Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([C:16]2[N:17]=[C:18]([CH3:44])[N:19]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:20](=[O:37])[C:21]=2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[CH2:15][CH2:14]1>C(OCC)(=O)C>[CH:13]1([C:16]2[N:17]=[C:18]([CH3:44])[N:19]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:20](=[O:37])[C:21]=2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:3][C:4](=[O:7])[O:5][N:36]=3)=[CH:25][CH:24]=2)[CH2:15][CH2:14]1
Reactant: Cc1nc(C2CC2)c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n1-c1ccccc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc(C2CC2)c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n1-c1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.62 g), sodium hydrogen carbonate (0.89 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-[(4-cyclopropyl-2-methyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.44 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.19 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.29 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:20]=1.C(N(CC)C(C)C)(C)C.CCCP(=O)=O>CC1CCCO1>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([NH:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:20]=1)=[O:6]
Reactant: O=C(O)c1cc(-c2ccccn2)c(F)cc1Cl
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC1CCCO1
Product: CCOC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(F)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Yield: 299.7 %

Procedure:
To a refluxing mixture of 2-chloro-4-fluoro-5-(pyridin-2-yl)benzoic acid (Preparation 22A, 9.2 g, 36.6 mmol), ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (8.45 g, 36.6 mmol), N,N-diisopropylethylamine (19.2 mL, 110 mmol) and 2-methyltetrahydrofuran (320 mL), was added propylphosphonic anhydride solution (255 mL, 429 mmol, >50% by weight in EtOAc) dropwise under argon, and the reaction maintained at reflux for 5 hours. After cooling to room temperature, the reaction was filtered and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate (350 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (300 mL). The organic layer was filtered under vacuum and the solids washed with EtOAc (20 mL) and TBME (200 mL) to give the title compound (51 g, 78%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C1(N=C=NC2CCCCC2)CCCCC1.[C:23](O)(=[O:35])[CH2:24][C:25]1[CH:34]=[CH:33][C:30]([O:31][CH3:32])=[C:27]([O:28][CH3:29])[CH:26]=1>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:23](=[O:35])[CH2:24][C:25]1[CH:34]=[CH:33][C:30]([O:31][CH3:32])=[C:27]([O:28][CH3:29])[CH:26]=1
Reactant: COC(CN)OC
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(CC(=O)NCC(OC)OC)cc1OC

Procedure:
To a cooled solution of aminoacetaldehyde dimethylacetal (21 g., 0.2 mole) and dicyclohexylcarbodimide (42.5 g., 0.205 mole) in 500 ml. of methylene chloride was added homoveratric acid (39.2 g., 0.2 mole) portionwise with cooling and stirring. After the addition was completed, the reaction mixture was stirred at room temperature for 1/2 hour, kept in refrigerator overnight and filtered. The filtrate was evaporated to dryness to give an oil which was chilled to form the solid N-(2,2-dimethoxyethyl)-3,4-dimethoxyphenylacetamide, m.p. 60°-63° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][N:5]([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:4]1.C(N(CC)CC)C.[S:34](Cl)([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>ClCCl.CN(C)C1C=CN=CC=1>[N:26]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:5]1[CH2:6][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[O:20][CH:3]([CH2:2][O:1][S:34]([C:37]2[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1ncccn1)CC(CO)O2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CN(c3ncccn3)CC3(CCN(C(=O)OC(C)(C)C)CC3)O2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
To a solution of tert-butyl 10-(hydroxymethyl)-8-pyrimidin-2-yl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.45 g, 3.98 mmol) in dichloromethane (15 mL) was added triethylamine (1.66 mL, 11.9 mmol) and 4-(dimethylamino)-pyridine (195 mg, 1.59 mmol) at 0° C. Tosyl chloride (910 mg, 4.78 mmol) was then added in one portion. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with water and the layers were separated. The aqueous layer was extracted with dichloromethane, and the combined organic layers washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Silica gel column chromatography (0-80% ethyl acetate/hexanes) provided tert-butyl 4-(pyrimidin-2-yl)-2-(tosyloxymethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (1.83 g, 3.53 mmol, 89%). ESI-MS m/z calc. 518.2. Found 519.3 (M+1)+; Retention time: 1.83 minutes (3 min run). 1H NMR (400 MHz, MeOD) δ 8.31 (d, J=4.8 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H), 7.45 (d, J=8.2 Hz, 2H), 6.60 (t, J=4.8 Hz, 1H), 4.67-4.48 (m, 2H), 4.12 (d, J=4.6 Hz, 2H), 3.89 (ddd, J=12.0, 7.5, 4.6 Hz, 1H), 3.71-3.56 (m, 2H), 3.05 (ddd, J=20.6, 17.0, 8.8 Hz, 2H), 2.80-2.65 (m, 2H), 2.46 (s, 3H), 1.88 (d, J=14.1 Hz, 1H), 1.50 (dt, J=7.9, 4.0 Hz, 2H), 1.45 (s, 9H), 1.38-1.27 (m, 1H).
