Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1>>[NH2:1][C:2]1[C:7]([Br:8])=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[N:3]=1
Reactant: Nc1cccc(O)c1
Reactant: Nc1nc(Cl)ncc1Br
Product: Nc1nc(Nc2cccc(O)c2)ncc1Br

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine, 4-amino-5-bromo-2-chloropyrimidine and 3-aminophenol were reacted to give 4-amino-5-bromo-N2-(3-hydroxyphenyl)-2-pyrimidineamine. 1H NMR (DMSO-d6): δ 10.33 (br s, 1H), 8.27 (s, 1H), 7.14–6.06 (m, 2H), 7.01 (d, 1H, J=1.7 Hz), 6.54 (td, 1H, J=1.7 Hz and 7.0 Hz).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][OH:13])[CH:8]=[C:7]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C1COCC1.CC(=O)OCC>[CH2:33]([O:32][C:30]([N:17]1[CH2:16][CH2:15][N:14]([C:7]2[CH:8]=[C:9]([CH2:11][CH2:12][OH:13])[N:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:6]=2)[CH2:19][CH2:18]1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)c1nc(CCO)cc(N2CCNCC2)n1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(CCO)cc(N2CCN(C(=O)OCc3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a solution of 2-tert-Butyl-4-(2-hydroxy-ethyl)-6-piperazin-1-yl-pyrimidine (5.1 g, 19.29 mmol) and N,N-diisopropylethylamine (7.48 g, 57.9 mmol) in THF (150 mL) was added benzyl chloroformate (CbzCl, 3.29 g, 19.29 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with EA, washed with water, brine, dried over Na2SO4, filtered and concentrated to afford the crude title compound as an oil which was purified by column chromatography to afford the product (2.3 g, yield 29%) as a yellow oil.
Reaction SMILES: [Br:1]Br.[CH3:3][S:4][C:5]1[N:10]=[C:9]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][N:6]=1>C(O)(=O)C>[Br:1][CH:11]([C:9]1[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH3:3])[N:10]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: BrBr
Reactant: CSc1nccc(CC(=O)c2ccccc2)n1
Solvent: CC(=O)O
Product: CSc1nccc(C(Br)C(=O)c2ccccc2)n1

Procedure:
Bromine (24.1 g, 0.15 mol) is added with stirring to 2-(2-methylthio-pyrimidin-4-yl)-1-phenyl-ethanone (36.8 g, 0.15 mol) in acetic acid (300 ml) in such a way that the reaction temperature does not exceed +25° C. and the color of the bromine is discharged immediately. After the addition of the bromine solution the solvent is removed by evaporation under vacuum. The pH of the resulting oil is adjusted to 8 using an aqueous saturated sodium bicarbonate solution and the product is extracted several times with diethylther. Drying the combined extracts with magnesium sulfate, filtering and evaporation of the solvent gives the crude 2-bromo-2-(2-methylthio-pyrimidin-4-yl)-1-phenyl-ethanone in form of an oil of sufficient purity for the following step.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:29]=3)[C:24](O)=[O:25])=[C:18]([F:44])[CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:69][C:70]1[S:71][CH:72]=[CH:73][N:74]=1>CN(C=O)C.O>[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:29]=3)[C:24]([NH:69][C:70]3[S:71][CH:72]=[CH:73][N:74]=3)=[O:25])=[C:18]([F:44])[CH:17]=2)=[O:15])[CH2:11][CH2:12][CH2:13]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)O)c1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[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: O
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)Nc2nccs2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
DIPEA (0.5 mL, 3.0 mmol) was added to a suspension of 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (503 mg, 1.0 mmol), HATU (495 mg, 1.3 mmol) and 2-amino-1,3 thiazole (300 mg, 3.0 mmol) in DMF (6 mL). The resulting mixture was stirred at RT for 16 hours, water (90 mL) was added and the mixture extracted with ethyl acetate. The extracts were combined, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with 75% ethyl acetate in isohexane, to give the desired compound (585 mg).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[CH3:5][C:6](=[CH:9][CH2:10][CH3:11])[CH:7]=[O:8].[Cl-].[NH4+]>O1CCCC1>[C:1]([CH:7]([OH:8])[C:6]([CH3:5])=[CH:9][CH2:10][CH3:11])#[CH:2]
Reactant: CCC=C(C)C=O
Reactant: C#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)C(C)=CCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 364.8 %

