Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][CH:4]([CH3:11])[CH2:5][CH2:6][C:7](OC)=[O:8]>CO>[CH3:3][CH:4]([CH3:11])[CH2:5][CH2:6][C:7]([NH:1][NH2:2])=[O:8]
Reactant: NN
Reactant: COC(=O)CCC(C)C
Solvent: CO
Product: CC(C)CCC(=O)NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Under nitrogen, a solution of 53.8 g (1.68 mol) of anhydrous hydrazine in 300 mL of methanol was cooled to 0° C. and treated with 186 g (1.4 mol) of methyl 4-methylvalerate. The reaction was allowed to warm to ambient temperature and stir overnight prior to stirring at reflux for 4 h. The reaction was concentrated in vacuo giving 166 g (93%) of 4-methylvaleric acid hydrazide as a colorless solid: 49°-51° C.; NMR (CDCl3) δ0.89 (d, J=7 Hz, 6H), 1.48-1.64 (m, 3H), 2.15 (t, J=7 Hz, 2H), 3.91 (br s, 2H), 6.94 (br s, 1H). A 7.86 g (60 mmol) sample of the hydrazide was dissolved in 50 mL of methanol and treated with 7.8 g (60 mmol) of ethyl iminovalerate under nitrogen. The reaction was stirred at reflux overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (40:60) gave 9.6 g (82%) of 3-butyl-5-isopentyl-1H-1,2,4-triazole as a colorless solid which melts close to ambient temperature: NMR (CDCl3) δ0.81-0.90 (m, 9H), 1.25-1.40 (m, 2H), 1.47-1.74 (m, 5H), 2.70 (t, J=7 Hz, 4H); MS (FAB) m/e (rel intensity) 196 (100); HRMS. Calcd for M+H: 196.1814. Found: 196.1832.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](C)=[CH:7][CH:8]=[C:9](CBr)[CH:10]=1)=[O:4].[SH:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[CH2:21](N(CC)CC)C>C1(C)C=CC=CC=1>[N:18]1[CH:19]=[CH:20][C:15]([S:14][CH2:21][C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:16][CH:17]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)c1cc(CBr)ccc1C
Reactant: Sc1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CSc2ccncc2)cc1
Temperature: 25 °C

Procedure:
A mixture containing 11.0 grams of methyl-p-(bromomethyl)toluate (0.048 mole), 5.3 grams of 4-mercaptopyridine (0.048 mole), 25 ml of triethylamine and 200 ml of toluene was refluxed for 16 hours and then cooled to room temperature. The reaction mixture was washed twice with 300 ml of water. The toluene layer was dried over anhydrous sodium sulfate and then concentrated to give a dark red oil which solidified upon cooling.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:9])[CH2:7][NH:8][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(S(=O)(=O)NCC(=O)OC(C)(C)C)cc1
Reaction time: 24 h