Reaction SMILES: [O:1]([CH2:9][CH3:10])[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[N:11]12[CH2:18][CH2:17][N:14]([CH2:15][CH2:16]1)[CH2:13][CH2:12]2>C(#N)C>[O-:4][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1].[CH2:18]([N+:11]12[CH2:10][CH2:9][N:14]([CH2:15][CH2:16]1)[CH2:13][CH2:12]2)[CH3:17]
Reactant: C1CN2CCN1CC2
Reactant: CCOS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CC[N+]12CCN(CC1)CC2
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
Ethyl triflate (3.56 g, 20.0 mmol) was added dropwise to a cold (0° C.) stirred solution of 1,4-diazabicyclo[2,2,2]octane (3.26 g, 29.1 mmol) in dry acetonitrile (25 cm3) under dry nitrogen. The reaction mixture was stirred at 0° C. for 1 hour and then at 20° C. for 3 hours; no precipitate appeared. The solution was rotary evaporated at water-pump pressure, and the white solid residue remaining was washed with cold diethyl ether to remove unreacted 1,4-diazabicyclo-[2,2,2]octane and then dried in vacuo, to give 1-ethyl-4-aza-1-azoniabicyclo[2,2,2]octane triflate (5.30 g, 18.3 mmol, 91.5%) shown by 1H n.m.r. analysis to contain a trace of 1,4-diethyl-1,4-diazoniabicyclo[2,2,2]octane ditriflate. A pure sample of the monoquaternary salt, m.p. 117°-119° C., δH (D2O soln.) 1.32 (tt; N+CH2CH), 3.18 (m; 3×ring CH2), 3.25-3.4 (complex, two overlapping absorption systems; 3×ring CH2 +N+CH2CH3), p.p.m., δF (same soln.; ext. CF3CO2H ref.) 0.03 (s; CF3SO3-) p.p.m., was obtained by recrystallizing the slightly impure product from an ethanol-diethyl ether mixture.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH3:11][C:12]([CH3:14])=O.C(O)(=O)C.N1CCOCC1>CC(OC)(C)C>[CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[C:6](=[C:12]([CH3:14])[CH3:11])[C:4](=[O:5])[O:3]1
Reactant: CC(C)=O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Solvent: C1COCCN1
Product: CC(C)=C1C(=O)OC(C)(C)OC1=O
Reaction time: 0.08 h
Yield: 70.4 %

Procedure:
Meldrum's acid (100.0 g) was charged to a dry, nitrogen flushed reactor. Acetone (632.1 mL) was then charged to the reactor and the mixture was agitated for about 5 minutes at 20° C.-25° C. until a solution was obtained. Acetic acid (0.791 mL) was then charged to the reactor, followed by 1.215 mL of morpholine, and the solution was agitated at 20° C.-25° C. for about 48 hours. An aliquot (˜0.2 mL) was withdrawn for analysis of the conversion, which may be monitored by either GC or 1H-NMR. If the ratio of the area % of 2,2-dimethyl-5-(propan-2-ylidene)-1,3-dioxane-4,6-dione to Meldrum's acid is ≧80:20, proceed to the next step; if it is not, the batch should be aged for an additional 3 hours before repeating the check. The acetone was distilled at about 40° C. and 150-200 mmHg. After approximately two-thirds of the reaction volume was distilled out, 563 mL of methylcyclohexane was charged and the distillation continued until the acetone stopped distilling over. A total of 645 mL (508 g) of distillate was collected for this run. MTBE (500 mL) was charged to the batch at 40° C. and the batch was cooled to 20° C.