Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH:3]=1.[NH2:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.O1CCOCC1>[CH:20]1([CH2:19][O:18][C:4]2[CH:3]=[C:2]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH3:10])[CH:5]=2)[CH2:22][CH2:21]1
Reactant: Nc1cnccn1
Reactant: C[C@H](Nc1cc(OCC2CC2)cc(Cl)n1)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(OCC2CC2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
112 mg of (S)-6-chloro-4-(cyclopropylmethoxy)-N-[1-(4-fluorophenyl)ethyl]pyridine-2-amine, 43 mg of 2-aminopyrazine, 67 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 51 mg of sodium t-butoxide and 36 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 2 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 1.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 103 mg of the objective compound as brown powder.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:3]=1.[NH:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[H-].[Na+].O>CS(C)=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[N:3]=[C:2]([N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)[S:6][N:5]=2)=[CH:8][CH:9]=1
Reactant: c1cc[nH]c1
Reactant: Clc1ccc(-c2nsc(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Clc1ccc(-c2nsc(-n3cccc3)n2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 44.7 %

Procedure:
The 5-chloro-1,2,4-thiadiazole compound (102 mg, 0.445 mmol) was dissolved in DMSO (2 mL) and pyrrol (300 mg, 2.22 mmol) added at room temperature. The mixture was heated for 18 h to 55° C. ext. temperature, however no conversion was found (sample tested by 1H-NMR). Sodium hydride (55% wetted with mineral oil, 20 mg, 0.467 mmol) was added and the mixture heated to 80° C. ext. temperature for 5 h. As the conversion was not complete (sample tested by 1H-NMR) the mixture was heated to 100° C. ext. temperature for 6 h. The reaction mixture was poured into water (10 mL) and crude product isolated by filtration. The purification by column chromatography (SiO2, 0-10% ethyl acetate inheptanes) afforded 3-(4-chlorophenyl)-5-(1H-pyrrol-1-yl)-1,2,4-thiadiazole (52 mg, 0.199 mmol, 45%), which was 98% pure (HPLC 254 nm). 1H-NMR spectra is in accordance with the chemical structure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:16]=1[CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:16]=1[CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1cccc(C)c1Cc1cccc(CO)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCc2cccc(Cc3c(C)cccc3C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a solution of methyl 3-(4-hydroxyphenyl)propanoate (180 mg), 3-(2,6-dimethylbenzyl)benzyl alcohol (226 mg) and triphenylphosphine (286 mg) in toluene (2 mL) was added dropwise diethyl azodicarboxylate (40% toluene solution 500 mg) at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was purified by silica gel column chromatography with ethyl acetate-hexane (gradient of 1:9 to 3:2 by volume ratio) to give the title compound (125 mg, yield 32%) as a pale-yellow oil.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Si:19]([O:26][CH2:27][CH:28]([CH2:33][N:34]1[C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=2)=[C:41]2[C:36]([N:37]([CH3:53])[C:38](=[O:52])[N:39]([CH3:51])[C:40]2=[O:50])=[CH:35]1)[CH2:29][C:30](O)=[O:31])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C.Cl.[CH3:64][NH:65][O:66][CH3:67]>CN(C=O)C.C(OCC)(=O)C>[Si:19]([O:26][CH2:27][CH:28]([CH2:33][N:34]1[C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=2)=[C:41]2[C:36]([N:37]([CH3:53])[C:38](=[O:52])[N:39]([CH3:51])[C:40]2=[O:50])=[CH:35]1)[CH2:29][C:30]([N:65]([O:66][CH3:67])[CH3:64])=[O:31])([C:22]([CH3:24])([CH3:25])[CH3:23])([CH3:20])[CH3:21]
Reactant: CNOC
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC(CO[Si](C)(C)C(C)(C)C)CC(=O)O)cc2n(C)c1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)CC(CO[Si](C)(C)C(C)(C)C)Cn1cc2c(c1-c1cccc(F)c1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
T3P® (2.62 mL, 4.5 mmol) was added to a suspension of 4-((tert-butyldimethylsilyl)oxy)-3-((5-(3-fluorophenyl)-1,3-dimethyl-2,4-dioxo-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)methyl)butanoic acid (1.13 g, 2.2 mmol), DIPEA (2.16 mL, 12.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (263 mg, 2.7 mmol) in DMF (8 mL) at 0° C. The mixture was stirred at room temperature for 30 minutes. The reaction was diluted with ethyl acetate (40 mL) and was washed with water (1×20 mL), 1M HCl(aq) (1×20 mL) and saturated NaHCO3(aq) (1×20 mL). The organic phase was dried over magnesium sulfate and the solvent was removed under vacuum. Purification by chromatography on silica, eluting with 0-3% MeOH/DCM, afforded the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=[CH:3]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Al]>C1C=CC=CC=1.C(OCC)(=O)C.C(=O)([O-])[O-].[Ag+2]>[CH2:12]([O:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(=O)[nH]c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: [Al]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)nc1
Reaction time: 85 h

