11]1=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCCOS(C)(=O)=O)c(=O)n2CCCC
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: [Cs+]
Solvent: CO
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(CCCCn2nnc(-c3ccccc3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 50 °C
Reaction time: 60 h
Yield: 28.2 %

Procedure:
A mixture of 4-[3-butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]butyl methanesulfonate (50 mg, 0.12 mmol), Cs2CO3 (45 mg, 0.14 mmol) and DMF (3 ml) was treated with 5-phenyl-1H-tetrazole (20 mg, 0.14 mmol) and stirred for 60 h at 50° C. After cooling, the mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh3)4 (20 mg, 0.017 mmol) was added and the mixture degassed once more. Morpholine (150 μl, 1.7 mmol) was added and the mixture was stirred under nitrogen for 18 h, then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted again with EtOAc. The combined extracts were concentrated, giving a yellow residue. MeOH was added and then passed down an NH2-propyl column with the product eluting with 2% AcOH/MeOH. Further purification by MDAP gave the title compound as an off-white solid (15 mg, 29%).
Reaction SMILES: [CH3:1][Li].[CH3:3][C@:4]12[CH2:20][CH2:19][C:18]3[C@@H:9]([CH2:10][CH2:11][C:12]4[C:17]=3[CH2:16][CH2:15][C:14](=[O:21])[CH:13]=4)[C@@H:8]1[CH:7]=[CH:6][C:5]2=[O:22]>C(OCC)C.O1CCCC1.N.[Cu]I.[Cu](I)I>[CH3:1][C@H:7]1[C@H:8]2[C@H:9]3[C:18]([CH2:19][CH2:20][C@:4]2([CH3:3])[C:5](=[O:22])[CH2:6]1)=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3
Reactant: [Li]C
Reactant: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1C=CC2=O
Agent: I[Cu]I
Agent: [Cu]I
Agent: N
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H]1CC(=O)[C@@]2(C)CCC3=C4CCC(=O)C=C4CC[C@H]3[C@H]12
Temperature: -20 °C

Procedure:
5.2 ml of a 5% solution of methyllithium in diethyl ether are mixed with 570 mg of copper(I) iodide by portions at -5° C. Stirring is performed at a temperature between -5° and 0° C. until the copper iodide is fully dissolved. Then it is cooled to -20° C. and a solution of 1.1 g of 4,9,15-estratriene-3,17-dione in 15 ml of absolute tetrahydrofuran is slowly added drop by drop. It is stirred for 20 minutes at -20° C., then poured in concentrated aqueous ammonia solution and extracted with ethyl acetate. After chromatography with silica gel with hexane/ethyl acetate and crystallization of the main fraction from ethyl acetate/diisopropyl ether, 720 mg of 15β-methyl-4,9-estradiene-3,17-dione with a melting point of 125° to 126° C. are obtained.
Reaction SMILES: [OH-:1].[Na+].CO.[CH2:5]([O:7][P:8]([CH2:13][CH2:14][CH2:15]Br)(=[O:12])[O:9][CH2:10][CH3:11])[CH3:6].Cl.[NH2:18]O>O>[CH2:5]([O:7][P:8]([CH2:13][CH2:14][CH2:15][NH:18][OH:1])(=[O:12])[O:9][CH2:10][CH3:11])[CH3:6]
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: [OH-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOP(=O)(CCCNO)OCC
Yield: 74.3 %