Procedure:
To a solution of glycine t-butyl ester (5.0 grams, 29.82 mmol) in methylene chloride (50 ml) is added triethylamine (6.65 ml, 62.63 mmol) followed by 4-methoxybenzenesulfonyl chloride (29.82 mmol, 6.2 grams). The solution is stirred for 24 hours, diluted with water and extracted with ethyl acetate. The combined extracts are dried (sodium sulfate), filtered and concentrated. The crude product is purified by silica gel chromatography (elution with 6:1 hexane-ethyl acetate) to provide (4-methoxybenzenesulfonylamino) acetic acid t-butyl ester.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=O)(C)(C)C.O[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[N+:24]([O-:26])=[O:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N+:24]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:14]=1[O:11][CH2:10][C@@H:9]([NH2:8])[CH3:12])[C:18]([O:20][CH3:21])=[O:19])([O-:26])=[O:25]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@H](C)N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
To a stirred solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (0.90 g, 5.13 mmol), methyl 4-hydroxy-3-nitrobenzoate (1.01 g, 5.12 mmol), and Ph3P (1.75 g, 6.67 mmol) in THF (15 mL) was added diisopropyl azodicarboxylate (DIAD) (1.31 mL, 6.65 mmol) at room temp, and the resulting mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH2Cl2 (20 mL) and TFA (10 mL). The mixture was stirred at room temp for 3 hr. The mixture was concentrated in vacuo. The residue was dissolved in CHCl3, washed with sat. NaHCO3, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with 5% MeOH in CHCl3 as eluent to give 313 mg (24%) methyl(S)-3-nitro-4-(2-amino-1-propoxy)benzoate as a pale yellow oil. 1H-NMR (CDCl3) δ 1.22 (d, 3 H, J=6.8 Hz), 3.43–3.48 (m, 1 H), 3.69–3.87 (m, 2 H), 3.89 (s, 3 H), 6.93–6.95 (m, 1 H), 7.99–8.02 (m, 1 H), 8.18–8.21 (m, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].CN(C=O)C.[NH2:16][C:17]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=1[OH:27].C(N(CC)CC)C>O>[C:23]([C:21]1[CH:20]=[CH:19][C:18]([OH:27])=[C:17]([NH:16][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][N:9]=[CH:10][C:2]=2[F:1])[CH:22]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(O)c(N)c1
Reactant: O=C(Cl)c1ccncc1F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(O)c(NC(=O)c2ccncc2F)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.5 g of 3-fluoroisonicotinic acid, 5 ml of thionyl chloride and 50 mg of DMF was heated to reflux for two hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure to give 3-fluoroisonicotinic acid chloride. A mixture of the resultant 3-fluoroisonicotinic acid chloride and 5 ml of DMF was added dropwise to a mixture of 1.76 g of 2-amino-4-tert-butylphenol, 2.18 g of triethylamine and 10 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hours and at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then water was added. Precipitated crystals were collected by filtration. The resultant crystals were dissolved in ethyl acetate, washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give 2.41 g of N-(5-tert-butyl-2-hydroxyphenyl)-3-fluoroisonicotinamide.
Reaction SMILES: C1(C(C)C)C=CC=CC=1.[Na].C(O)(C1C=CC=CC=1)(C)C.[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:29]1([CH2:35][CH2:36][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH3:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO.O>[C:23]1([CH2:22][CH2:21][CH:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:36][C:37]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)([CH3:39])[CH3:38])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(CCc1ccccc1)c1ccccc1
Reactant: C=Cc1ccccc1
Agent: CC(C)(O)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CC(C)c1ccccc1
Solvent: CO
Product: CC(C)(CC(CCc1ccccc1)c1ccccc1)c1ccccc1
Temperature: 135 °C
Reaction time: 2 h

