Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-]CC.[Na+].[CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[CH2:17].Cl>C(O)C.O>[N:21]1[CH:22]=[CH:23][C:18]([CH2:16][CH2:17][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:19][CH:20]=1
Reactant: C=Cc1ccncc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccncc1)C(=O)OCC
Yield: 46.4 %

Procedure:
To a solution of diethyl malonate (9.6 g, 0.06mol) in 20 ml of absolute ethanol was added sodium ethoxide (4.1 g) portionwise at room temperature while stirring and the mixture was further stirred for 4 hours followed by dropwise addition of 4-vinylpyridine (2.1 g, 0.02 mol). The mixture was then stirred overnight. Evaporation of ethanol under reduced pressure gave a residue to which was added water followed by neutralization with 3N hydrochloric acid. The mixture was extracted with ethyl acetate. The extracted liquid was treated according to conventional techniques. Evaporation of solvent yielded a residue which was subjected to purification using column chromatography on silica gel to afford diethyl 2-(pyridin-4-yl)ethylmalonate as an oil (2.46 g, 46%).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[CH3:21][O:22][C:23](=[O:35])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=1>C(Cl)(Cl)(Cl)Cl>[C:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([CH:24]([Br:8])[C:23]([O:22][CH3:21])=[O:35])=[CH:26][CH:27]=1)(=[O:34])[CH3:33]
Reactant: COC(=O)Cc1ccc(OC(C)=O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(OC(C)=O)cc1
Yield: 0.1 %

Procedure:
9.5 g of NBS and 0.7 g of AIBN are added to a solution of 10 g of methyl(4-acetoxyphenyl)acetate in 100 mL of carbon tetrachloride in a 500 mL flask equipped with a magnetic stirrer and a condenser. After 16 hours under reflux, the mixture is filtered, the solid is washed with dichloromethane then the filtrate is concentrated. The residue is purified over a silica column with pure dichloromethane to yield 13 mg of expected product (oil, Yd=95%).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[C:5](Cl)(=[O:9])[C:6]([Cl:8])=[O:7].Cl>>[Cl:8][C:6](=[O:7])[C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
The propan-2-ol (38.2 mL, 499 mmol) was added drop wise over 15 min to a cold (0° C.), nitrogen purged solution of oxalyl dichloride (101 g, 799 mmol) and the reaction was stirred at room temperature for 2.5 h. Then a reflux condenser was fitted and a slight vacuum was applied for about 1 h until HCl gas was removed (the HCl was trapped in by a sat'd solution of NaHCO3). The reflux condenser was removed and the flask was fitted with a short path distillation head. Excess reagent was removed by distillation under house vacuum (oil bath heated to 65° C.), and then the temperature was raised to between 85-95° C. and the product was distilled (NOTE: The 1st fraction of ˜5 mL was discarded) to provide isopropyl 2-chloro-2-oxoacetate 52.62 g (70%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=N[CH:7]=1.[C:10](=O)([O-])[O-].[Cs+].[Cs+].[F:16][C:17]1[CH:39]=[CH:38][CH:37]=[CH:36][C:18]=1[O:19][C:20]1[C:34]([OH:35])=[CH:33][C:23]2[NH:24][C:25]([C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)=[N:26][C:22]=2[CH:21]=1>CN1CCCC1=O>[F:16][C:17]1[CH:39]=[CH:38][CH:37]=[CH:36][C:18]=1[O:19][C:20]1[C:34]([O:35][C:2]2[CH:7]=[CH:10][C:5]([C:8]#[N:9])=[N:4][CH:3]=2)=[CH:33][C:23]2[NH:24][C:25]([C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)=[N:26][C:22]=2[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ncc(Br)cn1
Reactant: Oc1cc2[nH]c(-c3cnccn3)nc2cc1Oc1ccccc1F
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccccc2F)cn1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
7.0 mg of 5-bromo-2-cyano-pyrimidine and 15 mg of cesium carbonate were added to an N-methylpyrrolidinone (0.5 ml) solution of 7.0 mg of 5-(2-fluorophenoxy)-6-hydroxy-2-pyrazin-2-yl-1H-benzimidazole obtained in the step 1, and the reaction liquid was stirred at 90° C. for 15 minutes. The reaction mixture was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound a colorless solid.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]C(O)=O)=[CH:9][CH:8]=1.O[CH2:18][CH:19]([CH2:21][OH:22])O.II>>[N:6]1[C:7]2[C:12](=[CH:18][C:19]([C:21]([OH:22])=[O:2])=[CH:9][CH:8]=2)[CH:11]=[CH:10][CH:13]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=S(=O)(O)O
Reactant: OCC(O)CO
Agent: II
Product: O=C(O)c1ccc2ncccc2c1
Temperature: 140 °C

