Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7](=[O:14])[O:8][CH2:9][C:10]([Cl:13])([Cl:12])[Cl:11])[C@H:3]1[C:15]([OH:17])=[O:16].CC1(C)[C@@H](/C=C\C(=O)OCCOC)[C@H]1C(O[CH:35]([CH3:49])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:37]=1)=O.O(C1C=C(C(O)C)C=CC=1)C1C=CC=CC=1>>[CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7](=[O:14])[O:8][CH2:9][C:10]([Cl:13])([Cl:11])[Cl:12])[C@H:3]1[C:15]([O:17][CH:35]([CH3:49])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:37]=1)=[O:16]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Reactant: COCCOC(=O)/C=C\[C@H]1[C@@H](C(=O)OC(C)c2cccc(Oc3ccccc3)c2)C1(C)C
Agent: CC(O)c1cccc(Oc2ccccc2)c1
Product: CC(OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(Cl)(Cl)Cl)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure of Step D of Example 9, 6 g of (1R,cis) 2,2-dimethyl-3-[3-oxo-3-(2,2,2-trichloroethoxy)-1-propynyl]-cyclopropane-carboxylic acid and 4.1 g of 1-(R) (3-phenoxyl-phenyl)- ethanol were reacted to obtain after chromatography and elution with an 8-2 mixture of cyclohexaneethyl acetate 4.38 g of (R)α-methoxy-3-phenoxy-benzyl (1R, cis) 2,2-dimthyl-3-[3-oxo-3-(2,2,2-trichloroethoxy)-1-propynyl]-cyclopropane-carboxylate.
Reaction SMILES: [CH3:1][Si:2]([Cl:5])(Cl)[Cl:3].C(OCC)C.Cl[Mg][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15]>CCCCCC>[CH3:13][Si:14]([CH2:17][Si:2]([CH3:1])([Cl:5])[Cl:3])([CH3:16])[CH3:15]
Reactant: C[Si](Cl)(Cl)Cl
Reactant: C[Si](C)(C)C[Mg]Cl
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)C[Si](C)(Cl)Cl
Reaction time: 2 h
Yield: 43 %

Procedure:
In a 1-1 flask equipped with a dropping funnel, reflux condenser, stirrer and nitrogen gas introducing tube were placed 149 g (1 mol) of methyltrichlorosilane and 250 ml of diethyl ether. While stirring the mixture, the above chlorotrimethylsilylmethyl magnesium was dropwise added thereto over a period of 2 hours. After completion of the addition, the mixture was refluxed with heating and stirring for 36 hours. After cooling, 200 ml of hexane was added to the reaction mixture, and the salts formed were filtered off. The filtrate was condensed and vaccum-distilled. 11.7 g (yield: 43%) of (trimethylsilylmethyl)methyldichlorosilane was obtained.
Reaction SMILES: [N:1]#[C:2]Br.[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][C:6]=1[CH3:12]>C(OCC)C.C1COCC1>[Br:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:2]#[N:1])=[CH:7][C:6]=1[CH3:12]
Reactant: N#CBr
Reactant: Cc1cc(N)ccc1Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(NC#N)ccc1Br
Yield: 26.4 %

Procedure:
A mixture of cyanogen bromide (0.550 g, 5.19 mmol), and (4-bromo-3-methylaniline (2.04 g, 11 mmol) (Aldrich Chemical Company) in diethyl ether/THF (8 mL) was stirred for 3 days under nitrogen. The reaction was filtered, the filtrate evaporated, and the residue flash chromatographed on silica gel using 9/1 Hexane/acetone to give (4-bromo-3-methylphenyl)cyanamide (0.289 g, 13%). HRMS: calcd for 2 C8H7BrN2+H+, 420.96579; found (ESI-FT/MS, [2M+H]+), 420.966.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.Cl>O1CCCC1>[F:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(F)n1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 163.2 %

Procedure:
To a solution of 6-fluoro-2-pyridinecarboxylic acid (15.0 g, 106.3 mmol) in tetrahydrofuran (200 ml) was added 1,1′-carbonylbis-1H-imidazole (19.0 g, 116.9 mmol), and the mixture was heated under reflux for 30 min. The reaction solution was cooled and monoethyl malonate magnesium salt (16.8 g, 58.5 mmol) was added. The mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid (200 ml) was added to the reaction solution and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(6-fluoro-2-pyridyl)-3-oxopropionate (20.16 g, 90%) as a brown oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[Cl-].[NH4+]>[Fe].O>[CH2:1]([NH:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccccc1)N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(S(=O)(=O)N2CCN(C(=O)NCc3ccccc3)CC2)cc1
Temperature: 80 °C
Yield: 104.6 %