Procedure:
To a solution of methyl 6-oxo-1,6-dihydropyridine-3-carboxylate (2.00 g, 13.1 mmol) in 45 mL of benzene was added benzyl bromide (1.86 mL, 15.7 mmol) and silver carbonate (3.96 g, 14.4 mmol). The flask was covered with aluminum foil, and after 85 hr, the mixture was diluted with ethyl acetate, filtered through celite, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes to provide methyl 6-(benzyloxy)pyridine-3-carboxylate.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:22])[CH2:7][NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].[N:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1>>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[S:9]([NH:8][CH2:7][C:6]([NH:5][CH2:4][CH2:3][NH:2][C:23]([N:44]1[CH2:43][CH2:42][N:41]([C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)[CH2:46][CH2:45]1)=[O:24])=[O:22])(=[O:11])=[O:10]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCNC(=O)CNS(=O)(=O)c1ccc2ccccc2c1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: Cl
Product: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NCCNC(=O)N1CCN(c2ccncc2)CC1
Yield: 10 %

Procedure:
Using an analogous procedure to that described in Example 3, N-(2-aminoethyl)-2-(2-naphthalenesulphonamido)acetamide hydrochloride salt, 1,1'-carbonyldiimidazole and 1-(4-pyridyl)piperazine were reacted to give 2-(2-naphthalenesulphonamido)-N-{2-[4-(4-pyridyl)piperazin-1-ylcarbonylamino]ethyl}acetamide in 10% yield;
Reaction SMILES: O=S(Cl)Cl.[CH2:5]([O:12][CH2:13][C@@:14]12[CH2:26][CH2:25][CH2:24][N:15]1[C@@H](C(Cl)(Cl)Cl)[O:17][C:18]2=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OC[C@@]1(C(OC)=O)CCCN1)C1C=CC=CC=1.[Li+].[BH4-]>CO.CCOCC>[CH2:5]([O:12][CH2:13][C@@:14]1([CH2:18][OH:17])[CH2:26][CH2:25][CH2:24][NH:15]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12COCc1ccccc1
Agent: COC(=O)[C@]1(COCc2ccccc2)CCCN1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: OC[C@]1(COCc2ccccc2)CCCN1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
SOCl2 (2.5 eq) was added at 0° C. to a 0.2M solution of (3R,7aR)-7a-[(benzyloxy)methyl]-3-(trichloromethyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-1-one in dry MeOH, and the mixture was stirred at RT for 20 min, then at reflux for 4 h. After removal of volatiles the residue was taken in EtOAc and washed with sat NaHCO3, water and brine, dried and concentrated. A 0.2M solution in dry Et2O of crude methyl 2-[(benzyloxy)methyl]-L-prolinate was added at 0° C. to a stirred mixture of LiBH4 (1.6 eq.) and MeOH (1.6 eq.) in dry Et2O (0.3M); the mixture was stirred for 2 h at RT, then quenched with water, diluted with EtOAc, washed with water and brine, dried and concentrated to afford {(2S)-2-[(benzyloxy)methyl]pyrrolidin-2-yl}methanol that was used as such. The material was dissolved in dry DCM (0.2M) and treated with carbonyl diimidazol (2.5 eq.) at RT overnight; after dilution with DCM the mixture was washed with 1N HCl, sat NaHCO3 and brine, dried over Na2SO4 and concentrated. Flash chromatography (PE:EtOAc 2:1) afforded the title compound in 43% overall yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([OH:13])=[CH:7][C:6]([CH3:14])=[CH:5]2.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[O:17]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([OH:13])=[C:7]([CH:16]([OH:17])[C:15]([O:19][CH2:20][CH3:21])=[O:18])[C:6]([CH3:14])=[CH:5]2
Reactant: CCOC(=O)C=O
Reactant: Cc1cc(O)c2cc(F)c(Cl)cc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(O)c1c(C)cc2cc(Cl)c(F)cc2c1O
Reaction time: 0.75 h
Yield: 58.7 %