Procedure:
A one-liter glass flask equipped with a stirrer, a dropping funnel with a gas introduction conduit, a reflux with a calcium chloride tube, and a thermometer was charged with 240 grams (2.0 moles) of commercially available cumene saturated with water, 4.0 grams (0.17 mole) of metallic sodium, and 2.7 grams (0.02 mole) of cumyl alcohol while introducing argon gas through the gas introduction conduit, and the resulting mixture was heated to 135° C. A mixture of 69 grams (0.66 mole) of commercially available styrene saturated with water and 60 grams (0.50 mole) of commercially available cumene saturated with water was dropped thereto over 2 hours with stirring while maintaining the temperature of the reaction system at 135°-140° C. After dropwise addition was completed, the reaction mixture was further stirred while heating for 1 hour and then cooled to room temperature. An excess of metallic sodium was decomposed by dropping methanol in small portions while stirring. Introduction of argon gas was stopped, and the contents were transferred to a separating funnel and then washed with water. The aqueous layer was removed, and the remaining oily layer was analyzed by gas chromatography. This gas chromatographic analysis showed that 58.7 grams (0.26 mole) of 1,3-diphenyl-3-methylbutane and 36.9 grams (0.11 mole) of 1,3,5-triphenyl-5-methylhexane were formed. The total yield (per styrene) was 73 mole %.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:33][CH2:32]1.[NH2:43][C:44]1[C:49]([C:50]([F:53])([F:52])[F:51])=[CH:48][C:47]([CH2:54][C@@H:55]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:56](O)=[O:57])=[CH:46][C:45]=1[Cl:67]>C1COCC1>[NH2:43][C:44]1[C:49]([C:50]([F:51])([F:52])[F:53])=[CH:48][C:47]([CH2:54][C@@H:55]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:56]([N:40]2[CH2:41][CH2:42][CH:37]([N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)[CH2:38][CH2:39]2)=[O:57])=[CH:46][C:45]=1[Cl:67]
Reactant: Nc1c(Cl)cc(C[C@@H](OCc2ccccc2)C(=O)O)cc1C(F)(F)F
Reactant: CN1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.35 g (4.20 mmol) TBTU, 0.70 mL (5.0 mmol) triethylamine and 0.75 g (4.01 mmol) 1-methyl-4-piperidin-4-yl-piperazine were added to a solution of 1.5 g (4.01 mmol) (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-benzyloxy-propionic acid in 50 mL THF and the reaction mixture was stirred overnight at RT. The reaction solution was evaporated down i.vac., the residue was combined with 200 mL EtOAc and 200 mL saturated NaHCO3 solution, the organic phase was separated off and extracted with 100 mL of 5% citric acid solution. The citric acid extract was made alkaline with K2CO3 and extracted twice with 100 mL EtOAc in each case. The combined organic phases were evaporated down i.vac. and the residue further reacted without purification.
Reaction SMILES: [F-].[Cs+].[C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][C:10]=1[F:11])#[N:4].Cl[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=1)[C:19]([O:21][CH3:22])=[O:20]>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.COCCOC>[C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][N:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH:8]=[CH:9][C:10]=1[F:11])#[N:4]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1

Procedure:
Cesium fluoride and tetrakis(triphenylphosphine)palladium were added to a 1,2-dimethoxyethane solution of (3-cyano-4-fluorophenyl)boronic acid and methyl 2-chloroisonicotinate, followed by reaction under heating to reflux to obtain methyl 2-(3-cyano-4-fluorophenyl)isonicotinate. F: 257.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:16]#[N:17])[C:7](=[O:15])[NH:8][C:9]=1[CH:10]=[CH:11][N:12](C)C)(=O)[CH3:2].C(O)(=O)C.C(N)=N>CN(C)C=O>[CH3:2][C:1]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:16]#[N:17])[C:7](=[O:15])[NH:8]2
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C=CN(C)C
Agent: N=CN
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1nccc2[nH]c(=O)c(C#N)cc12
Yield: 103.1 %