Procedure:
4-(4-Nitro-benzenesulfonyl)-piperazine-1-carboxylic acid benzylamide (0.5 g, 1.2 mmol) was suspended in a 5:1 mixture of ethanol and water (30 ml). To this solution was added iron powder (0.18 g, 3.1 mmol) followed by saturated ammonium chloride solution (1 ml) and the mixture was heated to 80° C. for three hours. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of celite, the celite was washed with ethanol (10 ml) and ethyl acetate (50 ml) and the solution was concentrated under vacuum. The resulting residue was partitioned between DCM (50 ml) and water (20 ml), the organic layer was separated, dried with MgSO4, filtered and concentrated to afford the title compound (0.47 g, 100% yield) as a colourless oil. Tr=1.60 min, m/z (ES+) (M+H)+ 375.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[NH:4][N:3]=1.[C:14]1([CH2:20][C:21](O)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:4][N:3]=[C:2]([NH:1][C:21](=[O:22])[CH2:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nc1cc(-c2ccc(Cl)cc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)Nc1cc(-c2ccc(Cl)cc2)[nH]n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
3-Amino-5-(4-chlorophenyl)pyrazole (96.8 mg) and phenylacetic acid (74.9 mg) were dissolved in pyridine (2.5 ml) to which was subsequently added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (143.8 mg), and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate (30 ml), washed with 1 N aqueous potassium hydrogensulfate solution (15 ml×2) and saturated brine (15 ml) and then dried over anhydrous magnesium sulfate. The solvent was distilled away under a reduced pressure, and the resulting residue was crystallized from ethyl acetate and hexane to obtain the title compound (107.8 mg) as white crystals (melting point: 222-224° C.).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:13]=1[Cl:12])=[O:9]
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1ccc(C(F)(F)F)cc1Cl)c1cc(Br)ccc1O
Yield: 34.9 %

Procedure:
Using 5-bromosalicylic acid and 2-chloro-4-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 1(1) gave the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:13]=[CH:12]2.[CH2:25]([O:27][Si:28]([O:38][CH2:39][CH3:40])([O:35][CH2:36][CH3:37])[CH2:29][CH2:30][CH2:31][N:32]=[C:33]=[O:34])[CH3:26].C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>C(Cl)Cl>[CH2:36]([O:35][Si:28]([O:38][CH2:39][CH3:40])([O:27][CH2:25][CH3:26])[CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:13]=[CH:12]2)=[O:34])[CH3:37]
Reactant: COC(=O)/C=C/c1ccc2cc(OCCCCCCO)ccc2c1
Reactant: CCO[Si](CCCN=C=O)(OCC)OCC
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClCCl
Product: CCO[Si](CCCNC(=O)OCCCCCCOc1ccc2cc(/C=C/C(=O)OC)ccc2c1)(OCC)OCC
Temperature: 25 °C

Procedure:
A mixture of 500 mg of methyl (E)-3-[6-(6-hydroxyhexyloxy)naphthalen-2-yl]acrylate, 25 ml of methylene chloride, 0.376 ml of 3-triethoxysilanylpropyl isocyanate and 0.009 ml of dibutyltin dilaurate was heated under reflux for 3 hrs. Thereafter, a further 0.009 ml of dibutyltin dilaurate was added and the mixture was left to react under reflux for 16 hrs. Then, the reaction solution was cooled to room temperature, evaporated completely and the residue was chromatographed on 150 g of silica gel with ether/hexane. This gave 830 mg of methyl 3-{6-[6-(3-triethoxysilanylpropylcarbamoyloxy)hexyloxy]naphthalen-2-yl}acrylate as a colorless solid, λmax. (CH2Cl2): 326 nm (ε=26200).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].[C:20](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:20])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(CC(=O)O)ccc2c1Cc1cc(O)ccc1-2
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc2c(c1)Cc1c-2ccc(CC(=O)O)c1C

Procedure:
A mixture of 59mg. of methyl 7-hydroxyfluorene-2-acetic acid, 1.3g. of potassium carbonate, and 0.5ml. methyl iodide in 11ml. of acetone is refluxed for 22 hr., filtered and the solid washed with additional acetone. The filtrate is evaporated and the residue plate chromatographed on silica gel employing chloroform-hexane (2:1) as the developing solvent. Elution of the least polar band with ethyl acetate, evaporation and crystallization of the residue from ethyl acetate-isopropyl ether gives 17mg. of the title compound, mp 114-115°. Recrystallization from ethyl acetate-isopropyl ether gives the analytical sample, mp 114.5°-115.5°; λKBr 5.80μ.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>CO>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: BrCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(OCCCCCBr)cc1
Yield: 17.9 %