Procedure:
Sulphuric acid (67.5 ml) was added to 4-Aminophenylacetic acid (45 g, 297 mmol), glycerol (61.7 g, 67 mmol), and iodine (1.14 g, 4 mmol) drop-wise at rt. The mixture was heated to 140° C. for 5 h. After that reaction mixture quenched with ice and solid that formed was filtered Solid was dissolved in MeOH and charcoal was added to it and refluxed for 1 h. This mixture was filtered through celite and methanol was removed to obtain the title compound (7 g) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][CH:12]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][C:12]=2[CH:20]([CH3:21])[C:19]([O:23][CH3:24])=[O:22])=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2)co1
Reactant: C=CC(=O)OC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: COC(=O)C(C)c1oc(=O)[nH]c1-c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-oxo-4-oxazoline (794.3 g) in acetonitrile (2383 mL) was added dropwise conc. sulfuric acid (1195 g) under ice-cooling at not higher than 10° C. Then methyl acrylate (731 mL) was added at not higher than 10° C., and the mixture was taken out from an ice-bath and stirred at room temperature for 3 h. Water (7.94 L) was added under ice-cooling at not higher than 20° C. The precipitated crystals were collected by filtration and washed successively with 1% aqueous sodium hydrogencarbonate, water, isopropyl ether to give methyl 2-(4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl)propionate (1017.8 g; yield 89%). Recrystallization from methanol gave colorless crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21].CN(C)[CH:24]=[O:25]>C1COCC1>[Br:13][C:14]1[C:15]([F:21])=[CH:16][CH:17]=[C:18]([F:20])[C:19]=1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: Fc1ccc(F)c(Br)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc(F)c1Br
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
To solution of diisopropylamine (13.29 mL, 93 mmol) in THF (300 mL) at −78° C., was added n-butyllithium (34.2 mL of 2.5M in hexanes, 85 mmol), dropwise over 10 mins. The mixture was stirred at −78° C. for 15 mins and then 2-bromo-1,4-difluorobenzene (15 g, 78 mmol) in THF (100 mL) was added dropwise over 15 mins maintaining the temperature below −65° C. After stirring for 1 hr at −78° C., N,N-dimethylformamide (6.62 mL, 85 mmol) was added via syringe. The mixture was stirred at −78° C. for 30 mins and then quenched with sat. NH4Cl solution and the mixture was allowed to reach room temperature. The product was extracted into ether and the extracts were dried (Na2SO4) and evaporated. Chromatography (silica, 0-100% dichloromethane in hexane) gave the title compound (D14) as a yellow solid (12.73 g)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([CH3:15])([C:6]1[CH:7]=[N:8][C:9]([N+:12]([O-])=O)=[CH:10][CH:11]=1)[CH3:5].[H][H]>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:6]1[CH:7]=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=1)([CH3:15])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)c1ccc(N)nc1
Yield: 91.9 %

Procedure:
2-Methyl-2-(6-nitropyridin-3-yl)-propionic acid methyl ester (1.88 g, 8.4 mmol) was dissolved in THF and 200 mg of 10% palladium on carbon was added. The reaction was exposed to hydrogen at a pressure of 50 psi for 5 hrs. NMR showed the reduction was incomplete. More palladium on carbon was added and the reaction was exposed to hydrogen again at 50 psi for several hrs. The reaction was filtered through celite and concentrated to give 1.5 g (92%) of 2-(6-amino-pyridin-3-yl)-2-methyl-propionic acid methyl ester which was used without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][O:10][C:11](=[O:28])[C:12]1[C:13](=[C:18]([NH:22]CCCCC)[CH:19]=[CH:20][CH:21]=1)[C:14]([O:16][CH3:17])=[O:15]>C(OCC)C>[CH3:9][O:10][C:11](=[O:28])[C:12]1[C:13](=[C:18]([NH:22][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:19]=[CH:20][CH:21]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: O=Cc1cccnc1
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Solvent: CCOCC
Product: COC(=O)c1cccc(NCc2cccnc2)c1C(=O)OC
Yield: 61 %