-25° C. The solution was observed to make sure a cloudy solution was obtained (no solids). If there is solid present, additional MTBE may be charged to effect dissolution. The batch was quickly washed with two 50 g portions of 5 wt. % NaOH solution (prepared from 5 g of NaOH and 95 mL of water). The MTBE was distilled out at 40° C.-45° C. and 150-200 mmHg. A total of 400 mL (300 g) distillate was collected for this run. As distillation proceeds, a white slurry formed. The internal temperature was ramped to 0° C.-5° C. over 1 hour and then held at this temperature for at least 1 hour. The slurry was filtered, the cake was washed with two 100 mL portions of cold (˜0° C.-5° C.) methylcyclohexane, and the solid was dried at 20° C.-35° C. and 25-50 mmHg for no less than 4 hours. 2,2-Dimethyl-5-(propan-2-ylidene)-1,3-dioxane-4,6-dione was obtained as a white solid (93.7 g, 70.4% yield, 96.0 wt. % purity by assay).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.[OH-].[K+]>C(O)COCCO>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: O=C(CCc1ccccc1)c1ccc(Cl)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Clc1ccc(CCCc2ccccc2)cc1

Procedure:
p-chlorophenyl phenylethyl ketone (25 g) was refluxed with hydrazine hydrate (13 g) and potassium hydroxide (18 g) in Digol (diethylene glycol) for one hour. The mixture was then distilled until the solution temperature in the still reached 175°. The mixture was then refluxed for 3 hours, cooled, poured into water and extracted with petroleum ether (Bpt 40°-60°). Evaporation of the extracts gave 1-(4-chlorophenyl)-3-phenylpropane Bbt. 110°/10-3 mm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][CH:11]([C:18]1([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C>C1COCC1.C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]([C:18]2([CH3:23])[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CCOC(=O)CC(N)C1(C)CCCC1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(Nc1nc(Cl)ncc1F)C1(C)CCCC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a solution of 2,4-dichloro-5-fluoro-pyrimidine (0.184 g, 1.100 mmol) and racemic ethyl 3-amino-3-(1-methylcyclopentyl)propanoate, 33a, (0.199 g, 1.000 mmol) in THF (10 mL) and ethanol (1 mL) was added triethylamine (0.307 mL, 2.200 mmol). The reaction mixture was stirred at 70° C. for 5 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified via silica gel chromatography (25% EtOAc/Hexanes) to afford 180 mg of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=2.7 Hz, 1H), 5.54 (d, J=9.2 Hz, 1H), 4.74-4.54 (m, 1H), 4.08 (q, J=7.2 Hz, 2H), 2.68 (dd, J=14.8, 3.7 Hz, 1H), 2.46 (dd, J=14.8, 9.3 Hz, 1H), 1.69 (dd, J=12.8, 8.8 Hz, 4H), 1.63-1.50 (m, 2H), 1.46-1.38 (m, 1H), 1.37-1.23 (m, 1H), 1.23-1.14 (m, 3H), 1.00 (s, 3H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.54 minutes (M+H) 330.17.