Procedure:
To a solution of hydroquinone (2.0 g, 18.2 mmol) in MeOH (10 mL), KOH (1.02 g, 18.2 mmol) was added. Then 1,5-dibromopentane (3.1 mL, 22.7 mmol) was added dropwise over 10 min and the mixture was refluxed for 12 hours. The reaction mixture was concentrated, quenched with water (100 mL), and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was washed water, brine, and dried over Na2SO4. The compound was purified by column chromatography to isolate intermediate 13a as a colorless oil (0.94 g, 3.26 mmol, 20% yield). 1H NMR (CDCl3, 400 MHz) δ 6.76-6.84 (m, 4H), 4.50 (s, 1H), 3.93 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.4 Hz, 2H), 1.92-1.96 (m, 2H), 1.77-1.84 (m, 2H), 1.60-1.67 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[C:56]1([CH2:62][C@H:63]([C:65]2[O:66][C:67]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)=[N:68][N:69]=2)[NH2:64])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@@H:35]([CH3:36])[C:37](=[O:38])[NH:64][C@@H:63]([C:65]1[O:66][C:67]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)=[N:68][N:69]=1)[CH2:62][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: N[C@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C

Procedure:
First, N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1R)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide was synthesized by analogy with the synthesis of intermediate 17 by reacting 20 mg (29 μmol) N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (intermediate 7) with 12.2 mg (32 μmol) (1R)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethanamine trifluoroacetic acid salt (intermediate 15).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[S:4][C:5]([CH3:12])=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.[C:15]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH2:30])[CH3:29])=[CH:23][CH:22]=1)([O:17][CH3:18])=[O:16]>>[C:15]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:30][CH2:9][CH:8]([OH:11])[C:6]2[N:7]=[C:3]([C:2]([F:14])([F:13])[F:1])[S:4][C:5]=2[CH3:12])[CH3:29])=[CH:23][CH:22]=1)([O:17][CH3:18])=[O:16]
Reactant: COC(=O)COc1ccc(CC(C)N)cc1
Reactant: Cc1sc(C(F)(F)F)nc1C(=O)CBr
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2nc(C(F)(F)F)sc2C)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-trifluoromethyl-5-methyl-4-bromoacetyl-thiazole with 2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine followed by reduction. The compound is purified on a silica gel column using ethyl acetate/methanol=9/1 as eluant.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH:19]=[C:18]([C:21]2[N:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1.CO>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH:17]=[C:18]([C:21]2[N:26]=[CH:25][C:24]([C:27]([O:29][CH3:1])=[O:28])=[CH:23][N:22]=2)[CH2:19][CH2:20]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ncc(C(=O)O)cn2)CC1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(C2=CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
(Trimethylsilyl)diazomethane, 2M in hexanes (4.19 ml, 8.38 mmol) was added dropwise to 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylic acid (1.28 g, 4.19 mmol) in toluene (12 ml) and methanol (3.00 ml) at 25° C. over a period of 2 mins under nitrogen. The resulting solution was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with the dropwise addition of acetic acid until bubbling ceased, then the reaction mixture was diluted with EtOAc (100 mL) and water (100 mL). The organic layer was removed and the aqueous further extracted with EtOAc (2×50 mL). The combined organics were washed with sodium hydrogen carbonate solution (100 mL), water (100 mL), brine (100 mL) and dried over MgSO4, filtered and evaporated to afford methyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylate (1.182 g, 88%) as a yellow solid. This was used directly with no further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O.S(N(C1C=C(C(O)=O)C(N(S(=O)(=O)N)C2C=CC=CC=2)=CC=1C(O)=O)C1C=CC=CC=1)(=O)(=O)N>[CH:3]1[C:2]([Cl:1])=[CH:28][C:27]2[C:9]([C:8]3[C:7]([NH:6][C:5]=2[CH:4]=1)=[CH:15][C:14]1[C:16]([C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[NH:19][C:13]=1[CH:12]=3)=[O:18])=[O:11]
Reactant: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Agent: NS(=O)(=O)N(c1ccccc1)c1cc(C(=O)O)c(N(c2ccccc2)S(N)(=O)=O)cc1C(=O)O
Agent: O=P(O)(O)O
Solvent: CO
Solvent: O
Product: O=c1c2cc(Cl)ccc2[nH]c2cc3c(=O)c4cc(Cl)ccc4[nH]c3cc12
Temperature: 95 °C
Reaction time: 5 h
Yield: 95.8 %