Procedure:
To a solution of ethynyl magnesium bromide (prepared from 2.91 g of magnesium) in 100 ml of tetrahydrofuran, was added dropwise 9.8 g of 2-methyl-2-pentenal at a temperature from 0° C to 10° C under cooling with ice-bath. The resulting reaction solution was stirred for 3 hours at room temperature to complete the reaction and then the reaction solution was poured into a saturated ammonium cloride solution with 50 g of ice. After stirring, the solution was extracted twice with 100 ml of ether and the organic layers were combined, and then washed with 50 ml of a saturated sodium chloride solution. After the organic layer had been dried over anhydrous sodium sulfate, the ether was evaporated. The remaining liquid was purified by distillation at reduced pressure to obtain 10.2 g of a colorless oily 1-ethynyl-2-methyl-2-pentenyl alcohol, b.p. 85°-88° C/20 mmHg.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[F:11][C:12]1[CH:13]=[C:14]([C@H:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([CH:24]=[CH2:25])[NH:19]2)[CH:15]=[CH:16][CH:17]=1.[CH:26]([CH2:28][C:29](O)=[O:30])=[CH2:27].Cl>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[F:11][C:12]1[CH:13]=[C:14]([C@H:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([CH:24]=[CH2:25])[N:19]2[C:29](=[O:30])[CH2:28][CH:26]=[CH2:27])[CH:15]=[CH:16][CH:17]=1
Reactant: C=C[C@@H]1CCC[C@H](c2cccc(F)c2)N1
Reactant: C=CCC(=O)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCC(=O)N1[C@H](C=C)CCC[C@@H]1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 27 h

Procedure:
Diethyl cyanophosphonate (1.78 mL) was added to a solution of (2R*,6S*)-2-(3-fluorophenyl)-6-vinylpiperidine (748 mg), vinylacetic acid (0.96 mL), and triethylamine (3.1 mL) in DMF (15 mL) at room temperature, and the reaction solution was stirred at room temperature for 27 hours. Ethyl acetate and 1 N hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was sequentially washed with saturated sodium bicarbonate water and brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 587 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[CH:3]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].C(N(CC)CC)C>C(O[Pd]OC(=O)C)(=O)C>[CH3:17][O:16][C:12](=[O:15])/[CH:13]=[CH:14]/[C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Cc1nc2ccc(I)cc2s1
Agent: CC(=O)O[Pd]OC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc2nc(C)sc2c1
Temperature: 100 °C

Procedure:
A mixture of 6-iodo-2-methylbenzo[d]thiazole (275 mg, 1 mmol), methyl acrylate (103 mg, 1.2 mmol), diacetoxypalladium (22 mg, 0.1 mmol) and triethylamine (304 mg, 3 mmol) MeCN (8 mL) is heated in a microwave apparatus at 100° C. for 10 min. The solvent is removed under reduce pressure and the residue is purified by flash chromatography (heptane:EtOAc, 2:1) to give (E)-3-(2-methyl-benzothiazol-6-yl)-acrylic acid methyl ester. MS 234.3 (M+1).
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][CH2:6][CH3:7])[CH:3]=[O:4].[CH2:8]([O:10][C:11](=[O:15])[CH2:12][N+:13]#[C-:14])[CH3:9]>>[CH2:8]([O:10][C:11]([CH:12]1[CH:3]([C:2]([CH2:5][CH2:6][CH3:7])=[CH2:1])[O:4][CH:14]=[N:13]1)=[O:15])[CH3:9]
Reactant: C=C(C=O)CCC
Reactant: [C-]#[N+]CC(=O)OCC
Product: C=C(CCC)C1OC=NC1C(=O)OCC