Procedure:
A mixture containing 33.2 g of 5-acetyl-1,2-dihydro-6-(2-dimethylaminoethenyl)-2-oxo-3-pyridincarbonitrile, 32.1 g of formamidine acetate and 300 ml of dimethylformamide was heated in a oil bath at 120°-130° C. for 3 hours, the original yellow solid dissolving and dark solution resulting. The reaction mixture was evaporated to dryness and then treated with 400 ml of water followed by 30 ml of acetic acid. The resulting insoluble solid was collected, washed with water, air-dried, recrystallized from dimethylformamide and dried at 90° C. to yield 27.4 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile as a compound containing 1/2 mole of dimethylformamide, m.p. 278°-280° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][N:3]=1.[H-].[Na+].[C:14]1(C)C=CC=CC=1.C(OC(=O)C)C.CC1C=CC(C(OC)=O)=CN=1>C(OCC)(=O)C.O.CN(C=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:8])[CH3:14])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(C)nc1
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C)nc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
50 g of methyl 6-methylnicotinate was dissolved in 200 ml of ethyl acetate; 60% NaH 26.5 g, toluene 400 ml and DMF 34 ml were added to a three-necked bottle, 10% methyl 6-methylnicotinate ethyl acetate solution 20 ml was added, heated to 80° C., stirred for 0.5 h. To the reaction bottle, the residual methyl 6-methylnicotinate ethyl acetate solution was added dropwise slowly within about 1.5 h. After addition, the reaction was conducted at 80° C. for 8 h. The reaction stopped, cooled to room temperature. 300 ml of water was added to the reaction bottle, skimmed, the water layer was extracted with ethyl acetate three times, 200 ml per time. All ethyl acetate layers were combined, distillated at a reduced pressure to evaporate ethyl acetate, then 10% H2SO4 aqueous solution 400 ml was added, heated to 110° C., refluxed for 2 h. The reaction was then stopped, cooled to room temperature. Solid K2CO3 was used to adjust PH to 9, suction filtration was performed, the filter cake was washed with ethyl acetate. The filtrate was extracted with ethyl acetate four times, combined and rotary evaporated to dry, to obtain 35 g of 2-methyl-5-acetylpyridine, yield was about 65%.
Reaction SMILES: [OH:1][OH:2].[F:3][C:4]([F:9])([F:8])[C:5]([OH:7])=O>O>[F:3][C:4]([F:9])([F:8])[C:5]([O:1][O:2][C:5](=[O:7])[C:4]([F:9])([F:8])[F:3])=[O:7]
Reactant: OO
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(OOC(=O)C(F)(F)F)C(F)(F)F

Procedure:
It is possible to use a lower concentration of hydrogen peroxide. For example, from a commercially available 30% solution of hydrogen peroxide in water it is possible to produce an 8% (mole) solution of bis(trifluoroacetyl) peroxide (BPFAP) in trifluoroacetic acid. This solution was obtained when 30% H2O2 (1.77 g, 15.6 mmol H2O2) was added dropwise into a well-stirred solution of RfCOOK (6.8 mg, 0.047 mmol) in freshly distilled bis(trifluoroacetyl) anhydride (21 g, 100 mmol) at 0° C. After adding the H2O2, the reaction mixture was stirred for 10 minutes (min) at 0° C. The concentration of BPFAP was measured by 19F NMR spectra.
Reaction SMILES: C([O-:5])(C)(C)C.[K+].[Br-].[C:8]([C:12]1[CH:37]=[CH:36][C:15]([CH2:16][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:14][CH:13]=1)([O:10][CH3:11])=[O:9].[CH3:38][C:39]1([CH3:54])[CH2:48][CH2:47][C:46]([CH3:50])([CH3:49])[C:45]2[CH:44]=[C:43]([C:51](Cl)=[O:52])[CH:42]=[CH:41][C:40]1=2>C1(C)C=CC=CC=1>[C:8]([C:12]1[CH:13]=[CH:14][C:15]([C:16](=[O:5])[C:51]([C:43]2[CH:42]=[CH:41][C:40]3[C:39]([CH3:54])([CH3:38])[CH2:48][CH2:47][C:46]([CH3:50])([CH3:49])[C:45]=3[CH:44]=2)=[O:52])=[CH:36][CH:37]=1)([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Reactant: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 0.17 h
Yield: 12 %