Procedure:
To a mixture of 6-chloro-7-fluoro-3-methylnaphthalen-1-ol (2.24 g, 13.78 mmol) in anhydrous dichloromethane (100 mL) at −40° C. was added a 1 M titanium(IV) chloride solution in dichloromethane (13.78 mL, 13.78 mmol) and stirred for 45 min. Ethyl glyoxylate (1.69 g, 16.54 mmol) dissolved in dichloromethane (5 mL) was added over 15 minutes and stirred for 1 hour at −40° C. The reaction was quenched by the addition of Rochelle's salt solution and stirred at room temperature for 2.5 hours. The resulting mixture was washed with water and aqueous layer back-extracted with dichloromethane (2×). The combined organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 5 to 30% ethyl acetate/hexanes) to give an off-white solid (2.53 g). 1H-NMR: 400 MHz, (CDCl3) δ: 8.48 (s, 1H), 7.89 (d, J=10.5 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.11 (s, 1H), 5.67 (s, 1H), 4.30 (dq, J=10.8, 7.1 Hz, 1H), 4.15 (dq, J=10.8, 7.1 Hz, 1H), 3.61 (s, 1H), 2.52 (s, 3H), 1.20 (t, J=7.1 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C15H13ClFO4: 311.7; found: 311.0.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[N:25]([C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:24][CH2:23]2
Reactant: CC[C@H](COC)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Br)c2c(c1)CCN2
Agent: Cl
Product: CC[C@H](COC)n1cc(Cl)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 102–104° C.; 1H NMR (300 MHz, CDCl3): δ 7.00 (s, 1 H), 6.92 (d, J=2.5 Hz, 1 H), 6.78 (d, J=2.2 Hz, 1 H), 4.99–4.90 (m, 1 H), 4.35 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.67 (dd, J=10.6, 5.5 Hz, 1 H), 3.56 (dd, J=10.6, 3.7 Hz, 1 H), 3.35 (s, 3 H), 3.10 (t, J=7.9 Hz, 2 H), 1.92–1.72 (m, 2 H), 0.93 (t, J=7.3 Hz, 3 H); HRMS (CI) calcd for C18H22N3O3BrCl (M+H)+: 442.0533; found m/z 442.0532.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5].[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[CH2:22]([N:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:9][C:8]3[CH:18]=[CH:19][CH:20]=[N:21][C:7]2=3)=[O:5])[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CC(C)O
Product: O=C1Nc2cccnc2N(C(=O)CCN2CCN(Cc3ccccc3)CC2)c2ccccc21
Yield: 78 %

