Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:16](B1OC(C)(C)C(C)(C)O1)=[CH2:17].CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC>[CH:16]([C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH2:17]
Reactant: COC(=O)c1cc(Br)cc2ccccc12
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCO
Product: C=Cc1cc(C(=O)OC)c2ccccc2c1
Temperature: 90 °C

Procedure:
Methyl 3-bromo-1-naphthalenecarboxylate (1 eq.) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 eq.) were combined in a 2:1 (v/v) mixture of DMF:n-PrOH (0.1 M). To this solution was first added Pd(PPh3)2Br2 (0.05 eq.) followed by 2 N aq. Na2CO3 (2 eq.). The biphasic suspension was evacuated and back-filled three times with nitrogen before it was heated at 90° C. for 8 h. The now black suspension was cooled to RT, diluted with water and extracted with 1:1 (v/v) hexanes:ether. The combined organic extracts were then washed further with 1 N aq. NaOH, 10% aq. HCl, water and brine. This was then dried over Na2SO4 and filtered through a pad of silica gel. Concentration of the filtrate in vacuo afforded the crude title compound as a golden yellow oil.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2]O.O[CH2:6][CH:7]([CH2:9][OH:10])O>>[C:9]([O:10][CH3:1])(=[O:10])[C:7]1[CH:6]=[CH:7][C:2]([C:1]([O:4][CH3:2])=[O:4])=[CH:9][CH:6]=1
Reactant: OCC(O)CO
Reactant: OCCO
Product: COC(=O)c1ccc(C(=O)OC)cc1
Yield: 490.7 %

Procedure:
A polyester is produced in known manner from 388 g of dimethyl terephthalate, 112 g of ethylene glycol and 75 g of glycerin are further worked up as described in Example 1. However, instead of the 137 g of diimidodicarboxylic acid of Example A there is used 125 g of the reaction product of Example G. The obtained lacquer has a solid body content of 33% and viscosity of 111 seconds and copper wire is lacquered therewith as described in Example 1.
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:10]\[CH3:11])(C)C)(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:39]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[C:12]1([C:9](=[O:8])[C@H:10]([OH:39])[CH3:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1ccccc1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: CS(N)(=O)=O
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@@H](O)C(=O)c1ccccc1
Yield: 57.2 %