Reaction SMILES: [CH3:1][P:2]([C:5]1[N:10]=[C:9]([O:11][CH3:12])[C:8](N)=[CH:7][CH:6]=1)([CH3:4])=[O:3].Cl[C:15]1[N:20]=[C:19]([Cl:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=1>CN(C)C(=O)C.C(N(C(C)C)CC)(C)C>[Cl:21][C:19]1[C:18]([C:22]([F:24])([F:23])[F:25])=[CH:17][N:16]=[C:15]([C:8]2[C:9]([O:11][CH3:12])=[N:10][C:5]([P:2]([CH3:4])([CH3:1])=[O:3])=[CH:6][CH:7]=2)[N:20]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: COc1nc(P(C)(C)=O)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1nc(P(C)(C)=O)ccc1-c1ncc(C(F)(F)F)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in Example 32: 2.2 mmol) in 15 mL of N,N-Dimethylacetamide and 3.6 mL of Diisopropylethylamine, is allowed to stirred at room temperature for 15 minutes until a clear solution is obtained. 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (5.7 g, 2.6 mmol) is added in four portions over 5 minutes. The reaction mixture is stirred at 60 degrees for 1 hour. The reaction mixture is cooled to room temperature and filtered to obtain a white solid. The white solid is washed with 50 mL of water three times and followed by 50 mL of Ethyl ether three times. The white solid is dried under vacuum to yield 4-chloro-2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-(trifluoromethyl)pyrimidine.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][OH:5].C(N(CC)CC)C.[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[CH:20]=[CH:21][C:22](O)=[O:23].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[CH:20]=[CH:21][C:22]([NH:2][C@H:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][OH:5])=[O:23]
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(=O)C=Cc1ccccc1F
Yield: 97.8 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-serinate hydrochloride (2.5 g), triethylamine (2.4 mL), 2-fluorocinnamic acid (2.8 g), WSC.HCl (3.2 g), and methylene chloride (100 mL), to give the captioned compound (4.2 g, 98%) as an oily product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)[CH:13]=[C:12](I)[CH:11]=1)[CH3:7].[F:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:8][C:9]([C:10]1[CH:11]=[C:12]([C:25]2[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=2[F:23])[CH:13]=[C:14]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)[CH:15]=1)=[O:22])[CH3:7]
Reactant: Cc1ccc(B(O)O)c(F)c1
Reactant: CC(NC(=O)c1cc(I)cc(-n2cnnn2)c1)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C(=O)NC(C)c3ccco3)cc(-n3cnnn3)c2)c(F)c1
Temperature: 130 °C
Yield: 99.7 %

Procedure:
A mixture of N-(1-Furan-2-yl-ethyl)-3-iodo-5-tetrazol-1-yl-benzamide (60 mg, 0.146 mmol), 2-fluoro-4-methyl-phenylboronic acid (27.1 mg, 0.176 mmol), Cs2CO3 (0.35 mL, 0.5 N, 0.176 mmol) and Pd(Ph3P)4 (8.5 mg, 0.00735 mmol) in toluene (1.5 mL) and THF (1.5 mL) was stirred under microwave heating for 30 minutes at 130° C. After reaction mixture was cooled down, the solvent was removed under vacuum and the residue was purified by column chromatography (hexane/EtOAc=1:2) to afford 2′-Fluoro-4′-methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid (1-furan-2-yl-ethyl)-amide as a white solid (57 mg, 98%). MS (M+H)=392.
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([F:12])[C:7](Br)=[C:6]([CH3:14])[C:3]=1[C:4]#[N:5].[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([F:12])[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([CH3:14])[C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1ccccc1
Reactant: COc1c(N)c(C#N)c(C)c(Br)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(N)c(C#N)c(C)c(-c2ccccc2)c1F
Temperature: 110 °C
Reaction time: 15 h

Procedure:
Under nitrogen atmosphere, 2-amino-5-bromo-4-fluoro-3-methoxy-6-methylbenzonitrile (I-45) (20.0 g, 77.20 mmol), phenylboronic acid (11.3 g, 92.64 mmol), potassium phosphate (34.4 g, 162.11 mmol) were dissolved in a mixed liquid of 1,4-dioxane (400 ml) and water (20 ml), tetrakis(triphenylphosphine)palladium (2.6 g, 2.32 mmol) was added, followed by stirring at 110° C. for 15 hours. After cooling, the insoluble matter was separated by filtration through Celite, the reaction solvent was evaporated away under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water and saturated brine, the organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, eluted wrath a mixed solvent of n-hexane/ethyl acetate (3:1, v/v) to obtain the entitled compound (20.12 g, quant) as a yellow white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH:12]([CH2:14][C:15]([OH:17])=[O:16])[CH3:13].