Procedure:
The starting material is manufactured as follows: Reaction of 2-methylene-pentanal with isocyanoacetic acid ethyl ester analogously to Example 1 yields 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester. By hydrolysis of the 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester in a manner analogous to that described in Example 15, 2-formylamino-3-hydroxy-4-propyl-4-pentenoic acid ethyl ester is obtained.Reaction of the 2-formylamino-3-hydroxy-4-propyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite in a manner analogous to that described in Example 1 yields E-2-formylamino-4-propyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26]=[C:27]=[S:28]>C(O)C>[CH3:25][NH:26][C:27]([NH:24][C:21]1[CH:22]=[N:23][C:18]([O:17][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15]3)=[CH:19][CH:20]=1)=[S:28]
Reactant: CN=C=S
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Solvent: CCO
Product: CNC(=S)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1

Procedure:
Solution of 6-(2-phenylchroman-6-yloxy)pyridin-3-ylamine (150 mg) and methyl isothiocyanate (94 μl) in ethanol was refluxed for 10 hours. After cooling solvents were evaporated. Crude product of 1-methyl-3-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]thiourea was purified by column chromatography (5% methanol in dichloromethane). 1H NMR (400 MHz, d6-DMSO) δ: 9.45 (bs, 1H), 8.02 (d, 1H, J 2.7 Hz), 7.81 (dd, 1H, J 2.7, 8.8 Hz), 7.70 (bs, 1H), 7.47-7.38 (m, 4H), 7.36-7.32 (m, 1H), 6.94-6.86 (m, 4H), 5.12 (dd, 1H J 2.3, 10.1 Hz), 2.98-2.93 (m, 1H), 2.90 (d, 3H, J 4.3 Hz), 2.76-2.71 (m, 1H), 2.19-2.15 (m, 1H), 2.15-1.99 (m, 1H).
Reaction SMILES: C([Si]1(C(C)C)[O:11][C@H:10]2[CH2:12][C@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][C@@H:9]2[CH2:8][O:7][Si](C(C)C)(C(C)C)O1)(C)C.O.[F-].C([N+](CC)(CC)CC)C>O1CCCC1>[OH:11][C@@H:10]1[C@@H:9]([CH2:8][OH:7])[CH2:14][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:12]1
Reactant: CC(C)[Si]1(C(C)C)OC[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2O[Si](C(C)C)(C(C)C)O1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](CO)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (-)-(6aR, 8R, 9aS)-tert-butyl N-(hexahydro-2,2,4,4-tetraisopropylcyclopenta [f]-1,3,5,2,4-trioxadisilocin-8-yl)carbamate(74.32 g, 0.1569 mol, corresponding to the first portion of product in the above Example) in tetrahydrofuran (300 mL) was added tetraethyl ammonium fluoride hydrate (24.62 g, about 0.15 mol, Aldrich). The lumps of solid were broken up, the mixture was degassed (nitrogen), then refluxed for 45 minutes. After cooling to room temperature, the reaction mixture was applied to a column of silica gel (200 g) and eluted with tetrahydrofuran (3 L). The eluate was concentrated under vacuum to an amber oil, which was taken up in hexanes (150 mL). Crystallization began spontaneously, and was allowed to continue at -5° for two days. The crystals of crude title compound were collected by filtration, washed sparingly with 10% ethyl acetate-hexanes, and dried by suction to constant weight (25.08 g, 0.1084 mol). The procedure was repeated on the second portion of product from the above Example (73.82 g, 0.1558 mol), giving additional crude title compound (27.28 g, 0.1180 mol). The two portions of crude title compound were combined and recrystallized from boiling ethyl acetate (250 mL), giving white crystals of the title compound (46.67 g., 0.2018 mol, 53.7% of theoretical from the triol product of Example 5) having the following characteristics: m.p. 126-127.9° C.; 1H-NMR (DMSO-d6), δ: 6.75 (dr d, J=7.8 Hz, 1H, NH), 4.49 (t, J=4.5 Hz, CH2OH) overlapping 4.47 (d,J=4.3 Hz, CHOH) with total integration of 2H, 3.80-3.93 (m, 2H, CHN and CHOH), 3.34 (m, w1/2=20 Hz, CH2OH), 2.25 (dt, 1H, CHCH2), 1.79-1.63 (m, 2H, CH2CHOH), 1.63-1.50 (m, 1H, 1/2CH2), 1.38 (s, 9H, C(CH3)3), 1.11-0.96 (m, 1H, 1/2CH2); Cl-MS (CH4): 232(M+1).
Reaction SMILES: [CH2:1]1[O:9][C@@H:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(C)(O)[C:12]#[N:13].C(N(CC)CC)C>O1CCCC1>[C:3]1([C@@H:2]([OH:9])[CH2:1][C:12]#[N:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc([C@@H]2CO2)cc1
Reactant: CC(C)(O)C#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CC[C@H](O)c1ccccc1
Yield: 70 %