Procedure:
7.9 g (33 mmol) of potassium tert-butanolate were added a little at a time to a suspension of 34.5 g (66 mmol) of 4-carbomethoxybenzyltriphenylphosphonium bromide were added in 200 ml of dry toluene at room temperature. The mixture was stirred for 10 min and then heated to reflux, and 7.5 g (33 mmol) of 5,6,7, 8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carbonyl chloride were added dropwise. After the solution had become colorless again it was allowed to cool and solids were filtered off. The filtrate was concentrated, and the remaining oil was recrystallized from methanol (11.2 g of the ylide intermediate of melting point 101°-203° C.). 3.2 g of the ylide and 3.1 g of sodium periodate were refluxed in a mixture of 40 ml of ethanol and 10 ml of water for 1 h. Saturated brine was added to the cooled reaction mixture, which was then extracted with methylene chloride. The organic phase was dried over magnesium sulfate and concentrated. The residue was triturated in n-heptane, the solids were filtered off, and the filtrate was concentrated. Recrystallization from ethanol yielded 1.5 g of the title compound of melting point 93°-96° C.
Reaction SMILES: [CH:1](=O)[CH3:2].BrCC[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19].[Mg].Cl.CC[O:24][CH2:25][CH3:26]>>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:8]1[CH:7]=[CH:12][C:11]([CH2:1][CH2:2][CH:25]([OH:24])[CH3:26])=[CH:10][CH:9]=1
Reactant: Fc1ccccc1-c1ccccc1CCBr
Reactant: CCOCC
Reactant: CC=O
Agent: Cl
Agent: [Mg]
Product: CC(O)CCc1ccc(-c2ccccc2F)cc1
Temperature: 0 °C

Procedure:
A solution of 5.82 gm (0.132 mol) of acetaldehyde in 10 ml of dry ether was added dropwise to a stirred Grignard reagent prepared under exclusion of air from 47.0 gm (0.168 mol) of 1-bromo-2-(2'-fluoro-biphenylyl)-ethane and 4.0 gm (0.165 mol) of magnesium in 60 ml of anhydrous ether. All of these operations were carried out in an atmosphere of very pure nitrogen. The resulting mixture was heated for 2 hours on a water bath, while stirring, then cooled and hydryolized by addition of 50 gm of crushed ice, and subsequently half-concentrated hydrochloric acid was added until the precipitate which had formed just went into solution again. The ethereal phase was separated, the aqueous phase was extracted twice with ether, and the ethereal extracts were combined with the ethereal phase, washed with water, with an aqueous saturated sodium bicarbonate solution and again with water, dried over sodium sulfate and evaporated. The residue was recrystallized twice from petroleum ether in the presence of activated charcoal, yielding 9.0 gm (28% of theory) of the colorless crystalline compound of the formula ##SPC23##
Reaction SMILES: C([C:3]1([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[S:7][CH:6]([C:8]([O-:10])=O)[N:5]=[C:4]1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])C.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].O>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:3]2[S:7][C:6]([C:8]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:10])=[N:5][C:4]=2[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[CH:20][CH:21]=1
Reactant: Nc1ccccc1
Reactant: CCC1(c2ccc(Cl)cc2)SC(C(=O)[O-])N=C1c1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
5-Ethyl-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate (1.65 gram, 4.0 mmol) is dissolved in anhydrous THF (25 mL) and aniline (0.37 mL, 4.0 mmol) is added. The resulting solution is cooled to 0° C. and sodium hexamethyidisilazide (4.4 mL of a 1M solution in THF) is added. The reaction mixture is stirred for 2 hours. Water is added and the mixture is extracted twice with ethyl acetate. The combined organic layer is washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is crystallised from diisopropyl ether to give 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-N-phenyl-thiazole-2-carboxamide (1.42 g, 77% yield). Melting point: 167-168° C.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][N:17]([C@H:20]4[C@@H:24]5[O:25]C(C)(C)[O:27][C@@H:23]5[C@H:22]([CH2:30][OH:31])[CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[S:39]([NH2:42])(=[O:41])=[O:40]>C(C#N)(C)=O.C(Cl)Cl>[S:39](=[O:41])(=[O:40])([O:31][CH2:30][C@@H:22]1[CH2:21][C@@H:20]([N:17]2[C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][C@@H:1]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:3][CH2:2]4)[C:12]=3[CH:19]=[CH:18]2)[C@H:24]([OH:25])[C@@H:23]1[OH:27])[NH2:42]
Reactant: CC1(C)O[C@@H]2[C@H](CO)C[C@@H](n3ccc4c(N[C@H]5CCc6ccccc65)ncnc43)[C@@H]2O1
Reactant: NS(=O)(=O)Cl
Agent: CC(=O)C#N
Solvent: c1ccncc1
Solvent: ClCCl
Product: NS(=O)(=O)OC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 2 h
Yield: 46 %