Procedure:
To 720 g of polyphosphoric acid (116.5%) heated at 90° C. were added 1.2 g of 2,5di(sulfamoylanilino)terephthalic acid followed by 120 g of 2,5-di(4-chloroanilino)terephthalic acid over a period of approximately 45 minutes, the temperature being maintained below 110° C. by adjustment of the addition rate. The reaction mixture was held at 113° C. of five hours and then cooled to 95° C. To this mixture was added 89.4 g of phosphoric acid (75%) dropwise over a period of 20 minutes. The resultant melt was allowed to stir for 15 minutes at 92° C. and then poured slowly into 1240 g of methanol, the temperature being maintained below reflux by adjustment of the addition rate. The slurry was allowed to cool to room temperature and stand for 16 hours. The pigment slurry was heated at reflux for one hour, cooled below 65° C., diluted with water, collected by filtration, and washed with water until free of acid. The resultant wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 105 g of 2,9-dichloroquinacridone as a magenta pigment.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C([O-])(=O)C.[K+].C(N(CC)CC)C.[CH3:20][C@@H:21]([CH2:25][CH2:26][CH:27]=[C:28](C)[CH3:29])[CH2:22]C=O>O>[C:5]([O:4][CH:1]=[CH:2][C@@H:28]([CH3:29])[CH2:27][CH2:26][CH:25]=[C:21]([CH3:22])[CH3:20])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCC[C@H](C)CC=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OC=C[C@@H](C)CCC=C(C)C
Temperature: 120 °C

Procedure:
A 50 mL round-bottom-flask equipped with a condenser was charged with acetic anhydride (6.1 mL, 64.8 mmol), potassium acetate (0.51 g, 5.18 mmol) and triethylamine (4.5 mL, 32.4 mmol). To the stirred mixture was (S)-3,7-dimethyloct-6-enal (5.0 g, 32.4 mmol) slowly. The reaction mixture was heated to 120° C. for 7.5 hours. After cooling to room temperature, the reaction mixture was poured into water (25 mL) and then extracted with toluene (10 mL). The organic layer was washed with saturated aqueous sodium carbonate (25 mL×2) and brine (25 mL). The material was transferred to a 50 ml round-bottom-flask and the separatory funnel was washed with toluene (1 mL). The solution of the title compound in toluene (11 ml) (15.7 g) was used directly for the next step. Mass spectrum (ESI +ve) m/z 187 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:7](=[O:14])[CH:8]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[N:10]=1)[CH2:2][CH2:3][CH3:4].[Br:30]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:30][C:8]1[C:7](=[O:14])[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:10][C:9]=1[CH:11]1[CH2:13][CH2:12]1
Reactant: BrBr
Reactant: CCCCc1nc(C2CC2)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCc1nc(C2CC2)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 4′-[(2-butyl-4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (5.22 g) in acetic acid (60 mL) was added bromine (1.39 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (5.4 g, 80%) as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[S:15][CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=2)[CH:11]=[CH:12][CH:13]=1.[Cl:23][C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C>C(OCC)(=O)C>[Cl:23][C:24]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[S:15][CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=2)[CH:11]=[CH:12][CH:13]=1)=[O:26]
Reactant: COC(=O)c1csc(-c2cccc(OCCCCCO)c2)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(-c2cccc(OCCCCCOC(=O)Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(3-(5-hydroxypentyloxy)phenyl)thiazole-4-carboxylate (26), (32 mg, 0.10 mmol, 1.0 eq.) in ethyl acetate (1 mL) was added triphosgene (14 mg, 0.047 mmol, 1.4 eq) dissolved in a minimum amount of ethyl acetate, followed immediately by DIEA (26 μL, 20 mg, 0.15 mmol, 1.5 eq). The mixture was stirred at room temperature for 30 min, the precipitated DIEA hydrochloride was filtered off, and the filtrate evaporated to dryness in vacuo. The oily residue of crude compound 27 was used directly for the next step.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:17])=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][C:25](OCC)=O)[CH2:20][CH2:19]2)[CH:9]=1.C[Si](C)(C)CCOC[N:46](COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(CC#N)CC2)C=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(CC(OCC)=O)CC2)C=1>>[CH3:38][Si:2]([CH3:39])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:17])=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:19][CH2:20][CH:21]([CH2:24][C:25]#[N:46])[CH2:22][CH2:23]2)[CH:9]=1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(CC#N)CC2)nc2ccnn12
Agent: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(CC#N)CC2)nc2c(I)cnn12

Procedure:
2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetonitrile was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but with 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetonitrile substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](O)=O)[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24]2[O:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]4[N:4]=[CH:3][N:2]([CH3:1])[C:6]=4[CH:7]=3)=[N:13][N:14]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Cn1cnc2ccc(C(=O)NN)cc21
Reactant: O=C(O)CCc1cccc(F)c1
Product: Cn1cnc2ccc(-c3nnc(CCc4cccc(F)c4)o3)cc21
Yield: 66 %

Procedure:
In the same manner as in Example 14 and using 1-methyl-1H-benzimidazole-6-carbohydrazide instead of 1H-benzotriazole-5-carbohydrazide and 3-(3-fluorophenyl)propionic acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 66%) was obtained as colorless crystals.