Procedure:
A mixture of 8.0 g of 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one and 30 ml of 1-benzyl-piperazine in 100 ml of isopropanol was refluxed for 1 hour. Then, the mixture was evaporated in vacuo to dryness and the residue was treated with sodium hydroxide solution. The base was extracted therefrom with chloroform and the chloroform extract was distilled to dryness. The residue was crystallized from xylene to obtain a 78% yield of 11-[3-(4-benzyl-1-piperazinyl)-propionyl]-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one with a melting point of 205°-207° C. The dihydro chloride salt of the acid base melted at 212°-214° C. after crystallization from methanol.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[Mg].[Si:7](Cl)([CH3:10])([CH3:9])[CH3:8].[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>C1COCC1>[CH3:5][C:3](=[CH2:4])[CH:2]([C:12]1([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:1][Si:7]([CH3:10])([CH3:9])[CH3:8].[CH3:5][C:3]([C:12]1([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH2:4][Si:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:1]
Reactant: C=CC(=C)C
Reactant: O=C1CCCCC1
Reactant: C[Si](C)(C)Cl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=C(C)C(C[Si](C)(C)C)C1(O)CCCCC1
Product: C=CC(C)(C[Si](C)(C)C)C1(O)CCCCC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a typical regioselective reaction of an unsymmetrical (2-butene-1,4-diyl)magnesium complex, a THF solution of the complex (20 mL) prepared from isoprene (0.281 g, 2.06 mmol, technical grade) and activated magnesium (3.44 mmol) was cooled to -78° C. Me3SiCl (0.171 g, 1.57 mmol) was added via a disposable syringe. The reaction mixture was stirred at -78° C. for 1 hour, and then it was gradually warmed to 0° C. Excess cyclohexanone (0.278 g, 2.83 mmol) was added at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 hour. An aqueous solution of HCl (1.5N, 10 mL) was added at 0° C. The mixture was washed with diethyl ether (20 mL), and the aqueous layer was extracted with diethyl ether (2×20 mL). The combined organic phases were washed with a saturated aqueous solution of NaHCO3 (2×15 mL) and brine (20 mL) and dried over MgSO4. Removal of solvents and flash column chromatography (eluted by hexanes/Et2O, 98:2) gave 1-(2-methyl-1-trimethylsilylmethyl-2-propenyl)cyclohexanol as the major isomer (0.372 g, 77%) and 1-( 1-methyl-1-trimethylsilylmethyl-2-propenyl)cyclohexanol as the minor isomer (0.025 g, 5%) the major isomer was eluted out before the minor isomer in 82% total yield.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]([Mg]Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.Cl>CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1Br
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: OC(Cc1ccccc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
A solution of 2-bromobenzaldehyde (18.50 g) in dry ether (20 ml ) was added dropwise to a stirred solution of benzylmagnesium chloride [prepared from benzyl chloride (12.64 g) and magnesium (2.68 g)] in dry ether (120 ml), a thick precipitate forming during the addition. The mixture was stirred for 1 hour at room temperature then poured into water, acidified with 2M hydrochloric acid, and extracted with ether. The extracts were washed with water, dried, concentrated and chromatographed using dichloromethane and petrol (1:1) as eluant to give 1-(2-bromophenyl)-2-phenylethan-1-ol (10.95 g, 40%) as a white solid, melting point 84°-85° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][CH:9]([F:21])[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].[CH2:22]([O:24][C:25](=[NH:29])[O:26][CH2:27][CH3:28])[CH3:23]>CC(C)=O>[CH2:22]([O:24][C:25](=[N:29][S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH:9]([F:21])[F:8])(=[O:19])=[O:18])[O:26][CH2:27][CH3:28])[CH3:23]
Reactant: CCOC(=N)OCC
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)F
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCOC(=NS(=O)(=O)c1ccccc1OC(F)F)OCC
Temperature: 25 °C

Procedure:
11.1 g (0.11 mol) of triethylamine are added dropwise at room temperature, with stirring, to a solution of 24.3 g (0.1 mol) of 2-difluoromethoxy-benzenesulfonyl chloride and 11.7 g (0.1 mol) of imidocarbonic acid diethyl ester in 70 ml of acetone. The reaction proceeds slightly exothermically. The reaction mixture is stirred for some hours at room temperature, and the triethylamine hydrochloride is then filtered off. The mother liquor is concentrated by evaporation, and the oil remaining is chromatographed by means of chloroform/ether/petroleum ether (3:3:2) on a silica gel column. After the eluate has been evaporated, there remain 23 g of the above ester, which crystallise (72% of theory), m.p. 80°-81° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[Cl:11][CH2:12][C:13](Cl)=[O:14]>C1(C)C(C)=CC=CC=1>[Cl:11][CH2:12][C:13]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)=[O:14]
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1C
Product: O=C(CCl)Nc1nc(C(Cl)(Cl)Cl)ns1
Temperature: -10 °C
Yield: 72.5 %