Procedure:
3-Pyridinecarboxaldehyde (0.94 ml, 10 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester. After removal of pyridine the residue was dissolved in methylene chloride (100 ml) and washed with water (2×100 ml), saturated NaHCO3 (2×100 ml), brine (1×100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated in vacuo to give an oil. The oil was dissolved in diethyl ether (100 ml) and extracted with 0.1 N HCl (2×100 ml). The combined aqueous HCl extracts were washed with diethyl ether (2×100 ml) and the pH adjusted to 10 by dropwise addition of saturated Na2CO3. The product was extracted with diethyl ether (3×100 ml). The combined ether extracts were washed with brine (1×100 ml), dried (magnesium sulfate), and filtered. The solvent was evaporated in vacuo to give 0.91 g (61%) of product as a light yellow oil which was used without further purification: 1H NMR (CDCl3) δ 8.61 (d, J=2.0 Hz, 1H), 8.53 (dd, J=1.1 Hz and 4.8 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.31-7.21 (m, 3H), 6.85 (d, J=7.3 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 4.45 (d, J=5.7 Hz, 2H), 3.87 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:35][C:36]1[S:37][C:38]([S:42](Cl)(=[O:44])=[O:43])=[C:39]([CH3:41])[N:40]=1>CN(C=O)C>[CH3:35][C:36]1[S:37][C:38]([S:42]([N:25]2[CH2:26][CH2:27][CH:22]([O:21][C:16]3[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=4)[C:17]=3[N+:18]([O-:20])=[O:19])[CH2:23][CH2:24]2)(=[O:44])=[O:43])=[C:39]([CH3:41])[N:40]=1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(S(=O)(=O)N2CCC(Oc3ncnc(Nc4ccc(S(C)(=O)=O)cc4)c3[N+](=O)[O-])CC2)s1

Procedure:
Compound A32 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (20 μl), 2,4-dimethyl-thiazole-5-sulfonyl chloride (10 mg, 0.047 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 2.09 (m, 4H), 2.67 (s, 3H), 2.75 (s,3H), 3.08 (s, 3H), 3.21 (m, 2H), 3.50 (m, 2H), 5.58 (m, 1H), 7.85 (d,2H), 7.97 (d, 2H), 8.38 (s, 1H), 10.14 (s, 1H). Exact mass calculated for C21H24N6O7S3 568.09, found 569.4 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[Br:66][C:67]1[CH:68]=[C:69]([CH2:74][NH2:75])[CH:70]=[CH:71][C:72]=1[CH3:73]>ClCCl>[Br:66][C:67]1[CH:68]=[C:69]([CH2:74][NH:75][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:70]=[CH:71][C:72]=1[CH3:73]
Reactant: Cc1ccc(CN)cc1Br
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(Br)c2)n1
Temperature: 25 °C
Yield: 134.4 %