Procedure:
Firstly 32.0 g (0.8 mol) of sodium hydroxide dissolved in 75 ml water then 75 ml methanol, and finally 25.5 g (0.098 mol) 3-bromopropyl phosphonic acid diethylester were added drop by drop to a solution of 55.6 g (0.8 mol) hydroxylamine hydrochloride in 100 ml water with cooling with ice. This led to a clouding of the solution. After 3 hours stirring at a temperature of 40 to 45° C. methanol was removed under reduced pressure, the resulting aqueous solution was saturated with NaHCO3 (pH=8), shaken out three times with 60 ml toluene in each case (the toluene phase was discarded) and then shaken out with chloroform (1× with 90 ml, 2× with 50 ml in each case). The slightly yellowy chloroform phase was dried over MgSO4. After filtering of the dehydrating agent the solution was concentrated under reduced pressure. 15.43 g (0.0728 mol) 3-(N-hydroxyamino)-propylphosphonic acid diethylester were obtained as an almost colourless oil. This corresponds to a yield of 74.3% (DE-A-27 33 658).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[C:5]([CH3:23])=[CH:4][CH:3]=1.[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([S:35]([F:40])([F:39])([F:38])([F:37])[F:36])[CH:34]=1)[C:29](O)=[O:30])#[N:25]>>[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([S:35]([F:39])([F:40])([F:36])([F:37])[F:38])[CH:34]=1)[C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[C:7]=1[OH:8])=[O:30])#[N:25]
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)c(O)c1-n1ccn2nc(-c3cccnc3)cc12
Product: Cc1ccc(NC(=O)c2cc(C#N)cc(S(F)(F)(F)(F)F)c2)c(O)c1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
Analogously to the process described in Example 155, 37 mg (0.109 mmol) of the compound of Example 82A and 28 mg (0.104 mmol) of the compound of Example 23A were reacted to give 9 mg (15% of theory) of the title compound. Here, preparative HPLC purification was carried out according to Method 37.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]1([CH2:41]O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:41]([O:15][C:14](=[O:16])[C@@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
(S)-6-tert-Butoxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid (5.00 g, 10.67 mmol) and phenyl-methanol (2.305 g, 21.34 mmol) were dissolved in 25 mL of CH2Cl2 and treated successively with N-hydroxybenzotriazole (1.933 g, 11.74 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 2.250 g, 11.74 mmol), and ethyl-diisopropyl-amine (2.137 ml, 12.49 mmol). After stirring for 90 min, the volatiles were removed i.V. at ambient temperature, the residue taken up in ethyl acetate, washed with water, NH4Cl-solution and brine, dried over Na2SO4, and evaporated. The crude mixture was then dissolved in 20 mL of ethanol, and the product precipitated by adding 10 mL of water. Filtration and drying yielded 5.669 g of the title compound which was recrystallized from ethanol/hexane to give 4.27 g of pure benzyl ester. MS (ISP): 559.2 [M+H]+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O.[O:13]1[CH2:18][CH2:17][CH2:16][O:15][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[C:29]([C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH2:35])[N:28]=3)=[C:21]([F:42])[CH:20]=1.O>CS(C)=O.C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][O:13][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[C:29]([C:34]2([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:1][CH2:35]2)[N:28]=3)=[C:21]([F:42])[CH:20]=1
Reactant: C=C(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1

Procedure:
To a solution of potassium tert-butoxide (4.02 g, 35.8 mmol) in 100 mL DMSO under nitrogen was added trimethyl sulfoxonium iodide (7.89 g, 35.8 mmol) in 4 portions over about 20 minutes. 2-(4-(1,3-Dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylvinyl)thiazolo[5,4-b]pyridine (10.0 g, 23.9 mmol) was suspended in 150 mL THF and filtered through a glass frit, rinsing with 25 mL THF. The filtrate was added to the reaction dropwise very slowly from an addition funnel over 1.5-2 h. The resulting orange reaction was allowed to stir 30 min, at which point the THF was removed in vacuo, resulting in a precipitate. Water and ice was added slowly with stirring (approximately 400 mL total). The solid was isolated by filtration rinsing with water and MeOH. The solid was dried in vacuo to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine as a light orange solid. MS (ESI) m/z: Calculated: 432.1; Observed: 433.1 (M++1).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13]CC)=[O:12].[OH-].[Li+]>C1COCC1.CO.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1[nH]c2ccccc2c1Br
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 58.3 %

Procedure:
Ethyl 3-bromo-1H-indole-2-carboxylate (0.070 g, 0.30 mmol) and powdered lithium hydroxide (0.073 g, 3.0 mmol) were dissolved in 1:1:1 mixture of THF/MeOH/water (3.0 mL) and the solution was stirred at RT for 4.5 h. The solvent was evaporated. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford (0.042 g, 67%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.09 (br. s., 1H), 7.50 (d, 1H), 7.43 (d, 1H), 7.30 (t, 1H), 7.15 (t, 1H). MS: m/z 240.1 (M+1).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].B.[OH-:10].[Na+].OO>O.O1CCCC1>[CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCCCC=C
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCCCO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture containing 1.7 liter of anhydrous tetrahydrofuran (distilled from sodium/benzophenone ketyl) and 600 g (5.4 mol) of distilled 1,7-octadiene (Aldrich Chemical Co. Inc.) was prepared under nitrogen. Borane in tetrahydrofuran (1 M, 600 ml, 0.60 mol) was added dropwise to the mixture over a 1.0 hr period while the mixture was maintained at 25° C. The resultant solution was stirred for 1 hr at room temperature and then 25 ml of water was added thereto followed by 300 ml of 3 M sodium hydroxide. These additions were followed by 300 ml of 30% aqueous hydrogen peroxide while maintaining the mixture at 30° to 40° C. The mixture was stirred for 15 min and the phases which formed were separated. The aqueous phase was extracted 3 times with an equal volume of pentane. The combined pentane extracts were washed with 200 ml of 10% aqueous sodium bisulfite, then with saturated aqueous sodium chloride and then dried over magnesium sulfate. The mixture was filtered and the filtrate was evaporated and distilled to yield the title compound (bp 62°-64° C., 20 mm) as a colorless oil having the following physical characteristics:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1Cl