Procedure:
Compound 10b was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-phenprop-1-enyloxy)dimethylsilane (9b, 7.2 g, 0.029 mol), AD-mix-β (40.7 g), and CH3SO2NH2 (2.8 g, 0.0294 mol) in tert-butyl alcohol-water (110 mL:110 mL) The reaction was quenched with sodium sulfite (29.1 g). After purification, 2.49 g (80%) of the title product was isolated: [α]20D +84.9° (c 1.6, CHCl3); 1H NMR (CDCl3) δ 7.96-7.90 (m, 2H), 7.66-7.58 (m, 1H), 7.54-7.47 (m, 2H), 5.23-5.12 (m, 1H), 3.84 (d, 1H, J=6.3 Hz), 1.45 (d, 3H, J=7.05 Hz); 13C NMR (CDCl3) δ 202.4, 134.0, 133.4, 128.9, 128.7, 69.3, 22.3. C9H10O2.
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[H-].[Na+].Cl[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][N:19]=1>O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:9][CH:8]=1
Reactant: OCc1ccc(Br)cc1
Reactant: Fc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccnc1OCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
To an N,N-dimethylformamide (15 mL) solution of (4-bromo-phenyl)-methanol (1.56 g, 8.34 mmol) was added sodium hydride (401 mg, 8.35 mmol, 50% in oil), which was stirred for 5 minutes at room temperature. Then, an N,N-dimethylformamide (5 mL) solution of 2-chloro-3-fluoropyridine (967 mg, 7.35 mmol) was added to this mixture, which was stirred for 1 hour and 10 minutes at room temperature. Water was to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=2:1) to obtain the title compound (2.03 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:28]=[C:12]3[CH:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:26])[F:25])[CH2:14][CH:15]([OH:17])[CH2:16][N:11]3[N:10]=2)[CH:6]=[CH:5][C:4]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:28]=[C:12]3[CH:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:26])[F:25])[CH2:14][C:15](=[O:17])[CH2:16][N:11]3[N:10]=2)[CH:6]=[CH:5][C:4]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1
Reactant: COc1nc(-c2nc3n(n2)CC(O)CC3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1nc(-c2nc3n(n2)CC(=O)CC3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
2-[6-Methoxy-5-(4-methylimidazol-1-yl)pyridin-2-yl]-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-6-ol obtained in Example 26 (125 mg) was dissolved in methylene chloride (3 mL), and Dess-Martin reagent (226 mg) was added at room temperature. After stirring for 30 minutes, the reaction solution was partitioned with a saturated sodium bicarbonate solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 100%→methanol/ethyl acetate=10%) to obtain the title compound (28 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[K+].I[CH3:14].O>CN(C=O)C>[CH3:14][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: CI
Reactant: Clc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To room temperature solution of 5-chloroindole (4.97 g) in dry DMF (40 mL) was added potassium hydroxide pellets (2.76 g) and stirred 1 h until most of the solid dissolved. The resulting mixture was cooled to 0° C. in an ice bath and iodomethane (2.45 mL) was added dropwise and later stirred overnight at room temperature under argon. The reaction mixture was poured into water and extracted twice with ETOAc. The combined ETOAc portions were combined, washed with water, dried over magnesium sulfate, concentrated, and flash chromatographed with 10% ETOAc/Hexane to give 1-methyl-5-chloroindole as a pink liquid (5.43 g).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[C:21](=[O:22])[C:20]3[S:23][C:24]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)=[CH:25][C:19]=3[N:18]=[CH:17]2)=[CH:10][CH:9]=1)[CH3:6])=[O:4].[CH3:33][NH2:34]>CO.CN(C)C=O.C(OCC)(=O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]2[S:23][C:20]3[C:21](=[O:22])[N:16]([CH2:15][CH2:14][C:11]4[CH:12]=[CH:13][C:8]([CH2:7][N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:34][CH3:33])=[CH:9][CH:10]=4)[CH:17]=[N:18][C:19]=3[CH:25]=2)=[CH:27][CH:28]=1
Reactant: CN
Reactant: CN(Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1)C(=O)CCl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNCC(=O)N(C)Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the compound (0.12 g) obtained in Example 27, 40% methylamine in methanol solution (0.28 ml) and N,N-dimethylformamide (2 ml) was stirred at room temperature for 1 hr, diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane (1:1, volume ratio) to give the title compound (53 mg) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[CH:12]1[O:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][O:13]1.[CH:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:18][C:15]1([CH3:19])[CH2:16][O:17][CH:12](/[CH:11]=[CH:10]/[C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:27])[O:13][CH2:14]1
Reactant: Cc1cc(C)c(/C=C/C2OCC(C)(C)CO2)c(Br)c1
Reactant: O=Cc1ccccc1
Product: Cc1cc(C)c(/C=C/C2OCC(C)(C)CO2)c(C(O)c2ccccc2)c1
Yield: 81 %

Procedure:
In the manner described in Example 1, (E)-2-[2-(2-bromo-4,6-dimethylphenyl)ethenyl]-5,5-dimethyl-1,3-dioxane was reacted with benzaldehyde to obtain (E)-2-[2-(5,5-dimethyl-1,3-dioxan-2-yl)ethenyl]3,5-dimethyl-α-phenylbenzenemethanol as a clear foam (271 mg, 81%): IR (film) 3420, 2940, 2840, 1660 and 1605 cm-1 ; NMR (DMSO-d6) δ 0.72 (3H, s), 1.14 (3H, s), 2.20 (3H, s), 2.24 (3H, s), 3.56 (2H, d, J=12 Hz), 3.64 (2H, d, J=12 Hz), 5.08 (1H, d, J=5 Hz), 5.64 (1H, dd, J=5, 15 Hz), 5.74 (1H, d, J=3 Hz, exchangeable), 5.90 (1H, d, J=3 Hz), 6.76 (1H, d, J=15 Hz), 6.96 (1H, s), 7.14 (1H, s), 7.16-7.36 (5H, m).
Reaction SMILES: C(OC([N:8]=[C:9]([NH:39]C(OC(C)(C)C)=O)[NH:10][C:11]1[CH:38]=[CH:37][C:14]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([Cl:36])[CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])[CH2:19][CH2:18]2)=[O:16])=[CH:13][CH:12]=1)=O)(C)(C)C.Cl.CCOCC>C(OCC)(=O)C>[ClH:36].[NH:10]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([Cl:36])[CH:32]=4)[CH:27]=3)(=[O:24])=[O:25])[CH2:19][CH2:18]2)=[O:16])=[CH:37][CH:38]=1)[C:9]([NH2:39])=[NH:8]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: N=C(N)Nc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1
Reaction time: 3 h
Yield: 171.2 %