Procedure:
A mixture of 40.0 g of (R)-styrene oxide, 31.12 g of acetone cyanohydrin, 36.96 g of triethylamine, and 150 ml of tetrahydrofuran was heated at reflux for 18 hours. The reaction mixture was cooled, concentrated in vacuo, diluted with 200 ml of 2N potassium hydroxide, and extracted with diethyl ether. The ether extracts were combined, dried over magnesium sulfate, and concentrated in vacuo providing 34.3 g of the title intermediate.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[NH:12][C:11]3=[O:19])=[CH:4][C:3]=2[O:2]1.[CH2:20]([N:24]=[C:25]=[O:26])[CH2:21][CH2:22][CH3:23].C1OC2C=CC(N3C4=NC=CC=C4NC3=O)=CC=2[O:28]1.C(C(N)=O)CCC>C(COC)OC>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[NH:12][C:11]3=[O:19])=[CH:4][C:3]=2[O:2]1.[CH2:20]([N-:24][C:25]([OH:28])=[O:26])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN=C=O
Agent: CCCCC(N)=O
Agent: O=c1[nH]c2cccnc2n1-c1ccc2c(c1)OCO2
Solvent: COCCOC
Product: CCCC[N-]C(=O)O

Procedure:
A suspension of 1.2 g. of 1,3-dihydro-3-(3,4-methylenedioxyphenyl)imidazo[4,5-b]pyridin-2-one in 75 ml. of dry dimethoxyethane was treated with 1 g. of n-butyl isocyanate and refluxed until solution was complete. The solution was filtered and evaporated to near dryness and diluted with petroleum ether. The precipitate was recrystallized from 30 ml. of ethanol by addition of water to give 400 mg. of 1,3-dihydro-3-(3,4-methylenedioxyphenyl)-2-oxoimidazo[4,5-b]pyridine-1-n-butylcarboxamide,. m.p. 129°-130° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([CH:12]=[O:13])[C:3]=1[Cl:14].CC(=CC)C.P([O-])([O-])(O)=[O:21].[Na+].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([C:12]([OH:21])=[O:13])[C:3]=1[Cl:14]
Reactant: O=P([O-])([O-])O
Reactant: CCCc1nc(C=O)c(Cl)c(N)c1F
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCCc1nc(C(=O)O)c(Cl)c(N)c1F
Temperature: 85 °C