Procedure:
To a suspension of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (50.8 g, 112 mmol) in a 2 L 3-neck flask was added dichloromethane (DCM) (600 mL) followed by DIPEA (98 ml, 561 mmol), giving a solution. To it was added TBTU (39.7 g, 123 mmol) and the mixture was then stirred at room temperature for 2 min whereupon 1-(3-bromo-4-methylphenyl)methanamine hydrochloride (29.2 g, 123 mmol) was added. The mixture was stirred under nitrogen at room temperature. After 2.5 h the mixture was partitioned between dichloromethane and water and the aqueous layer extracted well with dichloromethane. The combined organics were washed with water, saturated sodium bicarbonate, brine, dried (MgSO4), filtered and evaporated to give 95.5 g of a pale golden foam that was purified on a 750 g Companion XL silica cartridge, eluting with 0-100% ethyl acetate in dichloromethane over 8 column volumes. However, halfway through loading, the material started to crystallise on the column, blocking the loading so this material already on the column was eluted as above to give 30.01 gm, (26%) of a white solid (combined theoretical yield of the two preparations was 116.6 g). The lab HPLC showed 99.4% purity (retention time 2.22 min). LC-MS m/z 634, 636 (M+H)+, 1.06 min (ret time).
Reaction SMILES: C[C:2]1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1[CH:16]=[CH:15][CH:14]=[CH:13]C=1.C1([ClH]C(Cl)=O)CCC1>ClCCl>[CH3:2][O:9][C:7](=[O:8])[CH2:6][C:4]([CH:13]1[CH2:14][CH2:15][CH2:16]1)=[O:5]
Reactant: c1ccncc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Product: COC(=O)CC(=O)C1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
22 g of meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) (152.7 mmol) and 36.9 ml of pyridine (457.2 mmol) were dissolved in 200 ml of dichloromethane. 18.1 g of cyclobutylcarbonic acid chloride were added at 0 to 10° C. The reaction mixture was stirred overnight at room temperature, washed with 1 N HCl and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered, and then concentrated to dryness. The oily residue was dissolved in 300 ml of methanol and heated under reflux for 2 h. The reaction mixture was concentrated to dryness and the residue purified via silica gel chromatography with ethyl acetate as eluent. Yield: 21.2 g
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=2)=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>O.C(O)(=O)C.[Fe]>[NH2:22][C:18]1[CH:17]=[C:16]([CH2:15][NH:14][C:12]([C:10]2[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Br:1])[CH:11]=2)=[O:13])[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(C(=O)NCc2cccc([N+](=O)[O-])c2)cc1Br
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(C(=O)NCc2cccc(N)c2)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8.7 %

Procedure:
Iron powder (135 mg, 2.4 mmol) was added to a suspension of 2-bromo-4-[[[(3-nitrophenyl)methyl]amino]carbonyl]benzoic acid, methyl ester (Example 16; 125 mg, 3.18 mmol) in water (530 μL) and acetic acid (111 μL) at 25° C. The reaction was heated to reflux for 30 min and then cooled to 25° C. The suspension was diluted with water (20 mL), stirred for 15 min, and filtered through Celite. The filter cake was washed well with water (100 mL). The filtrate was extracted with ethyl acetate (50 mL) followed by ethyl acetate containing 2% methanol (50 mL). The organic layers were combined, dried (MgSO4), filtered, and concentrated. The residue was diluted with 10% methanol in dichloromethane and stirred with Celite. After 1 h, the suspension was filtered and washed well with 10% methanol in dichloromethane. Concentration of the filtrate afforded 4-[[[(3-aminophenyl)methyl]amino]carbonyl]-2-bromobenzoic acid, methyl ester (100 mg, 87%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)([CH3:5])[C:3]#[CH:4].C(C1(C2C=CC(OC)=C(C=2)[CH:24]=[O:25])CC1)#N>>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]([CH3:1])([CH3:5])[C:3]#[CH:4])=[CH:7][C:8]=1[CH:24]=[O:25]
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Reactant: C#CC(C)(C)c1ccc(OC)cc1
Product: C#CC(C)(C)c1ccc(OC)c(C=O)c1

Procedure:
This compound was prepared from Compound 21 in the same manner of Compound 2.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CCN(C(C)C)C(C)C.C1N=CN([C:34]([N:36]2[CH:40]=N[CH:38]=[CH:37]2)=[O:35])C=1.[Cl:41][C:42]1[CH:43]=[C:44]([C@@H:48]([C@@H:57]2CCCN[CH2:58]2)[O:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH3:56])=[O:54])[CH:45]=[CH:46][CH:47]=1>C(Cl)Cl>[C:7]([O:6][C:5]([N:4]([CH3:12])[CH2:3][C@@H:2]([NH:1][C:34]([N:36]1[CH2:37][CH2:38][CH2:58][C@@H:57]([C@H:48]([C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([Cl:41])[CH:43]=2)[O:49][CH2:50][CH2:51][CH2:52][C:53]([O:55][CH3:56])=[O:54])[CH2:40]1)=[O:35])[CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:11])([CH3:9])([CH3:10])[CH3:8]
Reactant: CN(C[C@@H](N)CC1CCCCC1)C(=O)OC(C)(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)CCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 22.1 %