Procedure:
To 1-[4-(2,3-di-tert-butoxycarbonylguanidino)benzoyl]-4-(6-chloronaphthalene-2-sulfonyl)piperazine (295 mg) was added 4 N hydrochloric acid in ethyl acetate solution (20 ml) and the solution was allowed to stand at room temperature for 3 hours, to which was added ether. The precipitate was filtered, washed with ether and dried to give a colorless solid of the title compound (191 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C@H:13]([CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[Cl:33][CH2:34][C:35](=N)OCC.C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl>ClCCCl>[Si:25]([O:24][CH2:23][C@@H:13]([N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:35]1[CH2:34][Cl:33])[CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c(N)cnc2ccccc12
Reactant: CCOC(=N)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC[C@@H](CO[Si](C)(C)C(C)(C)C)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 65 °C
Yield: 61 %

Procedure:
tert-Butyl (2S)-2-[(3-aminoquinolin-4-yl)amino]-3-{[tert-butyl(dimethyl)silyl]oxy}propylcarbamate (4.51 g, 10.1 mmol) was dissolved in 80 mL of anhydrous 1,2-dichloroethane and the solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (2.39 g, 15.1 mmol) was then added and the reaction mixture was heated to 65° C. After stirring overnight, the reaction mixture was cooled and treated with 100 mL of saturated sodium bicarbonate (NaHCO3) solution and 100 mL of CHCl3. The layers were separated and the organic portion was washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 50% ethyl acetate/hexanes) gave tert-butyl (2S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate (3.11 g) as a golden foam.
Reaction SMILES: C[N:2](/[CH:4]=[C:5](\[CH2:11][CH3:12])/[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH:13]([C:15]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][N:16]=1)N>>[C:21]([C:19]1[CH:18]=[CH:17][N:16]=[C:15]([NH:13][NH:2]/[CH:4]=[C:5](\[CH2:11][CH3:12])/[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:20]=1)#[N:22]
Reactant: N#Cc1ccnc(NN)c1
Reactant: CCOC(=O)/C(=C/N(C)C)CC
Product: CCOC(=O)/C(=C/NNc1cc(C#N)ccn1)CC

Procedure:
The title compound was prepared from ethyl (2E)-2-(dimethylaminomethylidene)butanoate and 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) according to the procedure for the preparation of Example 84, part B. [M+H] Calc'd for C13H16N4O2, 261. Found, 261.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH2:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: COc1ccccc1OCC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1ccccc1OCC1CCNC1
Yield: 42.6 %

Procedure:
5.0 g of 10% palladium on activated carbon were added to a solution of 5.0 g (17 mmol) of 1-benzyl-3-(2-methoxyphenoxy)methyl-pyrrolidine and 10.6 g (0.17 mol) of ammonium formate in 300 ml of methanol and the mixture was heated to reflux for 1 hour. After cooling, the solution was separated from the catalyst by filtration and the filtrate was freed from solvent in vacuo. The residue was rendered basic using 1N NaOH and the mixture was extracted using ether. After drying and evaporating, 1.5 g (43%) of the title compound were obtained as an oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH2:29][CH3:30]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:28][CH2:29][CH3:30])[CH2:19]1
Reactant: CCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCN(CCC)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(3-piperidinyl)propyl]-9H-purin-6-amine and 1-iodopropane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:19][CH2:20][CH2:21][O:22]C3CCCCO3)[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:19][CH2:20][CH2:21][OH:22])[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc2c(c1)COC2(CCCOC1CCCCO1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: N#Cc1ccc2c(c1)COC2(CCCO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 1-(4-fluorophenyl)-1-[3-(tetrahydropyranyloxy)propyl]-1,3-dihydro-5-isobenzofurancarbonitrile (1.5 g, 4.1 mmol) in methanol was added catalytic amount of p-toluenesulfonic acid monohydrate (60 mg) and the resulting mixture was stirred at room temperature for 1 h and then evaporated. Silica gel chromatography (heptane, EtOAc 5:1) gave the title product (1.0 g, 91%). 1H NMR (CDCl3) was identical with that obtained from 1-[(3-benzyloxy)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](I)=[CH:16][C:15]=1[F:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:30]([N:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].[Cl-].[NH4+].Cl>CCCCCC.O1CCCC1>[C:33]([O:32][C:30]([N:37]1[CH2:42][CH2:41][CH:40]([C:17]2[CH:16]=[C:15]([F:29])[C:14]([O:13][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:19][C:18]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:39][CH2:38]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: Fc1cc(I)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(c2cc(F)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Temperature: -70 °C
Reaction time: 0.42 h