Procedure:
A microwave vial equipped with a magnetic stir bar was charged with 4-amino-3-chloro-6-propyl-5-fluoropicolinaldehyde (15.9 mg, 0.072 mmol) and t-butanol (1.0 mL). The mixture was treated with H2O (0.40 mL), 2-methylbut-2-ene (100 μL, 0.10 mmol), sodium hydrogenphosphate (21.6 mg, 0.100 mmol), and finally sodium chlorite (19.28 mg, 0.206 mmol) was added in one portion. The mixture was heated to 85° C. for 16 h. An aliquot of the reaction mixture was analyzed by LC-MS. LC-MS analysis showed one major product with the correct mass for the desired product. The reaction mixture was evaporated to dryness under N2. Purification via reverse phase chromatography yielded 4-amino-3-chloro-6-propyl-5-fluoropicolinic acid (4.7 mg, 27.9%): 1H NMR (400 MHz, CDCl3) δ 11.60 (s, 1H), 4.98 (m, 2H), 2.76 (m, 2H), 1.75 (m, 2H), 0.99 (m, 3H); 19F NMR (376 MHz, CDCl3) δ−139.98; ESIMS m/z 231.2 ([M−H]−).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]2[NH:15][C:16](=[O:27])[C:17]3[C:18](=[C:20]([CH2:24][CH2:25][CH3:26])[N:21]([CH3:23])[N:22]=3)[N:19]=2)[C:6]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:7][CH:8]=1)#[CH:2].C[Si]([N:32]=[N+:33]=[N-:34])(C)C>>[CH2:10]([O:9][C:6]1[C:5]([C:14]2[NH:15][C:16](=[O:27])[C:17]3[C:18](=[C:20]([CH2:24][CH2:25][CH3:26])[N:21]([CH3:23])[N:22]=3)[N:19]=2)=[CH:4][C:3]([C:1]2[NH:34][N:33]=[N:32][CH:2]=2)=[CH:8][N:7]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1cnc(OCC(C)C)c(-c2nc3c(CCC)n(C)nc3c(=O)[nH]2)c1
Product: CCCc1c2nc(-c3cc(-c4cnn[nH]4)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Yield: 49.4 %

Procedure:
5-(5-Ethynyl-2-isobutoxy-3-pyridinyl)-2-methyl-3-propyl-2,6-dihydro-7H-pyrazolo[4,3-a]pyrimidin-7-one (Example 27) (200 mg, 0.54 mmol) and trimethylsilylazide (630 mg, 5.4 mmol) were stirred at 170° C. in a sealed pressure vessel for 14 h. The reaction mixture was cooled and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The brown precipitate was filtered off and the 2 phases separated. The organic phase was washed with more sodium bicarbonate solution and brine, dried with (MgSO4) and concentrated. This residue was combined with the original precipitate and purified by flash column chromatography (gradient elution from dichloromethane to 5% methanol:dichloromethane) to give 109 mg of a white solid (49%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.[Cl:15][C:16]1[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:17]=1[CH2:18][CH:19]([C:23](=O)[CH3:24])[C:20](=O)[CH3:21]>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:20]([CH3:21])=[C:19]([CH2:18][C:17]1[CH:26]=[CH:27][C:28]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:29][C:16]=1[Cl:15])[C:23]([CH3:24])=[N:13]2
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Reactant: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(C)=O
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(S(C)(=O)=O)cc3Cl)c(C)c12
Temperature: 100 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (0.35 g), 3-(2-chloro-4-methanesulfonylbenzyl)pentane-2,4-dione (0.5 g) and polyphosphoric acid (5.0 g) was heated at 100° C. for 3.5 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (2:8 to 3:7 by volume) to afford title compound as a pale yellow waxy solid, 0.36 g.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[Br:31][C:32]1[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=1)[CH2:35][C:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Br:45])[CH:40]=1)=O.[C:49]1(C)C=CC=CC=1>>[Br:31][C:32]1[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=1)[CH2:35][C:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Br:45])[CH:40]=1)=[CH:49][CH2:6][C:5]1[CH:26]=[CH:27][CH:28]=[C:3]([Br:2])[CH:4]=1
Reactant: Cc1ccccc1
Reactant: O=C(Cc1cccc(Br)c1)Cc1cccc(Br)c1
Reactant: Brc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: Brc1cccc(CC=C(Cc2cccc(Br)c2)Cc2cccc(Br)c2)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
164.2 g (320 mmol) of 3-bromobenzyltriphenylphosphonium bromide were added to a suspension of 7.2 g (300 mmol) of sodium hydride in 2000 ml of toluene. This mixture was stirred at 80° C. for 3 h. A solution of 110.4 g (300 mmol) of bis(3-bromobenzyl)ketone in 500 ml of toluene was subsequently added dropwise, and the mixture was stirred at 80° C. for a further 48 h. After the reaction mixture had been cooled, the precipitate formed was filtered off with suction. The precipitate was washed with 100 ml of toluene, and the combined organic phases were evaporated to dryness. The residue was taken up in 1000 ml of n-hexane, the hexane was decanted off, and the residue was again extracted twice with 300 ml of n-hexane each time. The combined hexane phases were concentrated to a volume of about 500 ml and filtered through 200 g of aluminium oxide (activity grade 4). The filtrate was evaporated, leaving the product as a pale-yellow oil. The yield, with a purity of about 97%, was 152.3 g (292 mmol), corresponding to 97.4% of theory.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[CH3:9][C:10](O)([CH3:12])[CH3:11].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([O:8][C:10]([CH3:12])([CH3:11])[CH3:9])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCC(=O)O
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hex-5-ynoic acid (Compound SP424) (8.0 g, 71.3 mmol), 2-methylpropan-2-ol (10.6 g, 143.0 mmol) and 4-(dimethylamino)pyridine (0.44 g, 3.60 mmol) were dissolved in DCM (17.5 ml), a solution of dicyclohexylcarbodiimide (16.2 g, 78.5 mmol) in DCM (17.5 ml) was added, and the mixture was stirred at room temperature overnight. The white solid in the reaction solution was removed by filtration, after which the filtrate was washed with a 0.5 M aqueous hydrochloric acid solution and a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The residue obtained by filtration and concentration under reduced pressure was purified by column chromatography (hexane:ethyl acetate=100:0-90:10) to afford the title compound SP423 (6.73 g, 56.1%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH:4]=1.[C-:16]#[N:17].[K+]>CN(C=O)C.O>[CH:13]1([CH2:12][O:11][C:5]2[CH:4]=[C:3]([CH2:2][C:16]#[N:17])[CH:8]=[CH:7][C:6]=2[O:9][CH3:10])[CH2:15][CH2:14]1
Reactant: COc1ccc(CCl)cc1OCC1CC1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CC#N)cc1OCC1CC1
Temperature: 60 °C
Yield: 87.4 %