Procedure:
To a suspension of ((3aR,4S,6R,6aS)-6-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]-dioxol-4-yl)methanol (45.9 mg, 0.109 mmol) and pyridine (0.0180 mL, 0.222 mmol) in AcCN (1.10 mL) and DCM (0.500 mL) at 0° C. under an atmosphere of nitrogen was added dropwise a 2.00 M solution of chlorosulfonamide in AcCN (0.110 mL, 0.220 mmol, as prepared in 1j). The suspension was stirred for 2 h and more 2.00 M of chlorosulfonamide in AcCN solution (0.150 mL, 3.00 mmol) was added. After 5 min the reaction was quenched with MeOH (1.00 mL) and the solvent was removed in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound as a white solid (23.1 mg, 46%). 1H NMR (400 MHz, CD3OD, δ): 8.36 (s, 1H), 7.62 (d, J=3.1 Hz, 1H), 7.43-7.33 (m, 4H), 7.04 (d, J=3.0 Hz, 1H), 5.67 (br s, 1H), 5.25-5.20 (m, 1H), 4.61 (dd, J=3.8, 9.3 Hz, 1H), 4.48 (dd, J=2.0, 9.9 Hz, 1H), 4.27-4.22 (m, 2H), 3.74 (s, 1H), 3.27-3.20 (m, 1H), 3.13-3.05 (m, 1H), 3.02-2.90 (m, 1H), 2.87-2.77 (m, 1H), 2.35-2.19 (m, 3H) ppm. LC/MS: Rt=0.94 min, ES+ 460. (FA standard).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[C:4]([N:12]([CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)[S:13]([CH3:16])(=[O:15])=[O:14])[N:3]=1.[NH3:25]>CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:25])=[O:9])[CH:5]=[C:4]([N:12]([CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)[S:13]([CH3:16])(=[O:15])=[O:14])[N:3]=1
Reactant: N
Reactant: COC(=O)c1cc(N(CC2COC(C)(C)O2)S(C)(=O)=O)nc(Cl)n1
Solvent: CO
Product: CC1(C)OCC(CN(c2cc(C(N)=O)nc(Cl)n2)S(C)(=O)=O)O1
Yield: 82 %

Procedure:
To a mixture of methyl 2-chloro-6-(N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methylsulfonamido)pyrimidine-4-carboxylate (0.911 g, 2.40 mmol) in MeOH (10 mL) was added 7M ammonia in MeOH (10 mL, 70 mmol). It started as a suspension, then dissolved, and then gave a precipitate. After 3 h the solid was filtered, rinsed once with 5 mL MeOH and air-dried to give the product 2-chloro-6-(N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methylsulfonamido)pyrimidine-4-carboxamide as a white powder (0.715 g, 1.96 mmol, 82% yield). LC/MS: m/z=365.2 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[Ca+2:5].[OH:6][P:7]([OH:10])([OH:9])=[O:8].[O:11]=[P:12]12[O:23]P3(OP(OP(O3)([O:19]1)=O)(=O)[O:13]2)=O>>[P:7]([O-:10])([O-:9])([O-:8])=[O:6].[Ca+2:5].[P:12]([O-:23])([O-:19])([O-:13])=[O:11].[Ca+2:5].[Ca+2:5]
Reactant: O=P(O)(O)O
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=P([O-])([O-])[O-]

Procedure:
CaCO3 and H3PO4 were mixed in such amounts that correspond to 47 mol % (26% by weight) of CaO and 53 mol % (74% by weight) of P2O5, respectively. The mixture was treated in the same manner as in Example 1 to obtain calcium phosphate type crystallizable glass. The glass was subjected to crystallizing treatment at 650° C. for 20 hours. The properties of the crystallized glass having an atomic ratio of Ca/P of 0.44 thereby obtained, are shown in Table 1.