Procedure:
4.0 ml (9.9 mmol, 1.2 eq) of 2.5M n-butyllithium in hexane are added to a solution of 3.59 g (8.26 mmol, 1 eq) of 1,5-bis(benzyloxy)-2-fluoro-4-iodobenzene in 40 ml of tetrahydrofuran, cooled to −70° C. The reaction medium is stirred at −70° C. for 25 minutes and 1.97 g (9.9 mmol, 1.2 eq) of 1-boc-4-piperidone in solution in 20 ml of tetrahydrofuran are added. The reaction medium is stirred at −70° C. for 1 hour and is then left to return to ambient temperature overnight. 30 ml of a saturated solution of ammonium chloride, to which 4 ml of 2M hydrochloric acid have been added, are added to the reaction medium, which is stirred for 20 minutes and is then extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulphate and evaporated. The residue is chromatographed on silica gel, elution being carried out with 95/5 heptane/ethyl acetate then 75/25 heptane/ethyl acetate (with 0.1% of TEA).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([N:11]([CH3:13])[CH3:12])[N:8]=[C:7]([NH:14][NH:15][C:16]([C@H:18]([CH2:31][CH2:32][CH2:33][CH2:34]C=C)[CH2:19][N:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[O:22])=[O:17])[N:6]=1)[CH2:2][CH:3]=[CH2:4]>ClCCl.CC1C=C(C)C(N2[CH-]N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[CH3:12][N:11]([CH3:13])[C:9]1[N:10]=[C:5]2[N:6]=[C:7]([N:8]=1)[NH:14][NH:15][C:16](=[O:17])[C@@H:18]([CH2:19][N:20]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:21]=[O:22])[CH2:31][CH2:32][CH2:33][CH2:34][CH:4]=[CH:3][CH2:2][CH2:1]2
Reactant: C=CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)NNc1nc(CCC=C)nc(N(C)C)n1
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1cc(C)c(N2[CH-]N(c3c(C)cc(C)cc3C)CC2)c(C)c1
Solvent: ClCCl
Product: CN(C)c1nc2nc(n1)NNC(=O)[C@@H](CN(C=O)OCc1ccccc1)CCCCC=CCC2