Procedure:
A mixture of 4-(chloromethyl)-2-(cyclopropylmethoxy)-1-methoxybenzene (7.4 g) in DMF (68 ml) was stirred at 60° C. A mixture of potassium cyanide (4.26 g) in water (3.4 ml), previously heated to 80° C., was added dropwise. The resulting reaction mixture was stirred for 30 minutes at 60° C. The reaction mixture was cooled, treated with water (47 ml), and extracted with DIPE. The separated organic layer was dried (Na2SO4), filtered, and the solvent was evaporated, yielding 6.2 g (85%) of 3-(cyclopropylmethoxy)-4-methoxybenzeneacetonitrile (interm. 16).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14].C(OCC)C>O.O1CCCC1>[CH3:14][C:13]([O:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1)=[O:15]
Reactant: CC(=O)OC(C)=O
Reactant: OCCc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(=O)Oc1ccc(CCO)cc1
Yield: 66.6 %

Procedure:
5.6 g (0.1 mole) potassium hydroxide in 10 ml water was added to a cooled solution of 13.8 g (0.1 mole) p-hydroxyphenethyl alcohol in 50 ml tetrahydrofuran. 10.2 g (0.1 mole) acetic anhydride was slowly added under stirring. After 2 hours diethyl ether and water were added. The phases were separated and the organic phase was dried, filtered and evaporated in vacuo. The product contained 15% starting material and was therefore redissolved in diethyl ether and washed twice with dilute sodium carbonate. Drying, filtration and evaporation of solvents in vacuo gave 12 g (yield 67%) of 2-(4-methylcarbonyloxyphenyl)-1-ethanol which was used without further purification.