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:12]([CH2:14][C:15]([OH:17])=[O:16])[CH3:13])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CNCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN(CC(=O)O)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitro-benzene (9 g, 40 mmol), sarcosine (3.6g, 40 mmol), and potassium carbonate (5.5 g, 40 mmol) in ethanol (100 ml) and water (40 ml) was heated to reflux for 5 hours. After cooling to room temperature, the mixture was diluted with water and was adjusted to pH 6 with 1N aqueous HCl solution. The yellow precipitate was collected, washed with water and dried in vacuo to obtain crude [(5-bromo-2-nitro-phenyl)-methyl-amino]-acetic acid (10 g, 87%). A portion of the crude sample was recrystallized from EtOAc/hexane to afford the pure [(5-bromo-2-nitro-phenyl)-methyl-amino]-acetic acid: mp 152-155° C.; 1H-NMR (DMSO-d6) δ 2.81 (s, 3H), 4.00 (s, 2H), 7.06 (dd, 1H, J=8.79, 1.98 Hz), 7.22 (d, 1H, J=1.98 Hz), 7.69 (d, 1H, J=8.79 Hz), 12.8 (s, 1H); MS (+APCI) m/z 289/291 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][CH2:12][CH:13]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[O:2].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.BrC1C=C2C(=C(C(OC)=O)C=1)NC=C2.C([SiH](CC)CC)C>ClCCl>[OH:2][CH2:1][CH:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][CH2:12][CH:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]2[C:25]1=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:10]
Reactant: O=CC1COCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC[SiH](CC)CC
Agent: COC(=O)c1cc(Br)cc2cc[nH]c12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCOCC1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 9H-fluoren-9-ylmethyl 3-formyl-4-morpholinecarboxylate (610 mg, 1.808 mmol) in dichloromethane (DCM) (6 mL) cooled in an ice-water bath, was added trimethylsilyl trifluoromethanesulphonate (0.470 mL, 2.60 mmol). To the solution was added dropwise a solution of methyl 5-bromo-1H-indole-7-carboxylate (333 mg, 1.311 mmol) in DCM (18 mL). The resulting orange solution was stirred at 0° C. for 1 hour, under nitrogen. To the dark orange solution was added triethylsilane (1 mL, 6.26 mmol) and the mixture stirred between 5-10° C. for 1.5 hours. The solution was allowed to warm to ambient temperature over 6 hours, then stored overnight at 5° C. The reaction was quenched with saturated aqueous sodium hydrogen carbonate (75 mL) and DCM (50 mL). The phases were separated and the aqueous phase washed with DCM (2×40 mL). The combined organic extracts were concentrated in vacuo to leave a yellow foam. The residue was loaded in dichloromethane and purified on silica (Si) using 0-100% ethyl acetate-cyclohexane over 40 minutes. The appropriate fractions were combined and evaporated in vacuo to give the product, 142 mg, as a yellow gum. LCMS [LCMS4] Rt 2.61 min, m/z (ES+) 340 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:5](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH:14]([CH3:16])[CH3:15])=[C:10]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:9]2=[O:24])(=O)[CH3:2].C([O-])(=O)C.[NH4+:42].S([O-])([O-])(=O)=O.[Mg+2].O.[NH2:50]N>C1(C)C=CC=CC=1.O.C(O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:10]2[C:9](=[O:24])[C:8]3[C:13]([O:12][C:11]=2[CH:14]([CH3:15])[CH3:16])=[C:4]2[C:5](=[CH:6][CH:7]=3)[NH:50][N:42]=[C:1]2[CH3:2])=[CH:18][CH:19]=1
Reactant: [NH4+]
Reactant: NN
Reactant: CC(=O)c1c(OS(=O)(=O)c2c(C)cc(C)cc2C)ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc12
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1n[nH]c2ccc3c(=O)c(-c4ccc(Cl)cc4)c(C(C)C)oc3c12
Temperature: 140 °C

Procedure:
2,4,6-Trimethylbenzenesulfonic acid 8-acetyl-3-(4-chlorophenyl)-2-isopropyl-4oxo-4H-chromen-7-yl ester (470 mg, 0.87 mmol), ammonium acetate (339 mg, 4.4 mmol) and magnesium sulfate (530 mg, 4.4 mmol) are dissolved/suspended in toluene (7 ml) and ethanol (7 ml) in a 20 ml capacity microwave tube. Hydrazine hydrate (0.136 ml, 4.4 mmol) is added, the tube is sealed, and the mixture is heated at 140° C. under microwave irradiation for 2 h. The reaction mixture is then poured into water (20 ml) and extracted with ethyl acetate (3×20 ml). The ethyl acetate extracts are combined, washed with saturated brine (50 ml), dried (MgSO4), filtered and evaporated to give a light brown solid. This is absorbed onto silica gel and purified by chromatography on silica gel using n-hexane/ethyl acetate (0-50% ethyl acetate) as eluant to give the product as a colourless solid.