Procedure:
A solution of 10.9 grams (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 11.3 grams (0.1 mole) chloroacetyl chloride in 200 milliliters xylene was refluxed at about 140° C. for 20 hours. Upon cooling the reaction mixture to -10° C., 10.7 grams (73% yield) pure product precipitated; m.p. 146.0° C.
Reaction SMILES: [C:1]([O:10][CH:11]([CH3:13])[CH3:12])(=[O:9])[CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[CH:14]([O:23][CH:24]([CH3:26])[CH3:25])([O:19][CH:20]([CH3:22])[CH3:21])OC(C)C.C(OC(=O)C)(=O)C>>[C:3]([O:5][CH:6]([CH3:8])[CH3:7])(=[O:4])[CH2:2][C:1]([O:10][CH:11]([CH3:12])[CH3:13])=[O:9].[CH:11]([O:10][CH:1]=[C:2]([C:14]([O:19][CH:20]([CH3:21])[CH3:22])=[O:23])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4])([CH3:12])[CH3:13].[CH:24]([O:23][CH:14]([O:19][CH:20]([CH3:21])[CH3:22])[CH:2]([C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4])[C:1]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])([CH3:25])[CH3:26]
Reactant: CC(C)OC(OC(C)C)OC(C)C
Agent: CC(C)OC(=O)CC(=O)OC(C)C
Solvent: CC(=O)OC(C)=O
Product: CC(C)OC(=O)C(C(=O)OC(C)C)C(OC(C)C)OC(C)C
Product: CC(C)OC=C(C(=O)OC(C)C)C(=O)OC(C)C
Temperature: -10 °C
Reaction time: 10 h
Yield: 6.5 %
Yield: 80.2 %

Procedure:
188 g (1 mol) of diisopropyl malonate, 571 g (3 mol) of triisopropyl orthoformate and 0.05 g of catalyst from Example 5 were initially introduced into the apparatus mentioned in Example 1 and the mixture was heated to -10° C. 102 g of acetic anhydride were then metered in over the course of 5 hours. The bottom temperature was raised to 150° C. At the same time a low-boiling fraction was removed under reflux at a boiling temperature of 60° C. After 10 hours, the formation of low-boiling component decreased. The mixture was then fractionated in vacuo, first at 15 mbar and then at 0.3 mbar. 7.6% of diisopropyl malonate, 80.2% of diisopropyl isopropoxymethylenemalonate and 6.5% of diisopropyl diisopropoxy-methylmalonate were obtained. The last-mentioned compound was converted into diisopropyl isopropoxymethylenemalonate by heating with 0.2 g of H3PO4.
Reaction SMILES: [OH:1][C:2]1[C:15]([OH:16])=[C:14](O)[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[C:37](=[O:40])([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:19]([O:1][C:2]1[C:15]([O:16][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])=[C:14]([O:40][CH2:37][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: O=C(c1ccccc1)c1ccc(O)c(O)c1O
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)c2ccccc2)c(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
Under an argon atmosphere, 2,3,4-trihydroxybenzophenone (1.61 g, 7.00 mmol), 1-bromooctadecane (7.32 g, 22.0 mmol) and potassium carbonate (4.35 g, 31.5 mmol) were added to dehydrating N,N-dimethylformamide (30 mL), and the mixture was stirred at 80° C. overnight. After completion of the reaction, purified water (200 mL) was added to the reaction mixture, the mixture was stirred for 1 hr, and the precipitated solid was collected by filtration. The obtained solid was slurry-washed in methanol and, after filtration, dried under reduced pressure to give the title compound (6.31 g, 91.1%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30](O)=[O:31])=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.[NH2:33][C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1.C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[OH:40][C:36]1[CH:35]=[C:34]([NH:33][C:30]([C:29]2[C:22]3[C:21]([NH:20][C@H:18]([C:7]4[N:8]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=5)[C:9](=[O:11])[C:10]5=[C:2]([CH3:1])[CH:3]=[CH:4][N:5]5[N:6]=4)[CH3:19])=[N:26][CH:25]=[N:24][C:23]=3[NH:27][CH:28]=2)=[O:31])[CH:39]=[CH:38][CH:37]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)O)c34)n(-c3ccccc3)c(=O)c12
Reactant: Nc1cccc(O)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)Nc5cccc(O)c5)c34)n(-c3ccccc3)c(=O)c12
Reaction time: 0.5 h
Yield: 6.4 %

Procedure:
(S)-4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (25 mg, 0.06 mmol), 3-aminophenol (7 mg, 0.07 mmol) and diisopropylethylamine (41 μl, 0.23 mmol) were dissolved in DMF (1.5 ml) and stirred for 30 min. The reaction flask was then sealed and T3P® (50% in DMF, 140 μl, 0.24 mmol) was added dropwise and the reaction mixture stirred overnight at room temperature. The mixture was poured into ice and extracted with ethyl acetate. The resulting organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography using SP1® Purification System (0% to 5% DCM/MeOH) to give 2 mg (6% yield) of the title compound as a white solid.