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-chloro-4-fluoroaniline were reacted to yield N2-(3-chloro-4-fluorophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.75 (bd, 1H), 7.70 (bd, 1H), 7.18 (m, 1H), 7.10 (m, 1H), 6.90 (m, 2H), 6.75 (m, 1H), 4.20 (bs, 4H); LCMS: ret. time: 25.04 min.; purity: 99%; MS (m/e): 392 (MH+).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:16]2[O:15][CH:14]=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[O:17]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]1>O1CCCC1>[CH3:6][O:7][C:8]1[C:16]2[O:15][C:14]([C:19]3([OH:22])[CH2:20][CH2:21][O:17][CH2:18]3)=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: COc1cccc2ccoc12
Reactant: O=C1CCOC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc2cc(C3(O)CCOC3)oc12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 27 %

Procedure:
Methyl sulfoxide (1.16 ml) was added dropwise to a stirred solution of oxalyl chloride (0.71 ml) in dry dichloromethane (15 ml) at −60° C. under an inert atmosphere. After stirring at this temperature for 30 minutes a solution of 3-hydroxytetrahydrofuran (0.55 ml) in dry dichloromethane was added carefully. After a further 30 minutes triethylaamine was added dropwise and the reaction allowed to warm to room temperature. The reaction was poured onto water (40 ml) and extracted with dichloromethane (30 ml). The organic phase was washed with water (50 ml), brine (2×50 ml) and saturated aqueous sodium hydrogen carbonate solution (2×50 ml). After drying over magnesium sulphate the solvent was removed in vacuo to afford tetrahydro-furan-3-one as a yellow gum (0.19 g). n-Butyllithium (0.72 ml, 1.6M in hexanes) was added dropwise to a stirred solution of 7-methoxybenzofuran (0.15 g) in dry tetrahydrofuran (5 ml) at −78° C. under a dry nitrogen atmosphere. After stirring for 20 minutes a solution of tetrahydrofuran-3-one (90 mg) in dry tetrahydrofuran (2 ml) was added carefully. After stirring for a further 15 minutes at −78° C. the reaction was allowed to warm to room temperature. The reaction was carefully quenched with water and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (2×15 ml ) and water (15 ml). The combined organic extracts were dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 50% ethyl acetate in hexane to give the title compound as an orange gum (64 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:17])[CH:14]=[N+]=[N-])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([OH:21])(=[O:20])[CH3:19]>>[C:18]([O:21][CH2:14][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:17])(=[O:20])[CH3:19]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)C=[N+]=[N-]
Product: CC(=O)OCC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
(S)-1-(tert-Butoxycarbonyl)-2-(diazoacetyl)pyrrolidine (16.2 g) was dissolved in acetic acid and the mixture was heated at 100° C. for 10 minutes. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with an aqueous solution of sodium bicarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated to give the title compound (8.9 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:18][C:19]1[CH:24]=[C:23]([CH:25]=[CH2:26])[CH:22]=[CH:21][C:20]=1[C:27]1[S:28][C:29]2[C:34]([N:35]=1)=[CH:33][CH:32]=[C:31]([C:36]1([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:38][CH2:37]1)[N:30]=2.Cl>CN(C=O)C>[F:18][C:19]1[CH:24]=[C:23]([CH:22]=[CH:21][C:20]=1[C:27]1[S:28][C:29]2[C:34]([N:35]=1)=[CH:33][CH:32]=[C:31]([C:36]1([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:38][CH2:37]1)[N:30]=2)[CH2:25][CH2:26][CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In reactor bottle under N2 were combined fine cesium carbonate (0.209 g, 0.644 mmol) and diethyl malonate (0.195 mL, 1.29 mmol) in DMF (3 mL). The resulting slurry was allowed to stir for 1 h at ambient temperature. To the mixture was added 2-(2-fluoro-4-vinylphenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (0.200 g, 0.537 mmol) and the reaction mixture was heated to 35° C. for 1.5 h. The reaction mixture was cooled to 0° C. and acidified using 1 N aq. HCl, extracted with EtOAc, and the organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography provided diethyl 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenethyl)malonate. MS (ESI) m/z: calculated: 532.2; Observed: 533.1 (M++1).