Procedure:
To a solution of N-[(2R)-2-({2-[4-(3-buten-1-yl)-6-(dimethylamino)-1,3,5-triazin-2-yl]hydrazino}carbonyl)-7-octen-1-yl]-N-benzoxyformamide (280 mg, 0.566 mmol) in dichloromethane (225 mL, 0.0025M) at room temperature was added tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydro-imidazol-2-ylidene][benzylidene]ruthenium(IV) dichloride (2nd generation Grubbs catalyst, 48 mg, 0.057 mmol). The reaction mixture was stirred and heated to reflux for 48 hours, the solvent was evaporated in vacuo, and the residue was then purified by HPLC to afford the title compound as a white solid. MH+468.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=2)[CH:18]=[N:19][CH:20]=1.C=O.[CH3:33]C1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.CC([O-])=O.[Na+].C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O>C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:33][N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][OH:30])[CH:24]=[CH:25][CH:26]=2)[CH:18]=[N:19][CH:20]=1
Reactant: OCCCc1cccc(-c2cncc(OC[C@@H]3CCCN3)c2)c1
Reactant: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: C=O
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC[C@H]1COc1cncc(-c2cccc(CCCO)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of 3-[3-[5-[(2(S)-pyrrolidinyl)methoxy]-3-pyridyl]phenyl]-1-propanol trifluoroacetate (C19H24N2O2.3.02CF3COOH.0.57H2O, 296 mg, 443 μmol) in ethanol (1.5 mL) in a 15 mL round bottom flask was added formalin (0.18 mL, 6.6 mmol, 15 equiv.). A small amount of bromocresol green was added to the reaction mixture to monitor the pH, which was adjusted to 4-5 by addition of NaOAc. The mixture was stirred at room temperature for 30 min. Sodium cyanoborohydride (42 mg, 0.67 mmol, 1.5 equiv.) was added, whereon the pH increased. Small amounts of CF3COOH were added over several hours to keep the pH between 4 and 5. The resulting mixture was stirred at room temperature for an additional 24 h. The solvents were evaporated, and the residue was purified by CC on silica gel (38×1.0 cm, CH2Cl2/methanol/saturated aqueous ammonia 20:1:0.1). The crude product was purified by preparative HPLC (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 8% to 25% CH3CN in water within 20 min, from 25% to 100% for another 20 min, then 100% CH3CN for 20 min, both solvents containing 0.1 vol % CF3COOH; tR 18.0-24.3 min) to give the methylation product as a trifluoroacetate (colorless oil, 131 mg, 44%). 1H NMR (CD3OD, 500 MHz) δ 8.66 (s, 1H), 8.48 (s, 1H), 8.06 (d, 1H, J=1.9 Hz), 7.61 (s, 1H), 7.58 (d, 1H, J=7.8 Hz), 7.51-7.45 (m, 1H), 7.38 (d, 1H, J=7.8 Hz), 4.92-4.88 (m, 1H, overlapping with the CD3OH peak), 4.68 (dd, 1H, J=11.2, 3.0 Hz), 4.52 (dd, 1H, J=11.0, 6.8 Hz), 4.03-3.94 (m, 1H), 3.84-3.76 (m, 1H), 3.65-3.59 (m, 2H), 3.13 (d, 3H, J=3.7 Hz), 2.82 (t, 2H, J=7.8 Hz), 2.50-2.42 (m, 1H), 2.32-2.22 (m, 1H), 2.22-2.08 (m, 2H), 1.96-1.88 (m, 2H). Anal. Calcd. for C20H26N2O2.3.00CF3COOH (FW 668.5) C, 46.71; H, 4.37; N, 4.19; F, 25.58. Found: C, 46.93; H, 4.49; N, 4.26; F, 25.83.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[C:13]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])([CH3:16])([CH3:15])[CH3:14]>O1CCOCC1>[C:13]([C:17]1[CH:18]=[C:19]([NH:20][C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]3[N:3]=2)[CH:21]=[CH:22][CH:23]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: CC(C)(C)c1cccc(N)c1
Solvent: C1COCCO1
Product: CC(C)(C)c1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Temperature: 120 °C
Yield: 96 %

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.276 mmol) in dioxane was added 3-tert-butylaniline (206 mg, 1.381 mmol). The mixture was heated in microwave for 10 minutes at 120° C. The solid formed was isolated by filtration and air dried to yield 78 mg 5-(3-tert-butylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (96% yield). LCMS (M+1=295)
Reaction SMILES: [C:1]([C:3]([C:18](=[O:27])[NH:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][CH:6]=1)#[N:2].[OH-].[Na+:29]>CO>[C:1]([C:3]([C:18](=[O:27])[NH:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([O-:13])=[O:12])=[CH:16][CH:17]=1)#[N:2].[Na+:29]
Reactant: CCOC(=O)COc1ccc(C=C(C#N)C(=O)NCc2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC(=Cc1ccc(OCC(=O)[O-])cc1)C(=O)NCc1cccnc1

Procedure:
A solution of ethyl [4-[2-cyano-2-[N-(3-pyridylmethyl)carbamoyl]ethenyl]phenoxy]acetate (730 mg) in 30 ml methanol was stirred with 10 ml of 0.2 mol/l aqueous sodium hydroxide at room temperature for 18 hours. After evaporation of methanol, the reaction mixture was mixed with 100 ml water and then extracted with 30 ml ethyl acetate to remove unreacted components. The aqueous layer was concentrated until a solid came out. A part of the resulting solid was filtered, and then dried over diphosphorus pentaoxide by heating under reduced pressure to give the compound of interest (156 mg, 22%) as a pale yellow solid.