Procedure:
To a solution of (S)-tert-butyl 2-amino-3-cyclohexylpropyl(methyl)carbamate (165 mg, 0.61 mmol) and DIEA (3 mL) in anhydrous CH2Cl2 (10 mL) was added CDI (98 mg, 0.61 mmol) with ice bath. After addition, the mixture was stirred for 1 h at 0° C., followed by the addition of methyl 4-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)butanoate (165 mg, 0.51 mmol) in anhydrous CH2Cl2 (2 mL). The reaction mixture was allowed to warm to rt and stirred overnight. The reaction mixture was washed with water (10 mL) and the aqueous layer extracted with CH2Cl2 (15 mL×2), the combined organic layers was washed with saturated brine, dried over Na2SO4, filtered, then evaporated to give a residue, which was purified via preparative TLC to afford methyl 4-((R)—((R)-1-((S)-1-(tert-butoxycarbonyl(methyl)amino)-3-cyclohexylpropan-2-ylcarbamoyl)piperidin-3-yl)(3-chlorophenyl)methoxy)butanoate (70 mg, 22% yield). 1H NMR (CD3OD, 400 MHz) δ 7.34-7.28 (m, 3H), 7.19 (t, 1H), 4.25 (d, 1H), 4.11 (d, 1H), 3.95 (m, 2H), 3.64 (t, 3H), 3.27 (m, 1H), 3.10 (m, 1H), 2.87 (s, 2H), 2.69 (m, 2H), 2.43 (t, 1H), 1.84 (t, 2H), 1.72-1.52 (m, 6H), 1.45 (d, 9H), 1.39-1.22 (m, 10H), 1.14 (d, 1H), 0.97 (d, 2H), 0.85 (t, 1H).
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[CH:10][C:9](=[O:19])[C:8]=2[C:7]([O:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[Na+].C(O)C>O>[CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[N:15]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:16]=[N:17][N:18]=3)=[CH:10][C:9](=[O:19])[C:8]=2[C:7]([O:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnn[nH]3)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnnn3Cc3ccccc3)oc12

Procedure:
A mixture of 30 parts of 5-[8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-yl]tetrazole, 16.6 parts of benzyl bromide, 3.53 parts of sodium hydroxide, 120 parts of ethanol and 60 parts of water was refluxed for 64 hours. The mixture was cooled, was extracted with chloroform and the chloroform extract washed with sodium bicarbonate solution and water. Evaporation of the chloroform gave a residue which was chromatographed on silica gel. Elution with 3 : 1 toluene/acetic acid and chloroform gave, after crystallisation from ethanol, a total of 7.31 parts of 5-[8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-yl]-N-benzyltetrazole, m.p. 92.5-94° C.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][Cl:4].[FH:7]>>[F:1][C:2]([F:6])([F:5])[CH2:3][F:7].[F:1][C:2]([F:5])=[CH:3][Cl:4]
Reactant: F
Reactant: FC(F)(F)CCl
Product: FC(F)=CCl
Product: FCC(F)(F)F

Procedure:
reacting 1,1,1-trifluorochloroethane from the first reaction zone with hydrogen fluoride in the gas phase in the presence of a fluorination catalyst to obtain 1,1,1,2-tetrafluoroethane and by-product 1,1-difluorochloroethylene in the second reaction zone,
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:20][CH:17]([C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[CH:3][CH:2]=[N:1]3)=[CH:6][CH:7]=2)=[CH:12][CH:13]=1)[C:18]#[N:19]
Reactant: N#CCc1ccc(-c2ccc3cccnc3c2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(Br)c1ccc(-c2ccc3cccnc3c2)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
A solution of 2-(4-(quinolin-7-yl)phenyl)acetonitrile (0.409 mmol) in carbon tetrachloride (2 mL) was degassed for three minutes with a stream of nitrogen. The solution was then treated with N-bromosuccinimide (0.450 mmol) and azobisisobutyronitrile (0.020 mmol). The reaction vessel was purged with nitrogen and sealed and the mixture was allowed to stir overnight in a 75° C. oil bath. The reaction mixture was then directly loading onto silica gel and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-80% ethyl acetate/hexanes) afforded the title compound (30 mg, 17%). MS(ES)+ m/e 322.9/325.0 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[OH:27]>>[OH:27][C:21]1[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Cc1ccc(N)c(O)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: Cc1ccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c(O)c1
Yield: 78.1 %

Procedure:
The product is prepared according to the procedure described in Example 2, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 466 mg of 2-amino-5-methylphenol in place of the 2,4-difluoroaniline. 515 mg of N-(2-hydroxy-4-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a purplish solid, the characteristics of which are the following: